CME

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

Youth are particularly at risk. In a 2018 survey,⁷ 20.8% of high school students reported using e-cigarettes on more than 1 day in the previous 30 days (Table 1), a significant increase from 1.5% in 2011. Additionally, 11.3% of high school students reported using 2 or more types of tobacco products; in middle school students, the number was 4.9%—nearly 1 in 20—up from 0.6% in 2011.⁸

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

E-cigarettes, the most common type of electronic nicotine delivery system,¹ look like conventional cigarettes. Designs vary, but the devices generally contain a power source (typically a lithium battery), a heating element, and a reservoir for the “e-liquid” (Figure 1). The e-liquid typically consists of a solvent (propylene glycol or vegetable glycerin), flavorings (eg, tobacco, mint, fruit, bubblegum), and, often, nicotine in various doses. When the user inhales, the negative pressure closes a switch, turning on the heater, which turns some of the liquid into an aerosol, which is inhaled. The aerosol may contain nicotine, but formulations are proprietary and not currently regulated.

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

In 2016, the FDA published rules and regulations for the sale of tobacco products—including e-cigarettes—deeming them to be subject to the Federal Food, Drug, and Cosmetic Act as amended by the Family Smoking Prevention and Tobacco Control Act, placing restrictions on their sale and distribution, and requiring warning statements on them.²³ Notably, it prohibited sale of tobacco products to anyone younger than 18 (and 18 US states now require buyers to be at least 21; Table 2). The FDA also prohibited sales in vending machines, except in locations that are inaccessible to youth.

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

Youth are particularly at risk. In a 2018 survey,⁷ 20.8% of high school students reported using e-cigarettes on more than 1 day in the previous 30 days (Table 1), a significant increase from 1.5% in 2011. Additionally, 11.3% of high school students reported using 2 or more types of tobacco products; in middle school students, the number was 4.9%—nearly 1 in 20—up from 0.6% in 2011.⁸

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

E-cigarettes, the most common type of electronic nicotine delivery system,¹ look like conventional cigarettes. Designs vary, but the devices generally contain a power source (typically a lithium battery), a heating element, and a reservoir for the “e-liquid” (Figure 1). The e-liquid typically consists of a solvent (propylene glycol or vegetable glycerin), flavorings (eg, tobacco, mint, fruit, bubblegum), and, often, nicotine in various doses. When the user inhales, the negative pressure closes a switch, turning on the heater, which turns some of the liquid into an aerosol, which is inhaled. The aerosol may contain nicotine, but formulations are proprietary and not currently regulated.

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

In 2016, the FDA published rules and regulations for the sale of tobacco products—including e-cigarettes—deeming them to be subject to the Federal Food, Drug, and Cosmetic Act as amended by the Family Smoking Prevention and Tobacco Control Act, placing restrictions on their sale and distribution, and requiring warning statements on them.²³ Notably, it prohibited sale of tobacco products to anyone younger than 18 (and 18 US states now require buyers to be at least 21; Table 2). The FDA also prohibited sales in vending machines, except in locations that are inaccessible to youth.

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

Youth are particularly at risk. In a 2018 survey,⁷ 20.8% of high school students reported using e-cigarettes on more than 1 day in the previous 30 days (Table 1), a significant increase from 1.5% in 2011. Additionally, 11.3% of high school students reported using 2 or more types of tobacco products; in middle school students, the number was 4.9%—nearly 1 in 20—up from 0.6% in 2011.⁸

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

E-cigarettes, the most common type of electronic nicotine delivery system,¹ look like conventional cigarettes. Designs vary, but the devices generally contain a power source (typically a lithium battery), a heating element, and a reservoir for the “e-liquid” (Figure 1). The e-liquid typically consists of a solvent (propylene glycol or vegetable glycerin), flavorings (eg, tobacco, mint, fruit, bubblegum), and, often, nicotine in various doses. When the user inhales, the negative pressure closes a switch, turning on the heater, which turns some of the liquid into an aerosol, which is inhaled. The aerosol may contain nicotine, but formulations are proprietary and not currently regulated.

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

In 2016, the FDA published rules and regulations for the sale of tobacco products—including e-cigarettes—deeming them to be subject to the Federal Food, Drug, and Cosmetic Act as amended by the Family Smoking Prevention and Tobacco Control Act, placing restrictions on their sale and distribution, and requiring warning statements on them.²³ Notably, it prohibited sale of tobacco products to anyone younger than 18 (and 18 US states now require buyers to be at least 21; Table 2). The FDA also prohibited sales in vending machines, except in locations that are inaccessible to youth.

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

Functional heartburn is defined as retrosternal burning in the absence of objective evidence of GERD, mucosal abnormality (ie, erosive esophagitis), or major motility disorder.⁵ The symptoms are theorized to result from hypersensitivity of the visceral nerves of the esophagus, which may be exacerbated by central sensitization, hypervigilance, stress, and anxiety.⁶ The pathogenesis is poorly understood, but it may involve activation of inflammatory mediators in the esophagus, alterations in esophageal mucosal integrity, increased chemical and pressure sensation in the esophagus, and both peripheral and central sensitization (Figure 1).⁷

DIAGNOSTIC EVALUATION

When evaluating patients with heartburn symptoms refractory to PPI therapy, the differential diagnosis is broad and includes GERD, eosinophilic esophagitis, infectious esophagitis, pill-induced esophagitis, esophageal motility disorder, and functional heartburn (Table 1). Of these, functional heartburn is the most common, accounting for more than 50% of cases of PPI-refractory heartburn.⁸

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

 

 

Esophageal manometry

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

The Rome IV diagnostic criteria for functional heartburn⁵ require that a patient experience retrosternal burning, discomfort, or pain at least twice a week for at least 6 months. By definition, the symptoms have not responded to antisecretory drugs (an H₂-receptor antagonist or PPI) in optimal doses. Also, inflammatory disorders such as erosive esophagitis and eosinophilic esophagitis and motility disorders such as achalasia (Table 1) need to be ruled out.

CASE CONTINUED: NORMAL RESULTS ON TESTING

The patient undergoes esophageal manometry and esophagogastro-duodenoscopy with placement of a wireless pH probe. Results of esophageal manometry are normal. She has normal lower esophageal resting pressure and relaxation and normal peristalsis in the esophagus body (Figure 2). Wireless pH testing shows a total acid exposure time of 1.7% and a strongly negative symptom association with heartburn, chest pain, and regurgitation (Figure 3).

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

 

 

TREATMENT

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

No drug has yet been approved by the US Food and Drug Administration to treat functional heartburn, and clinical evidence for treating this condition is minimal. Using neuromodulators to reduce pain perception is the mainstay of treatment for functional gastrointestinal disorders, including functional heartburn. Table 2 lists neuromodulators used to treat functional esophageal disorders, with recommended dosing intervals.

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

Functional heartburn is defined as retrosternal burning in the absence of objective evidence of GERD, mucosal abnormality (ie, erosive esophagitis), or major motility disorder.⁵ The symptoms are theorized to result from hypersensitivity of the visceral nerves of the esophagus, which may be exacerbated by central sensitization, hypervigilance, stress, and anxiety.⁶ The pathogenesis is poorly understood, but it may involve activation of inflammatory mediators in the esophagus, alterations in esophageal mucosal integrity, increased chemical and pressure sensation in the esophagus, and both peripheral and central sensitization (Figure 1).⁷

DIAGNOSTIC EVALUATION

When evaluating patients with heartburn symptoms refractory to PPI therapy, the differential diagnosis is broad and includes GERD, eosinophilic esophagitis, infectious esophagitis, pill-induced esophagitis, esophageal motility disorder, and functional heartburn (Table 1). Of these, functional heartburn is the most common, accounting for more than 50% of cases of PPI-refractory heartburn.⁸

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

 

 

Esophageal manometry

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

The Rome IV diagnostic criteria for functional heartburn⁵ require that a patient experience retrosternal burning, discomfort, or pain at least twice a week for at least 6 months. By definition, the symptoms have not responded to antisecretory drugs (an H₂-receptor antagonist or PPI) in optimal doses. Also, inflammatory disorders such as erosive esophagitis and eosinophilic esophagitis and motility disorders such as achalasia (Table 1) need to be ruled out.

CASE CONTINUED: NORMAL RESULTS ON TESTING

The patient undergoes esophageal manometry and esophagogastro-duodenoscopy with placement of a wireless pH probe. Results of esophageal manometry are normal. She has normal lower esophageal resting pressure and relaxation and normal peristalsis in the esophagus body (Figure 2). Wireless pH testing shows a total acid exposure time of 1.7% and a strongly negative symptom association with heartburn, chest pain, and regurgitation (Figure 3).

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

 

 

TREATMENT

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

No drug has yet been approved by the US Food and Drug Administration to treat functional heartburn, and clinical evidence for treating this condition is minimal. Using neuromodulators to reduce pain perception is the mainstay of treatment for functional gastrointestinal disorders, including functional heartburn. Table 2 lists neuromodulators used to treat functional esophageal disorders, with recommended dosing intervals.

