Pain

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

 

 

Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

 

 

CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

 

 

Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

 

 

CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

 

 

Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

 

 

CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

COVID-19 survivors are at risk from a possible second pandemic, this time of opioid addiction, given the high rate of painkillers being prescribed to these patients, health experts say.

sdominick/Getty Images

A new study in Nature found alarmingly high rates of opioid use among COVID survivors with lingering symptoms at Veterans Affairs facilities. About 10% of COVID survivors develop “long COVID,” struggling with often disabling health problems even 6 months or longer after a diagnosis.

For every 1,000 long-COVID patients, known as “long-haulers,” who were treated at a VA facility, doctors wrote nine more prescriptions for opioids than they otherwise would have, along with 22 additional prescriptions for benzodiazepines, which include Xanax and other addictive pills used to treat anxiety.

Although previous studies have found many COVID survivors experience persistent health problems, the new article is the first to show they’re using more addictive medications, said Ziyad Al-Aly, MD, the paper’s lead author.

He’s concerned that even an apparently small increase in the inappropriate use of addictive pain pills will lead to a resurgence of the prescription opioid crisis, given the large number of COVID survivors. More than 3 million of the 31 million Americans infected with COVID develop long-term symptoms, which can include fatigue, shortness of breath, depression, anxiety, and memory problems known as “brain fog.”

The new study also found many patients have significant muscle and bone pain.

The frequent use of opioids was surprising, given concerns about their potential for addiction, said Dr. Al-Aly, chief of research and education service at the VA St. Louis Health Care System.

“Physicians now are supposed to shy away from prescribing opioids,” said Dr. Al-Aly, who studied more than 73,000 patients in the VA system. When Dr. Al-Aly saw the number of opioids prescriptions, he said, he thought to himself: “Is this really happening all over again?”

Doctors need to act now, before “it’s too late to do something,” Dr. Al-Aly said. “We must act now and ensure that people are getting the care they need. We do not want this to balloon into a suicide crisis or another opioid epidemic.”

As more doctors became aware of their addictive potential, new opioid prescriptions fell, by more than half since 2012. But U.S. doctors still prescribe far more of the drugs – which include OxyContin, Vicodin, and codeine – than physicians in other countries, said Andrew Kolodny, MD, medical director of opioid policy research at Brandeis University, Waltham, Mass.

Some patients who became addicted to prescription painkillers switched to heroin, either because it was cheaper or because they could no longer obtain opioids from their doctors. Overdose deaths surged in recent years as drug dealers began spiking heroin with a powerful synthetic opioid called fentanyl.

More than 88,000 Americans died from overdoses during the 12 months ending in August 2020, according to the Centers for Disease Control and Prevention. Health experts now advise doctors to avoid prescribing opioids for long periods.

The new study “suggests to me that many clinicians still don’t get it,” Dr. Kolodny said. “Many clinicians are under the false impression that opioids are appropriate for chronic pain patients.”

Hospitalized COVID patients often receive a lot of medication to control pain and anxiety, especially in ICUs, said Greg Martin, MD, president of the Society of Critical Care Medicine. Patients placed on ventilators, for example, are often sedated to make them more comfortable.

Martin said he’s concerned by the study’s findings, which suggest patients are unnecessarily continuing medications after leaving the hospital.

“I worry that COVID-19 patients, especially those who are severely and critically ill, receive a lot of medications during the hospitalization, and because they have persistent symptoms, the medications are continued after hospital discharge,” Dr. Martin said.

While some COVID patients are experiencing muscle and bone pain for the first time, others say the illness has intensified their preexisting pain.

Rachael Sunshine Burnett has suffered from chronic pain in her back and feet for 20 years, ever since an accident at a warehouse where she once worked. But Ms. Burnett, who first was diagnosed with COVID in April 2020, said the pain soon became 10 times worse and spread to the area between her shoulders and spine. Although she was already taking long-acting OxyContin twice a day, her doctor prescribed an additional opioid called oxycodone, which relieves pain immediately. She was reinfected with COVID in December.

“It’s been a horrible, horrible year,” said Ms. Burnett, 43, of Coxsackie, N.Y.

Doctors should recognize that pain can be a part of long COVID, Dr. Martin said. “We need to find the proper nonnarcotic treatment for it, just like we do with other forms of chronic pain,” he said.

The CDC recommends a number of alternatives to opioids – from physical therapy to biofeedback, over-the-counter anti-inflammatories, antidepressants, and antiseizure drugs that also relieve nerve pain.

The country also needs an overall strategy to cope with the wave of post-COVID complications, Dr. Al-Aly said.

“It’s better to be prepared than to be caught off guard years from now, when doctors realize: ‘Oh, we have a resurgence in opioids,’ ” Dr. Al-Aly said.

Dr. Al-Aly noted that his study may not capture the full complexity of post-COVID patient needs. Although women make up the majority of long-COVID patients in most studies, most patients in the VA system are men.

The study of VA patients makes it “abundantly clear that we are not prepared to meet the needs of 3 million Americans with long COVID,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute in San Diego. “We desperately need an intervention that will effectively treat these individuals.”

Dr. Al-Aly said COVID survivors may need care for years.

“That’s going to be a huge, significant burden on the health care system,” Dr. Al-Aly said. “Long COVID will reverberate in the health system for years or even decades to come.”

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

COVID-19 survivors are at risk from a possible second pandemic, this time of opioid addiction, given the high rate of painkillers being prescribed to these patients, health experts say.

sdominick/Getty Images

A new study in Nature found alarmingly high rates of opioid use among COVID survivors with lingering symptoms at Veterans Affairs facilities. About 10% of COVID survivors develop “long COVID,” struggling with often disabling health problems even 6 months or longer after a diagnosis.

For every 1,000 long-COVID patients, known as “long-haulers,” who were treated at a VA facility, doctors wrote nine more prescriptions for opioids than they otherwise would have, along with 22 additional prescriptions for benzodiazepines, which include Xanax and other addictive pills used to treat anxiety.

Although previous studies have found many COVID survivors experience persistent health problems, the new article is the first to show they’re using more addictive medications, said Ziyad Al-Aly, MD, the paper’s lead author.

He’s concerned that even an apparently small increase in the inappropriate use of addictive pain pills will lead to a resurgence of the prescription opioid crisis, given the large number of COVID survivors. More than 3 million of the 31 million Americans infected with COVID develop long-term symptoms, which can include fatigue, shortness of breath, depression, anxiety, and memory problems known as “brain fog.”

The new study also found many patients have significant muscle and bone pain.

The frequent use of opioids was surprising, given concerns about their potential for addiction, said Dr. Al-Aly, chief of research and education service at the VA St. Louis Health Care System.

“Physicians now are supposed to shy away from prescribing opioids,” said Dr. Al-Aly, who studied more than 73,000 patients in the VA system. When Dr. Al-Aly saw the number of opioids prescriptions, he said, he thought to himself: “Is this really happening all over again?”

Doctors need to act now, before “it’s too late to do something,” Dr. Al-Aly said. “We must act now and ensure that people are getting the care they need. We do not want this to balloon into a suicide crisis or another opioid epidemic.”

As more doctors became aware of their addictive potential, new opioid prescriptions fell, by more than half since 2012. But U.S. doctors still prescribe far more of the drugs – which include OxyContin, Vicodin, and codeine – than physicians in other countries, said Andrew Kolodny, MD, medical director of opioid policy research at Brandeis University, Waltham, Mass.

Some patients who became addicted to prescription painkillers switched to heroin, either because it was cheaper or because they could no longer obtain opioids from their doctors. Overdose deaths surged in recent years as drug dealers began spiking heroin with a powerful synthetic opioid called fentanyl.

More than 88,000 Americans died from overdoses during the 12 months ending in August 2020, according to the Centers for Disease Control and Prevention. Health experts now advise doctors to avoid prescribing opioids for long periods.

The new study “suggests to me that many clinicians still don’t get it,” Dr. Kolodny said. “Many clinicians are under the false impression that opioids are appropriate for chronic pain patients.”

Hospitalized COVID patients often receive a lot of medication to control pain and anxiety, especially in ICUs, said Greg Martin, MD, president of the Society of Critical Care Medicine. Patients placed on ventilators, for example, are often sedated to make them more comfortable.

Martin said he’s concerned by the study’s findings, which suggest patients are unnecessarily continuing medications after leaving the hospital.

“I worry that COVID-19 patients, especially those who are severely and critically ill, receive a lot of medications during the hospitalization, and because they have persistent symptoms, the medications are continued after hospital discharge,” Dr. Martin said.

While some COVID patients are experiencing muscle and bone pain for the first time, others say the illness has intensified their preexisting pain.

