Neurology

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

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

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

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

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

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

GABAPENTIN REDUCES EXCITATION

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

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

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

 

 

ALCOHOL’S ACTIONS

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

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

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

Alcohol withdrawal increases excitatory effects

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

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

GABAPENTIN FOR ALCOHOL WITHDRAWAL

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

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

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

Inpatient trials show no benefit over standard treatments

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

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

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

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

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

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

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

Outpatient trials reveal benefits over benzodiazepines

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

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

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

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

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

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

 

 

Bottom line: Gabapentin is useful for mild withdrawal

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

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

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

GABAPENTIN FOR RELAPSE PREVENTION

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

Gabapentin alone is better than placebo

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

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

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

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

High-dose gabapentin is better

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

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

Gabapentin plus naltrexone is better than naltrexone alone

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

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

All participants received medical management.

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

Gabapentin enacarbil is no better than placebo

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

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

Bottom line: Evidence of benefits mixed but risk low

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

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

 

 

POTENTIAL FOR MISUSE

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

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

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

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

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

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

Are people with AUD at higher risk of gabapentin abuse?

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

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

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

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

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

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

For alcohol withdrawal

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

For relapse prevention

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

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

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

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

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

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

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

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

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

GABAPENTIN REDUCES EXCITATION

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

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

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

 

 

ALCOHOL’S ACTIONS

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

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

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

Alcohol withdrawal increases excitatory effects

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

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

GABAPENTIN FOR ALCOHOL WITHDRAWAL

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

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

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

Inpatient trials show no benefit over standard treatments

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

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

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

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

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

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

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

Outpatient trials reveal benefits over benzodiazepines

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

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

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

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

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

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

 

 

Bottom line: Gabapentin is useful for mild withdrawal

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

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

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

GABAPENTIN FOR RELAPSE PREVENTION

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

Gabapentin alone is better than placebo

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

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

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

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

High-dose gabapentin is better

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

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

Gabapentin plus naltrexone is better than naltrexone alone

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

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

All participants received medical management.

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

Gabapentin enacarbil is no better than placebo

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

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

Bottom line: Evidence of benefits mixed but risk low

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

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

 

 

POTENTIAL FOR MISUSE

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

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

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

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

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

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

Are people with AUD at higher risk of gabapentin abuse?

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

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

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

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

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

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

For alcohol withdrawal

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

For relapse prevention

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

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

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

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

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

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

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

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

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

GABAPENTIN REDUCES EXCITATION

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

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

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

 

 

ALCOHOL’S ACTIONS

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

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

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

Alcohol withdrawal increases excitatory effects

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

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

GABAPENTIN FOR ALCOHOL WITHDRAWAL

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

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

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

Inpatient trials show no benefit over standard treatments

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

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

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

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

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

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

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

Outpatient trials reveal benefits over benzodiazepines

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

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

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

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

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

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

 

 

Bottom line: Gabapentin is useful for mild withdrawal

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

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

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

GABAPENTIN FOR RELAPSE PREVENTION

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

Gabapentin alone is better than placebo

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

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

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

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

High-dose gabapentin is better

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

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

Gabapentin plus naltrexone is better than naltrexone alone

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

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

All participants received medical management.

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

Gabapentin enacarbil is no better than placebo

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

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

Bottom line: Evidence of benefits mixed but risk low

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

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

 

 

POTENTIAL FOR MISUSE

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

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

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

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

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

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

Are people with AUD at higher risk of gabapentin abuse?

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

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

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

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

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

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

For alcohol withdrawal

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

For relapse prevention

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

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

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

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

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients, according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.

“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
 

A gap in guidance

Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.

Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.

Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
 

Trial was stopped for futility

The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.

In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).

At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.

In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.

“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.

The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.

Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.

The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.

Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.

jremaly@mdedge.com

SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.

Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients, according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.

“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
 

A gap in guidance

Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.

Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.

Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
 

Trial was stopped for futility

The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.

In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).

At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.

In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.

“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.

The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.

Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.

The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.

Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.

jremaly@mdedge.com

SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.

Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients, according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.

“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
 

A gap in guidance

Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.

Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.

Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
 

Trial was stopped for futility

The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.

In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).

At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.

In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.

“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.

The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.

Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.

The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.

Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.

jremaly@mdedge.com

SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.

Among patients with uncontrolled focal seizures, adjunctive treatment with cenobamate reduces focal-onset seizure frequency, according to recently published trial results.

In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.

During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.

On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.

Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.

The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”

Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”

Hypersensitivity reactions led to protocol adjustments

During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.

“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”

The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.

A double-blind, randomized, placebo-controlled trial

The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.

“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.

The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.

The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.

The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).

The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.

Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.

The implications of seizure freedom

The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”

Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.

“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”

The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.

jremaly@mdedge.com

SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.

Among patients with uncontrolled focal seizures, adjunctive treatment with cenobamate reduces focal-onset seizure frequency, according to recently published trial results.

In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.

During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.

On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.

Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.