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

Functional heartburn is defined as retrosternal burning in the absence of objective evidence of GERD, mucosal abnormality (ie, erosive esophagitis), or major motility disorder.⁵ The symptoms are theorized to result from hypersensitivity of the visceral nerves of the esophagus, which may be exacerbated by central sensitization, hypervigilance, stress, and anxiety.⁶ The pathogenesis is poorly understood, but it may involve activation of inflammatory mediators in the esophagus, alterations in esophageal mucosal integrity, increased chemical and pressure sensation in the esophagus, and both peripheral and central sensitization (Figure 1).⁷

DIAGNOSTIC EVALUATION

When evaluating patients with heartburn symptoms refractory to PPI therapy, the differential diagnosis is broad and includes GERD, eosinophilic esophagitis, infectious esophagitis, pill-induced esophagitis, esophageal motility disorder, and functional heartburn (Table 1). Of these, functional heartburn is the most common, accounting for more than 50% of cases of PPI-refractory heartburn.⁸

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

 

 

Esophageal manometry

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

The Rome IV diagnostic criteria for functional heartburn⁵ require that a patient experience retrosternal burning, discomfort, or pain at least twice a week for at least 6 months. By definition, the symptoms have not responded to antisecretory drugs (an H₂-receptor antagonist or PPI) in optimal doses. Also, inflammatory disorders such as erosive esophagitis and eosinophilic esophagitis and motility disorders such as achalasia (Table 1) need to be ruled out.

CASE CONTINUED: NORMAL RESULTS ON TESTING

The patient undergoes esophageal manometry and esophagogastro-duodenoscopy with placement of a wireless pH probe. Results of esophageal manometry are normal. She has normal lower esophageal resting pressure and relaxation and normal peristalsis in the esophagus body (Figure 2). Wireless pH testing shows a total acid exposure time of 1.7% and a strongly negative symptom association with heartburn, chest pain, and regurgitation (Figure 3).

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

 

 

TREATMENT

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

No drug has yet been approved by the US Food and Drug Administration to treat functional heartburn, and clinical evidence for treating this condition is minimal. Using neuromodulators to reduce pain perception is the mainstay of treatment for functional gastrointestinal disorders, including functional heartburn. Table 2 lists neuromodulators used to treat functional esophageal disorders, with recommended dosing intervals.

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

Chlamydia treatment is also detailed in Table 2.¹²

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

Chlamydia treatment is also detailed in Table 2.¹²

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

Chlamydia treatment is also detailed in Table 2.¹²

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

All cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus.¹ But most cases of Barrett esophagus go undiagnosed. And Barrett esophagus is seen in 5% to 15% of patients with gastroesophageal reflux disease.² These facts clearly emphasize the need for screening. Here, we review the rationale and recommendations for screening and surveillance, as well as the range of treatment options.

SCOPE OF THE PROBLEM

The American Cancer Society estimated there were 17,290 new cases of esophageal cancer and 15,850 deaths from it in the United States in 2018.³ Of the 2 main histologic types of esophageal cancer, adenocarcinoma and squamous cell cancer, adenocarcinoma is more common in the United States.

The precursor lesion is Barrett esophagus, defined as an extension of salmon-colored mucosa at least 1 cm into the tubular esophagus proximal to the gastroesophageal junction, with biopsy confirmation of intestinal metaplasia.⁴

The natural course of progression to dysplasia and cancer in Barrett esophagus is unknown but is thought to be stepwise, from no dysplasia to low-grade dysplasia to high-grade dysplasia and cancer, and the cancer risk depends on the degree of dysplasia: the annual risk is 0.33% if there is no dysplasia, 0.54% with low-grade dysplasia, and 7% with high-grade dysplasia.⁴

Although all cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus,¹ more than 90% of patients with newly diagnosed esophageal adenocarcinoma do not have a prior diagnosis of Barrett esophagus.⁵ Therefore, there is a substantial unmet need to expand screening for Barrett esophagus in people at risk.

GASTROESOPHAGEAL REFLUX DISEASE IS A RISK FACTOR FOR CANCER

The rationale behind screening is that detecting Barrett esophagus early and intervening in a timely manner in patients at higher risk of developing adenocarcinoma will decrease mortality.

Chronic gastroesophageal reflux disease is a strong risk factor for esophageal adenocarcinoma (odds ratio [OR] 7.7, 95% confidence interval [CI] 5.3–11.4), and the risk increases when symptoms are long-standing (> 20 years) or severe (OR 43.5, 95% CI 18.3–103.5) or occur daily (OR 5.5, 95% CI 3.2–9.3).⁶

Reflux symptoms are scored as follows:

• Heartburn only, 1 point
• Regurgitation only, 1 point
• Heartburn with regurgitation, 1.5 points
• Nightly symptoms (2 points if yes, 0 if no)
• Symptoms once a week, 0 points; 2 to 6 times a week, 1 point; 7 to 15 times a week, 2 points; more than 15 times a week, 3 points.⁶

A score of 4.5 or higher indicates severe reflux disease. However, it is worth noting that the annual incidence of esophageal adenocarcinoma in patients with long-term gastroesophageal reflux disease is less than 0.001%.⁷

RISK FACTORS FOR BARRETT ESOPHAGUS

Risk factors for Barrett esophagus include:

Male sex. Barrett esophagus is more prevalent in men than in women, at a ratio of 2 to 1; but in individuals under age 50, the ratio is 4 to 1.⁸

Age 50 or older. Barrett esophagus is usually diagnosed in the sixth to seventh decade of life, and the prevalence increases from 2.1% in the third decade to 9.3% in the sixth decade.⁹

White race. It is more prevalent in whites than in blacks (5.0% vs 1.5%, P < .0001).¹⁰

Central obesity. Waist circumference is an independent risk factor: every 5-cm increase carries an OR of 1.14 (95% CI 1.03–1.27, P = .02).¹¹

Cigarette smoking increases the risk of Barrett esophagus (OR 1.42; 95% CI 1.15–1.76).¹²

A family history of Barrett esophagus or esophageal adenocarcinoma is a strong risk factor (OR 12, 95% CI 3.3–44.8). In 1 study, the risk in first- and second-degree relatives of patients with Barrett esophagus was 24%, compared with 5% in a control population (P < .005).¹³

SCREENING GUIDELINES AND DRAWBACKS

American College of Gastroenterology guidelines recommend screening for Barrett esophagus in men who have chronic reflux disease (> 5 years) or frequent symptoms (weekly or more often), and 2 or more risk factors.⁴ In women, screening is recommended only in the presence of multiple risk factors.⁴

The standard screening method is esophagogastroduodenoscopy with sedation, with careful visual inspection and 4-quadrant biopsies every 2 cm using the Seattle protocol, ie, including biopsy of any mucosal irregularities in salmon-colored mucosa above the gastroesophageal junction (Figure 1).⁴

Endoscopic screening is cost-effective, costing $10,440 per quality-adjusted life-year saved, which is well below the accepted threshold of less than $100,000.¹⁴ However, it is still expensive, invasive, and not ideal for screening large populations.

Less-invasive methods under study

Less-invasive, less-expensive methods being tested for mass screening include:

Unsedated transnasal endoscopy. Done with only topical anesthesia, it has high diagnostic accuracy and is quicker and more cost-effective than standard esophagogastroduodenoscopy, with fewer adverse effects. However, the procedure has not yet gained widespread acceptance for regular use by gastroenterologists.¹⁵

A swallowable sponge. Another promising test is cell collection using the Cytosponge Cell Collection Device (Medtronic, Minneapolis, MN). An encapsulated compressed sponge with a string attached is swallowed; in the stomach, the capsule dissolves, and the sponge expands and is then withdrawn using the attached string. The obtained cytology sample from the lower esophagus is then tested for trefoil factor 3, a protein biomarker for Barrett esophagus.¹⁶

A retractable balloon. The EsoCheck Cell Collection Device is a retractable balloon attached to a string. When swallowed, it gathers distal esophageal cells for detecting methylated DNA markers for Barrett esophagus.¹⁷

Esophageal capsule endoscopy uses a camera to visualize the esophagus, but lacks the ability to obtain biopsy samples.

Other screening methods are being tested, although data are limited. Liquid biopsy uses a blood sample to detect microRNAs that are dysregulated in cancer. The “electronic nose” is a device that detects exhaled volatile organic compounds altered in Barrett esophagus. Another test involves taking an oral wash sample to study the oral microbiome for a pattern associated with adenocarcinoma.^18–21

 

 

SURVEILLANCE: WHAT’S INVOLVED, WHAT’S AVAILABLE

Surveillance in Barrett esophagus aims to detect premalignant changes or early-stage adenocarcinoma to provide longer survival and lower cancer-related mortality. Recent evidence suggests that patients with esophageal adenocarcinoma that is diagnosed in a Barrett esophagus surveillance program have an earlier stage of disease and therefore a survival benefit.²²

Patient education is essential

Before enrolling a patient in a surveillance program, the clinician should explain the risks, benefits, and limitations, the importance of periodic endoscopy, and the possible eventual need for endoscopic therapy or surgery.

The endoscopic procedure

Surveillance involves examination by high-definition white-light endoscopy, with random 4-quadrant biopsies every 2 cm (or every 1 cm in patients with a history of dysplasia) and biopsy of any mucosal irregularity (nodule, ulcer, or other visible lesion). The degree of dysplasia determines the frequency of follow-up surveillance intervals and the need for endoscopic eradication therapy, as presented in professional society guidelines (Table 1).^4,23,24

Advanced methods for detecting dysplasia

Newer endoscopic surveillance techniques include dye-based chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy, volumetric laser endomicroscopy, and wide-area transepithelial sampling with computer-assisted 3-dimensional analysis. All these techniques are used to increase the detection of dysplasia. Of these, dye-based chromoendoscopy, narrow-band imaging, and confocal laser endomicroscopy meet current criteria of the American Society for Gastrointestinal Endoscopy for preservation and incorporation of valuable endoscopic innovations.²³

MANAGEMENT OF NONDYSPLASTIC BARRETT ESOPHAGUS

A proton pump inhibitor (PPI) is recommended to control reflux symptoms in patients with nondysplastic Barrett esophagus. But it is important to counsel patients on additional ways to protect against esophageal adenocarcinoma, such as:

• Low to moderate alcohol consumption
• Regular physical activity
• Increased dietary intake of fruits, vegetables, folate, fiber, beta-carotene, and vitamin C
• Weight control
• Smoking cessation.²⁵

Surveillance endoscopy with 4-quadrant biopsies at 2-cm intervals is recommended every 3 to 5 years (Table 1).

