Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials: A Secondary Analysis of 3 Randomized Clinical Trials
Open accessAbstract
Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results: Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]). Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial Registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.
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A reduction in heavy drinking days matches the treatment objectives of numerous patients.
“matches the treatment objectives of numerous patients [95]”
From Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial (2024) · cites this paper as [95]
The Discussion says many patients prefer to reduce their drinking, and the Conclusions call drinking reduction the preferred goal of most patients. But the paper links that preference to reductions in WHO drinking risk levels, not specifically to a reduction in the number of heavy drinking days; it treats no heavy drinking days as a separate outcome. Page numbers are not available in our copy. (LLM, conf=0.86)
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“A reduction in heavy drinking days yields clinically significant health ameliorations [94], matches the treatment objectives of numerous patients [95] and is recognized by the European Medicines Agency as an adequate measure of efficacy [96].”
Background
- Authors
- Falk, D. E., O’Malley, S. S., Witkiewitz, K., Anton, R. F., Litten, R. Z., Slater, M., Kranzler, H. R., Mann, K. F., Hasin, D. S., Johnson, B., Meulien, D., Ryan, M., Fertig, J., & Workgroup, F. T. A. C. T. I. (.
- Affiliations
- National Institutes of Health (US)
- Yale University (US)
- University of New Mexico (US)
- Medical University of South Carolina (US)
- CSR, Incorporated
- University of Pennsylvania (US)
- Central Institute of Mental Health (DE)
- Columbia University (US)
- University of Maryland, Baltimore (US)
- Lundbeck (Denmark) (DK)
- Corresponding author
- Falk, Daniel E.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-04-01
- Volume
- 76
- Issue
- 4
- Pages
- 374
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6450273
- OpenAlex
- W2921551456
- Cited by
- 120
- References
- 27
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 16 · 2023: 8 · 2022: 16 · 2021: 13 · 2020: 24 · 2019: 12 · 2018: 2
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Indivior
- Cerecor
- H. Lundbeck A/S
- National Institutes of Health (UL1TR001863)
- National Institute on Alcohol Abuse and Alcoholism (R01AA025309, P50AA010761)
- National Institute on Drug Abuse
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Keywords
- alcoholism, alcohol pharmacotherapy, total abstinence, naltrexone, varenicline, topiramate, treatment response, outcome definitions, effect size, responder definition, relapse prevention, cost-effectiveness
- MeSH terms
- Varenicline, Topiramate, Adult, Alcohol Deterrents, Alcohol Drinking, Alcoholism, Female, Humans, Male, Middle Aged, Naltrexone, Risk Assessment, Alcohol Abstinence
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