The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”

Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”

Hypersensitivity reactions led to protocol adjustments

During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.

“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”

The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.

A double-blind, randomized, placebo-controlled trial

The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.

“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.

The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.

The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.

The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).

The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.

Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.

The implications of seizure freedom

The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”

Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.

“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”

The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.

jremaly@mdedge.com

SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.

Among patients with uncontrolled focal seizures, adjunctive treatment with cenobamate reduces focal-onset seizure frequency, according to recently published trial results.

In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.

During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.

On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.

Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.

The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”

Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”

Hypersensitivity reactions led to protocol adjustments

During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.

“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”

The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.

A double-blind, randomized, placebo-controlled trial

The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.

“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.

The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.

The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.

The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).

The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.

Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.

The implications of seizure freedom

The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”

Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.

“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”

The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.

jremaly@mdedge.com

SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.

ST. LOUIS – Late-onset multiple sclerosis (MS), with symptoms starting at or after age 50, is more severe than earlier-onset disease, with faster accrual of disability, according to a review of 1,524 patients with MS treated at the University of Virginia, Charlottesville.

Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.

The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.

“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.

Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.

It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.

There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).

Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).

Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.

Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.

The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.

There was no external funding, and Ms. Wruble had no disclosures.

aotto@mdedge.com

SOURCE: Wruble M et al. ANA 2019. Abstract S234.

ST. LOUIS – Late-onset multiple sclerosis (MS), with symptoms starting at or after age 50, is more severe than earlier-onset disease, with faster accrual of disability, according to a review of 1,524 patients with MS treated at the University of Virginia, Charlottesville.

Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.

The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.

“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.

Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.

It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.

There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).

Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).

Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.

Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.

The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.

There was no external funding, and Ms. Wruble had no disclosures.

aotto@mdedge.com

SOURCE: Wruble M et al. ANA 2019. Abstract S234.

ST. LOUIS – Late-onset multiple sclerosis (MS), with symptoms starting at or after age 50, is more severe than earlier-onset disease, with faster accrual of disability, according to a review of 1,524 patients with MS treated at the University of Virginia, Charlottesville.

Whether the pathophysiology is different, or if the disease is simply compounded by the effects of aging, is uncertain. It is likely, however, that patients with late onset are at greater risk of misdiagnosis and delayed treatment, said Mattia Wruble, a 4th-year medical student at the University of Virginia.

The reason is that MS usually presents in young women as relapsing-remitting disease, but late onset is more typically primary progressive, with a higher proportion of men, which is something that has been demonstrated in previous work and also found in the new study.

“What we didn’t expect to find,” however, was greater “disability and higher disability accrual rates” across all subtypes. Late-onset MS “is a worse disease, a more severe disease” that might even need different treatment options, Ms. Wruble said at the American Neurological Association annual meeting.

Ms. Wruble and colleagues compared the charts of 1,381 patients with MS onset before age 50 years, at a median age of 33 years, with 143 patients whose symptoms began at age 50 years or later, at a median of 55 years.

It was one of the largest late-onset MS samples to date. Incidence of the condition is on the rise, but research has been limited. The investigators hoped to address a need for “a better and more thorough characterization of” the disease to aid treatment and improve outcomes, Ms. Wruble said.

There was a higher proportion of men in the late-onset group, 38% vs. 26%. About 75% of patients with early onset had relapsing remitting disease, and 10% had primary progressive disease. The late-onset group was about evenly split between relapsing-remitting and primary progressive MS (P less than .001).

Patients with late onset MS also had a higher degree of disability at their most recent visit across all subtypes (median Expanded Disability Status Scale score of 5 versus 3), despite having a shorter duration of disease (mean 12 vs. 17 years from symptom onset).

Overall disease accrual rate in the late-onset group was twice that of early-onset group, a decline of 0.647 points per year on the EDSS versus 0.357 points (P less than .001). The finding held when limited to early and late relapsing-remitting cases. The accrual rate for late-onset primary and secondary progressive MS was 1.5 times that of early-onset cases.

Transition to secondary progressive disease also was faster in the late-onset group, a mean of about 7 years versus 15-19 years. Patients with late onset also were more likely to have a history of smoking.

The cerebrospinal fluid in late-onset MS generally has fewer unique oligoclonal bands, which are part of the McDonald diagnostic criteria for MS. “The McDonald criteria were made for patients between 20 and 50 years old; maybe they are not the best criteria to diagnose this late-onset group,” Ms. Wruble said.

There was no external funding, and Ms. Wruble had no disclosures.

aotto@mdedge.com

SOURCE: Wruble M et al. ANA 2019. Abstract S234.

Episodic visual snow was tied to migraine attacks in a case series of three adults who denied any visual snow outside of the migraines, based on data collected at an outpatient headache center.

Visual snow, a condition in which patients experience visual distortion of tiny, flickering dots resembling analog television static, is often a comorbid condition in migraine patients with and without aura. However, “to our knowledge, this is the first report of patients with an episodic form of visual snow strictly occurring with migraine attacks,” wrote Julius Hodak, MD, of the University of Bern (Switzerland) and colleagues.