DOES CHEMOPREVENTION HAVE A ROLE?

Chemoprevention is an exciting area of research in preventing progression to adenocarcinoma in patients with Barrett esophagus. Various drugs such as aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), PPIs, metformin, and statins have been studied.

Aspirin

Aspirin has been shown to prevent development of Barrett esophagus in patients with reflux disease,²⁶ but more studies are needed to validate those findings.

PPIs

Gastroesophageal reflux disease is a primary risk factor for esophageal adenocarcinoma, and gastric acid suppression with PPIs reduces cancer risk. PPI therapy is associated with a 71% decrease in the risk of high-grade dysplasia and adenocarcinoma in patients with Barrett esophagus (OR 0.29, 95% CI 0.12–0.79).²⁷ Long-term therapy (> 2 to 3 years) has a higher protective effect (adjusted OR 0.45, 95% CI 0.19–1.06) than short-term therapy (< 2 to 3 years) (adjusted OR 1.09, 95% CI 0.47–2.56).²⁷

NSAIDs

NSAIDs, including aspirin, have been associated with decreased risk of colon, stomach, lung, breast, and esophageal cancer due to their potential to inhibit cyclooxygenase 2 (COX-2) enzymes.

A meta-analysis demonstrated that aspirin and NSAIDs led to a 32% reduction in the risk of adenocarcinoma (OR 0.68, 95% CI 0.56–0.83). The benefit was even greater if the drug was taken daily or more frequently (OR 0.56, 95% CI 0.43–0.73, P < .001) or was taken for 10 or more years (OR 0.63, 95% CI 0.45–0.90, P = .04).²⁸

PPI plus aspirin

The best evidence for the role of PPIs and aspirin in reducing the risk of dysplasia comes from the Aspirin and Esomeprazole Chemoprevention in Barrett’s Metaplasia Trial.²⁹ This randomized, controlled trial compared 4 regimens consisting of esomeprazole (a PPI) in either a high dose (40 mg twice daily) or a low dose (20 mg once daily) plus either aspirin (300 or 320 mg per day) or no aspirin in 2,557 patients with Barrett esophagus. The composite end point was the time to all-cause mortality, adenocarcinoma, or high-grade dysplasia.

At a median follow-up of 8.9 years, the combination of high-dose esomeprazole plus aspirin had the strongest effect compared with low-dose esomeprazole without aspirin (time ratio 1.59, 95% CI 1.14–2.23, P = .0068). The number needed to treat was 34 for esomeprazole and 43 for aspirin.²⁹

Based on these data, we can conclude that aspirin and PPIs can prevent dysplasia and all-cause mortality in Barrett esophagus.

Metformin: No evidence of benefit

Metformin was studied as a protective agent against obesity-associated cancers including esophageal adenocarcinoma, as it reduces insulin levels.

In a randomized controlled trial³⁰ in 74 patients with Barrett esophagus, metformin (starting at 500 mg daily, increasing to 2,000 mg/day by week 4) was compared with placebo. At 12 weeks, the percent change in esophageal levels of the biomarker pS6K1—an intracellular mediator of insulin and insulin-like growth factor activation in Barrett epithelium—did not differ significantly between the 2 groups (1.4% with metformin vs −14.7% with placebo; 1-sided P = .80). This suggested that metformin did not significantly alter proliferation or apoptosis in Barrett epithelium, despite reducing serum insulin levels and insulin resistance. Thus, metformin did not demonstrate a chemoprotective effect in preventing the progression of Barrett esophagus to adenocarcinoma.

 

 

Vitamin D: No evidence of benefit

Vitamin D affects genes regulating proliferation, apoptosis, and differentiation, and has therefore been studied as a potential antineoplastic agent. Its deficiency has also been associated with increased risk of esophageal adenocarcinoma. However, its efficacy in chemoprevention is unclear.³¹

One study found no association between serum 25-hydroxyvitamin D levels and prevalence of dysplasia in Barrett esophagus (P = .90). An increase in vitamin D levels had no effect on progression to dysplasia or cancer (for every 5-nmol/L increase from baseline, hazard ratio 0.98, P = .62).³²

In another study, supplementation with vitamin D₃ (cholecalciferol 50,000 IU weekly) plus a PPI for 12 weeks significantly improved the serum 25-hydroxyvitamin D levels without significant changes in gene expression from Barrett epithelium.³³ These findings were confirmed in a meta-analysis that showed no consistent association between vitamin D exposure and risk of esophageal neoplasm.³⁴

Thus, there is currently no evidence to support vitamin D for chemoprevention in Barrett esophagus or esophageal adenocarcinoma.

Statins

In addition to lowering cholesterol, statins have antiproliferative, pro-apoptotic, anti-angiogenic, and immunomodulatory effects that prevent cancer, leading to a 41% reduction in the risk of adenocarcinoma in patients with Barrett esophagus in one study (adjusted OR 0.59, 95% CI 0.45–0.78); the number needed to treat with statins to prevent 1 case of adenocarcinoma was 389.³⁵

A meta-analysis also showed that statin use was associated with a lower risk of progression of Barrett esophagus (OR 0.48, 95% CI 0.31–0.73).³⁶

In general, statins appear promising for chemoprevention, but more study is needed.

When is chemoprevention appropriate?

Chemoprevention is not recommended for all patients with Barrett esophagus, given that the condition affects 1% to 2% of the US adult population, and very few patients have progression to esophageal adenocarcinoma. Rather, chemoprevention may be considered in patients with Barrett esophagus and multiple risk factors for adenocarcinoma.

INDEFINITE DYSPLASIA

In Barrett esophagus with indefinite dysplasia, either the epithelial abnormalities are insufficient for a diagnosis of dysplasia, or the nature of the epithelial abnormalities is uncertain due to inflammation or technical difficulties with specimen processing. The risk of high-grade dysplasia or cancer within 1 year of the diagnosis of indefinite dysplasia varies between 1.9% and 15%.³⁷ The recommendation for management is to optimize acid-suppressive therapy for 3 to 6 months and then to repeat esophagogastroduodenoscopy. If indefinite dysplasia is noted again, repeat endoscopy in 12 months is recommended.²

ENDOSCOPIC ERADICATION: AN OVERVIEW

Because dysplasia in Barrett esophagus carries a high risk of progression to cancer, the standard of care is endoscopic mucosal resection of visible lesions, followed by ablation of the flat mucosa, with the aim of achieving complete eradication of intestinal metaplasia.^4,38 The initial endoscopic treatment is followed by outpatient sessions every 8 to 10 weeks until the dysplasia is eradicated. A key part of treatment during this time is maximal acid suppression with a PPI twice daily and a histamine-2 blocker at night. In rare cases, fundoplication is required to control reflux refractory to medical therapy.

After eradication is confirmed, continued surveillance is necessary, as recurrences have been reported at a rate of 4.8% per year for intestinal metaplasia, and 2% per year for dysplasia.³⁹

Current endoscopic resection techniques

Endoscopic resection techniques include mucosal resection, submucosal dissection, radio­frequency ablation, cryotherapy, argon plasma coagulation, and photodynamic therapy (Figure 2).

In mucosal resection, the lesion is either suctioned into a band ligator, after which a band is placed around the lesion, or suctioned into a cap fitted at the end of the endoscope, after which the lesion is removed using a snare.

In submucosal dissection, a liquid is injected into the submucosa to lift the lesion, making it easier to remove. The procedure is technically complex and requires additional training.

In radiofrequency ablation, a special catheter is passed through the endoscope to ablate the affected epithelium by thermal injury. Argon plasma coagulation works in a similar way, but uses ionized argon gas to induce thermal coagulation of metaplastic epithelium.

Cryotherapy produces cellular injury by rapid freezing and thawing of tissue using a cryogen such as liquid nitrogen or nitrous oxide.

In photodynamic therapy, a photosensitizer (porfimer sodium) is administered and taken up preferentially by metaplastic epithelium; it is then activated by transmission of red light using the endoscope, leading to destruction of the metaplastic epithelium.

Of the different techniques, radiofrequency ablation has the most evidence for efficacy and hence is the most commonly used.

All of these procedures are generally well tolerated and have favorable side-effect profiles. After radiofrequency ablation with or without mucosal resection, esophageal strictures are noted in 5.6% of patients, and bleeding and perforation occur rarely (1% and 0.6% of patients, respectively).⁴⁰ Submucosal dissection is associated with a higher rate of complications such as stricture formation (11% of patients) and bleeding or perforation (1.5% of patients).⁴¹

 

 

LOW-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

Most patients with low-grade dysplasia (73%) are down-staged to nondysplastic Barrett esophagus or to indefinite for dysplasia after review by expert pathologists.⁴² Patients with confirmed and persistent low-grade dysplasia are at higher risk of progression.⁴³

Once low-grade dysplasia is confirmed by a second gastrointestinal pathologist, the patient should undergo endoscopic ablation. A landmark study by Shaheen et al⁴⁴ demonstrated the benefit of radiofrequency ablation in achieving complete eradication of dysplasia (90.5% vs 22.7% for a sham procedure) and complete eradication of intestinal metaplasia (77.4% vs 2.3% for a sham procedure). In another trial of 136 patients with low-grade dysplasia followed for 3 years, Phoa et al⁴⁵ demonstrated that radiofrequency ablation reduced the rate of progression to high-grade dysplasia by 25% and to adenocarcinoma by 7.4% compared with endoscopic surveillance.

