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REVIEW

Vania Modesto-Lowe, MD, MPH Gregory C. Barron, MD Benjamin Aronow, BS Margaret Chaplin, MD University of Connecticut School of , University of Connecticut School University of Connecticut School Department of Psychiatry, Farrell Treatment Farmington, CT; Quinnipiac University, Hamden, of Medicine, Farmington, CT of Medicine, Farmington, CT Center, New Britain, CT; University of Connecticut CT; Connecticut Valley Hospital, Middletown, CT School of Medicine, Farmington; Capital Region Mental Health Center, Hartford, CT

Gabapentin for use disorder: A good option, or cause for concern?

ABSTRACT erceptions regarding the use of P for alcohol use disorder The gabapentin is used off-label to (AUD) have shifted over time.1–4 Early on, the treat alcohol-related withdrawal, cravings, , and drug was deemed to be benign and effective.4–6 . Although it is well tolerated and has demon- But more and more, concerns are being raised strated effi cacy for mild alcohol withdrawal and early about its recreational use to achieve ,7 abstinence, there is concern about its potential for abuse. and the drug is often misused by vulnerable Gabapentin should be prescribed only as a second-line al- populations, particularly those with use ternative to standard therapies, and only after screening disorder.7–9 for opioid or other abuse to determine Given the large number of gabapentin if heightened monitoring is warranted. Clinicians should prescriptions written off-label for AUD, it is incumbent on providers to understand be aware of gabapentin’s limitations for treating alcohol 7–9 use disorder and be attentive to emerging data on risks how to prescribe it responsibly. To that end, this article focuses on the benefi ts— and benefi ts. and concerns—of this treatment option. KEY POINTS We describe the effects of gabapentin on the and how it may Gabapentin has been shown to be safe and effective for mitigate alcohol withdrawal and increase mild alcohol withdrawal but is not appropriate as mono- the likelihood of abstinence. In addition, we therapy for severe withdrawal owing to risk of seizures. review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s During early abstinence, gabapentin may improve sleep, misuse potential, and suggest a framework for cravings, and mood—factors associated with relapse. its appropriate use in AUD management. ■ ALCOHOL USE DISORDER Gabapentin is being used recreationally to achieve or IS COMMON AND SERIOUS enhance euphoria, but its misuse potential appears to be AUD affects about 14% of US adults and low when taken at therapeutic doses by patients without represents a signifi cant health burden,1 often a history of drug abuse. 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 , anxiety, sweating, , and , and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol doi:10.3949/ccjm.86a.18128 withdrawal can be fatal.10

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TABLE 1 Agents used to treat alcohol use disorder FDA- Agent approved Potential issues Contraindications Side effects Disulfi ram Yes Poor compliance hinders Concurrent alcohol and toxicity, effectiveness exposure neuropathy Acamprosate Yes Limited benefi t Renal failure Naltrexone Yes Limited benefi t Opioid use, liver failure , nausea, Requires complete opioid abstinence Nalmefene No Limited benefi t Opioid use Nausea, , dizziness Not available in the Gabapentin No Limited data is a Dizziness, , Abuse potential in some relative contraindication individuals No Potential for neurocognitive None , neurocognitive side effects change, anorexia Varenicline No Limited data Seizure disorder is a Nausea Modest effect size relative contraindication No Effi cacy unclear Renal failure Somnolence, dizziness May require high doses Seizure disorder is a relative contraindication

Even though psychosocial treatments Gabapentin is believed to decrease for AUD by themselves are associated with excitation of the central nervous system in high relapse rates, pharmacotherapy is multiple ways: underutilized. Three approved by the • It reduces the release of glutamate, a key US Food and Drug Administration (FDA) component of the excitatory system16 are available to treat it, but they are often • It increases the concentration of gamma- poorly accepted and have limited effi cacy. For aminobutyric acid (GABA), the main these reasons, there is considerable interest inhibitory in the brain7 in fi nding alternatives. Gabapentin is one of • By binding the alpha-2-delta type 1 subunit several agents that have been studied (Table of voltage-sensitive calcium channels,8,15–17 1). The topic has been reviewed in depth by it inhibits excitatory synapse formation Soyka and Müller.11 independent of activity16 • By blocking excitatory neurotransmission, ■ GABAPENTIN REDUCES EXCITATION it also may indirectly increase the The anticonvulsant gabapentin is FDA- concentration of GABA in the central approved for treating , postherpetic nervous system16,17 , and restless leg syndrome.8,12–14 It • It modulates action of glutamic acid binds and selectively impedes voltage-sensitive decarboxylase (involved in the synthesis calcium channels, the pores in cell membrane of GABA) and glutamate synthesizing that permit calcium to enter a neuron in to increase GABA and decrease response to changes in electrical currents.15 glutamate.17