In a research letter published in JAMA Neurology, the investigators described 3 adults with histories of migraine but no aura who presented to a tertiary headache center between January 2016 and December 2017, in addition to 1,934 adults with migraine but no visual snow. The three patients initially presented with headaches, and neurologic and MRI results were normal.

Two patients experienced black and white episodic visual snow and one experienced black and yellow visual snow. In one patient, visual snow occurred for less than 2 minutes before and during a migraine attack. The other two patients experienced visual snow during the entire migraine attack.

Based on these patients, the researchers proposed distinguishing episodic visual snow from the distinct disorder of visual snow syndrome, in which patients experience continuous visual snow and other visual symptoms.

In addition, the cases were notable because of the lack of aura in the patients, the researchers wrote.

“In clinical practice, a detailed history in patients reporting visual flickering is therefore necessary to differentiate aura from [episodic visual snow],” they added, because an aura diagnosis would affect patient guidance on contraception use or the timing of triptans.

Dr. Hodak had no financial conflicts to disclose. The study was supported by Deutsche Migräne-und Kopfschmerzgesellschaft, Eye on Vision Foundation, and Baasch-Medicus Foundation.

SOURCE: Hodak J et al. JAMA Neurol. 2019 Nov 25. doi: 10.1001/jamaneurol.2019.4050.

Episodic visual snow was tied to migraine attacks in a case series of three adults who denied any visual snow outside of the migraines, based on data collected at an outpatient headache center.

Visual snow, a condition in which patients experience visual distortion of tiny, flickering dots resembling analog television static, is often a comorbid condition in migraine patients with and without aura. However, “to our knowledge, this is the first report of patients with an episodic form of visual snow strictly occurring with migraine attacks,” wrote Julius Hodak, MD, of the University of Bern (Switzerland) and colleagues.

In a research letter published in JAMA Neurology, the investigators described 3 adults with histories of migraine but no aura who presented to a tertiary headache center between January 2016 and December 2017, in addition to 1,934 adults with migraine but no visual snow. The three patients initially presented with headaches, and neurologic and MRI results were normal.

Two patients experienced black and white episodic visual snow and one experienced black and yellow visual snow. In one patient, visual snow occurred for less than 2 minutes before and during a migraine attack. The other two patients experienced visual snow during the entire migraine attack.

Based on these patients, the researchers proposed distinguishing episodic visual snow from the distinct disorder of visual snow syndrome, in which patients experience continuous visual snow and other visual symptoms.

In addition, the cases were notable because of the lack of aura in the patients, the researchers wrote.

“In clinical practice, a detailed history in patients reporting visual flickering is therefore necessary to differentiate aura from [episodic visual snow],” they added, because an aura diagnosis would affect patient guidance on contraception use or the timing of triptans.

Dr. Hodak had no financial conflicts to disclose. The study was supported by Deutsche Migräne-und Kopfschmerzgesellschaft, Eye on Vision Foundation, and Baasch-Medicus Foundation.

SOURCE: Hodak J et al. JAMA Neurol. 2019 Nov 25. doi: 10.1001/jamaneurol.2019.4050.

Episodic visual snow was tied to migraine attacks in a case series of three adults who denied any visual snow outside of the migraines, based on data collected at an outpatient headache center.

Visual snow, a condition in which patients experience visual distortion of tiny, flickering dots resembling analog television static, is often a comorbid condition in migraine patients with and without aura. However, “to our knowledge, this is the first report of patients with an episodic form of visual snow strictly occurring with migraine attacks,” wrote Julius Hodak, MD, of the University of Bern (Switzerland) and colleagues.

In a research letter published in JAMA Neurology, the investigators described 3 adults with histories of migraine but no aura who presented to a tertiary headache center between January 2016 and December 2017, in addition to 1,934 adults with migraine but no visual snow. The three patients initially presented with headaches, and neurologic and MRI results were normal.

Two patients experienced black and white episodic visual snow and one experienced black and yellow visual snow. In one patient, visual snow occurred for less than 2 minutes before and during a migraine attack. The other two patients experienced visual snow during the entire migraine attack.

Based on these patients, the researchers proposed distinguishing episodic visual snow from the distinct disorder of visual snow syndrome, in which patients experience continuous visual snow and other visual symptoms.

In addition, the cases were notable because of the lack of aura in the patients, the researchers wrote.

“In clinical practice, a detailed history in patients reporting visual flickering is therefore necessary to differentiate aura from [episodic visual snow],” they added, because an aura diagnosis would affect patient guidance on contraception use or the timing of triptans.

Dr. Hodak had no financial conflicts to disclose. The study was supported by Deutsche Migräne-und Kopfschmerzgesellschaft, Eye on Vision Foundation, and Baasch-Medicus Foundation.

SOURCE: Hodak J et al. JAMA Neurol. 2019 Nov 25. doi: 10.1001/jamaneurol.2019.4050.

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com