Patients with confirmed low-grade dysplasia who do not undergo eradication therapy should have surveillance endoscopy every 6 to 12 months (Table 1).

HIGH-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

As with low-grade dysplasia, the diagnosis of high-grade dysplasia needs to be confirmed by a second pathologist with gastrointestinal expertise. In the past, the treatment was esophagectomy, but due to lower morbidity and equivalent efficacy of radiofrequency ablation,⁴⁶ the current treatment of choice is endoscopic mucosal resection of raised lesions, followed by radiofrequency ablation of the entire affected segment.

In the study by Shaheen et al,⁴⁴ 42 patients with high-grade dysplasia were randomized to radiofrequency ablation and 21 to a sham procedure, and 81% of ablation patients achieved complete eradication of dysplasia vs 19% with the sham procedure. Eradication of intestinal metaplasia was achieved in 77% of ablation patients vs 2% of patients with the sham therapy. Results of 3-year follow-up from the same cohort showed complete eradication of dysplasia in 98% and of intestinal metaplasia in 91%.⁴⁷

Endoscopic eradication therapy is recommended for all patients with Barrett esophagus and high-grade dysplasia without a life-limiting comorbidity. Alternatively, surveillance every 3 months is an option if the patient does not wish to undergo eradication therapy. Radiofrequency ablation is more cost-effective than esophagectomy or endoscopic surveillance followed by treatment once patients develop adenocarcinoma.^48,49

EARLY ESOPHAGEAL ADENOCARCINOMA: RECOMMENDED MANAGEMENT

Adenocarcinoma limited to the mucosa and without evidence of nodal involvement can be resected endoscopically. In patients with localized cancer, mucosal resection is done not only for therapeutic purposes but also for staging. Ideal management is multidisciplinary, including a gastroenterologist, thoracic surgeon, oncologist, pathologist, and radiation oncologist.

If lesions have features suggesting submucosal invasion or are greater than 1.5 cm in size, or if it is difficult to separate (ie, lift) the mucosa from the submucosal layer with injection of saline, then submucosal dissection is recommended.⁵⁰ Because of the risk of metachronous lesions, ablation of the remaining Barrett esophagus mucosa is recommended after resection of cancer.

Endoscopic eradication is highly effective and durable for the treatment of intramucosal esophageal adenocarcinoma. In a study of 1,000 patients, 963 patients (96.3%) had achieved a complete response; 12 patients (3.7%) underwent surgery after eradication failed during a follow-up of almost 5 years.⁵¹ Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but were successfully treated endoscopically in 115, resulting in a long-term complete remission rate of 93.8%.

POSTABLATION MANAGEMENT

Because of the risk of recurrence of dysplasia after ablation, long-term PPI therapy and surveillance are recommended.

Surveillance endoscopy involves 4-quadrant biopsies taken every 1 cm from the entire length of segment where Barrett esophagus had been seen before ablation.

The timing of surveillance intervals depends on the preablation grade of dysplasia. For low-grade dysplasia, the recommendation is every 6 months for the first year after ablation and, if there is no recurrence of dysplasia, annually after that.² After treatment of high-grade dysplasia or intramucosal adenocarcinoma, the recommendation is every 3 months for the first year, every 6 months in the second year, and then annually.²

All cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus.¹ But most cases of Barrett esophagus go undiagnosed. And Barrett esophagus is seen in 5% to 15% of patients with gastroesophageal reflux disease.² These facts clearly emphasize the need for screening. Here, we review the rationale and recommendations for screening and surveillance, as well as the range of treatment options.

SCOPE OF THE PROBLEM

The American Cancer Society estimated there were 17,290 new cases of esophageal cancer and 15,850 deaths from it in the United States in 2018.³ Of the 2 main histologic types of esophageal cancer, adenocarcinoma and squamous cell cancer, adenocarcinoma is more common in the United States.

The precursor lesion is Barrett esophagus, defined as an extension of salmon-colored mucosa at least 1 cm into the tubular esophagus proximal to the gastroesophageal junction, with biopsy confirmation of intestinal metaplasia.⁴

The natural course of progression to dysplasia and cancer in Barrett esophagus is unknown but is thought to be stepwise, from no dysplasia to low-grade dysplasia to high-grade dysplasia and cancer, and the cancer risk depends on the degree of dysplasia: the annual risk is 0.33% if there is no dysplasia, 0.54% with low-grade dysplasia, and 7% with high-grade dysplasia.⁴

Although all cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus,¹ more than 90% of patients with newly diagnosed esophageal adenocarcinoma do not have a prior diagnosis of Barrett esophagus.⁵ Therefore, there is a substantial unmet need to expand screening for Barrett esophagus in people at risk.

GASTROESOPHAGEAL REFLUX DISEASE IS A RISK FACTOR FOR CANCER

The rationale behind screening is that detecting Barrett esophagus early and intervening in a timely manner in patients at higher risk of developing adenocarcinoma will decrease mortality.

Chronic gastroesophageal reflux disease is a strong risk factor for esophageal adenocarcinoma (odds ratio [OR] 7.7, 95% confidence interval [CI] 5.3–11.4), and the risk increases when symptoms are long-standing (> 20 years) or severe (OR 43.5, 95% CI 18.3–103.5) or occur daily (OR 5.5, 95% CI 3.2–9.3).⁶

Reflux symptoms are scored as follows:

• Heartburn only, 1 point
• Regurgitation only, 1 point
• Heartburn with regurgitation, 1.5 points
• Nightly symptoms (2 points if yes, 0 if no)
• Symptoms once a week, 0 points; 2 to 6 times a week, 1 point; 7 to 15 times a week, 2 points; more than 15 times a week, 3 points.⁶

A score of 4.5 or higher indicates severe reflux disease. However, it is worth noting that the annual incidence of esophageal adenocarcinoma in patients with long-term gastroesophageal reflux disease is less than 0.001%.⁷

RISK FACTORS FOR BARRETT ESOPHAGUS

Risk factors for Barrett esophagus include:

Male sex. Barrett esophagus is more prevalent in men than in women, at a ratio of 2 to 1; but in individuals under age 50, the ratio is 4 to 1.⁸

Age 50 or older. Barrett esophagus is usually diagnosed in the sixth to seventh decade of life, and the prevalence increases from 2.1% in the third decade to 9.3% in the sixth decade.⁹

White race. It is more prevalent in whites than in blacks (5.0% vs 1.5%, P < .0001).¹⁰

Central obesity. Waist circumference is an independent risk factor: every 5-cm increase carries an OR of 1.14 (95% CI 1.03–1.27, P = .02).¹¹

Cigarette smoking increases the risk of Barrett esophagus (OR 1.42; 95% CI 1.15–1.76).¹²

A family history of Barrett esophagus or esophageal adenocarcinoma is a strong risk factor (OR 12, 95% CI 3.3–44.8). In 1 study, the risk in first- and second-degree relatives of patients with Barrett esophagus was 24%, compared with 5% in a control population (P < .005).¹³

SCREENING GUIDELINES AND DRAWBACKS

American College of Gastroenterology guidelines recommend screening for Barrett esophagus in men who have chronic reflux disease (> 5 years) or frequent symptoms (weekly or more often), and 2 or more risk factors.⁴ In women, screening is recommended only in the presence of multiple risk factors.⁴

The standard screening method is esophagogastroduodenoscopy with sedation, with careful visual inspection and 4-quadrant biopsies every 2 cm using the Seattle protocol, ie, including biopsy of any mucosal irregularities in salmon-colored mucosa above the gastroesophageal junction (Figure 1).⁴

Endoscopic screening is cost-effective, costing $10,440 per quality-adjusted life-year saved, which is well below the accepted threshold of less than $100,000.¹⁴ However, it is still expensive, invasive, and not ideal for screening large populations.

Less-invasive methods under study

Less-invasive, less-expensive methods being tested for mass screening include:

Unsedated transnasal endoscopy. Done with only topical anesthesia, it has high diagnostic accuracy and is quicker and more cost-effective than standard esophagogastroduodenoscopy, with fewer adverse effects. However, the procedure has not yet gained widespread acceptance for regular use by gastroenterologists.¹⁵

A swallowable sponge. Another promising test is cell collection using the Cytosponge Cell Collection Device (Medtronic, Minneapolis, MN). An encapsulated compressed sponge with a string attached is swallowed; in the stomach, the capsule dissolves, and the sponge expands and is then withdrawn using the attached string. The obtained cytology sample from the lower esophagus is then tested for trefoil factor 3, a protein biomarker for Barrett esophagus.¹⁶

A retractable balloon. The EsoCheck Cell Collection Device is a retractable balloon attached to a string. When swallowed, it gathers distal esophageal cells for detecting methylated DNA markers for Barrett esophagus.¹⁷

Esophageal capsule endoscopy uses a camera to visualize the esophagus, but lacks the ability to obtain biopsy samples.