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■ ALCOHOL’S ACTIONS delirium tremens,24 but they are sedating and 3 The actions of alcohol on the are also cause psychomotor impairments. Because of 18 the potential for , complex. Alpha-2-delta type 1 subunits of 3 calcium channels are upregulated in the reward use is limited to acute alcohol withdrawal. centers of the brain by addictive substances, Gabapentin shows promise as an agent including alcohol.16 Alcohol interacts with that can be used in withdrawal and continued through early abstinence without the highly corticotropin-releasing factor and several 16 ,18 and specifi cally affects addictive potential of . It is neuropathways involving norepinephrine, thought to affect drinking behaviors during 19 early abstinence by normalizing GABA and GABA, and glutamate. Alcohol has 2,16 reinforcing effects mediated by the release of glutamate activity. dopamine in the nucleus accumbens.20 Early preclinical studies in mouse Acutely, alcohol promotes GABA release models found that gabapentin decreases and may also reduce GABA degradation, anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking producing and effects.21 , gabapentin has the benefi ts of Chronic alcohol use leads to a decrease in lacking elimination via hepatic , the number of GABA receptors. Clinically, A few pharmacokinetic interactions, and good this downregulation manifests as tolerance to reported tolerability in this population. alcohol’s sedating effects.21 Alcohol affects the signaling of glutamatergic Inpatient trials show no benefi t interaction with the N-methyl-d-aspartate over standard treatments (NMDA) receptor.22 Glutamate activates Bonnet et al25 conducted a double-blind this receptor as well as the voltage-gated placebo-controlled trial in Germany in ion channels, modifying calcium infl ux and inpatients experiencing acute alcohol increasing neuronal excitability.22,23 Acutely, withdrawal to determine whether gabapentin alcohol has an antagonistic effect on the NMDA might be an effective adjunct to , receptor, while chronic drinking upregulates a GABAA modulator commonly used in Alcohol use (increases) the number of NMDA receptors and for alcohol withdrawal. Participants disorder affects voltage-gated calcium channels.22,23 (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 about 14% Alcohol withdrawal hours, with tapering over the next 3 days. increases excitatory effects of US adults All patients could receive rescue doses of Patients experiencing alcohol withdrawal clomethiazole, using a symptom-triggered have decreased GABA-ergic functioning and protocol. increased glutamatergic action throughout 19,24 The study revealed no differences in the the central nervous system. amount of clomethiazole administered between Withdrawal can be subdivided into an the 2 groups, suggesting that gabapentin had acute phase (lasting up to about 5 days) and a no adjunctive effect. Side effects (vertigo, protracted phase (of undetermined duration). nausea, dizziness, and ataxia) were mild and During withdrawal, the brain activates its comparable between groups. “stress system,” leading to overexpression of Nichols et al26 conducted a retrospective corticotropin-releasing factor in the amygdala. cohort study in a South Carolina academic Protracted withdrawal dysregulates the psychiatric hospital to assess the adjunctive prefrontal cortex, increasing cravings and 16 effect of gabapentin on the as-needed use of worsening negative emotional states and sleep. benzodiazepines for alcohol withdrawal. The ■ active group (n = 40) received gabapentin as GABAPENTIN well as a symptom-triggered alcohol withdrawal FOR ALCOHOL WITHDRAWAL protocol of benzodiazepine. The control Benzodiazepines are the standard treatment group (n = 43) received only the symptom- for alcohol withdrawal.3,24 They relieve triggered alcohol withdrawal protocol without symptoms and can prevent seizures and gabapentin.

