Efficacy of Gabapentin for the Treatment of Alcohol Use Disorder in Patients with Alcohol Withdrawal Symptoms a Randomized Clinical Trial

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JAMA Internal Medicine | Original Investigation Efficacy of Gabapentin for the Treatment of Alcohol Use Disorder in Patients With Alcohol Withdrawal Symptoms A Randomized Clinical Trial

Raymond F. Anton, MD; Patricia Latham, PhD; Konstantin Voronin, MD, PhD; Sarah Book, MD; Michaela Hoffman, PhD; James Prisciandaro, PhD; Emily Bristol, BA

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IMPORTANCE Although an estimated 30 million people meet criteria for alcohol use disorder CME Quiz at (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific, jamacmelookup.com approach might improve efficacy and acceptance.

OBJECTIVE To examine whether gabapentin would be useful in the treatment of AUD, especially in those with the most alcohol withdrawal symptoms.

DESIGN, SETTING, AND PARTICIPANTS This double-blind randomized clinical trial conducted between November 2014 and June 2018 evaluated gabapentin vs placebo in community-recruited participants screened and treated in an academic outpatient setting over a 16-week treatment period. A total of 145 treatment-seeking individuals who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for AUD and were not receiving other AUD intervention were screened, and 96 who also met recent alcohol withdrawal criteria were randomized to treatment after 3 abstinent days. Daily drinking was recorded, and percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment.

INTERVENTIONS Gabapentin up to 1200 mg/d, orally, vs placebo along with 9 medical management visits (20 minutes each).

MAIN OUTCOMES AND MEASURES The percentage of individuals with no heavy drinking days and those with total abstinence were compared between treatment groups and further evaluated based on prestudy alcohol withdrawal symptoms.

RESULTS Of 96 randomized individuals, 90 were evaluable (44 in the gabapentin arm and 46 in the placebo arm), with a mean (SD) age of 49.6 (10.1) years; 69 were men (77%) and 85 were white (94%). The evaluable participants had 83% baseline heavy drinking days (4 or more drinks/day for women, 5 or more for men) and met 4.5 alcohol withdrawal criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). More gabapentin-treated individuals had no heavy drinking days (12 of 44 participants [27%]) compared with placebo (4 of 46 participants [9%]), a difference of 18.6% (95% CI, 3.1-34.1; P = .02; number needed to treat [NNT], 5.4), and more total abstinence (8 of 44 [18%]) compared with placebo (2 of 46 [4%]), a difference of 13.8% (95% CI, 1.0-26.7; P = .04; NNT, 6.2). The prestudy high–alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (P < .02; NNT, 3.1) and total abstinence (P = .003; NNT, 2.7) compared with placebo, while within the low–alcohol withdrawal group, there were no significant differences. These findings were similar for other drinking variables, where gabapentin was more efficacious than placebo in the high–alcohol withdrawal group only. Gabapentin caused more dizziness, but this did not affect efficacy.

CONCLUSIONS AND RELEVANCE These data, combined with others, suggest gabapentin might Author Affiliations: Addiction be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future Sciences Division, Department of Psychiatry and Behavioral Sciences, studies should evaluate sleep changes and mood during early recovery as mediators of Medical University of South Carolina, gabapentin efficacy. Charleston. Corresponding Author: Raymond F. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02349477 Anton, MD, Addiction Sciences Division, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President St, MSC 861, JAMA Intern Med. 2020;180(5):728-736. doi:10.1001/jamainternmed.2020.0249 Charleston, SC 29425 Published online March 9, 2020. ([email protected]).