Rachael Sunshine Burnett has suffered from chronic pain in her back and feet for 20 years, ever since an accident at a warehouse where she once worked. But Ms. Burnett, who first was diagnosed with COVID in April 2020, said the pain soon became 10 times worse and spread to the area between her shoulders and spine. Although she was already taking long-acting OxyContin twice a day, her doctor prescribed an additional opioid called oxycodone, which relieves pain immediately. She was reinfected with COVID in December.

“It’s been a horrible, horrible year,” said Ms. Burnett, 43, of Coxsackie, N.Y.

Doctors should recognize that pain can be a part of long COVID, Dr. Martin said. “We need to find the proper nonnarcotic treatment for it, just like we do with other forms of chronic pain,” he said.

The CDC recommends a number of alternatives to opioids – from physical therapy to biofeedback, over-the-counter anti-inflammatories, antidepressants, and antiseizure drugs that also relieve nerve pain.

The country also needs an overall strategy to cope with the wave of post-COVID complications, Dr. Al-Aly said.

“It’s better to be prepared than to be caught off guard years from now, when doctors realize: ‘Oh, we have a resurgence in opioids,’ ” Dr. Al-Aly said.

Dr. Al-Aly noted that his study may not capture the full complexity of post-COVID patient needs. Although women make up the majority of long-COVID patients in most studies, most patients in the VA system are men.

The study of VA patients makes it “abundantly clear that we are not prepared to meet the needs of 3 million Americans with long COVID,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute in San Diego. “We desperately need an intervention that will effectively treat these individuals.”

Dr. Al-Aly said COVID survivors may need care for years.

“That’s going to be a huge, significant burden on the health care system,” Dr. Al-Aly said. “Long COVID will reverberate in the health system for years or even decades to come.”

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

COVID-19 survivors are at risk from a possible second pandemic, this time of opioid addiction, given the high rate of painkillers being prescribed to these patients, health experts say.

sdominick/Getty Images

A new study in Nature found alarmingly high rates of opioid use among COVID survivors with lingering symptoms at Veterans Affairs facilities. About 10% of COVID survivors develop “long COVID,” struggling with often disabling health problems even 6 months or longer after a diagnosis.

For every 1,000 long-COVID patients, known as “long-haulers,” who were treated at a VA facility, doctors wrote nine more prescriptions for opioids than they otherwise would have, along with 22 additional prescriptions for benzodiazepines, which include Xanax and other addictive pills used to treat anxiety.

Although previous studies have found many COVID survivors experience persistent health problems, the new article is the first to show they’re using more addictive medications, said Ziyad Al-Aly, MD, the paper’s lead author.

He’s concerned that even an apparently small increase in the inappropriate use of addictive pain pills will lead to a resurgence of the prescription opioid crisis, given the large number of COVID survivors. More than 3 million of the 31 million Americans infected with COVID develop long-term symptoms, which can include fatigue, shortness of breath, depression, anxiety, and memory problems known as “brain fog.”

The new study also found many patients have significant muscle and bone pain.

The frequent use of opioids was surprising, given concerns about their potential for addiction, said Dr. Al-Aly, chief of research and education service at the VA St. Louis Health Care System.

“Physicians now are supposed to shy away from prescribing opioids,” said Dr. Al-Aly, who studied more than 73,000 patients in the VA system. When Dr. Al-Aly saw the number of opioids prescriptions, he said, he thought to himself: “Is this really happening all over again?”

Doctors need to act now, before “it’s too late to do something,” Dr. Al-Aly said. “We must act now and ensure that people are getting the care they need. We do not want this to balloon into a suicide crisis or another opioid epidemic.”

As more doctors became aware of their addictive potential, new opioid prescriptions fell, by more than half since 2012. But U.S. doctors still prescribe far more of the drugs – which include OxyContin, Vicodin, and codeine – than physicians in other countries, said Andrew Kolodny, MD, medical director of opioid policy research at Brandeis University, Waltham, Mass.

Some patients who became addicted to prescription painkillers switched to heroin, either because it was cheaper or because they could no longer obtain opioids from their doctors. Overdose deaths surged in recent years as drug dealers began spiking heroin with a powerful synthetic opioid called fentanyl.

More than 88,000 Americans died from overdoses during the 12 months ending in August 2020, according to the Centers for Disease Control and Prevention. Health experts now advise doctors to avoid prescribing opioids for long periods.

The new study “suggests to me that many clinicians still don’t get it,” Dr. Kolodny said. “Many clinicians are under the false impression that opioids are appropriate for chronic pain patients.”

Hospitalized COVID patients often receive a lot of medication to control pain and anxiety, especially in ICUs, said Greg Martin, MD, president of the Society of Critical Care Medicine. Patients placed on ventilators, for example, are often sedated to make them more comfortable.

Martin said he’s concerned by the study’s findings, which suggest patients are unnecessarily continuing medications after leaving the hospital.

“I worry that COVID-19 patients, especially those who are severely and critically ill, receive a lot of medications during the hospitalization, and because they have persistent symptoms, the medications are continued after hospital discharge,” Dr. Martin said.

While some COVID patients are experiencing muscle and bone pain for the first time, others say the illness has intensified their preexisting pain.

Rachael Sunshine Burnett has suffered from chronic pain in her back and feet for 20 years, ever since an accident at a warehouse where she once worked. But Ms. Burnett, who first was diagnosed with COVID in April 2020, said the pain soon became 10 times worse and spread to the area between her shoulders and spine. Although she was already taking long-acting OxyContin twice a day, her doctor prescribed an additional opioid called oxycodone, which relieves pain immediately. She was reinfected with COVID in December.

“It’s been a horrible, horrible year,” said Ms. Burnett, 43, of Coxsackie, N.Y.

Doctors should recognize that pain can be a part of long COVID, Dr. Martin said. “We need to find the proper nonnarcotic treatment for it, just like we do with other forms of chronic pain,” he said.

The CDC recommends a number of alternatives to opioids – from physical therapy to biofeedback, over-the-counter anti-inflammatories, antidepressants, and antiseizure drugs that also relieve nerve pain.

The country also needs an overall strategy to cope with the wave of post-COVID complications, Dr. Al-Aly said.

“It’s better to be prepared than to be caught off guard years from now, when doctors realize: ‘Oh, we have a resurgence in opioids,’ ” Dr. Al-Aly said.

Dr. Al-Aly noted that his study may not capture the full complexity of post-COVID patient needs. Although women make up the majority of long-COVID patients in most studies, most patients in the VA system are men.

The study of VA patients makes it “abundantly clear that we are not prepared to meet the needs of 3 million Americans with long COVID,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute in San Diego. “We desperately need an intervention that will effectively treat these individuals.”

Dr. Al-Aly said COVID survivors may need care for years.

“That’s going to be a huge, significant burden on the health care system,” Dr. Al-Aly said. “Long COVID will reverberate in the health system for years or even decades to come.”

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

 

 

Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu

Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

 

 

Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu

Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.¹ Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.¹

The highest rates are reported in northern European and African-American individuals, particularly in women.^1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans³ and is more likely to be chronic and fatal in African Americans.³ The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.⁴ Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.⁵

Likely factors in the development of sarcoidosis

The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.^1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.¹⁰ Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.^11-13

Sarcoidosis is a diagnosis of exclusion; one must rule out infections, occupational or environmental exposures, malignancies, and other disorders that cause granulomatous inflammation.

ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.¹⁴ Tobacco use was not associated with sarcoidosis.¹⁴ Recent studies have shown positive associations with service in the US Navy,¹⁵ metal working,¹⁶ firefighting,¹⁷ the handling of building supplies,¹⁸ and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.¹⁹ Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.¹⁴ Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.²⁰

Clinical manifestations are nonspecific

The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 1^21-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.^23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).²²

Diagnostic work-up

The primary objective of a diagnostic evaluation in most suspected cases of sarcoidosis is to corroborate the clinical and radiologic features with pathologic evidence of non-necrotizing granulomas and to exclude other causes of granulomatous inflammation.²²

Radiologic studies

Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).^21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.³² At presentation, radiographs are abnormal in approximately 90% of patients.³⁴ Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.^1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.³⁶ Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.

Continue to: High-resoluton computed tomography

High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 3^21,23,25,32 and FIGURE 2^21,23,25,32 summarize the common CT chest findings of sarcoidosis.

Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.

Tissue biopsy

Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.^21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.²⁵

Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).^21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.³⁷ The combination of EBUS with TBB improves the diagnostic yield to ~90%.³⁷

The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).^22,25,26

Continue to: Laboratory studies

 

 

Laboratory studies

Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).^22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.²⁵ Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.²¹

Additional tests to assess specific features or organ involvement

Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”

Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.³⁰ TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.

Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.²⁸

Pulmonary sarcoidosis

Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.^39,40

Continue to: Pathology of early and advanced pulmonary sarcoidosis

Pathology of early and advanced pulmonary sarcoidosis

Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.⁴¹ Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.

In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.⁴⁰ Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.

Clinical features, monitoring, and outcomes

Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.²³ Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.⁴² There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.⁴³

Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.⁴⁴ Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.^45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.

While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.⁴⁰ Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.⁴⁹ Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.^50,51

Continue to: Because sarcoidosis is a multisystem disease...

Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.

Determining prognosis

Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.

Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.⁴⁰ APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.

One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.⁵² Mortality and morbidity may be increasing.⁵³ The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.

Management

Management consists primarily of anti-­inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.

Continue to: General approach to treatment decisions

General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.⁵⁴ Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.

Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.^55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,⁵⁹ and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.^57,60-62

Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.⁶³ Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.^64-66

Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 5^58,64,67-81shows the major anti-inflammatory treatment agents used for sarcoidosis.

The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.

Continue to: Research and future directions

Research and future directions

Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.

There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.^82-85 However, no benefit in survival has been shown.

RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,⁸⁶ are awaited in the near future.

Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.

CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu

Reading the excellent article on urine drug screening by Drs. Hayes and Fox reminds me of 2 important aspects of primary care: (1) Diagnosing and treating patients with drug addiction is an important service we provide, and (2) interpreting laboratory tests requires training, skill, and clinical judgment.

Drs. Hayes and Fox describe the proper use of urine drug testing in the management of patients for whom we prescribe opioids, whether for chronic pain or for addiction treatment. Combining a review of the literature with their own professional experience treating these patients, Drs. Hayes and Fox highlight the potential pitfalls in interpreting urine drug screening results and admonish us to use good clinical judgment in applying those results to patient care. They emphasize the need to avoid racial bias and blaming the patient.

Use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.

This article is very timely because, amidst the COVID-19 pandemic, the opioid epidemic has continued unabated. The most recent data from the National Center for Health Statistics shows that the estimated number of opioid overdose deaths increased by a whopping 32%, from 47,772 for the 1-year period ending August 2019 to 62,972 for the 1-year period ending August 2020.¹ Although this increase began in fall 2019, there can be little doubt that the COVID-19 pandemic is partly responsible. A positive sign, however, is that opioid prescribing in the United States is trending downward, reaching its lowest level in 14 years in 2019.² In fact, use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.¹

Despite this positive news, the number of deaths associated with opioid use remains sobering. The statistics continue to underscore the fact that there simply are not enough addiction treatment centers to manage all of those who need and want help. All primary care physicians are eligible to prescribe suboxone to treat patients with opioid addiction—a treatment that can be highly effective in reducing the use of street opioids and, therefore, reducing deaths from overdose. Fewer than 10% of primary care physicians prescribed suboxone in 2017.³ I hope that more of you will take the required training and become involved in assisting your patients who struggle with opioid addiction.

Reading the excellent article on urine drug screening by Drs. Hayes and Fox reminds me of 2 important aspects of primary care: (1) Diagnosing and treating patients with drug addiction is an important service we provide, and (2) interpreting laboratory tests requires training, skill, and clinical judgment.

Drs. Hayes and Fox describe the proper use of urine drug testing in the management of patients for whom we prescribe opioids, whether for chronic pain or for addiction treatment. Combining a review of the literature with their own professional experience treating these patients, Drs. Hayes and Fox highlight the potential pitfalls in interpreting urine drug screening results and admonish us to use good clinical judgment in applying those results to patient care. They emphasize the need to avoid racial bias and blaming the patient.

Use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.

This article is very timely because, amidst the COVID-19 pandemic, the opioid epidemic has continued unabated. The most recent data from the National Center for Health Statistics shows that the estimated number of opioid overdose deaths increased by a whopping 32%, from 47,772 for the 1-year period ending August 2019 to 62,972 for the 1-year period ending August 2020.¹ Although this increase began in fall 2019, there can be little doubt that the COVID-19 pandemic is partly responsible. A positive sign, however, is that opioid prescribing in the United States is trending downward, reaching its lowest level in 14 years in 2019.² In fact, use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.¹

Despite this positive news, the number of deaths associated with opioid use remains sobering. The statistics continue to underscore the fact that there simply are not enough addiction treatment centers to manage all of those who need and want help. All primary care physicians are eligible to prescribe suboxone to treat patients with opioid addiction—a treatment that can be highly effective in reducing the use of street opioids and, therefore, reducing deaths from overdose. Fewer than 10% of primary care physicians prescribed suboxone in 2017.³ I hope that more of you will take the required training and become involved in assisting your patients who struggle with opioid addiction.

Reading the excellent article on urine drug screening by Drs. Hayes and Fox reminds me of 2 important aspects of primary care: (1) Diagnosing and treating patients with drug addiction is an important service we provide, and (2) interpreting laboratory tests requires training, skill, and clinical judgment.

Drs. Hayes and Fox describe the proper use of urine drug testing in the management of patients for whom we prescribe opioids, whether for chronic pain or for addiction treatment. Combining a review of the literature with their own professional experience treating these patients, Drs. Hayes and Fox highlight the potential pitfalls in interpreting urine drug screening results and admonish us to use good clinical judgment in applying those results to patient care. They emphasize the need to avoid racial bias and blaming the patient.

Use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.

This article is very timely because, amidst the COVID-19 pandemic, the opioid epidemic has continued unabated. The most recent data from the National Center for Health Statistics shows that the estimated number of opioid overdose deaths increased by a whopping 32%, from 47,772 for the 1-year period ending August 2019 to 62,972 for the 1-year period ending August 2020.¹ Although this increase began in fall 2019, there can be little doubt that the COVID-19 pandemic is partly responsible. A positive sign, however, is that opioid prescribing in the United States is trending downward, reaching its lowest level in 14 years in 2019.² In fact, use of cheap street fentanyl, rather than prescription drugs, accounts for nearly all of the increase in opioid overdose deaths.¹

Despite this positive news, the number of deaths associated with opioid use remains sobering. The statistics continue to underscore the fact that there simply are not enough addiction treatment centers to manage all of those who need and want help. All primary care physicians are eligible to prescribe suboxone to treat patients with opioid addiction—a treatment that can be highly effective in reducing the use of street opioids and, therefore, reducing deaths from overdose. Fewer than 10% of primary care physicians prescribed suboxone in 2017.³ I hope that more of you will take the required training and become involved in assisting your patients who struggle with opioid addiction.

The United States continues to confront an opioid crisis that also affects older adults. According to the Substance Abuse and Mental Health Services Administration from 1999 to 2010, there has been a 4-fold increase in opioid overdose deaths.¹ Between 2010 and 2015, the rate of opioid-related inpatient stays and emergency department (ED) visits for people aged ≥ 65 years increased by 34% and 74%, respectively, and opioid-related overdose deaths continue to increase among older patients.^1,2

Background

Chronic pain is estimated to affect 50 million US adults.³ Individuals receiving long-term opioid therapy may not have experienced relief with other medications or cannot take them for medical safety reasons. Losing access to opioid prescriptions can contribute to misuse of illicit opioids. Implementing best practices for prescription opioid management in older adults is challenging. Older adults have a high prevalence of chronic pain, which is linked to disability and loss of function, reduced mobility, falls, depression, anxiety, sleep disorders, social isolation, and suicide or suicidal ideation.⁴ Until recently, chronic pain in older adults was often treated primarily with long-term opioid prescriptions, despite little evidence for the effectiveness of that treatment for chronic conditions. The prevalence of long-term opioid use in adults has increased from 1.8% (1999-2000) to 5.4% (2013-2014), and 25% of adult long-term opioid users are aged ≥ 65 years.⁵

Older adults are especially vulnerable to developing adverse events (AEs) from opioid use, including constipation, confusion, nausea, falls, and overdose. These factors make safe prescribing more challenging even when opioids are an appropriate therapeutic choice. Older adults often have multiple chronic conditions and take multiple medications that increase risk of AEs due to drug-disease and drug-drug interactions. Finding appropriate alternatives for pain management can be challenging in the presence of dementia if other pharmacologic options are contraindicated or mobility issues limit access to other therapeutic options.

Pain treatment plans should be based on realistic functional goals using a shared decision-making approach accounting for patient and provider expectations. All reasonable nondrug and nonopioid treatments should be considered before opioids are initiated. A comprehensive, person-centered, approach to pain management in older adults that includes opioids, other medications, and complementary and integrative care could improve both pain control and function,and reduce the harms of unnecessary opioid exposure.⁶ A validated risk review should be performed and documented on all patients starting opioids except patients enrolled in hospice care.