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No effect was found of gabapentin use with fared worse for achieving for benzodiazepine treatment of alcohol early abstinence and were more likely to withdrawal. It is notable that Bonnet et al and return to drinking when the intervention was Nichols et al had similar fi ndings despite their discontinued. However, signifi cant relapse by studies being conducted in different countries day 12 occurred in both groups. using distinct comparators and methods. The authors concluded that gabapentin Bonnet et al,27 in another study, tried was at least as effective as lorazepam in the a different design to investigate a possible outpatient treatment of alcohol withdrawal, role for gabapentin in inpatient alcohol with the 1,200-mg gabapentin dosage being withdrawal. The study included 37 patients more effective than 900 mg. At 1,200 mg, with severe alcohol withdrawal (Clinical gabapentin was associated with better sleep, Institute Withdrawal Assessment of Alcohol less anxiety, and better self-reported ability to Scale, Revised [CIWA-Ar] > 15). work than lorazepam, and at the 900-mg dose All participants received gabapentin 800 it was associated with less depression than mg. Those whose CIWA-Ar score improved lorazepam. within 2 hours were considered “early Stock et al28 conducted a randomized, responders” (n = 27) and next received 2 days of double-blind study of gabapentin in acute gabapentin 600 mg 4 times a day before starting alcohol withdrawal in 26 military veterans a taper. The nonresponders whose CIWA-Ar in an outpatient setting. Patients were ran- score worsened (associated with greater anxiety domized to one of the following: and depressive symptoms; n = 10) were switched • Gabapentin 1,200 mg orally for 3 days, to standard treatment with clomethiazole followed by 900 mg, 600 mg, and 300 mg (n=4) or (n = 6). Scores of 3 for 1 day each (n = 17) early responders subsequently worsened; 2 of • 100 mg orally for 3 days, these participants developed seizures and were followed by 75 mg, 50 mg, and 25 mg for 1 switched to standard treatment. day each (n = 9). The authors concluded that gabapentin Withdrawal scores improved similarly Three drugs in a dose of 3,200 mg in the fi rst 24 hours in both groups. Early on (days 1–4), neither are approved is useful only for milder forms of alcohol cravings nor sleep differed signifi cantly withdrawal. Hence, subsequent efforts on the between groups; but later (days 5–7), to treat alcohol use of gabapentin for alcohol withdrawal have the gabapentin group had superior scores use disorder, focused on outpatients. for these measures. Gabapentin was also but they are associated with signifi cantly less sedation than Outpatient trials reveal benefi ts chlordiazepoxide and trended to less alcohol often poorly over benzodiazepines craving. Myrick et al3 compared gabapentin vs tolerated and lorazepam in 100 outpatients seeking Bottom line: have limited treatment for alcohol withdrawal. Participants Gabapentin is useful for mild withdrawal effi cacy were randomized to 1 of 4 groups: gabapentin Data suggest that gabapentin offers benefi ts 600 mg, 900 mg, or 1,200 mg, or lorazepam for managing mild alcohol withdrawal. 6 mg, each tapering over 4 days. Alcohol Improved residual craving and sleep measures withdrawal was measured by the CIWA-Ar are clinically important because they are risk score. Only 68 patients completed all follow- factors for relapse. Mood and anxiety also up appointments to day 12. improve with gabapentin, further indicating a Gabapentin 600 mg was discontinued therapeutic effect. because of seizures in 2 patients, but it was Gabapentin’s benefi ts for moderate generally well tolerated and was associated and severe alcohol withdrawal have not with diminished symptoms of alcohol been established. Seizures occurred during withdrawal, especially at the 1,200 mg dose. withdrawal despite gabapentin treatment, The gabapentin groups experienced less but whether from an insuffi cient dose, patient anxiety and sedation and fewer cravings susceptibility, or lack of gabapentin effi cacy is than the lorazepam group. Those treated not clear. Best results occurred at the 1,200-