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p to 30 million people in the United States meet criteria for alcohol use disorder (AUD), and the number Key Points is increasing over time,1 accounting for considerable U Question Is gabapentin efficacious in the treatment of alcohol use 2 morbidity and mortality. However, only 20% of those who disorder in adults with a history of alcohol withdrawal symptoms? might benefit from treatment receive it, and of those individu- Findings In this randomized clinical trial, gabapentin compared als, only 20% (or less than 1 million individuals) receive medi- with placebo significantly increased the number of people with cation to help them with maintaining abstinence or reducing total abstinence and reduced drinking. This effect was most drinking. One reason is that available medications are not uni- significantly observed in those with greater pretreatment alcohol versally efficacious.3 However, there is reason to believe that withdrawal symptoms—41% of participants with high alcohol some subgroups of patients might respond better to available withdrawal symptoms had total abstinence on gabapentin treatments.3 compared with 1% of participants in the placebo arm. One understudied phenotype or subtype of AUD are people Meaning This study showed that gabapentin is efficacious in who experience alcohol withdrawal syndrome (AWS).4 Al- promoting abstinence and reducing drinking in individuals with though the quantity and frequency of drinking might predict alcohol use disorder and especially so in those with more alcohol who is at risk for AWS, there is considerable variation (some withdrawal symptoms. likely genetic) as to who will experience AWS on the cessation of drinking. More than half of inpatients with AUD5 and 35% of community individuals with AUD reported alcohol with- current or historic alcohol withdrawal symptoms, consistent drawal symptoms, leading to a higher rate of alcohol prob- with basic science findings.36 Recent randomized clinical lems at follow-up.6 Similarly, those who have undergone pre- trials37,38 of gabapentin had mixed results but did not take al- vious medicated detoxifications relapse quicker after cessation cohol withdrawal symptoms into account. Gabapentin is nev- of alcohol use.7 While up to 30% of individuals with AUD ertheless worthy of further study given its earlier suggested presenting for clinical trials (who are similar to those seen in effectiveness in those with alcohol withdrawal symptoms, its addiction outpatient clinics and in primary care) have acute minimal cognitive effects,39,40 its lack of significant adverse AWS, it has been recognized that lower-grade AWS might be interaction with alcohol,30,41,42 and its kidney excretion, which present, and last longer, in considerably more individuals. makes it potentially safer for individuals with liver disease. Many individuals also stop or reduce drinking prior to initiat- The current study was a double-blind, placebo-controlled ing treatment and therefore may experience mild to severe AWS randomized clinical trial of treatment with gabapentin in out- without being formally diagnosed. In addition, a constella- patient individuals with AUD who reported current or histori- tion of problems, such as irritability, anxiety, dysphoria, dif- cal alcohol withdrawal symptoms. A secondary aim was to evalu- ficulties with concentration, and insomnia, might persist for ate the relationship of recently experienced alcohol withdrawal a time after initial abstinence. Some have labeled these lin- symptoms to gabapentin response, with the hypothesis that gab- gering symptoms as protracted withdrawal8 or protracted apentin would be more efficacious in those with higher levels abstinence.9 In general, this constellation of symptoms and any of self-reported alcohol withdrawal symptoms. desire to drink emanating from them are not likely to be in- fluenced by antireinforcement or anticraving medications, such as naltrexone, which are likely to target more reward-based Methods craving.10-14 Consistent with this notion, AWS is thought to be mediated primarily by γ-aminobutyric acid (GABA) and glu- Trial Design and Participants tamate brain signaling15-17 in contrast to reward-based crav- The study was a 16-week randomized clinical trial (Clinical- ing, in which opioid and dopamine brain signaling play a larger Trials.gov identifier: NCT02349477) of gabapentin vs pla- role.18,19 Therefore, medications that target brain GABA cebo. The trial protocol was approved by the Medical Univer- and glutamate brain signaling systems might be particularly sity of South Carolina Institutional Review Board for Human useful in the treatment of AWS and, by extension, in those who Research and is included in Supplement 1. Participants had to have previously shown a biological propensity to experience be aged 18 to 70 years; meet Diagnostic and Statistical Manual AWS.16,20,21 of Mental Disorders (Fifth Edition) (DSM-5) criteria for AUD, in- Gabapentin has unique pharmacologic characteristics, cluding alcohol withdrawal, as determined by Structured Clini- binding to voltage-sensitive calcium channels at the α2δ-1 cal Interview for DSM-543; have a minimum of 5 drinks per day site,22 affecting their function23 as well as influencing recep- in the 90 days prior to assessment; and be abstinent at least 3 tor trafficking.24 Through these mechanisms, gabapentin is days prior to randomization as measured by breath analysis thought to secondarily influence GABA and glutamate and urinary ethyl glucuronide testing. Participants could be tone/activity,25-27 which can be clinically measured.28 using cannabis or other drugs but not meet criteria for drug Gabapentin is efficacious for the treatment of acute alco- use disorder, except nicotine, and could have no other psy- hol withdrawal symptoms29,30 and also provides short-term choactive drug detected in the urine. Participants could not relapse prevention after medicated alcohol detoxification,31 be taking psychotropic medications other than antidepres- perhaps by an effect on sleep normalization.32,33 Post hoc analy- sants (with the dose stable for at least 1 month) or meet cur- sis has shown effectiveness of treatment with gabapentin, in rent criteria for any major depressive disorder, bipolar disor- combination with flumazenil34 or naltrexone,35 in patients with der, psychotic disorder, or eating disorder. A history of

