Benzodiazepines discontinuation tied to higher risk of death in long-term users: JAMA

The researchers suggest that efforts to promote discontinuation should carefully consider the potential discontinuation risks relative to continuation.

The comparative effectiveness study among 353 576 patients receiving stable long-term treatment with benzodiazepines revealed that discontinuation was tied to small absolute increases in mortality and other potential harms, including suicide attempts, nonfatal overdose, suicidal ideation, and emergency department visits.

There has been a rise in increases in overdose deaths involving benzodiazepines over the past several years, leading to several FDA actions including a 2016 warning related to co-prescribing with opioids and a 2020 class-wide boxed warning about the risks of misuse, abuse, physical dependence, addiction, and withdrawal reactions.

The FDA has also developed an evidence-based clinical practice guideline for the safe tapering of benzodiazepines. However, no studies have investigated the risks of discontinuation. Therefore, Donovan T. Maust, Department of Psychiatry, University of Michigan, Ann Arbor, and colleagues aimed to identify the association of benzodiazepine discontinuation with mortality and other adverse events in patients prescribed stable long-term benzodiazepine therapy, stratified by baseline opioid exposure.

The researchers assessed claims data from Optum on patients (mean age 62 years) with a benzodiazepine prescription from 2013 to 2019, totalling 213,011 without concomitant opioids and 140,565 with opioids. Benzodiazepine discontinuation was defined as no benzodiazepine prescription prescription for 31 consecutive days during 6 months after baseline. Patients were followed for about 1 year after baseline benzodiazepine prescriptions.

The primary outcome was mortality during 12 months of follow-up. Secondary outcomes included suicide attempts or self-inflicted injury, nonfatal overdose, emergency department use, and suicidal ideation.

The study led to the following findings:

• Among the nonopioid exposed, the adjusted cumulative incidence of death after one year was 5.5% for discontinuers, an absolute risk difference of 2.1 percentage points higher than for nondiscontinuers.
• The mortality risk was 1.6 times that of nondiscontinuers.
• Among those with opioid exposure, the adjusted cumulative incidence of death was 6.3% for discontinuers, an absolute risk difference of 2.4 percentage points higher than for nondiscontinuers and a mortality risk 1.6 times that of nondiscontinuers.
• The cumulative incidence of secondary outcomes was also higher among discontinuers.

The researchers identified small absolute increases in the risk of harm among patients with stable long-term prescription benzodiazepine treatment who appear to discontinue than in those continuing treatment, including those with and without recent prescription opioid exposure.

"Given questions raised about the safety of benzodiazepine discontinuation among stable long-term users, clinicians should be judicious in initiating new prescriptions and carefully limit conversion to long-term use," the researchers concluded.

Reference:

Maust DT, Petzold K, Strominger J, Kim HM, Bohnert ASB. Benzodiazepine Discontinuation and Mortality Among Patients Receiving Long-Term Benzodiazepine Therapy. JAMA Netw Open. 2023;6(12):e2348557. doi:10.1001/jamanetworkopen.2023.48557