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mg daily dose, but benefi ts may not apply to of 10 in the gabapentin group vs 9 of 11 in the patients with severe withdrawal. In addition, placebo group) and at 12 weeks (6 of 10 in the many studies were small, limiting the strength gabapentin group vs 11 of 11 in the placebo of conclusions. group, assuming the 2 patients lost to follow- Across most studies of gabapentin for up relapsed). No difference between groups alcohol withdrawal, advantages included a was detected for sleep measures in this small smoother transition into early abstinence study. However, other studies have found due to improved sleep, mood, and anxiety, that gabapentin for AUD improves measures alleviating common triggers for a return of insomnia and daytime drowsiness— to drinking. Gabapentin also carries less predictors of relapse—compared with other reinforcing potential than benzodiazepines. medications.16 These qualities fueled interest in trying High-dose gabapentin is better gabapentin to improve long-term abstinence. Mason et al2 randomized 150 outpatients ■ GABAPENTIN FOR RELAPSE PREVENTION with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 Although naltrexone and acamprosate are the mg or 1,800 mg) or placebo after at least 3 fi rst-line treatments for relapse prevention, days of abstinence. All participants received they do not help all patients and are more counseling. Drinking quantity and frequency effective when combined with cognitive were assessed by gamma-glutamyl transferase behavioral therapy.1,29,30 For patients in whom testing. standard treatments are not effective or Patients taking gabapentin had better tolerated, gabapentin may provide a reasonable rates of abstinence and cessation of heavy alternative, and several randomized controlled drinking than those taking placebo. During trials have examined its use for this role. the 12-week study, the 1,800-mg daily dose Gabapentin alone is better than placebo showed a substantially higher abstinence rate (17%) than either 900 mg (11%) or placebo Furieri and Nakamura-Palacios4 assessed (4%). Signifi cant dose-related improvements the use of gabapentin for relapse prevention Gabapentin were also found for heavy drinking days, total in Brazilian outpatients (N = 60) who had drinking quantity, and frequency of alcohol is believed averaged 27 years of drinking and consumed withdrawal symptoms that predispose to early 17 drinks daily for the 90 days before baseline. to decrease relapse, such as poor sleep, cravings, and poor After detoxifi cation with and mood. There were also signifi cant linear dose excitation vitamins, patients were randomized to either effects on rates of abstinence and nondrinking gabapentin 300 mg twice daily or placebo for of the central days at the 24-week posttreatment follow-up. 4 weeks. nervous system Compared with placebo, gabapentin Gabapentin plus naltrexone in multiple signifi cantly reduced cravings and lowered is better than naltrexone alone the percentage of heavy drinking days and the Anton et al5 examined the effi cacy of ways number of drinks per day, with a signifi cant gabapentin combined with naltrexone during increase in the percentage of abstinent days. early abstinence. The study randomly assigned These self-reported measures correlated with 150 people with AUD to one of the following decreases in gamma-glutamyl transferase, a groups: biological marker for heavy drinking. • 16 weeks of naltrexone (50 mg/day) alone Brower et al31 investigated the use of • 6 weeks of naltrexone (50 mg/day) plus gabapentin in 21 outpatients with AUD and gabapentin (up to 1,200 mg/day), followed insomnia who desired to remain abstinent. They by 10 weeks of naltrexone alone were randomized to gabapentin (up to 1,500 • Placebo. mg at night) or placebo for 6 weeks. Just 14 All participants received medical participants completed the study; all but 2 were management. followed without treatment until week 12. Over the fi rst 6 weeks, those receiving Gabapentin was associated with naltrexone plus gabapentin had a longer signifi cantly lower relapse rates at 6 weeks (3 interval to heavy drinking than those taking

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only naltrexone. By week 6, about half of as long as no contraindications exist. It was those taking placebo or naltrexone alone had a also noted that even small effects may be heavy drinking day, compared with about 35% clinically important, considering the signifi cant of those taking naltrexone plus gabapentin. morbidity associated with AUD. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per ■ POTENTIAL FOR MISUSE drinking day, and better sleep than the other The use of gabapentin has become controversial groups. Participants in the naltrexone-alone owing to the growing recognition that it may group were more likely to drink heavily during not be as benign as initially thought.7–9,34 A periods in which they reported poor sleep. No review of US legislative actions refl ects concerns signifi cant group differences were found in about its misuse.35 In July 2017, Kentucky measures of mood. classifi ed it as a schedule V with prescription drug monitoring,35 as did is no better than placebo in 201836 and in January Falk et al,32 in a 2019 preliminary analysis, 2019.37 Currently, 8 other states (Massachusetts, examined data from a trial of gabapentin Minnesota, Nebraska, North Dakota, Ohio, enacarbil, a formulation of Virginia, Wyoming, and ) require gabapentin. In this 6-month double-blind prescription drug monitoring of gabapentin, and study, 346 people with moderate AUD at 10 other states are considering it.35 sites were randomized to gabapentin enacarbil Efforts to understand gabapentin misuse extended-release 600 mg twice a day or derive largely from people with drug use disorders. placebo. All subjects received a computerized A review of postmortem toxicology reports in behavioral intervention. fatal drug overdoses found gabapentin present in No signifi cant differences between groups 22%.38 Although it was not necessarily a cause were found in drinking measures or alcohol of death, its high rate of detection suggests wide cravings, sleep problems, depression, or misuse among drug users. Because of anxiety symptoms. However, a dose-response Among a cohort of 503 prescription analysis found signifi cantly less drinking for opioid misusers in Appalachian Kentucky, the potential higher doses of the drug. 15% reported using gabapentin “to get high.” for addiction, Bottom line: Those who reported misusing gabapentin benzodiazepine Evidence of benefi ts mixed but risk low were 6 times more likely than nonusers to be abusing and benzodiazepines. The use is limited The effi cacy of gabapentin as a treatment for AUD has varied across studies as a function of main sources of gabapentin were doctors to acute alcohol dosing and formulation. Daily doses have ranged (52%) and dealers (36%). The average cost of from 600 mg to 1,800 mg, with the highest dose gabapentin on the street was less than $1.00 withdrawal 39 showing advantages in one study for cravings, per pill. insomnia, anxiety, dysphoria, and relapse.2 Gabapentin misuse by clinic Thus far, gabapentin immediate-release has patients is also reported. Baird et al40 surveyed performed better than gabapentin enacarbil patients in 6 addiction clinics in the United extended-release. All forms of gabapentin have Kingdom for gabapentin and abuse been well-tolerated in AUD trials. and found that 22% disclosed misusing these The 2018 American Psychiatric Association medications. Of these, 38% said they did so to guidelines stated that gabapentin had a small enhance the methadone high. positive effect on drinking outcomes, but In a review article, Quintero41 also cited the harm of treatment was deemed minimal, enhancement of methadone euphoria and especially relative to the harms of chronic treatment of opioid withdrawal as motivations drinking.33 The guidelines endorse the use of for misuse. Opioid-dependent gabapentin gabapentin in patients with moderate to severe misusers consumed doses of gabapentin 3 to 20 AUD who select gabapentin from the available times higher than clinically recommended and options, or for those who are nonresponsive to in combination with multiple drugs.4 Such use or cannot tolerate naltrexone or acamprosate, can cause and psychedelic effects.