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posttraumatic stress disorder with stable symptoms was al- During each medical management session, the calendar- lowed, given its comorbidity with AUD and the utility of gab- based timeline follow-back method55 was used to assess daily apentin in some anxiety disorders.44 Participants had to be drinking since the last visit. In addition, OCDS and SAFTEE as- medically stable (including liver enzymes alanine aminotrans- sessments were performed at each visit. To confirm verbal re- ferase and aspartate aminotransferase less than 3 times the up- port of abstinence or heavy drinking, %dCDT was collected on per limit of normal). Women could not be pregnant or breast- weeks 3, 6, 10, and 16. feeding, must be using a reliable form of contraception, or must be postmenopausal. A history of alcohol withdrawal seizure Outcome Measures or a Clinical Institute Withdrawal Assessment for Alcohol– The primary a priori defined drinking outcome (efficacy) mea- Revised (CIWA-Ar) scale45 score of 10 or more during assess- sure was the percentage of participants with no heavy drink- ment was exclusionary. This study followed the Consoli- ing days (defined as 5 or more drinks per day for men and 4 or dated Standards of Reporting Trials (CONSORT) reporting more drinks per day for women; standard drinks [defined as guideline. containing 14 g of ethanol, or translated into typical drinks: 1.5 oz of spirits, 5 oz of wine, or 12 oz of beer]) throughout the Recruitment study.38,56,57 The main secondary outcome measure was the Participants were recruited from November 2014 through June percentage of participants with no drinking days (ie, total ab- 2018 primarily by community advertisement and were not en- stinence) throughout the study. Verbal report was confirmed gaged in other alcohol treatment. Participants provided writ- by %dCDT testing and drinking status corrected—that is, those ten informed consent approved by the Medical University of who reported no drinking or no heavy drinking but had a South Carolina Institutional Review Board for Human Re- %dCDT greater than 1.7% at any time during the study were search before formal assessment. Individuals paid $50 for at- considered to have heavy drinking days and not be abstinent. tending the end-of-study assessment to provide drinking and This led to 3 individuals being reclassified prior to unblinding biological data. of medication group allocation. Additional analyses included the relationship of the level Interventions of reported recent alcohol withdrawal symptoms on the After at least 3 days of abstinence and assessment, partici- AWSC49 and medication response. Other drinking variables rou- pants were randomized (using prespecified computer ran- tinely reported in AUD randomized clinical trials that might dom assignment by the investigational pharmacy) to receive be useful to clinicians were also evaluated. These included the gabapentin (day 1: 300 mg at bedtime; day 2: 300 mg in the percentage of heavy drinking days, percentage of days absti- morning and at bedtime; days 3 and 4: 300 mg in the morn- nent, number of drinks per day, and number of drinks per drinking, at noon, and at bedtime; and days 5 through 112: 300 mg ing day. in the morning and at noon and 600 mg at bedtime for a total of 1200 mg) or identical placebo capsules (given at the same Assays and Biomarkers quantity and times) in blister packs for 16 weeks. Study medi- Urine riboflavin was assayed in the Medical University of cations were identically overencapsulated with 25 mg of South Carolina Clinical Neurobiology Laboratory (directed by riboflavin (added to measure adherence) and distributed in R.A.) using standard/calibration curves constructed from labeled blister packs. Medical management, which consisted known amounts of riboflavin against which unknown of a relatively brief (15-20 minutes) educational/supportive amounts of urine riboflavin were calculated by fluorescence and adherence-enhancing clinical interaction,46,47 was con- detection (448 nm excitation/510 nm emission). Values ducted on weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 when adher- greater than 1300 ng/mL indicated adherence. The %dCDT ence (pill count and urine riboflavin collection) and medica- was measured with a reference high-performance liquid tion adverse effects, using the Systematic Assessment for chromatography assay.54 Using this international standard- Treatment of Emergent Events (SAFTEE) instrument,48 were ized assay, a value greater than 1.7% is close to 100% specific assessed. for sustained heavy drinking in the weeks prior to testing and can be used to corroborate or independently evaluate drink- Assessment ing in clinical trials.58 Urine ethyl glucuronide (Microgenics Prior to randomization, multiple assessments were adminis- Diagnostics) and other blood chemistries, including GGT, tered, including the Structured Clinical Interview for DSM-5, were measured with an autoanalyzer. the Alcohol Withdrawal Symptom Checklist (AWSC),49 the Al- cohol Dependence Scale (ADS),50 the Obsessive Compulsive Power Calculations and Statistical Analysis Plan Drinking Scale (OCDS),51 Form 90 (alcohol consumption, drug Data from individuals with an alcohol withdrawal history in 2 use, daily calendar method),52 the CIWA-Ar scale,45 and base- prior AUD trials that included gabapentin treatment34,35 indi- line physical complaints. Laboratory tests included a health cated the percentage of individuals with no heavy drinking days screen, liver function tests, pregnancy test (in women), and (success rates) to be between 38% and 41% in the placebo- alcohol use markers γ-glutamyltransferase (GGT), urine ethyl treated groups and between 71% and 79% in the gabapentin- glucuronide, and percentage of disialo carbohydrate- treated group, estimating the power to detect a gabapentin ef- deficient transferrin (%dCDT).53,54 White blood cell DNA fect to be between 0.83 and 0.98 at α = .05 with a sample size samples were obtained for potential future analysis. of 45 individuals per medication group.

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For no heavy drinking (primary outcome) and no drinking/ Figure 1. CONSORT Diagram total abstinence (secondary outcome), the number of evaluable individuals who met that criteria by verbally reported 145 Individuals consented drinking only or by %dCDT verification over the whole 16-