In 2018, the US Department of Veterans Affairs (VA) required all facilities to complete case reviews for veterans identified in the Stratification Tool for Opioid Risk Mitigation (STORM) dashboard as being at particularly high risk for AEs among patients prescribed opioids.⁷ We present our experience with a 1-year management of 48 high-risk older patients receiving chronic prescription opioid therapy. These patients obtained all their care at the VA with complete record documentation.

Methods

The Tennessee Valley Healthcare System (TVHS) is an integrated VA health care system with > 100,000 veteran patients in middle Tennessee with 2 medical centers 40 miles apart, and 12 community-based outpatient clinics. In 2011, TVHS developed a geriatric patient-centered medical home model for geriatric primary care—the geriatric patient aligned care team (GeriPACT).⁸ GeriPACT consists of a GeriPACT primary care provider (geriatrician or geriatric nurse practitioner with a panel of about 800 outpatients), social worker, clinical pharmacist, registered nurse care manager, licensed vocational nurse, and clerical staff. GeriPACT is a special population PACT within primary care for complex geriatric and other high-risk vulnerable veterans providing integrated, interdisciplinary assessment and longitudinal management, and coordination of both VA and non-VA-funded (eg, Medicare and Medicaid) services for patients and caregivers. GeriPACT at the Nashville TVHS campus has an enrollment of 745 patients of whom 48 receive chronic prescription opioid therapy. The practice is supported by the VA Computerized Patients Record System (CPRS), including the electronic patient portal, My healtheVet, with telemedicine capabilities. Data were collected by chart review with operations data extracted from the Veterans Health Information System and Technology Architecture.

Best practices for prescription opioids for chronic pain follow the US Department of Health and Human Services Interagency Task Force pain management recommendations.⁴ These include: (1) Effective pain evaluation and management, including diagnostic evaluation and indicated referrals; (2) appropriately prescribed opioids when indicated; and (3) active management of opioid users to prevent AEs and misuse. Strategies used in GeriPACT were adopted from the pain management task force and designed to address needs and challenges associated with responsible chronic opioid prescribing (Table 1).

Results

Chronic opioid patients comprised 6.4% of the GeriPACT population. These patients had many comorbidities, including diabetes mellitus (35%), pulmonary disease (25%), congestive heart failure (18.8%), and dementia (8%). There were 54% with estimated glomerular filtration rates (eGFR) < 60 mL/min, indicating at least stage 3 chronic kidney disease (Table 2). Patients had an average RIOSORD Score of 21 and a 14% risk of opioid induced respiratory depression, and 20% received mental health services.

The mean CAN score was 83.1, suggesting a 1-year risk of 20% for a major AE and 5% mortality risk. Many patients with chronic opioid use were transferred to GeriPACT from primary care due to presence of complex medical issues in addition to need for chronic pain management. In this population, 8% were coprescribed benzodiazepines and opioids. Consults were obtained from interventional pain for 37.5% of patients and palliative care for 27% of patients, the majority for goals of care related to chronic illness and advance directive discussions, and in 1 patient for pain and symptom management. The majority of patients (81%) had advance care planning documents or discussions documented in the electronic health record, and 87.5% of patients received home and community-based support in addition to GeriPACT care.

Medication Reduction

Pharmacists routinely counseled patients regarding the appropriate timing of refills and made monthly calls to request refills of controlled drugs. Three patients agreed to opioid dose reduction due to improved clinical status. Two patients had 25% and 30% dose reductions, respectively, and 1 patient was able to be discontinue opioids. This was achieved through reduction of therapy and or substitution of alternative nonopioid pain medications. One patient was initiated on a slow benzodiazepine taper schedule after decades of benzodiazepine use in addition to engagement with a whole health coach and primary care mental health integration provider. Another patient was disenrolled from the clinic because of repeated nonadherence and positive UDSs for polysubstance use disorder.

Accidental Overdoses

There were 2 patients with accidental overdoses who survived, both on high morphine equivalent daily doses (MEDDs). One patient was admitted to the intensive care unit for increasing confusion after taking more than the prescribed opioids (120 mg MEDD) due to uncontrolled pain for 2 months following surgery. The second patient was taking 66 mg MEDD with multiple risk factors for respiratory depression (severe chronic obstructive pulmonary disease requiring oxygen, obstructive sleep apnea, and concomitant benzodiazepine use) who repeatedly refused tapering of opioids and benzodiazepines. He was found unresponsive in respiratory depression by home health staff. Both patients had naloxone kits in their home that were not administered.

Urine Drug Screening

There was an occasional negative opioid UDS attributed to patients on a low-dose opioid administered more than 24 hours before. Five patients (10.4%) had positive UDSs. Two patients were positive for cocaine, and because of chronic persistent pain and complex medical problems cared for in the clinic, counseled and continued on therapy with no repeat infractions. Two patients were positive for cannabinoids attributed to CBD oil products, which are legal in Tennessee. One patient had repeated positive UDSs for polysubstance abuse and was terminated from the clinic, preferring to use cannabinoids and other substances illegally. Meperidine, fentanyl, tramadol, and other synthetic opioids are not detected on a routine UDS.

Discussion

Primary care is critical in optimizing the prescribing and use of opioids in older adults. The patient-centered medical home can give health care providers the tools and support to provide evidence—based pain management for their older adult patients and to facilitate prescription and monitoring of appropriate opioid use to minimizing AEs and OUD risk. This includes a reliable health information technology monitoring system as part of a collaborative, person-centered care practice capable of managing frail older patients with multiple chronic conditions as well as social risk factors. GeriPACT was able to implement guideline—based evaluation and treatment of chronic pain patients through optimal management of opioids, risk reduction, and monitoring and management of AEs, misuse, and dose tapering using shared decision-making strategies when appropriate.

Complex older patients on chronic opioid treatment can do well and are best managed by an interdisciplinary team. Our panel had a high prevalence of chronic opioid patients and a high expected mortality based on the severity of comorbidities. Patients had frequent access to care with utilization of many support services. Patients received care for many chronic illnesses at the same time they received opioid therapy and generally were satisfied and adherent to their treatment plan. Published reports of the prevalence of coprescribing of benzodiazepines and opioids of 1.1 to 2.7% in the general population, may be lower than our veteran population.¹⁴ Despite the fact that nearly 20% of the population had a history of opioid misuse, only 1 patient was terminated from the clinic because of repeated episodes of polysubstance use disorder.

GeriPACT has the capability to be responsive to the changing needs of older chronic pain patients as a learning health system using continuous process improvement with frequent team meetings and interdisciplinary care.¹⁵ Our experience with chronic pain management demonstrates the feasibility and quality of guideline-based management and enhances our understanding of the intersection of care, chronic pain management, and opioid use disorder in older adults.

Limitations

Our experience with this population of older veterans may not be applicable to other geriatric populations. While all patients received their primary care at VA and patients were seen regularly, our data may not account for possible use of some community services, including hospitalization and long-term care.

Conclusions

Guideline-based patient-centered medical home management of patients with chronic pain treated with opioids can be an effective model to maintain and improve measures of health and well-being in older patients. Primary care management is critical in optimizing the prescribing and use of opioids in older adults. These complex older patients are best managed by an interdisciplinary team.

Acknowledgments

This work was supported in part by the Geriatric Workforce Enhancement Program, HRSA Grant: 1-U1Q-HP 033085-01-00.

The United States continues to confront an opioid crisis that also affects older adults. According to the Substance Abuse and Mental Health Services Administration from 1999 to 2010, there has been a 4-fold increase in opioid overdose deaths.¹ Between 2010 and 2015, the rate of opioid-related inpatient stays and emergency department (ED) visits for people aged ≥ 65 years increased by 34% and 74%, respectively, and opioid-related overdose deaths continue to increase among older patients.^1,2

Background

Chronic pain is estimated to affect 50 million US adults.³ Individuals receiving long-term opioid therapy may not have experienced relief with other medications or cannot take them for medical safety reasons. Losing access to opioid prescriptions can contribute to misuse of illicit opioids. Implementing best practices for prescription opioid management in older adults is challenging. Older adults have a high prevalence of chronic pain, which is linked to disability and loss of function, reduced mobility, falls, depression, anxiety, sleep disorders, social isolation, and suicide or suicidal ideation.⁴ Until recently, chronic pain in older adults was often treated primarily with long-term opioid prescriptions, despite little evidence for the effectiveness of that treatment for chronic conditions. The prevalence of long-term opioid use in adults has increased from 1.8% (1999-2000) to 5.4% (2013-2014), and 25% of adult long-term opioid users are aged ≥ 65 years.⁵

Older adults are especially vulnerable to developing adverse events (AEs) from opioid use, including constipation, confusion, nausea, falls, and overdose. These factors make safe prescribing more challenging even when opioids are an appropriate therapeutic choice. Older adults often have multiple chronic conditions and take multiple medications that increase risk of AEs due to drug-disease and drug-drug interactions. Finding appropriate alternatives for pain management can be challenging in the presence of dementia if other pharmacologic options are contraindicated or mobility issues limit access to other therapeutic options.

