02. Can Topiramate Replace FDA-Approved Medications for Alcohol Use Disorder?

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Prevalence and Treatment of Alcohol Use Disorder

Alcohol use disorder (AUD) is one of the most prevalent psychiatric conditions in the United States. An estimated 29 million US residents had AUD in 2022.

The FDA has approved three medications for the treatment of AUD – disulfiram, acamprosate, and naltrexone. However, none of these medications is broadly effective or widely used.

Disulfiram was first approved in 1951 but has very little use currently because of severe, potentially life-threatening effects when it is taken together with alcohol. Acamprosate and naltrexone have better safety profiles and tolerability with only modest efficacy.

Off-Label Use of Topiramate for AUD Treatment

Topiramate is an FDA-approved anticonvulsant. It is not FDA approved for the treatment of AUD but is commonly used off-label for this purpose.

Several randomized, double-blind clinical trials, so-called controlled clinical trials, found that topiramate was significantly better than placebo in treating AUD. Controlled clinical trials are the gold standard for evaluating medication efficacy.

These positive findings had led topiramate to be recommended as a second-line treatment of AUD by some clinical practice guidelines. In fact, topiramate is used more often in the treatment of AUD than are the three FDA-approved medications.

However, there has never been a high-quality head-to-head comparison of topiramate with any of the three FDA-approved medications.

Controlled Clinical Trial Comparing Topiramate and Naltrexone

Morley and colleagues remedied this gap by conducting a 12-week controlled clinical trial comparing oral topiramate with oral naltrexone in the treatment of AUD. The secondary aim of the study was to evaluate the influence of two genetic variations in genes for neurotransmitter receptors on the response to these medications.

Previous studies suggested that specific variants of the gene that codes for a type of glutamate receptor and of the gene that codes for the mu-opioid receptor were associated with a better response to topiramate and to naltrexone, respectively.

The trial was conducted in Australia and enrolled 147 patients with current AUD and heavy drinking. AUD was defined by DSM-5 criteria. Heavy drinking was defined as:

• Average consumption of at least 30 standard drinks per week for men
• Average consumption of at least 25 standard drinks per week for women over the month prior to study screening
• All participants had to average at least two heavy drinking days per week (at least five drinks for men and at least four drinks for women)

Study Design and Findings

72 patients were randomly assigned to receive topiramate titrated over six weeks to a maximum of 200 mg daily. 75 patients were randomly assigned to receive naltrexone up to 50 mg daily.

Assignment to each medication was stratified by genotype to allow for comparisons by genotype within each medication group. All patients received 20 to 30 minutes of medical management at each weekly visit.

The study found that topiramate and naltrexone had similar efficacy. There were no significant differences in alcohol consumption outcomes between the naltrexone and topiramate groups.

At the end of the first week, both groups had greater than 60% decreases from baseline in heavy drinking days per week and in drinks per drinking day, and the decreases persisted for the remainder of the study. Both groups experienced significant decreases in the intensity of self-reported alcohol craving, with the decrease being about 25% greater in the topiramate group.

The genotype differences were not associated with any significant differences in response to medication. Also, there were no significant group differences in medication adherence or tolerance, although the types of side effects differed between topiramate and naltrexone as would be expected.

Study Validity and Applicability

The rigorous design and conduct of the study make me confident in the validity of its findings. For example, self-reported alcohol consumption was generally confirmed by blood testing for the alcohol biomarker, phosphatidylethanol, and patients’ guesses of their medication assignment were no better than chance.

In the absence of a placebo-controlled group, it is theoretically possible that the observed improvement was due largely to the weekly patient education sessions which are not available in many clinical settings. However, I doubt that this is actually the case given the prior placebo-controlled trials showing efficacy separately for topiramate and for naltrexone.

Patient characteristics of the study generally resembled those of a typical psychiatric clinic population, middle-aged men and women with about 1/3 having major depressive disorder and/or generalized anxiety disorder. Patients with any other substance use disorder except for nicotine or tobacco or with current opioid use were excluded. So these results might not be as applicable to a specialized substance use disorder clinic.

Conclusion

The bottom line is that topiramate seems as effective as naltrexone for the treatment of AUD. Topiramate might be appropriate for first-line treatment, especially if reduction in alcohol craving is an important consideration and if the patient can tolerate a six-week dose titration period to minimize side effects.

Abstract

Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial

Morley KC, M.D., Kranzler HR, M.D., Luquin N, M.D., Jamshidi N, M.D., Adams C, M.D., Montebello M, M.D., Tremonti C, M.D., Dali G, M.D., Logge W, M.D., Baillie A, M.D., Teesson M, M.D., Trent R, M.D., Haber PS, M.D.

Objective:

There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms—rs2832407 (in GRIK1) and rs1799971 (in OPRM1)—on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications.

Methods:

In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate (maximum dosage of 200 mg/day) or naltrexone (50 mg/day), stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was a number of heavy drinking days (defined as ≥ four drinks for women, ≥ five drinks for men) per week. Predefined secondary outcomes included mean standard drinks per drinking day (SDDD) per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events.

Results:

For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response.

Conclusions:

Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Reference

Morley K, M.D., Kranzler H, M.D., Luquin N, M.D., Jamshidi N, M.D., Adams C, M.D., Montebello M, M.D., Tremonti C, M.D., Dali G, M.D., Logge W, M.D., Baillie A, M.D., Teesson M, M.D., Trent R, M.D., Haber PS, M.D. (2024). Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial. American Journal of Psychiatry, 1;181(5):403-411.