Other screening methods are being tested, although data are limited. Liquid biopsy uses a blood sample to detect microRNAs that are dysregulated in cancer. The “electronic nose” is a device that detects exhaled volatile organic compounds altered in Barrett esophagus. Another test involves taking an oral wash sample to study the oral microbiome for a pattern associated with adenocarcinoma.^18–21

 

 

SURVEILLANCE: WHAT’S INVOLVED, WHAT’S AVAILABLE

Surveillance in Barrett esophagus aims to detect premalignant changes or early-stage adenocarcinoma to provide longer survival and lower cancer-related mortality. Recent evidence suggests that patients with esophageal adenocarcinoma that is diagnosed in a Barrett esophagus surveillance program have an earlier stage of disease and therefore a survival benefit.²²

Patient education is essential

Before enrolling a patient in a surveillance program, the clinician should explain the risks, benefits, and limitations, the importance of periodic endoscopy, and the possible eventual need for endoscopic therapy or surgery.

The endoscopic procedure

Surveillance involves examination by high-definition white-light endoscopy, with random 4-quadrant biopsies every 2 cm (or every 1 cm in patients with a history of dysplasia) and biopsy of any mucosal irregularity (nodule, ulcer, or other visible lesion). The degree of dysplasia determines the frequency of follow-up surveillance intervals and the need for endoscopic eradication therapy, as presented in professional society guidelines (Table 1).^4,23,24

Advanced methods for detecting dysplasia

Newer endoscopic surveillance techniques include dye-based chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy, volumetric laser endomicroscopy, and wide-area transepithelial sampling with computer-assisted 3-dimensional analysis. All these techniques are used to increase the detection of dysplasia. Of these, dye-based chromoendoscopy, narrow-band imaging, and confocal laser endomicroscopy meet current criteria of the American Society for Gastrointestinal Endoscopy for preservation and incorporation of valuable endoscopic innovations.²³

MANAGEMENT OF NONDYSPLASTIC BARRETT ESOPHAGUS

A proton pump inhibitor (PPI) is recommended to control reflux symptoms in patients with nondysplastic Barrett esophagus. But it is important to counsel patients on additional ways to protect against esophageal adenocarcinoma, such as:

• Low to moderate alcohol consumption
• Regular physical activity
• Increased dietary intake of fruits, vegetables, folate, fiber, beta-carotene, and vitamin C
• Weight control
• Smoking cessation.²⁵

Surveillance endoscopy with 4-quadrant biopsies at 2-cm intervals is recommended every 3 to 5 years (Table 1).

DOES CHEMOPREVENTION HAVE A ROLE?

Chemoprevention is an exciting area of research in preventing progression to adenocarcinoma in patients with Barrett esophagus. Various drugs such as aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), PPIs, metformin, and statins have been studied.

Aspirin

Aspirin has been shown to prevent development of Barrett esophagus in patients with reflux disease,²⁶ but more studies are needed to validate those findings.

PPIs

Gastroesophageal reflux disease is a primary risk factor for esophageal adenocarcinoma, and gastric acid suppression with PPIs reduces cancer risk. PPI therapy is associated with a 71% decrease in the risk of high-grade dysplasia and adenocarcinoma in patients with Barrett esophagus (OR 0.29, 95% CI 0.12–0.79).²⁷ Long-term therapy (> 2 to 3 years) has a higher protective effect (adjusted OR 0.45, 95% CI 0.19–1.06) than short-term therapy (< 2 to 3 years) (adjusted OR 1.09, 95% CI 0.47–2.56).²⁷

NSAIDs

NSAIDs, including aspirin, have been associated with decreased risk of colon, stomach, lung, breast, and esophageal cancer due to their potential to inhibit cyclooxygenase 2 (COX-2) enzymes.

A meta-analysis demonstrated that aspirin and NSAIDs led to a 32% reduction in the risk of adenocarcinoma (OR 0.68, 95% CI 0.56–0.83). The benefit was even greater if the drug was taken daily or more frequently (OR 0.56, 95% CI 0.43–0.73, P < .001) or was taken for 10 or more years (OR 0.63, 95% CI 0.45–0.90, P = .04).²⁸

PPI plus aspirin

The best evidence for the role of PPIs and aspirin in reducing the risk of dysplasia comes from the Aspirin and Esomeprazole Chemoprevention in Barrett’s Metaplasia Trial.²⁹ This randomized, controlled trial compared 4 regimens consisting of esomeprazole (a PPI) in either a high dose (40 mg twice daily) or a low dose (20 mg once daily) plus either aspirin (300 or 320 mg per day) or no aspirin in 2,557 patients with Barrett esophagus. The composite end point was the time to all-cause mortality, adenocarcinoma, or high-grade dysplasia.

At a median follow-up of 8.9 years, the combination of high-dose esomeprazole plus aspirin had the strongest effect compared with low-dose esomeprazole without aspirin (time ratio 1.59, 95% CI 1.14–2.23, P = .0068). The number needed to treat was 34 for esomeprazole and 43 for aspirin.²⁹

Based on these data, we can conclude that aspirin and PPIs can prevent dysplasia and all-cause mortality in Barrett esophagus.

Metformin: No evidence of benefit

Metformin was studied as a protective agent against obesity-associated cancers including esophageal adenocarcinoma, as it reduces insulin levels.

In a randomized controlled trial³⁰ in 74 patients with Barrett esophagus, metformin (starting at 500 mg daily, increasing to 2,000 mg/day by week 4) was compared with placebo. At 12 weeks, the percent change in esophageal levels of the biomarker pS6K1—an intracellular mediator of insulin and insulin-like growth factor activation in Barrett epithelium—did not differ significantly between the 2 groups (1.4% with metformin vs −14.7% with placebo; 1-sided P = .80). This suggested that metformin did not significantly alter proliferation or apoptosis in Barrett epithelium, despite reducing serum insulin levels and insulin resistance. Thus, metformin did not demonstrate a chemoprotective effect in preventing the progression of Barrett esophagus to adenocarcinoma.

 

 

Vitamin D: No evidence of benefit

Vitamin D affects genes regulating proliferation, apoptosis, and differentiation, and has therefore been studied as a potential antineoplastic agent. Its deficiency has also been associated with increased risk of esophageal adenocarcinoma. However, its efficacy in chemoprevention is unclear.³¹

One study found no association between serum 25-hydroxyvitamin D levels and prevalence of dysplasia in Barrett esophagus (P = .90). An increase in vitamin D levels had no effect on progression to dysplasia or cancer (for every 5-nmol/L increase from baseline, hazard ratio 0.98, P = .62).³²

In another study, supplementation with vitamin D₃ (cholecalciferol 50,000 IU weekly) plus a PPI for 12 weeks significantly improved the serum 25-hydroxyvitamin D levels without significant changes in gene expression from Barrett epithelium.³³ These findings were confirmed in a meta-analysis that showed no consistent association between vitamin D exposure and risk of esophageal neoplasm.³⁴

Thus, there is currently no evidence to support vitamin D for chemoprevention in Barrett esophagus or esophageal adenocarcinoma.

Statins

In addition to lowering cholesterol, statins have antiproliferative, pro-apoptotic, anti-angiogenic, and immunomodulatory effects that prevent cancer, leading to a 41% reduction in the risk of adenocarcinoma in patients with Barrett esophagus in one study (adjusted OR 0.59, 95% CI 0.45–0.78); the number needed to treat with statins to prevent 1 case of adenocarcinoma was 389.³⁵

A meta-analysis also showed that statin use was associated with a lower risk of progression of Barrett esophagus (OR 0.48, 95% CI 0.31–0.73).³⁶

In general, statins appear promising for chemoprevention, but more study is needed.

When is chemoprevention appropriate?

Chemoprevention is not recommended for all patients with Barrett esophagus, given that the condition affects 1% to 2% of the US adult population, and very few patients have progression to esophageal adenocarcinoma. Rather, chemoprevention may be considered in patients with Barrett esophagus and multiple risk factors for adenocarcinoma.

INDEFINITE DYSPLASIA

In Barrett esophagus with indefinite dysplasia, either the epithelial abnormalities are insufficient for a diagnosis of dysplasia, or the nature of the epithelial abnormalities is uncertain due to inflammation or technical difficulties with specimen processing. The risk of high-grade dysplasia or cancer within 1 year of the diagnosis of indefinite dysplasia varies between 1.9% and 15%.³⁷ The recommendation for management is to optimize acid-suppressive therapy for 3 to 6 months and then to repeat esophagogastroduodenoscopy. If indefinite dysplasia is noted again, repeat endoscopy in 12 months is recommended.²

ENDOSCOPIC ERADICATION: AN OVERVIEW

Because dysplasia in Barrett esophagus carries a high risk of progression to cancer, the standard of care is endoscopic mucosal resection of visible lesions, followed by ablation of the flat mucosa, with the aim of achieving complete eradication of intestinal metaplasia.^4,38 The initial endoscopic treatment is followed by outpatient sessions every 8 to 10 weeks until the dysplasia is eradicated. A key part of treatment during this time is maximal acid suppression with a PPI twice daily and a histamine-2 blocker at night. In rare cases, fundoplication is required to control reflux refractory to medical therapy.

After eradication is confirmed, continued surveillance is necessary, as recurrences have been reported at a rate of 4.8% per year for intestinal metaplasia, and 2% per year for dysplasia.³⁹

Current endoscopic resection techniques

Endoscopic resection techniques include mucosal resection, submucosal dissection, radio­frequency ablation, cryotherapy, argon plasma coagulation, and photodynamic therapy (Figure 2).

In mucosal resection, the lesion is either suctioned into a band ligator, after which a band is placed around the lesion, or suctioned into a cap fitted at the end of the endoscope, after which the lesion is removed using a snare.

In submucosal dissection, a liquid is injected into the submucosa to lift the lesion, making it easier to remove. The procedure is technically complex and requires additional training.