Pain treatment plans should be based on realistic functional goals using a shared decision-making approach accounting for patient and provider expectations. All reasonable nondrug and nonopioid treatments should be considered before opioids are initiated. A comprehensive, person-centered, approach to pain management in older adults that includes opioids, other medications, and complementary and integrative care could improve both pain control and function,and reduce the harms of unnecessary opioid exposure.⁶ A validated risk review should be performed and documented on all patients starting opioids except patients enrolled in hospice care.

In 2018, the US Department of Veterans Affairs (VA) required all facilities to complete case reviews for veterans identified in the Stratification Tool for Opioid Risk Mitigation (STORM) dashboard as being at particularly high risk for AEs among patients prescribed opioids.⁷ We present our experience with a 1-year management of 48 high-risk older patients receiving chronic prescription opioid therapy. These patients obtained all their care at the VA with complete record documentation.

Methods

The Tennessee Valley Healthcare System (TVHS) is an integrated VA health care system with > 100,000 veteran patients in middle Tennessee with 2 medical centers 40 miles apart, and 12 community-based outpatient clinics. In 2011, TVHS developed a geriatric patient-centered medical home model for geriatric primary care—the geriatric patient aligned care team (GeriPACT).⁸ GeriPACT consists of a GeriPACT primary care provider (geriatrician or geriatric nurse practitioner with a panel of about 800 outpatients), social worker, clinical pharmacist, registered nurse care manager, licensed vocational nurse, and clerical staff. GeriPACT is a special population PACT within primary care for complex geriatric and other high-risk vulnerable veterans providing integrated, interdisciplinary assessment and longitudinal management, and coordination of both VA and non-VA-funded (eg, Medicare and Medicaid) services for patients and caregivers. GeriPACT at the Nashville TVHS campus has an enrollment of 745 patients of whom 48 receive chronic prescription opioid therapy. The practice is supported by the VA Computerized Patients Record System (CPRS), including the electronic patient portal, My healtheVet, with telemedicine capabilities. Data were collected by chart review with operations data extracted from the Veterans Health Information System and Technology Architecture.

Best practices for prescription opioids for chronic pain follow the US Department of Health and Human Services Interagency Task Force pain management recommendations.⁴ These include: (1) Effective pain evaluation and management, including diagnostic evaluation and indicated referrals; (2) appropriately prescribed opioids when indicated; and (3) active management of opioid users to prevent AEs and misuse. Strategies used in GeriPACT were adopted from the pain management task force and designed to address needs and challenges associated with responsible chronic opioid prescribing (Table 1).

Results

Chronic opioid patients comprised 6.4% of the GeriPACT population. These patients had many comorbidities, including diabetes mellitus (35%), pulmonary disease (25%), congestive heart failure (18.8%), and dementia (8%). There were 54% with estimated glomerular filtration rates (eGFR) < 60 mL/min, indicating at least stage 3 chronic kidney disease (Table 2). Patients had an average RIOSORD Score of 21 and a 14% risk of opioid induced respiratory depression, and 20% received mental health services.

The mean CAN score was 83.1, suggesting a 1-year risk of 20% for a major AE and 5% mortality risk. Many patients with chronic opioid use were transferred to GeriPACT from primary care due to presence of complex medical issues in addition to need for chronic pain management. In this population, 8% were coprescribed benzodiazepines and opioids. Consults were obtained from interventional pain for 37.5% of patients and palliative care for 27% of patients, the majority for goals of care related to chronic illness and advance directive discussions, and in 1 patient for pain and symptom management. The majority of patients (81%) had advance care planning documents or discussions documented in the electronic health record, and 87.5% of patients received home and community-based support in addition to GeriPACT care.

Medication Reduction

Pharmacists routinely counseled patients regarding the appropriate timing of refills and made monthly calls to request refills of controlled drugs. Three patients agreed to opioid dose reduction due to improved clinical status. Two patients had 25% and 30% dose reductions, respectively, and 1 patient was able to be discontinue opioids. This was achieved through reduction of therapy and or substitution of alternative nonopioid pain medications. One patient was initiated on a slow benzodiazepine taper schedule after decades of benzodiazepine use in addition to engagement with a whole health coach and primary care mental health integration provider. Another patient was disenrolled from the clinic because of repeated nonadherence and positive UDSs for polysubstance use disorder.

Accidental Overdoses

There were 2 patients with accidental overdoses who survived, both on high morphine equivalent daily doses (MEDDs). One patient was admitted to the intensive care unit for increasing confusion after taking more than the prescribed opioids (120 mg MEDD) due to uncontrolled pain for 2 months following surgery. The second patient was taking 66 mg MEDD with multiple risk factors for respiratory depression (severe chronic obstructive pulmonary disease requiring oxygen, obstructive sleep apnea, and concomitant benzodiazepine use) who repeatedly refused tapering of opioids and benzodiazepines. He was found unresponsive in respiratory depression by home health staff. Both patients had naloxone kits in their home that were not administered.

Urine Drug Screening

There was an occasional negative opioid UDS attributed to patients on a low-dose opioid administered more than 24 hours before. Five patients (10.4%) had positive UDSs. Two patients were positive for cocaine, and because of chronic persistent pain and complex medical problems cared for in the clinic, counseled and continued on therapy with no repeat infractions. Two patients were positive for cannabinoids attributed to CBD oil products, which are legal in Tennessee. One patient had repeated positive UDSs for polysubstance abuse and was terminated from the clinic, preferring to use cannabinoids and other substances illegally. Meperidine, fentanyl, tramadol, and other synthetic opioids are not detected on a routine UDS.

Discussion

Primary care is critical in optimizing the prescribing and use of opioids in older adults. The patient-centered medical home can give health care providers the tools and support to provide evidence—based pain management for their older adult patients and to facilitate prescription and monitoring of appropriate opioid use to minimizing AEs and OUD risk. This includes a reliable health information technology monitoring system as part of a collaborative, person-centered care practice capable of managing frail older patients with multiple chronic conditions as well as social risk factors. GeriPACT was able to implement guideline—based evaluation and treatment of chronic pain patients through optimal management of opioids, risk reduction, and monitoring and management of AEs, misuse, and dose tapering using shared decision-making strategies when appropriate.

Complex older patients on chronic opioid treatment can do well and are best managed by an interdisciplinary team. Our panel had a high prevalence of chronic opioid patients and a high expected mortality based on the severity of comorbidities. Patients had frequent access to care with utilization of many support services. Patients received care for many chronic illnesses at the same time they received opioid therapy and generally were satisfied and adherent to their treatment plan. Published reports of the prevalence of coprescribing of benzodiazepines and opioids of 1.1 to 2.7% in the general population, may be lower than our veteran population.¹⁴ Despite the fact that nearly 20% of the population had a history of opioid misuse, only 1 patient was terminated from the clinic because of repeated episodes of polysubstance use disorder.

GeriPACT has the capability to be responsive to the changing needs of older chronic pain patients as a learning health system using continuous process improvement with frequent team meetings and interdisciplinary care.¹⁵ Our experience with chronic pain management demonstrates the feasibility and quality of guideline-based management and enhances our understanding of the intersection of care, chronic pain management, and opioid use disorder in older adults.

Limitations

Our experience with this population of older veterans may not be applicable to other geriatric populations. While all patients received their primary care at VA and patients were seen regularly, our data may not account for possible use of some community services, including hospitalization and long-term care.

Conclusions

Guideline-based patient-centered medical home management of patients with chronic pain treated with opioids can be an effective model to maintain and improve measures of health and well-being in older patients. Primary care management is critical in optimizing the prescribing and use of opioids in older adults. These complex older patients are best managed by an interdisciplinary team.

Acknowledgments

This work was supported in part by the Geriatric Workforce Enhancement Program, HRSA Grant: 1-U1Q-HP 033085-01-00.