week trial was analyzed using a 2-sample z test to produce con- 49 Excluded fidence intervals and a χ2 P value; P values less than .05 were 16 Chose not to participate 11 Did not meet inclusion criteria considered significant. In addition, the number needed to treat 5 Did not meet drinking criteria (NNT) or the number needed to harm (NNH)59 is reported. For 5 Could not be abstinent 3 days 1 analytic purposes, the 9 placebo-treated and 5 gabapentin- Had no alcohol withdrawal history 22 Met exclusion criteria treated individuals that had missing drinking data were con- 13 Reported other drug use sidered to be drinking or heavy drinking. A sensitivity analysis 6 Were medically unstable 2 Were not using birth control evaluating the same effects in only those who completed the 1 Had criminal charges pending study and were adherent with medication was also performed. All outcome data were collected by study staff and ana- 96 Individuals randomized lyzed without knowledge of medication group assignment. For evaluation of the level of alcohol withdrawal symp- 46 Participants randomized 50 Participants randomized toms predicting gabapentin response, the prestudy AWSC (see to gabapentin to placebo eFigure in Supplement 2) was divided into low or high alcohol withdrawal based on median split. A χ2 test evaluating the 2 Excluded 4 medication within the different alcohol withdrawal groups on 1 Had no valid data Excluded because 1 Had a protocol no valid data no heavy drinking and total abstinence was conducted for the violation total study period. Evaluation of other drinking data was done using a linear 44 Participants analyzed 46 Participants analyzed 13 Dropped out 18 Dropped out mixed model with an unstructured variance/covariance ma- 1 Withdrew because of 1 Had medication trix in which drinking parameters (percentage of heavy drink- intestinal obstruction discontinued by PCP 1 Withdrew because of 7 Required more ing days, percentage of drinking days, number of drinks per weight gain intensive treatment day, and number of drinks per drinking day) were evaluated 6 Required more 2 Moved intensive treatment 8 Chose to discontinue over the 4 months of the study. These models measured the 5 Chose to discontinue main effects of time (month), medication group, and alcohol withdrawal symptom group (low or high) and their potential CONSORT indicates Consolidated Standards of Reporting Trials; PCP, primary interactions. In these models, missing data were assumed to care physician. be missing at random. Statistical analyses were performed using SPSS version 24 (IBM). tions. They met a mean of 4.5 of 8 possible DSM-5 criteria for alcohol withdrawal. Sixty-four participants (71%) had Results elevated %dCDT and 68 (76%) had elevated GGT, both markers of heavy drinking. There were no important signifi- Participant recruitment and disposition are summarized in cant differences in any prestudy variables between the pla- the CONSORT diagram (Figure 1). Essentially, 145 individu- cebo and gabapentin groups. als meeting DSM-5 AUD criteria provided written informed consent. Of these, 96 individuals were randomized to pla- Drinking Outcomes cebo (n = 50) or gabapentin (n = 46). Four participants Data for the primary outcome variable, the percentage of receiving placebo and 2 receiving gabapentin had no valid individuals with no heavy drinking days, and the secondary follow-up data or an early protocol violation (disclosure of outcome variable, the percentage of individuals with no an excluded medical disease that was withheld at screen- drinking days, are summarized in Table 2. For no heavy ing). Eighteen of 46 participants (39%) receiving placebo drinking, using verbal report only, gabapentin (12 of 44 par- and 13 of 44 participants (30%) receiving gabapentin did not ticipants [27%]) was superior to placebo (6 of 46 participants complete treatment (reasons given in Figure 1). Participants [13%]) at the trend level (14.2% difference; 95% CI, −2.1 to in both groups attended an average of 7 of 9 medical man- 30.6; P = .09; NNT, 7.0), but when verbal report was con- agement sessions. Table 1 summarizes the study entry firmed by the highly specific %dCDT heavy drinking demographic information and drinking variables. Of the 90 marker,60,61 the difference was statistically significant (18.6% participants included in the final analysis, the mean (SD) difference; 95% CI, 3.1-34.1; P = .02; NNT, 5.4). For the sec- age was 49.6 (10.1) years; 69 (77%) were men; 85 (94%) were ondary variable (no drinking days/total abstinence), when white; 63 (70%) were employed; and 39 (43%) used nicotine using verbal report only, gabapentin treatment (9 of 44 par- products. They drank a mean of 86% of pretreatment days, ticipants [21%]) was superior to placebo (2 of 46 participants with 83% being heavy drinking days, consuming 13 drinks [4%]) (16.1% difference; 95% CI, 2.8-29.4; P = .02; NNT, 6.2) per drinking day, and 25 participants (28%) had past treat- and in the same direction after %dCDT confirmation (13.8% ments and 12 (13%) had undergone past medical detoxifica- difference; 95% CI, 1.0-26.7; P = .04; NNT, 7.2).

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Table 1. Study Population Demographic Information and Drinking Variables

