Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation

Abstract

Background: Benzodiazepines (BZDs) are among the most prescribed sedative hypnotics and among the most misused and abused medications by patients, in parallel with opioids. It is estimated that more than 100 million Benzodiazepine (BZD) prescriptions were written in the United States in 2009. While medically useful, BZDs are potentially dangerous. The co-occurring abuse of opioids and BZD, as well as increases in BZD abuse, tolerance, dependence, and short- and long-term side effects, have prompted a worldwide discussion about the challenging aspects of medically managing the discontinuation of BZDs. Abrupt cessation can cause death. This paper addresses the challenges of medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse and associated medical complications. The focus of this review is on the challenges of several medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse, and associated medical complications.

Methods: An electronic search was performed of Medline, Worldwide Science, Directory of Open Access Journals, Embase, Cochrane Library, Google Scholar, PubMed Central, and PubMed from 1990 to 2017. The review includes double-blind, placebo-controlled studies for the most part, open-label pilot studies, and animal studies, in addition to observational research. We expand the search to review articles, naturalistic studies, and to a lesser extent, letters to the editor/case reports. We exclude abstract and poster presentations, books, and book chapters.

Results: The efficacy of these medications is not robust. While some of these medicines are relatively safe to use, some of them have a narrow therapeutic index, with severe, life-threatening side effects. Randomized studies have been limited. There is a paucity of comparative research. The review has several limitations. The quality of the documents varies according to whether they are randomized studies, nonrandomized studies, naturalistic studies, pilot studies, letters to the editors, or case reports.

Conclusions: The use of medications for the discontinuation of BZDs seems appropriate. It is a challenge that requires further investigation through randomized clinical trials to maximize efficacy and to minimize additional risks and side effects.

Keywords: Benzodiazepine discontinuation; benzodiazepine substitution; benzodiazepine withdrawal; benzodizaepine dependence.

Figure 1.

Benzodiazepine binds to γ-aminobutyric acid (GABA) receptor (blue) to open chloride channel (purple). Alcohol (green) cross reacts with the same receptor. The result is the modulation of GABA producing an anxiolytic effect. Adapted from the work of: BruceBlaus. Cell GABA Receptor. November 12 2015. https://commons.wikimedia.org/wiki/File:Cell_GABA_Receptor.png. This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International license. No permission is required.

Figure 2.

The number of deaths from benzodiazepines is trending up (from 2002 to 2015). Note that the number is higher for men than for women. Adapted from the work of the National Institutes of Health, part of the United States Department of Health and Human Services. “National Overdose Deaths—Number of Deaths from Benzodiazepines, with and without opioids. Source 2002–2015 chart from Overdose Death Rates. By National Institute on Drug Abuse (NIDA).

Figure 3.

Number of times a drug appeared at a level of evidence. Carbamazepine, flumazenil, propranolol, and melatonin seem to be the most studied. The highest number of studies for carbamazepine is at level III, but the highest number of studies for melatonin is at level I; 67% of the drugs fall at least in one randomized controlled trial (level I). Grey: level I; yellow: level II-1; light blue: level II-2; green: level II-3; dark blue: level III.