The United States continues to confront an opioid crisis that also affects older adults. According to the Substance Abuse and Mental Health Services Administration from 1999 to 2010, there has been a 4-fold increase in opioid overdose deaths.¹ Between 2010 and 2015, the rate of opioid-related inpatient stays and emergency department (ED) visits for people aged ≥ 65 years increased by 34% and 74%, respectively, and opioid-related overdose deaths continue to increase among older patients.^1,2

Background

Chronic pain is estimated to affect 50 million US adults.³ Individuals receiving long-term opioid therapy may not have experienced relief with other medications or cannot take them for medical safety reasons. Losing access to opioid prescriptions can contribute to misuse of illicit opioids. Implementing best practices for prescription opioid management in older adults is challenging. Older adults have a high prevalence of chronic pain, which is linked to disability and loss of function, reduced mobility, falls, depression, anxiety, sleep disorders, social isolation, and suicide or suicidal ideation.⁴ Until recently, chronic pain in older adults was often treated primarily with long-term opioid prescriptions, despite little evidence for the effectiveness of that treatment for chronic conditions. The prevalence of long-term opioid use in adults has increased from 1.8% (1999-2000) to 5.4% (2013-2014), and 25% of adult long-term opioid users are aged ≥ 65 years.⁵

Older adults are especially vulnerable to developing adverse events (AEs) from opioid use, including constipation, confusion, nausea, falls, and overdose. These factors make safe prescribing more challenging even when opioids are an appropriate therapeutic choice. Older adults often have multiple chronic conditions and take multiple medications that increase risk of AEs due to drug-disease and drug-drug interactions. Finding appropriate alternatives for pain management can be challenging in the presence of dementia if other pharmacologic options are contraindicated or mobility issues limit access to other therapeutic options.

Pain treatment plans should be based on realistic functional goals using a shared decision-making approach accounting for patient and provider expectations. All reasonable nondrug and nonopioid treatments should be considered before opioids are initiated. A comprehensive, person-centered, approach to pain management in older adults that includes opioids, other medications, and complementary and integrative care could improve both pain control and function,and reduce the harms of unnecessary opioid exposure.⁶ A validated risk review should be performed and documented on all patients starting opioids except patients enrolled in hospice care.

In 2018, the US Department of Veterans Affairs (VA) required all facilities to complete case reviews for veterans identified in the Stratification Tool for Opioid Risk Mitigation (STORM) dashboard as being at particularly high risk for AEs among patients prescribed opioids.⁷ We present our experience with a 1-year management of 48 high-risk older patients receiving chronic prescription opioid therapy. These patients obtained all their care at the VA with complete record documentation.

Methods

The Tennessee Valley Healthcare System (TVHS) is an integrated VA health care system with > 100,000 veteran patients in middle Tennessee with 2 medical centers 40 miles apart, and 12 community-based outpatient clinics. In 2011, TVHS developed a geriatric patient-centered medical home model for geriatric primary care—the geriatric patient aligned care team (GeriPACT).⁸ GeriPACT consists of a GeriPACT primary care provider (geriatrician or geriatric nurse practitioner with a panel of about 800 outpatients), social worker, clinical pharmacist, registered nurse care manager, licensed vocational nurse, and clerical staff. GeriPACT is a special population PACT within primary care for complex geriatric and other high-risk vulnerable veterans providing integrated, interdisciplinary assessment and longitudinal management, and coordination of both VA and non-VA-funded (eg, Medicare and Medicaid) services for patients and caregivers. GeriPACT at the Nashville TVHS campus has an enrollment of 745 patients of whom 48 receive chronic prescription opioid therapy. The practice is supported by the VA Computerized Patients Record System (CPRS), including the electronic patient portal, My healtheVet, with telemedicine capabilities. Data were collected by chart review with operations data extracted from the Veterans Health Information System and Technology Architecture.

Best practices for prescription opioids for chronic pain follow the US Department of Health and Human Services Interagency Task Force pain management recommendations.⁴ These include: (1) Effective pain evaluation and management, including diagnostic evaluation and indicated referrals; (2) appropriately prescribed opioids when indicated; and (3) active management of opioid users to prevent AEs and misuse. Strategies used in GeriPACT were adopted from the pain management task force and designed to address needs and challenges associated with responsible chronic opioid prescribing (Table 1).

Results

Chronic opioid patients comprised 6.4% of the GeriPACT population. These patients had many comorbidities, including diabetes mellitus (35%), pulmonary disease (25%), congestive heart failure (18.8%), and dementia (8%). There were 54% with estimated glomerular filtration rates (eGFR) < 60 mL/min, indicating at least stage 3 chronic kidney disease (Table 2). Patients had an average RIOSORD Score of 21 and a 14% risk of opioid induced respiratory depression, and 20% received mental health services.

The mean CAN score was 83.1, suggesting a 1-year risk of 20% for a major AE and 5% mortality risk. Many patients with chronic opioid use were transferred to GeriPACT from primary care due to presence of complex medical issues in addition to need for chronic pain management. In this population, 8% were coprescribed benzodiazepines and opioids. Consults were obtained from interventional pain for 37.5% of patients and palliative care for 27% of patients, the majority for goals of care related to chronic illness and advance directive discussions, and in 1 patient for pain and symptom management. The majority of patients (81%) had advance care planning documents or discussions documented in the electronic health record, and 87.5% of patients received home and community-based support in addition to GeriPACT care.

Medication Reduction

Pharmacists routinely counseled patients regarding the appropriate timing of refills and made monthly calls to request refills of controlled drugs. Three patients agreed to opioid dose reduction due to improved clinical status. Two patients had 25% and 30% dose reductions, respectively, and 1 patient was able to be discontinue opioids. This was achieved through reduction of therapy and or substitution of alternative nonopioid pain medications. One patient was initiated on a slow benzodiazepine taper schedule after decades of benzodiazepine use in addition to engagement with a whole health coach and primary care mental health integration provider. Another patient was disenrolled from the clinic because of repeated nonadherence and positive UDSs for polysubstance use disorder.

Accidental Overdoses

There were 2 patients with accidental overdoses who survived, both on high morphine equivalent daily doses (MEDDs). One patient was admitted to the intensive care unit for increasing confusion after taking more than the prescribed opioids (120 mg MEDD) due to uncontrolled pain for 2 months following surgery. The second patient was taking 66 mg MEDD with multiple risk factors for respiratory depression (severe chronic obstructive pulmonary disease requiring oxygen, obstructive sleep apnea, and concomitant benzodiazepine use) who repeatedly refused tapering of opioids and benzodiazepines. He was found unresponsive in respiratory depression by home health staff. Both patients had naloxone kits in their home that were not administered.

Urine Drug Screening

There was an occasional negative opioid UDS attributed to patients on a low-dose opioid administered more than 24 hours before. Five patients (10.4%) had positive UDSs. Two patients were positive for cocaine, and because of chronic persistent pain and complex medical problems cared for in the clinic, counseled and continued on therapy with no repeat infractions. Two patients were positive for cannabinoids attributed to CBD oil products, which are legal in Tennessee. One patient had repeated positive UDSs for polysubstance abuse and was terminated from the clinic, preferring to use cannabinoids and other substances illegally. Meperidine, fentanyl, tramadol, and other synthetic opioids are not detected on a routine UDS.

Discussion

Primary care is critical in optimizing the prescribing and use of opioids in older adults. The patient-centered medical home can give health care providers the tools and support to provide evidence—based pain management for their older adult patients and to facilitate prescription and monitoring of appropriate opioid use to minimizing AEs and OUD risk. This includes a reliable health information technology monitoring system as part of a collaborative, person-centered care practice capable of managing frail older patients with multiple chronic conditions as well as social risk factors. GeriPACT was able to implement guideline—based evaluation and treatment of chronic pain patients through optimal management of opioids, risk reduction, and monitoring and management of AEs, misuse, and dose tapering using shared decision-making strategies when appropriate.

Complex older patients on chronic opioid treatment can do well and are best managed by an interdisciplinary team. Our panel had a high prevalence of chronic opioid patients and a high expected mortality based on the severity of comorbidities. Patients had frequent access to care with utilization of many support services. Patients received care for many chronic illnesses at the same time they received opioid therapy and generally were satisfied and adherent to their treatment plan. Published reports of the prevalence of coprescribing of benzodiazepines and opioids of 1.1 to 2.7% in the general population, may be lower than our veteran population.¹⁴ Despite the fact that nearly 20% of the population had a history of opioid misuse, only 1 patient was terminated from the clinic because of repeated episodes of polysubstance use disorder.

GeriPACT has the capability to be responsive to the changing needs of older chronic pain patients as a learning health system using continuous process improvement with frequent team meetings and interdisciplinary care.¹⁵ Our experience with chronic pain management demonstrates the feasibility and quality of guideline-based management and enhances our understanding of the intersection of care, chronic pain management, and opioid use disorder in older adults.

Limitations

Our experience with this population of older veterans may not be applicable to other geriatric populations. While all patients received their primary care at VA and patients were seen regularly, our data may not account for possible use of some community services, including hospitalization and long-term care.

