Quitting benzos carries unexpected risks for long-term users

Stopping prescription benzodiazepine treatment may leave long-term users worse off, with a study finding increases in the risks of death and other unfavourable events.

Compared with benzodiazepine users who stayed on treatment, those who discontinued had a 60-percent higher risk of death after 1 year. This held true regardless of concomitant opioid exposure (nonexposed group: absolute risk difference, 2.1 percentage points; risk ratio [RR], 1.6, 95 percent confidence interval [CI], 1.6–1.7; exposed group: absolute risk difference, 2.4 percentage points; RR, 1.6, 95 percent CI, 1.5–1.7). [JAMA Netw Open  2023;6:e2348557]

Aside from increased mortality, benzodiazepine discontinuation was also associated with heightened risks of nonfatal overdose, suicidal ideation, and emergency department use. For these outcomes, the absolute risk differences for those with versus without opioid exposure were slightly higher, although the RRs were similar (nonfatal overdose: RR, 1.2; suicidal ideation: RR, 1.4; emergency department use: RR, 1.2).

While the absolute magnitude of the increase in the risk of the said outcomes was relatively small, the overall findings were unexpected, according to the investigators.

“Given the increased overdose risk and mortality associated with benzodiazepine prescribing, particularly when coprescribed with opioids, we anticipated that discontinuing benzodiazepine prescriptions would be associated with a lower mortality risk,” they said. [JAMA  2013;309:657-659; BMJ 2015;350:h2698; BMJ 2017;356:j760]

Indeed, the US Food and Drug Administration’s (FDA) call for benzodiazepine tapering guidelines, spurred by the Health Department’s antioverdose strategy, was aimed at reducing the risks of long-term use. [https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-22-027.html]

Moreover, in contrast to the present study, previous work suggested low rates of adverse events among individuals who discontinued benzodiazepine treatment. In the EMPOWER trial, none of the participants had any adverse events requiring hospitalization during a 6-month follow-up. Meanwhile, a primary care study reported only two serious events occurring among 542 participants after 12 months. [JAMA Intern Med  2014;174:890-898; Br J Psychiatry 2014;204:471-479]

“It is possible that, having become physiologically dependent on benzodiazepine, patients experience adverse outcomes from withdrawal. Alternatively, patients may experience adverse consequences if they seek alternative sedating substances (eg, cannabis or alcohol) following benzodiazepine discontinuation,” the investigators explained. [Addiction 1994;89:1455-1459]

More work is needed to validate the present data and identify which patients are most at risk of harms in relation to benzodiazepine cessation, they added.

“In addition, given questions raised about the safety of discontinuing benzodiazepine prescriptions among stable long-term users, clinicians should be judicious in initiating new prescriptions and carefully limit conversion to long-term use,” the investigators continued.

The analysis included 213,011 patients without recent opioid exposure (mean age 62.2 years, 64.1 percent female, 60.2 percent White) and 140,565 patients with recent opioid exposure (mean age 61.1 years, 65.3 percent female, 79.2 percent White). All of them were stable, long-term users of benzodiazepine.