Background and Aims
Studies of the efficacy of gabapentin for treating alcohol use disorder (AUD) have yielded mixed findings. The aims of our study were to estimate gabapentin's effects on six ...alcohol‐related outcomes, test potential moderators, examine publication bias and evaluate the quality of the studies.
Methods
Meta‐analysis of placebo‐controlled randomized controlled trials (RCTs). Using PubMed and ClinicalTrials.gov, we selected RCTs of gabapentin's effects on alcohol consumption or a biochemical correlate of it, excluding studies limited to other primary outcomes or that combined gabapentin with other medications. We assessed study quality and used a random‐effects model to analyze each outcome measure and the Egger regression test and funnel plots to assess publication bias.
Results
We identified seven RCTs of gabapentin that met study criteria. The quality of the studies overall was good, and there was no evidence of publication bias. Four to seven studies contributed to the analysis of the six outcome measures. For all outcome measures the effect estimates were in a direction that favored gabapentin over placebo. However, only for percentage of heavy drinking days was there good evidence of a benefit (g = −0.64, 95% confidence interval = −1.22 to −0.06).
Conclusions
Although gabapentin appears to be more efficacious than placebo in treating AUD, the only measure on which the analysis clearly favors the active medication is percentage of heavy drinking days. Additional studies are needed to define more clearly the role of gabapentin in AUD treatment.
Chronic heavy alcohol use impacts all major neurotransmitter systems and is associated with multiple medical, psychiatric, and social problems. Available evidence‐based medications to treat alcohol ...use disorder (AUD) are underutilized in clinical practice. These medications promote abstinence or reduce alcohol consumption, though there are questions regarding their optimal dosage, length of treatment, and utility in combination with one another. Pharmacogenetic approaches, which use a patient's genetic make‐up to inform medication selection, have garnered great interest but have yet to yield results robust enough to incorporate them in routine clinical care. This narrative review summarizes the evidence both for medications approved by the Food and Drug Administration (disulfiram, oral naltrexone, acamprosate, and extended‐release naltrexone) and those commonly used off‐label (e.g., gabapentin, baclofen, and topiramate) for AUD treatment. We discuss these drugs' mechanisms of action, clinical use, pharmacogenetic findings, and treatment recommendations. We conclude that the most consistent evidence supporting the pharmacotherapy of AUD is for the opioid antagonists, naltrexone and nalmefene (which is not approved in the United States), and topiramate. These medications demonstrate consistent small or moderate effects in reducing the frequency of drinking and/or heavy drinking. Lastly, we make suggestions for research needed to refine and expand the current literature on effective pharmacotherapy for AUD.
This article summarizes the evidence for medications approved to treat alcohol use disorder (AUD) and those commonly used off‐label. We discuss the drugs’ mechanisms of action, clinical use, pharmacogenetic findings, and treatment recommendations. We conclude that the most consistent evidence supporting the pharmacotherapy of AUD is for the opioid antagonists, naltrexone and nalmefene, and topiramate. Lastly, we make suggestions for research needed to refine and expand the current literature on effective pharmacotherapy for AUD.
Substance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRSs) and ...phenome-wide association studies are useful in evaluating pleiotropic effects. However, the comparatively low prevalence of SUDs in population samples and the lack of detailed information available in electronic health records limit these data sets’ informativeness for such analyses.
We used the deeply phenotyped Yale-Penn sample (n = 10,610 with genetic data; 46.3% African ancestry, 53.7% European ancestry) to examine pleiotropy for 4 major substance-related traits: alcohol use disorder, opioid use disorder, smoking initiation, and lifetime cannabis use. The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism, a comprehensive psychiatric interview.
In African ancestry individuals, PRS for alcohol use disorder, and in European individuals, PRS for alcohol use disorder, opioid use disorder, and smoking initiation were associated with their respective primary DSM diagnoses. These PRSs were also associated with additional phenotypes involving the same substance. Phenome-wide association study analyses of PRS in European individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in phenome-wide association study analyses, such as family environment and early childhood experiences.
Smaller, deeply phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.