Conclusions

Guideline-based patient-centered medical home management of patients with chronic pain treated with opioids can be an effective model to maintain and improve measures of health and well-being in older patients. Primary care management is critical in optimizing the prescribing and use of opioids in older adults. These complex older patients are best managed by an interdisciplinary team.

Acknowledgments

This work was supported in part by the Geriatric Workforce Enhancement Program, HRSA Grant: 1-U1Q-HP 033085-01-00.

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

Treatment was attempted for both a suspected spider bite (2 weeks of topical triamcinolone 0.1%) and presumed cellulitis (oral doxycycline 100 mg bid/5 d), but neither improved her condition. Concerned for the possibility of cutaneous breast cancer, a punch biopsy was ordered and revealed diffuse dermal angiomatosis (DDA).

DDA is an uncommon proliferation of cutaneous blood vessels causing a reticular blood vessel pattern, as seen in this image. Typically, DDA is associated with tissue hypoxia due to arterial insufficiency from peripheral artery disease. In recent years, there have been numerous case reports of painful ulcerated lesions and reticular blood vessels occurring in women with large, pendulous breasts, increased body mass index, and a history of smoking. One theory suggests that the weight of the breasts causes tissue to stretch, compressing the blood vessels. This, combined with smoking, leads to localized hypoxia and DDA.

Treatments have included oral isotretinoin, calcium channel blockers, aspirin, or pentoxifylline to help circulation. Smoking cessation is recommended, as well as reduction mammoplasty to decrease the stretch on the tissues and relieve the local hypoxia. Although invasive, breast reduction surgery has moved to the forefront of therapy, with reports having shown resolution of the ulcers and pain.¹

Two important aspects of clinical medicine are highlighted by this case. First, nonhealing lesions that are not responding to prescribed therapies may require biopsy to rule out malignancy. Second, when there is difficulty making a diagnosis, especially with uncommon diseases, biopsy and input from a pathologist can be extremely helpful.

In this case, the patient was referred to Plastic Surgery and scheduled for reduction mammoplasty. The patient was advised to stop smoking for at least 4 weeks prior to the surgery to possibly improve her condition and reduce the likelihood of postoperative complications.

‌

Photo courtesy of Michael Louie, MD, and text courtesy of Michael Louie, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.

In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.

“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”

The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.

The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”

jevans@mdedge.com

Older adults with chronic obstructive pulmonary disease who began using synthetic cannabinoids showed a 64% increase in all-cause mortality, compared with nonusers, findings from a large study have shown.

Synthetic cannabinoids drugs, such as nabilone and dronabinol, have been approved by the Food and Drug Administration for nausea and vomiting caused by chemotherapy. But their off-label use by adults with COPD to help manage chronic musculoskeletal pain, insomnia, and refractory dyspnea is on the rise, wrote Nicholas T. Vozoris, MD, of the University of Toronto and colleagues.

Cannabinoids may actually contribute to negative respiratory outcomes among individuals with COPD through several possible mechanisms including causing sedation, inducing anxiety, and provoking respiratory muscle weakness, they said.

“Possible adverse respiratory effects of cannabinoids may occur with greater likelihood among older adults (in whom COPD is more prevalent), as this group is known to less efficiently metabolise drugs,” they noted.

In a retrospective, population-based cohort study published in Thorax the researchers identified 185,876 adults aged 66 years and older with COPD using health administrative database information from 2006 to 2016. New cannabinoid users (those starting nabilone or dronabinol) were matched with control nonusers (defined as new users of noncannabinoid drugs). Individuals receiving palliative care, or having a diagnosis of cancer or HIV, were excluded because these are settings where synthetic cannabinoids may be prescribed for nausea or vomiting, and these patients are more likely to be in a poorer state of health.

Overall, new cannabinoid users had significantly higher all-cause mortality rates, compared with nonusers (hazard ratio, 1.64). The effects was greater in high-dose users.

Daniel R. Ouellette, MD, associate professor of medicine at Wayne State University and a senior staff physician at Henry Ford Hospital, both in Detroit, commented that this study has value for clinicians. “Many states are liberalizing cannabinoid use, and it is important to know the health effects of this type of drug on patients with chronic respiratory disease,” he noted. “The study is somewhat surprising. While one might have expected adverse consequences in patients with COPD who inhaled smoke from cannabinoids, it is somewhat unexpected that oral use would be associated with adverse consequences.” He added, “Pain in older adults is a complex problem. Cannabinoids are often recommended for pain in the general community, but pain per se is not a primary symptom for most patients with COPD from their respiratory problems. Physicians treating patients with COPD should diagnose the cause of the pain and provide appropriate treatment.”


 

Dose makes a difference

All-cause mortality increased by 231% and hospitalization for COPD or pneumonia increased by 178% among new users of higher-dose cannabinoids, compared with nonusers. Higher dose was defined in this study as more than 1.5mg/day of nabilone. No significant differences appeared in new users vs. nonusers in hospitalization for COPD or pneumonia at lower doses, and no significant differences appeared overall in outpatient respiratory exacerbations, emergency department visits for COPD or pneumonia, or COPD- or pneumonia-related mortality.
 

Potential limitations and implications

“The fact that COPD- or pneumonia-related mortality was not observed to occur with significantly greater rates among cannabinoid users with COPD may suggest that the increased all-cause mortality finding was not being driven by adverse respiratory-related drug effects, as we hypothesized, and instead was possibly a result of unresolved confounding,” the researchers noted.

The study findings were limited by several factors including the inability to prove causation in an observational study, and the potential for confounding based on unmeasured differences between cannabinoid users and nonusers, the researchers said. “Our findings may not be generalizable to all individuals with COPD, as our study included only those aged 66 years and older, and our COPD identification algorithm, while highly specific, had modest sensitivity,” they added. However, the results were strengthened by the large study population and suggest that cannabinoids are not contraindicated for older adults with COPD, the researchers said. “There can be legitimate reasons for using cannabinoids in this population, such as to help treat chemotherapy-related nausea and vomiting, and possibly for end-of-life care,” they emphasized.

The study findings serve to inform clinicians of the significantly increased mortality risk when older adults with COPD initiate cannabinoids, and “this information should be discussed with patients and incorporated in prescribing decision-making and management plans,” along with consideration of using lower doses when possible to minimize adverse events, they concluded.

The study was supported by The Lung Association – Ontario Grant Review/Grant-In-Aid. The researchers had no financial conflicts to disclose.

Older adults with chronic obstructive pulmonary disease who began using synthetic cannabinoids showed a 64% increase in all-cause mortality, compared with nonusers, findings from a large study have shown.

Synthetic cannabinoids drugs, such as nabilone and dronabinol, have been approved by the Food and Drug Administration for nausea and vomiting caused by chemotherapy. But their off-label use by adults with COPD to help manage chronic musculoskeletal pain, insomnia, and refractory dyspnea is on the rise, wrote Nicholas T. Vozoris, MD, of the University of Toronto and colleagues.

Cannabinoids may actually contribute to negative respiratory outcomes among individuals with COPD through several possible mechanisms including causing sedation, inducing anxiety, and provoking respiratory muscle weakness, they said.

“Possible adverse respiratory effects of cannabinoids may occur with greater likelihood among older adults (in whom COPD is more prevalent), as this group is known to less efficiently metabolise drugs,” they noted.

In a retrospective, population-based cohort study published in Thorax the researchers identified 185,876 adults aged 66 years and older with COPD using health administrative database information from 2006 to 2016. New cannabinoid users (those starting nabilone or dronabinol) were matched with control nonusers (defined as new users of noncannabinoid drugs). Individuals receiving palliative care, or having a diagnosis of cancer or HIV, were excluded because these are settings where synthetic cannabinoids may be prescribed for nausea or vomiting, and these patients are more likely to be in a poorer state of health.

Overall, new cannabinoid users had significantly higher all-cause mortality rates, compared with nonusers (hazard ratio, 1.64). The effects was greater in high-dose users.

Daniel R. Ouellette, MD, associate professor of medicine at Wayne State University and a senior staff physician at Henry Ford Hospital, both in Detroit, commented that this study has value for clinicians. “Many states are liberalizing cannabinoid use, and it is important to know the health effects of this type of drug on patients with chronic respiratory disease,” he noted. “The study is somewhat surprising. While one might have expected adverse consequences in patients with COPD who inhaled smoke from cannabinoids, it is somewhat unexpected that oral use would be associated with adverse consequences.” He added, “Pain in older adults is a complex problem. Cannabinoids are often recommended for pain in the general community, but pain per se is not a primary symptom for most patients with COPD from their respiratory problems. Physicians treating patients with COPD should diagnose the cause of the pain and provide appropriate treatment.”