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Gabapentin also potentiates the sedative shared decision-making regarding initiating, effects of opioids, thus increasing the risk of continuing, or discontinuing gabapentin. falls, accidents, and other adverse events.34,35 Risk of opioid-related deaths was increased For alcohol withdrawal with coprescription of gabapentin and with Before gabapentin is prescribed for alcohol moderate to high gabapentin doses.34 withdrawal, potential benefi ts (reduction of withdrawal symptoms), side effects (sedation, Are people with AUD at higher risk fatigue), and risks (falls) should be discussed with of gabapentin abuse? the patient.46 Patients should also be informed Despite concerns, patients in clinical trials that benzodiazepines are the gold standard for of gabapentin treatment for AUD were not alcohol withdrawal and that gabapentin is not identifi ed as at high risk for misuse of the effective for severe withdrawal.46 drug.2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting For relapse prevention in gabapentin discontinuation or side effects When initiating treatment for relapse that differed from placebo in frequency or prevention, the patient and the prescriber severity.2,4,5,16 should agree on specifi c goals (eg, reduction of Clinical laboratory studies also have drinking, anxiety, and insomnia).2,16 Ongoing found no signifi cant interactions between monitoring is essential and includes assessing alcohol and gabapentin.42,43 In fact, they and documenting improvement with respect showed no infl uence of gabapentin on the to these goals. of alcohol or on alcohol’s In the AUD studies, gabapentin was well subjective effects. Relative to placebo, tolerated.16 Frequently observed side effects gabapentin did not affect blood alcohol levels, including headache, insomnia, fatigue, the degree of intoxication, sedation, craving, muscle aches, and gastrointestinal distress or alcohol self-administration. did not occur at a statistically different rate Smith et al9 reported estimates that from placebo. However, patients in studies only 1% of the general population misuse are selected samples, and their experience With adequate gabapentin. Another review concluded that may not be generalizable to clinical practice. precautions, gabapentin is seldom a drug of choice.17 Thus, it is necessary to exercise caution Most patients prescribed gabapentin do not and check for comorbidities that may put off-label use experience cravings or loss of control, which patients at risk of complications.47 Older of gabapentin are hallmarks of addiction. Hence, with patients and those on hemodialysis are more adequate precautions, the off-label use of susceptible to gabapentin side effects such as is reasonable gabapentin for AUD is reasonable. sedation, dizziness, ataxia, and mental status changes,34 and prescribers should be alert for ■ CLINICAL IMPLICATIONS signs of toxicity (eg, ataxia, mental status OF GABAPENTIN PRESCRIBING changes).47,48 Overall, evidence for the benefi t of gabapentin Gabapentin misuse was not observed in in AUD is mixed. Subgroups of alcoholic AUD studies,2,4,5,16 but evidence indicates that patients, such as those who do not respond to patients with opioid use disorder, prisoners, and or tolerate standard therapies, may particularly polydrug users are at high risk for gabapentin benefi t, as may those with comorbid insomnia misuse.39–41 In all cases, clinicians should moni- or .44 Clinicians should tor for red fl ags that may indicate abuse, such as prescribe gabapentin only when it is likely to missed appointments, early refi ll requests, de- be helpful and should carefully document its mands for increased dosage, and simultaneous effi cacy.2,45 and benzodiazepine use.49 ■

At each visit, an open and honest assessment Acknowledgment: The authors wish to thank Nick Mulligan of the benefi ts and risks serves to promote for his invaluable assistance with formatting and grammar.

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