In radiofrequency ablation, a special catheter is passed through the endoscope to ablate the affected epithelium by thermal injury. Argon plasma coagulation works in a similar way, but uses ionized argon gas to induce thermal coagulation of metaplastic epithelium.

Cryotherapy produces cellular injury by rapid freezing and thawing of tissue using a cryogen such as liquid nitrogen or nitrous oxide.

In photodynamic therapy, a photosensitizer (porfimer sodium) is administered and taken up preferentially by metaplastic epithelium; it is then activated by transmission of red light using the endoscope, leading to destruction of the metaplastic epithelium.

Of the different techniques, radiofrequency ablation has the most evidence for efficacy and hence is the most commonly used.

All of these procedures are generally well tolerated and have favorable side-effect profiles. After radiofrequency ablation with or without mucosal resection, esophageal strictures are noted in 5.6% of patients, and bleeding and perforation occur rarely (1% and 0.6% of patients, respectively).⁴⁰ Submucosal dissection is associated with a higher rate of complications such as stricture formation (11% of patients) and bleeding or perforation (1.5% of patients).⁴¹

 

 

LOW-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

Most patients with low-grade dysplasia (73%) are down-staged to nondysplastic Barrett esophagus or to indefinite for dysplasia after review by expert pathologists.⁴² Patients with confirmed and persistent low-grade dysplasia are at higher risk of progression.⁴³

Once low-grade dysplasia is confirmed by a second gastrointestinal pathologist, the patient should undergo endoscopic ablation. A landmark study by Shaheen et al⁴⁴ demonstrated the benefit of radiofrequency ablation in achieving complete eradication of dysplasia (90.5% vs 22.7% for a sham procedure) and complete eradication of intestinal metaplasia (77.4% vs 2.3% for a sham procedure). In another trial of 136 patients with low-grade dysplasia followed for 3 years, Phoa et al⁴⁵ demonstrated that radiofrequency ablation reduced the rate of progression to high-grade dysplasia by 25% and to adenocarcinoma by 7.4% compared with endoscopic surveillance.

Patients with confirmed low-grade dysplasia who do not undergo eradication therapy should have surveillance endoscopy every 6 to 12 months (Table 1).

HIGH-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

As with low-grade dysplasia, the diagnosis of high-grade dysplasia needs to be confirmed by a second pathologist with gastrointestinal expertise. In the past, the treatment was esophagectomy, but due to lower morbidity and equivalent efficacy of radiofrequency ablation,⁴⁶ the current treatment of choice is endoscopic mucosal resection of raised lesions, followed by radiofrequency ablation of the entire affected segment.

In the study by Shaheen et al,⁴⁴ 42 patients with high-grade dysplasia were randomized to radiofrequency ablation and 21 to a sham procedure, and 81% of ablation patients achieved complete eradication of dysplasia vs 19% with the sham procedure. Eradication of intestinal metaplasia was achieved in 77% of ablation patients vs 2% of patients with the sham therapy. Results of 3-year follow-up from the same cohort showed complete eradication of dysplasia in 98% and of intestinal metaplasia in 91%.⁴⁷

Endoscopic eradication therapy is recommended for all patients with Barrett esophagus and high-grade dysplasia without a life-limiting comorbidity. Alternatively, surveillance every 3 months is an option if the patient does not wish to undergo eradication therapy. Radiofrequency ablation is more cost-effective than esophagectomy or endoscopic surveillance followed by treatment once patients develop adenocarcinoma.^48,49

EARLY ESOPHAGEAL ADENOCARCINOMA: RECOMMENDED MANAGEMENT

Adenocarcinoma limited to the mucosa and without evidence of nodal involvement can be resected endoscopically. In patients with localized cancer, mucosal resection is done not only for therapeutic purposes but also for staging. Ideal management is multidisciplinary, including a gastroenterologist, thoracic surgeon, oncologist, pathologist, and radiation oncologist.

If lesions have features suggesting submucosal invasion or are greater than 1.5 cm in size, or if it is difficult to separate (ie, lift) the mucosa from the submucosal layer with injection of saline, then submucosal dissection is recommended.⁵⁰ Because of the risk of metachronous lesions, ablation of the remaining Barrett esophagus mucosa is recommended after resection of cancer.

Endoscopic eradication is highly effective and durable for the treatment of intramucosal esophageal adenocarcinoma. In a study of 1,000 patients, 963 patients (96.3%) had achieved a complete response; 12 patients (3.7%) underwent surgery after eradication failed during a follow-up of almost 5 years.⁵¹ Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but were successfully treated endoscopically in 115, resulting in a long-term complete remission rate of 93.8%.

POSTABLATION MANAGEMENT

Because of the risk of recurrence of dysplasia after ablation, long-term PPI therapy and surveillance are recommended.

Surveillance endoscopy involves 4-quadrant biopsies taken every 1 cm from the entire length of segment where Barrett esophagus had been seen before ablation.

The timing of surveillance intervals depends on the preablation grade of dysplasia. For low-grade dysplasia, the recommendation is every 6 months for the first year after ablation and, if there is no recurrence of dysplasia, annually after that.² After treatment of high-grade dysplasia or intramucosal adenocarcinoma, the recommendation is every 3 months for the first year, every 6 months in the second year, and then annually.²

All cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus.¹ But most cases of Barrett esophagus go undiagnosed. And Barrett esophagus is seen in 5% to 15% of patients with gastroesophageal reflux disease.² These facts clearly emphasize the need for screening. Here, we review the rationale and recommendations for screening and surveillance, as well as the range of treatment options.

SCOPE OF THE PROBLEM

The American Cancer Society estimated there were 17,290 new cases of esophageal cancer and 15,850 deaths from it in the United States in 2018.³ Of the 2 main histologic types of esophageal cancer, adenocarcinoma and squamous cell cancer, adenocarcinoma is more common in the United States.

The precursor lesion is Barrett esophagus, defined as an extension of salmon-colored mucosa at least 1 cm into the tubular esophagus proximal to the gastroesophageal junction, with biopsy confirmation of intestinal metaplasia.⁴

The natural course of progression to dysplasia and cancer in Barrett esophagus is unknown but is thought to be stepwise, from no dysplasia to low-grade dysplasia to high-grade dysplasia and cancer, and the cancer risk depends on the degree of dysplasia: the annual risk is 0.33% if there is no dysplasia, 0.54% with low-grade dysplasia, and 7% with high-grade dysplasia.⁴

Although all cases of esophageal adenocarcinoma are thought to arise from Barrett esophagus,¹ more than 90% of patients with newly diagnosed esophageal adenocarcinoma do not have a prior diagnosis of Barrett esophagus.⁵ Therefore, there is a substantial unmet need to expand screening for Barrett esophagus in people at risk.

GASTROESOPHAGEAL REFLUX DISEASE IS A RISK FACTOR FOR CANCER

The rationale behind screening is that detecting Barrett esophagus early and intervening in a timely manner in patients at higher risk of developing adenocarcinoma will decrease mortality.

Chronic gastroesophageal reflux disease is a strong risk factor for esophageal adenocarcinoma (odds ratio [OR] 7.7, 95% confidence interval [CI] 5.3–11.4), and the risk increases when symptoms are long-standing (> 20 years) or severe (OR 43.5, 95% CI 18.3–103.5) or occur daily (OR 5.5, 95% CI 3.2–9.3).⁶

Reflux symptoms are scored as follows:

• Heartburn only, 1 point
• Regurgitation only, 1 point
• Heartburn with regurgitation, 1.5 points
• Nightly symptoms (2 points if yes, 0 if no)
• Symptoms once a week, 0 points; 2 to 6 times a week, 1 point; 7 to 15 times a week, 2 points; more than 15 times a week, 3 points.⁶

A score of 4.5 or higher indicates severe reflux disease. However, it is worth noting that the annual incidence of esophageal adenocarcinoma in patients with long-term gastroesophageal reflux disease is less than 0.001%.⁷

RISK FACTORS FOR BARRETT ESOPHAGUS

Risk factors for Barrett esophagus include:

Male sex. Barrett esophagus is more prevalent in men than in women, at a ratio of 2 to 1; but in individuals under age 50, the ratio is 4 to 1.⁸

Age 50 or older. Barrett esophagus is usually diagnosed in the sixth to seventh decade of life, and the prevalence increases from 2.1% in the third decade to 9.3% in the sixth decade.⁹

White race. It is more prevalent in whites than in blacks (5.0% vs 1.5%, P < .0001).¹⁰

Central obesity. Waist circumference is an independent risk factor: every 5-cm increase carries an OR of 1.14 (95% CI 1.03–1.27, P = .02).¹¹

Cigarette smoking increases the risk of Barrett esophagus (OR 1.42; 95% CI 1.15–1.76).¹²

A family history of Barrett esophagus or esophageal adenocarcinoma is a strong risk factor (OR 12, 95% CI 3.3–44.8). In 1 study, the risk in first- and second-degree relatives of patients with Barrett esophagus was 24%, compared with 5% in a control population (P < .005).¹³

SCREENING GUIDELINES AND DRAWBACKS

American College of Gastroenterology guidelines recommend screening for Barrett esophagus in men who have chronic reflux disease (> 5 years) or frequent symptoms (weekly or more often), and 2 or more risk factors.⁴ In women, screening is recommended only in the presence of multiple risk factors.⁴

The standard screening method is esophagogastroduodenoscopy with sedation, with careful visual inspection and 4-quadrant biopsies every 2 cm using the Seattle protocol, ie, including biopsy of any mucosal irregularities in salmon-colored mucosa above the gastroesophageal junction (Figure 1).⁴

Endoscopic screening is cost-effective, costing $10,440 per quality-adjusted life-year saved, which is well below the accepted threshold of less than $100,000.¹⁴ However, it is still expensive, invasive, and not ideal for screening large populations.

