By Barbara Greenwood Dufour

It’s well known that long-term, excessive alcohol use is dangerous. But quitting drinking can be dangerous too. Alcohol withdrawal syndrome, which can occur when a person with an alcohol dependence disorder suddenly stops drinking, can be an emergency situation.

In the first hours after the last drink, symptoms may be unpleasant but manageable (e.g., nausea, agitation, trouble sleeping) but, after three or four days, symptoms can become much more severe and may include seizures and delirium tremens — severe confusion, fever, drenching sweats, hallucinations, marked tremulousness (the “shakes”), severe hypertension (elevated blood pressure), and tachycardia (rapid heart rate). These symptoms require medical treatment, as they are potentially fatal.

Symptoms of alcohol withdrawal syndrome are typically managed in a hospital setting using benzodiazepines (e.g., diazepam, chlordiazepoxide). Benzodiazepines are central nervous system depressants that are also used to treat anxiety, insomnia, and seizures. They can cause severe side effects, such as respiratory depression, especially when high doses are needed to get alcohol withdrawal symptoms under control. Therefore, other drugs — including phenobarbital and gabapentin — have been suggested for use instead of, or in combination with, benzodiazepines.

To get a sense of how these other potential treatment options compare with benzodiazepines, CADTH — an independent agency that finds, assesses, and summarizes the research on drugs, medical devices, tests, and procedures — looked for recent research and evidence-based guidelines on this topic. Then, to balance timeliness with rigour, CADTH prepared a summary of the abstracts — this means CADTH reviewed only the abstracts and didn’t critically appraise the literature (read more about the types of Rapid Response reports CADTH produces at cadth.ca/about-cadth/what-we-do/products-services/rapid-response-service).

Phenobarbital is a barbiturate (another type of central nervous system depressant) — commonly used to treat insomnia, headaches, and seizures. The existing research suggests it might be an option for alcohol withdrawal syndrome, at least when used in addition to benzodiazepines. CADTH found two systematic reviews and seven non-randomized controlled studies comparing phenobarbital with benzodiazepines. In most of these studies, including both of the systematic reviews, phenobarbital alone or added to benzodiazepine treatment led to similar outcomes to benzodiazepines alone — including admission to the intensive care unit (ICU), length of time in the ICU or hospital, tolerability and safety profiles in the acute care setting, and improvement in severity and duration of alcohol withdrawal symptoms. In two of the non-randomized controlled trials, phenobarbital (on its own in one study and along with benzodiazepines in the other) led to more favorable outcomes, namely shorter ICU and hospital stays, than benzodiazepines alone.

Gabapentin, an anti-seizure drug, is another potential treatment for alcohol withdrawal. CADTH found three non-randomized studies comparing combination gabapentin and benzodiazepine therapy with benzodiazepines alone. According to two of these studies, patients on combination therapy had similar outcomes to those treated only with benzodiazepines in terms of the severity of their withdrawal symptoms, how long they were on an alcohol withdrawal protocol, and the length of their hospital stay. In the third study, patients on combination therapy had significantly reduced alcohol withdrawal symptoms on day three of hospitalization and a shorter length of hospital stay compared with those who received only benzodiazepines.

CADTH found four related evidence-based guidelines, all of which recommend benzodiazepines for managing alcohol withdrawal in the emergency department, and two of which suggest alternate treatments as well. The British Columbia Centre on Substance Abuse recommends in-patient administration of benzodiazepines for patients at a high risk of alcohol withdrawal. The Canadian Coalition of Seniors’ Mental Health recommends that older adults receive in-patient treatment with a short-acting benzodiazepine, such as lorazepam, which is safer in this population. The guideline from the National Institute for Health and Care Excellence in the UK recommends that acute alcohol withdrawal be treated in a hospital setting using a symptom-triggered regimen (providing medication only when a patient is having symptoms) of benzodiazepines, carbamazepine (an anticonvulsant), or clomethiazole (a sedative). And the US Department of Veteran Affairs and Department of Defense recommends treating moderate to severe alcohol withdrawal with a symptom-triggered regimen of benzodiazepines. They also recommend gabapentin, carbamazepine, or valproic acid (another anti-seizure drug), but only for patients with mild to moderate alcohol withdrawal for whom the risks associated with benzodiazepines outweigh the benefits.

The abuse, overdose, and diversion potential associated with benzodiazepines means they’re best administered in an in-patient setting. But treatment that could be safely provided on an outpatient basis could improve access to treatment and be a preferable option for those who are reluctant to be treated in a hospital — such as during the current COVID-19 pandemic when there may be concern about in-patient exposure to coronavirus. Phenobarbital and gabapentin, because they are considered to be safer than benzodiazepines, could potentially be given in an outpatient setting. But, it’s yet unclear how effective they are on their own for managing alcohol withdrawal syndrome.

Instead, the research appears to suggest that phenobarbital and gabapentin, when used in combination with benzodiazepines, might be a way to make in-patient treatment for alcohol withdrawal syndrome safer than treatment with benzodiazepines alone. Further analysis of the latest evidence would be needed, however, to make conclusions or suggest what the implications of this research might be for health care decision-making.

View CADTH’s full report at cadth.ca/gabapentin-phenobarbital-diazepam-and-lorazepam-treatment-alcohol-withdrawal-clinical-effectiveness. If you’d like to learn more about CADTH, visit cadth.ca, follow us on Twitter @CADTH_ACMTS, or speak to the CADTH Liaison Officer in your region: cadth.ca/liaison-officers.

Barbara Greenwood Dufour is a knowledge mobilization officer at CADTH.