No. (%) Gabapentin Placebo P Characteristic Total (n = 90) (n = 44) (n = 46) Valuea Age, mean (SD), y 49.6 (10.1) 50.3 (10.4) 48.9 (9.9) .53 PTSD (current or past) 23 (26) 12 (27) 11 (24) .72 Nicotine use 39 (43) 18 (41) 21 (46) .65 Antidepressant use 22 (24) 9 (21) 13 (28) .39 Sex (male) 69 (77) 34 (77) 35 (76) .89 Married/cohabitating 40 (44) 21 (48) 19 (41) .54 Education (≤12 y) 10 (11) 5 (11) 5 (11) .94 Employed 63 (70) 29 (66) 34 (74) .41 Race (white) 85 (94) 41 (93) 44 (96) .61 Alcohol use and severity indicators, mean (SD) Abbreviations: ADS, Alcohol Drinks per dayb 11.0 (4.4) 10.9 (4.4) 11.0 (4.6) .93 Dependence Scale; AW, alcohol Drinks per drinking dayb 12.9 (4.5) 13.2 (4.7) 12.5 (4.4) .46 withdrawal; DSM-5, Diagnostic and Statistical Manual of Mental Disorders b Days abstinent, % 13.9 (20.2) 15.1 (22.2) 12.8 (18.1) .59 (Fifth Edition); Heavy drinking days, %b 82.7 (22.2) 82.9 (23.0) 82.5 (21.6) .93 GGT, γ-glutamyltransferase; OCDS, Obsessive Compulsive c Days since last drink 4.4 (2.1) 4.4 (2.2) 4.4 (2.0) .93 Drinking Scale; %dCDT, percentage of ADSd 17.6 (7.3) 19.5 (7.6) 15.8 (6.8) .02 disialo carbohydrate-deficient transferrin. OCDSe score 26.3 (9.4) 27.5 (9.3) 25.1 (9.6) .22 a The χ2 statistic was used for all f Alcohol Withdrawal Symptom Checklist 9.6 (6.6) 10.5 (7.1) 8.8 (6.0) .22 categorical variables, and the DSM-5 AW items positive, mean (SD) 4.5 (1.3) 4.6 (1.2) 4.3 (1.3) .38 ANOVA statistic was used for all continuous variables. Had past alcohol treatments b Calculated using the 90 days prior Treatment 25 (28) 16 (36) 9 (20) .09 to screening. Detoxification 12 (13) 7 (16) 5 (11) .51 c Days abstinent prior to Alcohol blood tests (biomarkers) randomization. d Range, 0-47. %dCDT ≥ 1.7 64 (71) 31 (72) 33 (72) .97 e Range, 0-56. GGT > 36 U/L 68 (76) 34 (77) 34 (74) .71 f Range, 0-44.

Table 2. Number of Individuals With No Heavy Drinking Days or No Drinking Days by Medication Group

No. (%) Gabapentin Placebo P Value Outcome Variable (n = 44) (n = 46) Difference, % (95% CI) (χ2) No heavy drinking days Verbal report only 12 (27) 6 (13) 14.2 (−2.1 to 30.6) .09 %dCDT corrected 12 (27) 4 (9) 18.6 (3.1 to 34.1) .02 No drinking days (abstinent) Verbal report only 9 (21) 2 (4) 16.1 (2.8 to 29.4) .02 Abbreviation: %dCDT, percentage of disialo carbohydrate-deficient %dCDT corrected 8 (18) 2 (4) 13.8 (1.0 to 26.7) .04 transferrin.

Performing a sensitivity analysis on the 21 placebo- Effect of Alcohol Withdrawal Severity on Medication Effects treated and 26 gabapentin-treated participants who com- Because the main hypothesis of this study was that gabapen- pleted the study (had all 16-week drinking data) and who ad- tin would be more efficacious in individuals with AUD with hered to pill taking (at least 75% riboflavin-positive urine more alcohol withdrawal, as suggested in past work,29,30 and samples), there were 12 gabapentin-treated individuals com- because ethical and feasibility issues limited the ability to pared with 1 placebo-treated individual with no heavy drink- enroll people in acute withdrawal (CIWA-Ar scores greater 2 ingdays(χ1 = 5.08; P = .02; NNT, 2.4) and 8 gabapentin- than 10), we undertook an additional analysis of the level of treated individuals compared with 1 placebo-treated individual self-reported alcohol withdrawal symptoms when partici- 2 who remained abstinent throughout the study (χ 1 =9.95; pants reduced or stopped drinking in the 2 weeks before ran- P = .002; NNT, 3.9). These results were similar or stronger when domization using the modified AWSC (eFigure in Supple- drinking status was adjusted based on within-treatment ment 2). Figure 2 shows the percentage of individuals with %dCDT levels. heavy drinking days and any drinking days in the medication

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Figure 2. Percentage of Individuals With Heavy Drinking or No Drinking Days During the Study

Gabapentin/low AWS (n = 22) Gabapentin/high AWS (n = 22) Placebo/low AWS (n = 23) Placebo/high AWS (n = 23)

A No heavy drinking days B No drinking days (abstinent)

80 80

60 60

40 40

20 20 Individuals With No Drinking Days, % Individuals With No Heavy Drinking Days, % 0 0 1 2 3 4 1 2 3 4 Treatment, mo Treatment, mo

Percentage of individuals with either (A) no heavy drinking days or (B) no drinking days (complete abstinence) over the course of the study by medication and alcohol withdrawal level (AWS low or high). At baseline (data not shown), all study participants had drinking days and heavy drinking days, so in this depiction they would start at 0%. AWS indicates alcohol withdrawal symptoms.