 

Dose makes a difference

All-cause mortality increased by 231% and hospitalization for COPD or pneumonia increased by 178% among new users of higher-dose cannabinoids, compared with nonusers. Higher dose was defined in this study as more than 1.5mg/day of nabilone. No significant differences appeared in new users vs. nonusers in hospitalization for COPD or pneumonia at lower doses, and no significant differences appeared overall in outpatient respiratory exacerbations, emergency department visits for COPD or pneumonia, or COPD- or pneumonia-related mortality.
 

Potential limitations and implications

“The fact that COPD- or pneumonia-related mortality was not observed to occur with significantly greater rates among cannabinoid users with COPD may suggest that the increased all-cause mortality finding was not being driven by adverse respiratory-related drug effects, as we hypothesized, and instead was possibly a result of unresolved confounding,” the researchers noted.

The study findings were limited by several factors including the inability to prove causation in an observational study, and the potential for confounding based on unmeasured differences between cannabinoid users and nonusers, the researchers said. “Our findings may not be generalizable to all individuals with COPD, as our study included only those aged 66 years and older, and our COPD identification algorithm, while highly specific, had modest sensitivity,” they added. However, the results were strengthened by the large study population and suggest that cannabinoids are not contraindicated for older adults with COPD, the researchers said. “There can be legitimate reasons for using cannabinoids in this population, such as to help treat chemotherapy-related nausea and vomiting, and possibly for end-of-life care,” they emphasized.

The study findings serve to inform clinicians of the significantly increased mortality risk when older adults with COPD initiate cannabinoids, and “this information should be discussed with patients and incorporated in prescribing decision-making and management plans,” along with consideration of using lower doses when possible to minimize adverse events, they concluded.

The study was supported by The Lung Association – Ontario Grant Review/Grant-In-Aid. The researchers had no financial conflicts to disclose.

Older adults with chronic obstructive pulmonary disease who began using synthetic cannabinoids showed a 64% increase in all-cause mortality, compared with nonusers, findings from a large study have shown.

Synthetic cannabinoids drugs, such as nabilone and dronabinol, have been approved by the Food and Drug Administration for nausea and vomiting caused by chemotherapy. But their off-label use by adults with COPD to help manage chronic musculoskeletal pain, insomnia, and refractory dyspnea is on the rise, wrote Nicholas T. Vozoris, MD, of the University of Toronto and colleagues.

Cannabinoids may actually contribute to negative respiratory outcomes among individuals with COPD through several possible mechanisms including causing sedation, inducing anxiety, and provoking respiratory muscle weakness, they said.

“Possible adverse respiratory effects of cannabinoids may occur with greater likelihood among older adults (in whom COPD is more prevalent), as this group is known to less efficiently metabolise drugs,” they noted.

In a retrospective, population-based cohort study published in Thorax the researchers identified 185,876 adults aged 66 years and older with COPD using health administrative database information from 2006 to 2016. New cannabinoid users (those starting nabilone or dronabinol) were matched with control nonusers (defined as new users of noncannabinoid drugs). Individuals receiving palliative care, or having a diagnosis of cancer or HIV, were excluded because these are settings where synthetic cannabinoids may be prescribed for nausea or vomiting, and these patients are more likely to be in a poorer state of health.

Overall, new cannabinoid users had significantly higher all-cause mortality rates, compared with nonusers (hazard ratio, 1.64). The effects was greater in high-dose users.

Daniel R. Ouellette, MD, associate professor of medicine at Wayne State University and a senior staff physician at Henry Ford Hospital, both in Detroit, commented that this study has value for clinicians. “Many states are liberalizing cannabinoid use, and it is important to know the health effects of this type of drug on patients with chronic respiratory disease,” he noted. “The study is somewhat surprising. While one might have expected adverse consequences in patients with COPD who inhaled smoke from cannabinoids, it is somewhat unexpected that oral use would be associated with adverse consequences.” He added, “Pain in older adults is a complex problem. Cannabinoids are often recommended for pain in the general community, but pain per se is not a primary symptom for most patients with COPD from their respiratory problems. Physicians treating patients with COPD should diagnose the cause of the pain and provide appropriate treatment.”


 

Dose makes a difference

All-cause mortality increased by 231% and hospitalization for COPD or pneumonia increased by 178% among new users of higher-dose cannabinoids, compared with nonusers. Higher dose was defined in this study as more than 1.5mg/day of nabilone. No significant differences appeared in new users vs. nonusers in hospitalization for COPD or pneumonia at lower doses, and no significant differences appeared overall in outpatient respiratory exacerbations, emergency department visits for COPD or pneumonia, or COPD- or pneumonia-related mortality.
 

Potential limitations and implications

“The fact that COPD- or pneumonia-related mortality was not observed to occur with significantly greater rates among cannabinoid users with COPD may suggest that the increased all-cause mortality finding was not being driven by adverse respiratory-related drug effects, as we hypothesized, and instead was possibly a result of unresolved confounding,” the researchers noted.

The study findings were limited by several factors including the inability to prove causation in an observational study, and the potential for confounding based on unmeasured differences between cannabinoid users and nonusers, the researchers said. “Our findings may not be generalizable to all individuals with COPD, as our study included only those aged 66 years and older, and our COPD identification algorithm, while highly specific, had modest sensitivity,” they added. However, the results were strengthened by the large study population and suggest that cannabinoids are not contraindicated for older adults with COPD, the researchers said. “There can be legitimate reasons for using cannabinoids in this population, such as to help treat chemotherapy-related nausea and vomiting, and possibly for end-of-life care,” they emphasized.

The study findings serve to inform clinicians of the significantly increased mortality risk when older adults with COPD initiate cannabinoids, and “this information should be discussed with patients and incorporated in prescribing decision-making and management plans,” along with consideration of using lower doses when possible to minimize adverse events, they concluded.

The study was supported by The Lung Association – Ontario Grant Review/Grant-In-Aid. The researchers had no financial conflicts to disclose.

In the January 2019 article “Migraine: Expanding our Tx arsenal” (J Fam Pract. 2019;68:10-14,16-24), Table 2: Establishing the differential diagnosis of headache provided information that was incorrectly categorized. The table should not have included “Temporal arteritis” as a trigger for a headache caused by infection. Rather, the table should have listed “Temporal arteritis” among the triggers for a headache caused by an autoimmune disorder. In addition, “Acute and chronic sinusitis” and “Meningitis” should not have been listed as triggers for a headache with an iatrogenic or intoxication cause. Rather, they should have been the only triggers attributed to headaches with an infectious origin. The revised table can be found here.

In the January 2019 article “Migraine: Expanding our Tx arsenal” (J Fam Pract. 2019;68:10-14,16-24), Table 2: Establishing the differential diagnosis of headache provided information that was incorrectly categorized. The table should not have included “Temporal arteritis” as a trigger for a headache caused by infection. Rather, the table should have listed “Temporal arteritis” among the triggers for a headache caused by an autoimmune disorder. In addition, “Acute and chronic sinusitis” and “Meningitis” should not have been listed as triggers for a headache with an iatrogenic or intoxication cause. Rather, they should have been the only triggers attributed to headaches with an infectious origin. The revised table can be found here.

In the January 2019 article “Migraine: Expanding our Tx arsenal” (J Fam Pract. 2019;68:10-14,16-24), Table 2: Establishing the differential diagnosis of headache provided information that was incorrectly categorized. The table should not have included “Temporal arteritis” as a trigger for a headache caused by infection. Rather, the table should have listed “Temporal arteritis” among the triggers for a headache caused by an autoimmune disorder. In addition, “Acute and chronic sinusitis” and “Meningitis” should not have been listed as triggers for a headache with an iatrogenic or intoxication cause. Rather, they should have been the only triggers attributed to headaches with an infectious origin. The revised table can be found here.

Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.

Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.

“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.

“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.

Structural and functional tests

To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.

They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.

The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.

In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.

The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.

In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.

On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.

“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.

On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.

Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.

“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.

On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.

When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.

“This is a finding that merits further attention,” she commented.

In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
 

Why the discrepancies?

Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.

“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.

He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.

“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.

He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.

The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.

Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.

Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.

“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.

“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.

Structural and functional tests

To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.

They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.

The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.

In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.

The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.

In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.

On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.

“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.

On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.

Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.

“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.

On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.

When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.

“This is a finding that merits further attention,” she commented.

In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
 

Why the discrepancies?

Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.

“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.

He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.

“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.

He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.

The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.

Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.

Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.

“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.

“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.

Structural and functional tests

To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.

They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.

The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.

In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.

The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.

In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.

On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.

“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.

On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.

Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.

“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.

On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.

When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.

“This is a finding that merits further attention,” she commented.

In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
 

Why the discrepancies?

Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.

“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.

He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.

“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.

He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.

The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.