Less-invasive methods under study

Less-invasive, less-expensive methods being tested for mass screening include:

Unsedated transnasal endoscopy. Done with only topical anesthesia, it has high diagnostic accuracy and is quicker and more cost-effective than standard esophagogastroduodenoscopy, with fewer adverse effects. However, the procedure has not yet gained widespread acceptance for regular use by gastroenterologists.¹⁵

A swallowable sponge. Another promising test is cell collection using the Cytosponge Cell Collection Device (Medtronic, Minneapolis, MN). An encapsulated compressed sponge with a string attached is swallowed; in the stomach, the capsule dissolves, and the sponge expands and is then withdrawn using the attached string. The obtained cytology sample from the lower esophagus is then tested for trefoil factor 3, a protein biomarker for Barrett esophagus.¹⁶

A retractable balloon. The EsoCheck Cell Collection Device is a retractable balloon attached to a string. When swallowed, it gathers distal esophageal cells for detecting methylated DNA markers for Barrett esophagus.¹⁷

Esophageal capsule endoscopy uses a camera to visualize the esophagus, but lacks the ability to obtain biopsy samples.

Other screening methods are being tested, although data are limited. Liquid biopsy uses a blood sample to detect microRNAs that are dysregulated in cancer. The “electronic nose” is a device that detects exhaled volatile organic compounds altered in Barrett esophagus. Another test involves taking an oral wash sample to study the oral microbiome for a pattern associated with adenocarcinoma.^18–21

 

 

SURVEILLANCE: WHAT’S INVOLVED, WHAT’S AVAILABLE

Surveillance in Barrett esophagus aims to detect premalignant changes or early-stage adenocarcinoma to provide longer survival and lower cancer-related mortality. Recent evidence suggests that patients with esophageal adenocarcinoma that is diagnosed in a Barrett esophagus surveillance program have an earlier stage of disease and therefore a survival benefit.²²

Patient education is essential

Before enrolling a patient in a surveillance program, the clinician should explain the risks, benefits, and limitations, the importance of periodic endoscopy, and the possible eventual need for endoscopic therapy or surgery.

The endoscopic procedure

Surveillance involves examination by high-definition white-light endoscopy, with random 4-quadrant biopsies every 2 cm (or every 1 cm in patients with a history of dysplasia) and biopsy of any mucosal irregularity (nodule, ulcer, or other visible lesion). The degree of dysplasia determines the frequency of follow-up surveillance intervals and the need for endoscopic eradication therapy, as presented in professional society guidelines (Table 1).^4,23,24

Advanced methods for detecting dysplasia

Newer endoscopic surveillance techniques include dye-based chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy, volumetric laser endomicroscopy, and wide-area transepithelial sampling with computer-assisted 3-dimensional analysis. All these techniques are used to increase the detection of dysplasia. Of these, dye-based chromoendoscopy, narrow-band imaging, and confocal laser endomicroscopy meet current criteria of the American Society for Gastrointestinal Endoscopy for preservation and incorporation of valuable endoscopic innovations.²³

MANAGEMENT OF NONDYSPLASTIC BARRETT ESOPHAGUS

A proton pump inhibitor (PPI) is recommended to control reflux symptoms in patients with nondysplastic Barrett esophagus. But it is important to counsel patients on additional ways to protect against esophageal adenocarcinoma, such as:

• Low to moderate alcohol consumption
• Regular physical activity
• Increased dietary intake of fruits, vegetables, folate, fiber, beta-carotene, and vitamin C
• Weight control
• Smoking cessation.²⁵

Surveillance endoscopy with 4-quadrant biopsies at 2-cm intervals is recommended every 3 to 5 years (Table 1).

DOES CHEMOPREVENTION HAVE A ROLE?

Chemoprevention is an exciting area of research in preventing progression to adenocarcinoma in patients with Barrett esophagus. Various drugs such as aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), PPIs, metformin, and statins have been studied.

Aspirin

Aspirin has been shown to prevent development of Barrett esophagus in patients with reflux disease,²⁶ but more studies are needed to validate those findings.

PPIs

Gastroesophageal reflux disease is a primary risk factor for esophageal adenocarcinoma, and gastric acid suppression with PPIs reduces cancer risk. PPI therapy is associated with a 71% decrease in the risk of high-grade dysplasia and adenocarcinoma in patients with Barrett esophagus (OR 0.29, 95% CI 0.12–0.79).²⁷ Long-term therapy (> 2 to 3 years) has a higher protective effect (adjusted OR 0.45, 95% CI 0.19–1.06) than short-term therapy (< 2 to 3 years) (adjusted OR 1.09, 95% CI 0.47–2.56).²⁷

NSAIDs

NSAIDs, including aspirin, have been associated with decreased risk of colon, stomach, lung, breast, and esophageal cancer due to their potential to inhibit cyclooxygenase 2 (COX-2) enzymes.

A meta-analysis demonstrated that aspirin and NSAIDs led to a 32% reduction in the risk of adenocarcinoma (OR 0.68, 95% CI 0.56–0.83). The benefit was even greater if the drug was taken daily or more frequently (OR 0.56, 95% CI 0.43–0.73, P < .001) or was taken for 10 or more years (OR 0.63, 95% CI 0.45–0.90, P = .04).²⁸

PPI plus aspirin

The best evidence for the role of PPIs and aspirin in reducing the risk of dysplasia comes from the Aspirin and Esomeprazole Chemoprevention in Barrett’s Metaplasia Trial.²⁹ This randomized, controlled trial compared 4 regimens consisting of esomeprazole (a PPI) in either a high dose (40 mg twice daily) or a low dose (20 mg once daily) plus either aspirin (300 or 320 mg per day) or no aspirin in 2,557 patients with Barrett esophagus. The composite end point was the time to all-cause mortality, adenocarcinoma, or high-grade dysplasia.

At a median follow-up of 8.9 years, the combination of high-dose esomeprazole plus aspirin had the strongest effect compared with low-dose esomeprazole without aspirin (time ratio 1.59, 95% CI 1.14–2.23, P = .0068). The number needed to treat was 34 for esomeprazole and 43 for aspirin.²⁹

Based on these data, we can conclude that aspirin and PPIs can prevent dysplasia and all-cause mortality in Barrett esophagus.

Metformin: No evidence of benefit

Metformin was studied as a protective agent against obesity-associated cancers including esophageal adenocarcinoma, as it reduces insulin levels.

In a randomized controlled trial³⁰ in 74 patients with Barrett esophagus, metformin (starting at 500 mg daily, increasing to 2,000 mg/day by week 4) was compared with placebo. At 12 weeks, the percent change in esophageal levels of the biomarker pS6K1—an intracellular mediator of insulin and insulin-like growth factor activation in Barrett epithelium—did not differ significantly between the 2 groups (1.4% with metformin vs −14.7% with placebo; 1-sided P = .80). This suggested that metformin did not significantly alter proliferation or apoptosis in Barrett epithelium, despite reducing serum insulin levels and insulin resistance. Thus, metformin did not demonstrate a chemoprotective effect in preventing the progression of Barrett esophagus to adenocarcinoma.

 

 

Vitamin D: No evidence of benefit

Vitamin D affects genes regulating proliferation, apoptosis, and differentiation, and has therefore been studied as a potential antineoplastic agent. Its deficiency has also been associated with increased risk of esophageal adenocarcinoma. However, its efficacy in chemoprevention is unclear.³¹

One study found no association between serum 25-hydroxyvitamin D levels and prevalence of dysplasia in Barrett esophagus (P = .90). An increase in vitamin D levels had no effect on progression to dysplasia or cancer (for every 5-nmol/L increase from baseline, hazard ratio 0.98, P = .62).³²

In another study, supplementation with vitamin D₃ (cholecalciferol 50,000 IU weekly) plus a PPI for 12 weeks significantly improved the serum 25-hydroxyvitamin D levels without significant changes in gene expression from Barrett epithelium.³³ These findings were confirmed in a meta-analysis that showed no consistent association between vitamin D exposure and risk of esophageal neoplasm.³⁴

Thus, there is currently no evidence to support vitamin D for chemoprevention in Barrett esophagus or esophageal adenocarcinoma.

Statins

In addition to lowering cholesterol, statins have antiproliferative, pro-apoptotic, anti-angiogenic, and immunomodulatory effects that prevent cancer, leading to a 41% reduction in the risk of adenocarcinoma in patients with Barrett esophagus in one study (adjusted OR 0.59, 95% CI 0.45–0.78); the number needed to treat with statins to prevent 1 case of adenocarcinoma was 389.³⁵

A meta-analysis also showed that statin use was associated with a lower risk of progression of Barrett esophagus (OR 0.48, 95% CI 0.31–0.73).³⁶

In general, statins appear promising for chemoprevention, but more study is needed.

When is chemoprevention appropriate?

Chemoprevention is not recommended for all patients with Barrett esophagus, given that the condition affects 1% to 2% of the US adult population, and very few patients have progression to esophageal adenocarcinoma. Rather, chemoprevention may be considered in patients with Barrett esophagus and multiple risk factors for adenocarcinoma.