Table 3. Gabapentin vs Placebo Treatment on Various Drinking Variables

Mean (SD) P Valuea Gabapentin Placebo AWS × Variable (n = 44) (n = 46) Medication AWS Medication Heavy drinking days, % Low AWS 47.6 (6.2) 31.1 (6.2) .51 .01 .04 High AWS 19.5 (6.3) 28.2 (6.1) Days abstinent, % Low AWS 44.9 (6.7) 63.9 (6.6) .57 .02 .02 High AWS 75.5 (6.7) 63.9 (6.6) Number of drinks per day Low AWS 4.6 (0.7) 3.6 (0.7) .87 .05 .07 Abbreviation: AWS, alcohol High AWS 2.2 (0.7) 3.5 (0.7) withdrawal symptoms. Number of drinks per drinking day a All P values were derived from a Low AWS 8.4 (0.8) 7.8 (0.8) linear model with main effects of .79 .78 .71 medication and AWS and their High AWS 7.8 (1.1) 7.9 (0.8) interaction terms.

groups predicated by prestudy alcohol withdrawal scores AWSC score groups (as above) into account in a linear mixed (median split greater or less than 8.5) over the study period. model (Table 3). Although there was a main effect of time, it Those with high alcohol withdrawal scores had less relapse to did not significantly interact with medication group or AWSC 2 heavy drinking (χ 1 = 5.75; P = .02; NNT, 3.1) and more total scores; thus, time interaction terms were dropped from the 2 abstinence (χ 1 =8.69;P = .003; NNT, 2.7) when treated with model. In this analysis, there was no main effect of gabapen- gabapentin (10 of 22 [46%] and 9 of 22 [41%], respectively) tin over placebo on any drinking variable, but there were sig- compared with placebo (3 of 23 [13%] and 1 of 23 [4%]), while nificant interactions with AWSC scores such that in the high those with low alcohol withdrawal scores had similar relapse AWSC group, gabapentin compared with placebo reduced the 2 to heavy drinking (χ 1 = 0.18; P = .67; NNH, 25.3) and similar percentage of heavy drinking days (F1,86.802 = 4.53; P = .04) and 2 total abstinence (χ 1 = 0.98; P = .32; NNH, 23.0) when treated promoted more abstinence days (F1,86.419 = 5.68; P = .02) but

with gabapentin (2 of 22 [9%] and 0 of 22 [0%], respectively) did not decrease drinks per day (F1,85.252 = 3.40; P =.07)or

compared with placebo (3 of 23 [13%] and 1 of 23 [4%]). The drinks per drinking day (F1,71.659 = 0.14; P = .71). same pattern was found when the data were corrected for %dCDT. Adverse Medication Effects To evaluate gabapentin efficacy across a range of other Adverse effects as recorded with the SAFTEE interview at each drinking variables, we conducted sensitivity analyses taking study visit showed significantly more gabapentin-treated

