Comparative efficacy and safety of pharmacotherapies for alcohol withdrawal: a systematic review and network meta‐analysis

Abstract

Background and Aims: There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of pharmacotherapies for AW.Methods: Six databases were searched for randomized clinical trials through November 2021. Trials were included after a blinded review by two independent reviewers.Outcomes included incident seizures, delirium tremens, AW severity scores, adverse events, dropouts, dropouts from adverse events, length of hospital stay, use of additional medications, total benzodiazepine requirements, and death. Effect sizes were pooled using frequentist random-effects network meta-analysis models to generate summary ORs and Cohen's d standardized mean differences (SMDs).Results: Across the 149 trials, there were 10 692 participants (76% male, median 43.5 years old). AW severity spanned mild (n = 32), moderate (n = 51), and severe (n = 66). Fixed-schedule chlormethiazole (OR, 0.16; 95% CI, 0.04-0.65), fixed-schedule diazepam (OR, 0.16; 95% CI, 0.04-0.59), fixed-schedule lorazepam (OR = 0.19; 95% CI, 0.08-0.45), fixed-schedule chlordiazepoxide (OR = 0.21; 95% CI, 0.08-0.53), and divalproex (OR = 0.22; 95% CI, 0.05-0.86) were superior to placebo at reducing incident AW seizures. However, only fixed-schedule diazepam (OR, 0.19; 95% CI, 0.05-0.76) reduced incident delirium tremens. Oxcarbazepine (d = −3.69; 95% CI, −6.21 to −1.17), carbamazepine (d = −2.76; 95% CI, −4.13 to −1.40), fixed-schedule oxazepam (d = −2.55; 95% CI, −4.26 to −0.83), and γ-hydroxybutyrate (d = −1.80; 95% CI, −3.35 to −0.26) improved endpoint Clinical Institute Withdrawal Assessment for Alcohol-Revised scores over placebo. Promazine and carbamazepine were the only agents significantly associated with greater dropouts because of adverse events. The quality of evidence was downgraded because of the substantial risk of bias, heterogeneity, inconsistency, and imprecision.Conclusions: Although some pharmacotherapeutic modalities, particularly benzodiazepines, appear to be safe and efficacious for reducing some measures of alcohol withdrawal, methodological issues and a high risk of bias prevent a consistent estimate of their comparative performance.

Long‐term outcome of alcohol withdrawal seizures

“…The role of benzodiazepines, phenytoin, phenobarbital and pregabalin in preventing further AWS has already been studied, but most of the studies looked at short-term outcomes (e.g., length of hospital, ED or intensive care unit stay, seizure recurrence within the next 6-12 h) and found beneficial effects of some molecules [32,33]. Since published studies and meta-analyses mainly concern short-term treatments (days or few weeks) [34,35], the role of longterm ASM is still unclear. In our study, previously prescribed as well as de novo-introduced benzodiazepines or new ASM after AWS did not show long-term protection against AWS recurrence, but we do not know the effective length of the treatment, nor the patient compliance level.…”

Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study

“… 18 Use of clomethiazole as a prophylaxis agent in patients at risk for AWS is common in several European countries such as Germany or Spain. 19 In the US, prophylaxis is rarely used and patients do not receive any pharmacologic therapy until AWS symptoms start. To conduct a comparison, cases were defined as patients diagnosed with AH by an attending physician and requiring sedative therapy to control symptoms of AWS.…”

ACG Clinical Guideline: Alcohol-Associated Liver Disease

“…Benzodiazepines are the most used drugs to treat AWS. Long-acting benzodiazepines (e.g., diazepam and chlordiazepoxide) protect against seizures and delirium; short-acting and intermediate-acting benzodiazepines (e.g., lorazepam and oxazepam) are safer for patients with poor liver function (118,119). Oral administration is preferred for administration of benzodiazepines and barbiturates (112).…”