What information is available on the off-label use of gabapentin and topiramate for alcohol use disorder?
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Introduction
A problematic pattern of alcohol consumption leading to clinically substantial impairment or distress is defined as alcohol use disorder (AUD).1 AUD is categorized as mild, moderate, or severe depending on the number of diagnostic symptoms experienced within the preceding 12 months. Prominent symptoms include alcohol cravings, physical dependence on alcohol, withdrawal manifestations, and heightened tolerance, among others. Predisposing factors contributing to the development of AUD include genetic determinants, environmental stressors, mental health disorders, and excessive alcohol consumption. Long-term complications of AUD include liver disease, pancreatitis, gastrointestinal hemorrhage, impaired wound healing, morbidity and mortality due to alcohol-related accidents, and disrupted relationships, work productivity, and quality of life.2
Alcohol use disorder is a major public health issue that warrants appropriate and aggressive treatment.1 Some Food and Drug Administration (FDA)-approved medications for treatment of AUD include disulfiram, naltrexone, extended-release naltrexone, and acamprosate.2 Anticonvulsant agents, such as gabapentin and topiramate, have demonstrated promising outcomes in promoting abstinence and mitigating cravings.3 Evidence supporting these off-label AUD treatments is summarized below.
General treatment principles
The major treatment goal for patients with AUD is long-term abstinence from alcohol.1 Shorter term goals include reduced alcohol intake and controlling symptoms of craving, since complete abstinence may require many attempts over time to achieve.1,2 In addition to pharmacotherapy, which aims to decrease craving, psychosocial therapy may be needed to help with the behavioral aspects of AUD. Some patients may experience alcohol withdrawal symptoms in the process of decreasing alcohol intake, which may require short-term medical support.
Guideline recommendations
The American Psychiatric Association (APA) published a comprehensive guideline for assessing and treating AUD in 2018.4 The initial psychiatric evaluation should include a thorough assessment of the patient’s history of alcohol and tobacco use, along with other substance misuse. A personalized, evidence-based treatment plan is recommended, incorporating both nonpharmacological and pharmacological interventions. Specific pharmacotherapy recommendations are provided, with naltrexone and acamprosate suggested for moderate (4 to 5 qualifying DSM-5 symptoms) to severe (≥6 qualifying symptoms) AUD unless the patient has a contraindication for their use. Disulfiram is appropriate only for individuals seeking abstinence and is contraindicated in patients who are actively using alcohol or products containing alcohol. Off-label medications that may be efficacious in the treatment of moderate to severe AUD include topiramate and gabapentin. Although these medications will typically be used after trials of naltrexone and acamprosate, patient preference may lead to earlier use.
Literature summary
The efficacy of medications to manage AUD that are not FDA-approved for this indication has been evaluated. Meta-analyses of randomized trials for gabapentin and topiramate are summarized in the Table. Overall, the analyses are limited to comparisons with placebo and conclusions are limited by heterogeneity.
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| Table. Meta-analyses of off-label pharmacotherapy for alcohol use disorder.5-9 | ||||
|---|---|---|---|---|
| Article | Number of studies included (N) | Main treatment outcome | Results for main treatment outcome vs. Placebo | Author conclusion |
| All drugs |
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| McPheeters et al (2023)5 | 118 RCTs (N=20,976) | Any alcohol use | Topiramate: no difference in percentage of drinking days, percentage of heavy drinking days, or number of drinks per drinking day. Gabapentin: no difference in return to drinking or return to heavy drinking. | Topiramate had a moderate strength of evidence but was associated with adverse effects. Gabapentin had a low strength of evidence. |
| Bahji et al (2022)6 | 156 RCTs (N=27,334) | Total abstinence | Baclofen (RR, 1.8) Disulfiram (RR, 1.71) Gabapentin (RR, 1.66) Acamprosate (RR, 1.33) Oral naltrexone (RR, 1.15) | Acamprosate (2 to 3 g/day), disulfiram (250 to 500 mg/day), baclofen (30 mg/day), and oral naltrexone (50 mg/day) had the best evidence for improving abstinence. |
| Gabapentin |
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| Cheng et al (2020)7 | 16 RCTs (N=not reported) | Heavy drinking days | Fewer heavy drinking days with gabapentin (standard mean difference, 0.55; 95% CI, 0.01 to 1.08; I2=89%) | Gabapentin may be helpful to reduce heavy drinking behavior and withdrawal, but more studies are needed for drawing conclusions. |
| Kranzler et al (2019)8 | 7 RCTs (N=751) | Complete abstinence | RR, 1.33; 95% CI, 0.84 to 2.10; p=0.23 | Gabapentin was effective for only 1 of 6 AUD outcomes measured (percent heavy drinking days). |
| Topiramate |
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| Blodgett et al (2014)9 | 7 RCTs (N=1,125) | Abstinence | Overall effect size, 0.468; 95% CI, 0.250 to 0.687; p=0.02; I2=55.2% | The overall effects of topiramate on abstinence and heavy drinking are close to moderate (corresponding to overall effect size of 0.5 to 0.8) but significant. |
| Abbreviations: AUD, alcohol use disorder; CI, confidence interval; RCTs, randomized controlled trials; RR, relative risk |
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Clinical trials with gabapentin suggest that high doses may be more effective in managing AUD symptoms than lower doses.10 However, the risk of gabapentin dependence should be considered when higher doses are used.11 Combination therapy with naltrexone has been studied but further data are needed before combination therapy is routinely recommended.12
Most studies have compared topiramate to placebo, but one randomized, open-label study has compared topiramate (mean, 200 mg/day) to naltrexone (mean, 50 mg/day).13 After 6 months, assessment scales relating to alcohol intake, cravings, disability, and quality of life were lower in patients who received topiramate. However, the sample size was fairly small (n=182) and the study was not designed to find statistical differences between clinical outcomes such as abstinence or number of heavy drinking days. A shorter-term study compared topiramate (goal 300 mg/day) with naltrexone (50 mg/day) or placebo in patients (n=155) who had just completed 1 week of detoxification.14 There were no significant differences between topiramate and naltrexone, likely due to a lack of statistical power.