INDEFINITE DYSPLASIA

In Barrett esophagus with indefinite dysplasia, either the epithelial abnormalities are insufficient for a diagnosis of dysplasia, or the nature of the epithelial abnormalities is uncertain due to inflammation or technical difficulties with specimen processing. The risk of high-grade dysplasia or cancer within 1 year of the diagnosis of indefinite dysplasia varies between 1.9% and 15%.³⁷ The recommendation for management is to optimize acid-suppressive therapy for 3 to 6 months and then to repeat esophagogastroduodenoscopy. If indefinite dysplasia is noted again, repeat endoscopy in 12 months is recommended.²

ENDOSCOPIC ERADICATION: AN OVERVIEW

Because dysplasia in Barrett esophagus carries a high risk of progression to cancer, the standard of care is endoscopic mucosal resection of visible lesions, followed by ablation of the flat mucosa, with the aim of achieving complete eradication of intestinal metaplasia.^4,38 The initial endoscopic treatment is followed by outpatient sessions every 8 to 10 weeks until the dysplasia is eradicated. A key part of treatment during this time is maximal acid suppression with a PPI twice daily and a histamine-2 blocker at night. In rare cases, fundoplication is required to control reflux refractory to medical therapy.

After eradication is confirmed, continued surveillance is necessary, as recurrences have been reported at a rate of 4.8% per year for intestinal metaplasia, and 2% per year for dysplasia.³⁹

Current endoscopic resection techniques

Endoscopic resection techniques include mucosal resection, submucosal dissection, radio­frequency ablation, cryotherapy, argon plasma coagulation, and photodynamic therapy (Figure 2).

In mucosal resection, the lesion is either suctioned into a band ligator, after which a band is placed around the lesion, or suctioned into a cap fitted at the end of the endoscope, after which the lesion is removed using a snare.

In submucosal dissection, a liquid is injected into the submucosa to lift the lesion, making it easier to remove. The procedure is technically complex and requires additional training.

In radiofrequency ablation, a special catheter is passed through the endoscope to ablate the affected epithelium by thermal injury. Argon plasma coagulation works in a similar way, but uses ionized argon gas to induce thermal coagulation of metaplastic epithelium.

Cryotherapy produces cellular injury by rapid freezing and thawing of tissue using a cryogen such as liquid nitrogen or nitrous oxide.

In photodynamic therapy, a photosensitizer (porfimer sodium) is administered and taken up preferentially by metaplastic epithelium; it is then activated by transmission of red light using the endoscope, leading to destruction of the metaplastic epithelium.

Of the different techniques, radiofrequency ablation has the most evidence for efficacy and hence is the most commonly used.

All of these procedures are generally well tolerated and have favorable side-effect profiles. After radiofrequency ablation with or without mucosal resection, esophageal strictures are noted in 5.6% of patients, and bleeding and perforation occur rarely (1% and 0.6% of patients, respectively).⁴⁰ Submucosal dissection is associated with a higher rate of complications such as stricture formation (11% of patients) and bleeding or perforation (1.5% of patients).⁴¹

 

 

LOW-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

Most patients with low-grade dysplasia (73%) are down-staged to nondysplastic Barrett esophagus or to indefinite for dysplasia after review by expert pathologists.⁴² Patients with confirmed and persistent low-grade dysplasia are at higher risk of progression.⁴³

Once low-grade dysplasia is confirmed by a second gastrointestinal pathologist, the patient should undergo endoscopic ablation. A landmark study by Shaheen et al⁴⁴ demonstrated the benefit of radiofrequency ablation in achieving complete eradication of dysplasia (90.5% vs 22.7% for a sham procedure) and complete eradication of intestinal metaplasia (77.4% vs 2.3% for a sham procedure). In another trial of 136 patients with low-grade dysplasia followed for 3 years, Phoa et al⁴⁵ demonstrated that radiofrequency ablation reduced the rate of progression to high-grade dysplasia by 25% and to adenocarcinoma by 7.4% compared with endoscopic surveillance.

Patients with confirmed low-grade dysplasia who do not undergo eradication therapy should have surveillance endoscopy every 6 to 12 months (Table 1).

HIGH-GRADE DYSPLASIA: RECOMMENDED MANAGEMENT

As with low-grade dysplasia, the diagnosis of high-grade dysplasia needs to be confirmed by a second pathologist with gastrointestinal expertise. In the past, the treatment was esophagectomy, but due to lower morbidity and equivalent efficacy of radiofrequency ablation,⁴⁶ the current treatment of choice is endoscopic mucosal resection of raised lesions, followed by radiofrequency ablation of the entire affected segment.

In the study by Shaheen et al,⁴⁴ 42 patients with high-grade dysplasia were randomized to radiofrequency ablation and 21 to a sham procedure, and 81% of ablation patients achieved complete eradication of dysplasia vs 19% with the sham procedure. Eradication of intestinal metaplasia was achieved in 77% of ablation patients vs 2% of patients with the sham therapy. Results of 3-year follow-up from the same cohort showed complete eradication of dysplasia in 98% and of intestinal metaplasia in 91%.⁴⁷

Endoscopic eradication therapy is recommended for all patients with Barrett esophagus and high-grade dysplasia without a life-limiting comorbidity. Alternatively, surveillance every 3 months is an option if the patient does not wish to undergo eradication therapy. Radiofrequency ablation is more cost-effective than esophagectomy or endoscopic surveillance followed by treatment once patients develop adenocarcinoma.^48,49

EARLY ESOPHAGEAL ADENOCARCINOMA: RECOMMENDED MANAGEMENT

Adenocarcinoma limited to the mucosa and without evidence of nodal involvement can be resected endoscopically. In patients with localized cancer, mucosal resection is done not only for therapeutic purposes but also for staging. Ideal management is multidisciplinary, including a gastroenterologist, thoracic surgeon, oncologist, pathologist, and radiation oncologist.

If lesions have features suggesting submucosal invasion or are greater than 1.5 cm in size, or if it is difficult to separate (ie, lift) the mucosa from the submucosal layer with injection of saline, then submucosal dissection is recommended.⁵⁰ Because of the risk of metachronous lesions, ablation of the remaining Barrett esophagus mucosa is recommended after resection of cancer.

Endoscopic eradication is highly effective and durable for the treatment of intramucosal esophageal adenocarcinoma. In a study of 1,000 patients, 963 patients (96.3%) had achieved a complete response; 12 patients (3.7%) underwent surgery after eradication failed during a follow-up of almost 5 years.⁵¹ Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but were successfully treated endoscopically in 115, resulting in a long-term complete remission rate of 93.8%.

POSTABLATION MANAGEMENT

Because of the risk of recurrence of dysplasia after ablation, long-term PPI therapy and surveillance are recommended.

Surveillance endoscopy involves 4-quadrant biopsies taken every 1 cm from the entire length of segment where Barrett esophagus had been seen before ablation.

The timing of surveillance intervals depends on the preablation grade of dysplasia. For low-grade dysplasia, the recommendation is every 6 months for the first year after ablation and, if there is no recurrence of dysplasia, annually after that.² After treatment of high-grade dysplasia or intramucosal adenocarcinoma, the recommendation is every 3 months for the first year, every 6 months in the second year, and then annually.²

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Multiple sleep comorbidities are associated with migraine, including sleep apnea and insomnia.² Poor sleep itself has been described as a migraine trigger. Those with both migraine and poor sleep report having lower quality of life, more mood disorders, lower socioeconomic status, higher stress, and higher tendency for poor lifestyle habits.³ The number needed to treat by initiating routine lifestyle behaviors including sleep, diet, and exercise is 2, indicating that every other person could benefit from this type of intervention.⁴

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

 

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

 

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

 

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Stress and anxiety are associated with migraine. Either may lead to avoidance and hypervigilance of perceived triggers, and this association may affect migraines.^71,72 High stress and chronic migraine are associated with lifestyle factors such as medication overuse, smoking, sedentary habits, and obesity.⁷³ Fortunately, many evidence-based techniques used for management of stress and mood disorders can also be used in migraine, including cognitive behavioral therapy, biofeedback, mindfulness, and relaxation techniques (Table 2).

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Multiple sleep comorbidities are associated with migraine, including sleep apnea and insomnia.² Poor sleep itself has been described as a migraine trigger. Those with both migraine and poor sleep report having lower quality of life, more mood disorders, lower socioeconomic status, higher stress, and higher tendency for poor lifestyle habits.³ The number needed to treat by initiating routine lifestyle behaviors including sleep, diet, and exercise is 2, indicating that every other person could benefit from this type of intervention.⁴

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

 

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

 

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

 

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Stress and anxiety are associated with migraine. Either may lead to avoidance and hypervigilance of perceived triggers, and this association may affect migraines.^71,72 High stress and chronic migraine are associated with lifestyle factors such as medication overuse, smoking, sedentary habits, and obesity.⁷³ Fortunately, many evidence-based techniques used for management of stress and mood disorders can also be used in migraine, including cognitive behavioral therapy, biofeedback, mindfulness, and relaxation techniques (Table 2).

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Multiple sleep comorbidities are associated with migraine, including sleep apnea and insomnia.² Poor sleep itself has been described as a migraine trigger. Those with both migraine and poor sleep report having lower quality of life, more mood disorders, lower socioeconomic status, higher stress, and higher tendency for poor lifestyle habits.³ The number needed to treat by initiating routine lifestyle behaviors including sleep, diet, and exercise is 2, indicating that every other person could benefit from this type of intervention.⁴

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

 

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

 

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

 

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Stress and anxiety are associated with migraine. Either may lead to avoidance and hypervigilance of perceived triggers, and this association may affect migraines.^71,72 High stress and chronic migraine are associated with lifestyle factors such as medication overuse, smoking, sedentary habits, and obesity.⁷³ Fortunately, many evidence-based techniques used for management of stress and mood disorders can also be used in migraine, including cognitive behavioral therapy, biofeedback, mindfulness, and relaxation techniques (Table 2).

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.