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(n = 25) vs placebo-treated (n = 15) individuals reported mild and increased total abstinence in a less severe population, 2 to moderate dizziness (χ 1 = 5.34; P = .02), but in a separate based on alcohol consumption levels, and without signifi- analysis, the presence or absence of dizziness did not significant current alcohol withdrawal symptoms. However, in a cantly account for gabapentin’s effectiveness. While there was meta-analysis62 in which the alcohol withdrawal status of the no other significant between-group differences in unique in- populations was not considered, the percentage of heavy drink- dividuals reporting other symptoms, there were more within- ing days was the only variable that showed superior gabapen- 2 individual reports of nervousness (χ 1 =10.62;P = .001) and tin efficacy. In a larger clinical context, the NNT for gabapen- 2 headache (χ 1 = 9.70; P = .002) in the gabapentin-treated group tin efficacy was equal to or better than reported for naltrexone 2 47 (none severe), and more reports of insomnia (χ 1 = 10.81; in the COMBINE Study (NNT, 7), and with alcohol with- P = .001) in the placebo-treated group (1 severe). drawal status taken into account, gabapentin benefited even more people (NNT, 3). Many studies have supported the efficacy of gabapentin 44,63 Discussion in alcohol withdrawal treatment. Given gabapentin’s di- rect and indirect pharmacologic effects on brain GABA and glu- These results add to the growing literature on the use of gab- tamate systems15,17 and the role of these systems in alcohol apentin for the treatment of AUD. While some previous withdrawal and relapse drinking,16,64 its efficacy makes sense. studies37 have shown efficacy, others have not,38 and a re- Of additional biological interest, the gene regulating the volt- cent meta-analysis62 suggested weak support for its efficacy age-sensitive calcium channel α2δ-1 protein is upregulated by in treatment of AUD. Although multiple reasons might con- chronic alcohol exposure and withdrawal.65 Because this is the tribute to the variability of results, an important issue might putative site of gabapentin action,23 this site might be a fruit- be the individual’s alcohol withdrawal status/history.34,35 In ful target for potential future AUD pharmacologic treatment the current study, we chose to explicitly study the hypothesis development as well. that a history of alcohol withdrawal symptoms would influence gabapentin efficacy by evaluating gabapentin only in Limitations those who met current or historical criteria for DSM-5 alcohol This study had several limitations. Although the noncomple- withdrawal. We further used a previously validated alcohol tion rate was similar to that for other AUD gabapentin treat- withdrawal self-rating instrument49 to gauge the relation- ment trials37,38 and a National Institutes of Health National In- ship between the level of alcohol withdrawal symptoms in the stitute on Alcohol Abuse and Alcoholism–sponsored large weeks prior to randomization and gabapentin response. multisite study,47 it should be noted that 13 of 44 (30%) of in- In essence, we found gabapentin to be efficacious in pre- dividuals on gabapentin and 18 of 46 (39%) on placebo did not venting relapse to heavy drinking (NNT, 5.4) and, perhaps more complete the trial. Perhaps, adding other supportive counsel- importantly, in promoting abstinence (NNT, 7.2). These are con- ing or Alcoholics Anonymous attendance could increase re- servative outcomes for AUD randomized clinical trials,56 but tention in treatment. Also, self-reported alcohol withdrawal both are accepted by the US Food and Drug Administration as symptoms prior to study entry might not fully capture the ex- indicators of medication efficacy in AUD randomized clinical tent of withdrawal severity. In addition, those with complex trials.57 However, when taking the amount of alcohol with- psychiatric and medical conditions, including history of alco- drawal symptoms into account, significant gabapentin hol withdrawal seizures, were excluded. Furthermore, given effects were seen only in those with the higher levels of self- its kidney excretion, gabapentin should be studied in pa- reported alcohol withdrawal symptoms. There was less re- tients with AUD with more severe liver disease, a condition in lapse to heavy drinking (NNT, 3.1) and more total abstinence which medications are greatly needed.66 (NNT, 2.7) in those with more intense alcohol withdrawal symptoms treated with gabapentin, and we also found an interaction between the level of those symptoms on other continu- Conclusions ous drinking outcomes, including percentage of heavy drinking days, percentage of days abstinent, and to some extent the The weight of the evidence now suggests that gabapentin might number of drinks per day—all favoring gabapentin treatment be most efficacious after the initiation of abstinence to sus- over placebo. In fact, in our previous studies, we found more tain it and that it might work best in those with a history of abstinence when gabapentin was combined with flumazenil34 more severe alcohol withdrawal symptoms. To further con- compared with placebo and less relapse to heavy drinking when firm this, future studies should specifically evaluate symp- gabapentin was combined with naltrexone compared with nal- toms related to protracted alcohol withdrawal during gaba- trexone alone.35 In both studies, individuals with a greater his- pentin treatment. Armed with this knowledge, clinicians may tory of alcohol withdrawal showed the most efficacy on those have another alternative when choosing a medication to treat drinking outcomes. It is also of interest that Mason et al37 re- AUD and thereby encourage more patient participation in treat- ported that gabapentin decreased relapse to heavy drinking ment with enhanced expectation of success.

ARTICLE INFORMATION Published Online: March 9, 2020. Author Contributions: Drs Anton and Hoffman had Accepted for Publication: January 23, 2020. doi:10.1001/jamainternmed.2020.0249 full access to all of the data in the study and take