Conclusion
The evidence supporting topiramate for treatment of AUD is more promising than the evidence for gabapentin; however, most of the studies with topiramate reflect a comparison to placebo. Comparative evidence with topiramate or gabapentin with naltrexone or acamprosate are generally lacking. Until further data are available, it is reasonable for clinicians to follow the APA guideline recommendations and use gabapentin and topiramate second line in patients with lack of response to first-line therapies.
References
- Dupree L, and Li R. Substance use disorders II: alcohol, nicotine, and caffeine. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. McGraw Hill; 2023. http://accesspharmacy.mhmedical.com/content.aspx?bookid=3097§ionid=267918626#1201553997. Accessed October 13, 2023.
- U.S. Department of Health and Human Services. Core Resource on Alcohol. National Institute on Alcohol Abuse and Alcoholism. https://www.niaaa.nih.gov/health-professionals-communities/core-resource-on-alcohol. Accessed October 13, 2023.
- Marin MCD, Pedro MOP, Perrotte G, et al. Pharmacological treatment of alcohol cravings. Brain Sci. 2023;13(8):1206. doi:10.3390/brainsci13081206
- The American Psychiatric Association. Practice Guideline for The Pharmacological Treatment of Patients With Alcohol Use Disorder. psychiatryonline.org/doi/pdf/10.1176/appi.books.9781615371969. Accessed October 20, 2023.
- McPheeters M, O’Connor EA, Riley S, et al. Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis. JAMA. 2023;330(17):1653-1665. doi:10.1001/jama.2023.19761
- Bahji A, Bach P, Danilewitz M, et al. Pharmacotherapies for adults with alcohol use disorders: a systematic review and network meta-analysis. J Addict Med. 2022;16(6):630-638. doi:10.1097/ADM.0000000000000992
- Cheng YC, Huang YC, Huang WL. Gabapentinoids for treatment of alcohol use disorder: A systematic review and meta-analysis. Hum Psychopharmacol. 2020;35(6):1-11. doi:10.1002/hup.2751
- Kranzler HR, Feinn R, Morris P, Hartwell EE. A meta-analysis of the efficacy of gabapentin for treating alcohol use disorder. Addiction. 2019;114(9):1547-1555. doi:10.1111/add.14655
- Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res. 2014;38(6):1481-1488. doi:10.1111/acer.12411
- Mariani JJ, Pavlicova M, Basaraba C, et al. Pilot randomized placebo-controlled clinical trial of high-dose gabapentin for alcohol use disorder. Alcohol Clin Exp Res. 2021;45(8):1639-1652. doi:10.1111/acer.14648
- Deng H, Benhamou OM, Lembke A. Gabapentin dependence and withdrawal requiring an 18-month taper in a patient with alcohol use disorder: a case report. J Addict Dis. 2021;39(4):575-578. doi:10.1080/10550887.2021.1907502
- Anton RF, Myrick H, Wright TM, et al. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011;168(7):709-717. doi:10.1176/appi.ajp.2011.10101436
- Flórez G, Saiz PA, García-Portilla P, Alvarez S, Nogueiras L, Bobes J. Topiramate for the treatment of alcohol dependence: comparison with naltrexone. Eur Addict Res. 2011;17(1):29-36. doi:10.1159/000320471
- Baltieri DA, Daró FR, Ribeiro PL, de Andrade AG. Comparing topiramate with naltrexone in the treatment of alcohol dependence. Addiction. 2008;103(12):2035-2044. doi:10.1111/j.1360-0443.2008.02355.x
Prepared by:
Amber Vu
PharmD Candidate Class of 2026
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
January 2024
The information presented is current as of December 4, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.