Background and Aims
Genetic risk can influence disease progression. We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms.
...Design, Setting, Participants
Using findings from genome‐wide association studies (GWASs) of alcohol use disorder (AUD), opioid use disorder (OUD) and smoking trajectory (SMK) as discovery samples, we calculated polygenic risk scores (PRSs) in a deeply phenotyped independent target sample. Participants in the target sample were recruited from 2000 to 2020 from US inpatient or outpatient settings or through advertisements and comprised 5692 European‐ancestry individuals (EUR) (56.2% male) and 4918 African‐ancestry individuals (AFR) (54.9% male).
Measurements
This study measured age of first substance use, regular use, reported problems and dependence diagnosis and progression from regular use to onset of problems and dependence for alcohol, opioids and smoking. We examined the contribution of PRS to each milestone and progression measure.
Findings
EUR and males reported an earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol‐related milestones (P < 0.001). Although the AUD PRS was a stronger moderator of problem onset among females (P = 0.017), it was more predictive of the progression to problems among males (P = 0.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (P < 0.001). Among AFR, where power is lower due to the smaller discovery sample, AUD PRS predicted age of regular alcohol use (P = 0.039) and dependence (P = 0.001) and progression from regular use to diagnosis (P = 0.045), while SMK PRS predicted earlier age of initiation (P = 0.036).
Conclusions
Genetic risk for SUDs appears to predict substance use milestones and symptom progression among European‐ancestry individuals and, to a lesser extent, African‐ancestry individuals.
Background
Topiramate, which is increasingly being used to treat alcohol use disorder (AUD), is commonly associated with reduced serum bicarbonate concentrations. However, estimates of the prevalence ...and magnitude of this effect are from small samples and do not address whether topiramate's effects on acid–base balance differ in the presence of an AUD or by topiramate dosage.
Methods
Veterans Health Administration electronic health record (EHR) data were used to identify patients with a minimum of 180 days of topiramate prescription for any indication and a propensity score‐matched control group. We differentiated patients into two subgroups based on the presence of a diagnosis of AUD in the EHR. Baseline alcohol consumption was determined using Alcohol Use Disorders Identification Test–Consumption (AUDIT‐C) scores in the EHR. Analysis also included a three‐level measure representing mean daily dosage. The topiramate‐associated changes in serum bicarbonate concentration were estimated in difference‐in‐differences linear regression models. A serum bicarbonate concentration <17 mEq/L was considered to represent possible clinically significant metabolic acidosis.
Results
The cohort comprised 4287 topiramate‐treated patients and 5992 propensity score‐matched controls with a mean follow‐up period of 417 days. The mean topiramate‐associated reductions in serum bicarbonate concentration were <2 mEq/L in the low (≤88.75), medium (>88.75 and ≤141.70), and high (>141.70) mg/day dosage tertiles, irrespective of AUD history. Concentrations <17 mEq/L occurred in 1.1% of topiramate‐treated patients and 0.3% of controls and were not associated with alcohol consumption or an AUD diagnosis.
Conclusions
The excess prevalence of metabolic acidosis associated with topiramate treatment does not differ with dosage, alcohol consumption, or the presence of an AUD. Baseline and periodic serum bicarbonate concentration measurements are recommended during topiramate therapy. Patients prescribed topiramate should be educated about the symptoms of metabolic acidosis and urged to report their occurrence promptly to a healthcare provider.
Topiramate, used to treat alcohol use disorder (AUD), is commonly associated with reduced serum bicarbonate concentrations. We used Veterans Health Administration electronic health record (EHR) data for 4,287 topiramate‐treated patients and 5,992 propensity‐score‐matched controls to examine the effects. In difference‐in‐differences linear regression models there was an excess prevalence of metabolic acidosis associated with topiramate treatment, but no moderating effect of medication dosage, level of alcohol consumption, or an AUD diagnosis. Periodic serum bicarbonate concentration measurements are recommended during topiramate therapy.