734 JAMA Internal Medicine May 2020 Volume 180, Number 5 (Reprinted) jamainternalmedicine.com

responsibility for the integrity of the data and the efficacy and safety. Subst Abus. 2016;37(2):286-298. 18. Gonzales RA, Weiss F. Suppression of accuracy of the data analysis. doi:10.1080/08897077.2015.1133472 ethanol-reinforced behavior by naltrexone is Study concept and design: Anton. 4. Schuckit MA, Smith TL, Daeppen JB, et al. associated with attenuation of the ethanol-induced Acquisition, analysis, or interpretation of data: All Clinical relevance of the distinction between alcohol increase in dialysate dopamine levels in the nucleus authors. dependence with and without a physiological accumbens. J Neurosci. 1998;18(24):10663-10671. Drafting of the manuscript: Anton, Book, Bristol. component. Am J Psychiatry. 1998;155(6):733-740. doi:10.1523/JNEUROSCI.18-24-10663.1998 Critical revision of the manuscript for important 5. Caetano R, Clark CL, Greenfield TK. Prevalence, 19. Schacht JP, Anton RF, McNamara PJ, Im Y, King intellectual content: Anton, Latham, Voronin, Book, AC. The dopamine transporter VNTR polymorphism Hoffman, Prisciandaro. trends, and incidence of alcohol withdrawal symptoms: analysis of general population and moderates the relationship between acute Statistical analysis: Anton, Hoffman, Prisciandaro. response to alcohol and future alcohol use disorder Obtained funding: Anton. clinical samples. Alcohol Health Res World. 1998;22 (1):73-79. symptoms. Addict Biol. 2019;24(5):1109-1118. doi: Administrative, technical, or material support: 10.1111/adb.12676 Anton, Latham, Voronin, Book, Prisciandaro, 6. Schuckit MA, Danko GP, Smith TL, Hesselbrock Bristol. V, Kramer J, Bucholz K. A 5-year prospective 20. Addolorato G, Leggio L, Hopf FW, Diana M, Study supervision: Anton, Book, Prisciandaro. evaluation of DSM-IV alcohol dependence with and Bonci A. Novel therapeutic strategies for alcohol without a physiological component. Alcohol Clin and drug addiction: focus on GABA, ion channels Conflict of Interest Disclosures: Dr Anton and transcranial magnetic stimulation. reported receiving grants from the National Exp Res. 2003;27(5):818-825. doi:10.1097/01.ALC. 0000067980.18461.33 Neuropsychopharmacology. 2012;37(1):163-177. doi: Institute on Alcohol Abuse and Alcoholism during 10.1038/npp.2011.216 the conduct of the study; receiving grants and 7. Wright TM, Myrick H, Malcolm R, et al. Impact of consulting fees from Laboratorio Farmaceutico CT; lifetime alcohol quit attempts and medicated 21. Krystal JH, Staley J, Mason G, et al. receiving consulting fees from Alkermes, Allergan, detoxifications on time to relapse during an index Gamma-aminobutyric acid type A receptors and Indivior, Insys, Life Epigenetics, XenoPort (Arbor alcohol detoxification. J Addict Med. 2007;1(1):15-20. alcoholism: intoxication, dependence, vulnerability, Pharmaceuticals), and Alcohol Clinical Trials doi:10.1097/ADM.0b013e318044ce4f and treatment. Arch Gen Psychiatry. 2006;63(9): 957-968. doi:10.1001/archpsyc.63.9.957 Initiative (ACTIVE) outside the submitted work; and 8. Bonnet U, Banger M, Leweke FM, Maschke M, serving as a member and chair of ACTIVE, which Kowalski T, Gastpar M. Treatment of alcohol 22. Maneuf YP, Luo ZD, Lee K. Alpha2delta and the was partially supported by Alkermes, Amygdala withdrawal syndrome with gabapentin. mechanism of action of gabapentin in the Neurosciences, Arbor Pharmaceuticals, Ethypharm, Pharmacopsychiatry. 1999;32(3):107-109. doi:10. treatment of pain. Semin Cell Dev Biol. 2006;17(5): Indivior, Lundbeck, Mitsubishi, and Otsuka. Dr Book 1055/s-2007-979203 565-570. doi:10.1016/j.semcdb.2006.09.003 reported receiving grants from the National 23. Zamponi GW, Striessnig J, Koschak A, Dolphin Institutes of Health during the conduct of the study. 9. Mason BJ, Light JM, Williams LD, Drobes DJ. Proof-of-concept human laboratory study for AC. The physiology, pathology, and pharmacology Dr Prisciandaro reported receiving grants and of voltage-gated calcium channels and their future consulting fees from Farmaceutico Italiano and protracted abstinence in alcohol dependence: effects of gabapentin. Addict Biol. 2009;14(1):73-83. therapeutic potential. Pharmacol Rev. 2015;67(4): consulting fees from Laboratorio Farmaceutico CT 821-870. doi:10.1124/pr.114.009654 outside the submitted work. No other disclosures doi:10.1111/j.1369-1600.2008.00133.x were reported. 10. O’Malley SS, Krishnan-Sarin S, Farren C, Sinha R, 24. Hendrich J, Van Minh AT, Heblich F, et al. Pharmacological disruption of calcium channel Funding/Support: Funding for this work was Kreek MJ. Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects trafficking by the alpha2delta ligand gabapentin. provided by the National Institute on Alcohol Abuse Proc Natl Acad SciUSA. 2008;105(9):3628-3633. and Alcoholism (grant R01AA022364). and activates the hypothalamo-pituitary- adrenocortical axis. Psychopharmacology (Berl). doi:10.1073/pnas.0708930105 Role of the Funder/Sponsor: The National 2002;160(1):19-29. doi:10.1007/s002130100919 25. Sills GJ. The mechanisms of action of Institute on Alcohol Abuse and Alcoholism had no 11. Drobes DJ, Anton RF, Thomas SE, Voronin K. gabapentin and pregabalin. Curr Opin Pharmacol. role in the design and conduct of the study; 2006;6(1):108-113. doi:10.1016/j.coph.2005.11.003 collection, management, analysis, and Effects of naltrexone and nalmefene on subjective interpretation of the data; preparation, review, or response to alcohol among non-treatment-seeking 26. Yoshizumi M, Parker RA, Eisenach JC, approval of the manuscript; and decision to submit alcoholics and social drinkers. Alcohol Clin Exp Res. Hayashida K. Gabapentin inhibits γ-amino butyric the manuscript for publication. 2004;28(9):1362-1370. doi:10.1097/01.ALC. acid release in the locus coeruleus but not in the 0000139704.88862.01 spinal dorsal horn after peripheral nerve injury in Data Sharing Statement: See Supplement 3. 12. Anton RF. Naltrexone for the management of rats. Anesthesiology. 2012;116(6):1347-1353. doi:10. Additional Contributions: Mark Ghent, BA, alcohol dependence. N Engl J Med. 2008;359(7): 1097/ALN.0b013e318254e6fd Department of Psychiatry and Behavioral Sciences, 715-721. doi:10.1056/NEJMct0801733 27. Suto T, Severino AL, Eisenach JC, Hayashida K. Medical University of South Carolina, assisted in Gabapentin increases extracellular glutamatergic data collection, and Patrick Randall, PhD, 13. Ray LA, Hutchison KE. 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