Background
Although abstinence has traditionally been considered the only suitable outcome for alcohol treatment, reduced drinking is also associated with improved functioning and medical and ...psychiatric outcomes. The World Health Organization (WHO) risk drinking levels (RDLs) have been shown to be valid outcome measures in treatment trials for alcohol use disorder (AUD).
Methods
We conducted a secondary analysis of two 12‐week, randomized controlled trials (RCTs), in which a total of 308 individuals with problematic alcohol use received topiramate or placebo treatment. We compared the utility of the WHO RDLs with other treatment outcomes, including self‐reported measures of alcohol consumption, alcohol‐related problems, and quality of life, and the biomarker gamma‐glutamyltransferase.
Results
Topiramate treatment was associated with small effect sizes for both a 1‐level (d = 0.26) and a 2‐level (d = 0.19) reduction in WHO RDL, effects that were not significant after correction for multiple comparisons. No heavy drinking days, one of the outcome measures recommended by the US Food and Drug Administration for alcohol medication registration trials, also exhibited a small effect (0.21), while an effect size for abstinence could not be calculated. There were medium effects of topiramate on continuous measures of percent heavy drinking days (d = 0.49) and alcohol‐related problems (d = 0.41).
Conclusions
Topiramate is an efficacious pharmacotherapy for AUD. Although continuous measures of drinking and alcohol‐related problems yielded larger effect sizes than the WHO RDLs, the latter nonetheless provide a categorical alternative for use in both clinical care and pharmacotherapy trials.
Currently, the only acceptable outcomes for approval of medications to treat alcohol use disorder are abstinence and no heavy drinking. However, drinking reductions are consistently associated with better functioning and medical outcomes. Therefore, we compared the World Health Organization risk drinking levels (WHO RDLs) with other outcome measures in data from two placebo‐controlled topiramate trials for problematic alcohol use. Findings showed that topiramate is an efficacious pharmacotherapy and that the WHO RDLs are useful indicators of changes in drinking behavior.
Despite an estimated heritability of ~50%, genome-wide association studies of opioid use disorder (OUD) have revealed few genome-wide significant loci. We conducted a cross-ancestry meta-analysis of ...OUD in the Million Veteran Program (N = 425,944). In addition to known exonic variants in OPRM1 and FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1 and KCNN1. A meta-analysis including other datasets identified a locus in TSNARE1. In total, we identified 14 loci for OUD, 12 of which are novel. Significant genetic correlations were identified for 127 traits, including psychiatric disorders and other substance use-related traits. The only significantly enriched cell-type group was CNS, with gene expression enrichment in brain regions previously associated with substance use disorders. These findings increase our understanding of the biological basis of OUD and provide further evidence that it is a brain disease, which may help to reduce stigma and inform efforts to address the opioid epidemic.
In a prior study, topiramate reduced heavy drinking among individuals who sought to reduce their drinking, with the effect moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, ...which encodes the kainate GluK1 receptor subunit (Kranzler et al. 2014). The present study sought to replicate prospectively the effect of topiramate and rs2832407 in patients with DSM-5 alcohol use disorder (AUD) who sought to reduce or stop their drinking. We stratified the randomization on genotype (rs2832407*C-allele homozygotes vs. A-allele carriers) and assigned 170 European-American participants (71.2% male) to receive 12 weeks of treatment with topiramate (N = 85), at a maximal daily dosage of 200 mg, or matching placebo (N = 85). At each of nine treatment visits participants received brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients with the rs2832407*CC genotype would reduce heavy drinking days (HDDs) more than the other three groups. The rate of treatment completion was 91.8% in both groups. The mean number of HDDs per week in the placebo group was 1.67 (95% CI = (1.29, 2.16), p = 0.0001) times greater than in the topiramate group, which was confirmed by the topiramate group's significantly greater reduction in the concentration of the liver enzyme γ-glutamyltransferase and lower alcohol-related problems score. There was no significant difference in topiramate's effect on HDDs between genotype groups. Although consistent with other studies showing a reduction in heavy drinking with topiramate treatment, the prior finding of a moderating effect of rs2832407 genotype was not replicated in this prospective trial.
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