Stopping long-term benzodiazepine treatment was tied to a higher risk of death, according to a comparative effectiveness study using claims data.
An intention-to-treat analysis showed that among people who weren't simultaneously taking an opioid, the adjusted cumulative incidence of death over 1 year was 5.5% for those who stopped benzodiazepine treatment compared with 3.5% for those who didn't, according to Donovan Maust, MD, MS, of the University of Michigan in Ann Arbor, and colleagues.
Those who were on concomitant opioids also had a higher incidence of death over 1 year if they stopped benzodiazepines compared with those who continued treatment (6.3% versus 3.9%), they reported in JAMA Network Open.
Mortality risk for those who stopped benzodiazepines was 1.6 times higher than for those who stayed on treatment, with or without concomitant opioid use (95% CI 1.5-1.7 and 95% CI 1.6-1.7, respectively), they reported, noting that all of these risks held in a per-protocol analysis, and were slightly higher.
"Decades of research have demonstrated harms associated with benzodiazepine use, such as fall-related injury and increased risk of overdose -- so the assumption has been that less benzodiazepine use would mean fewer harms," Maust told MedPage Today in an email. "Our analysis suggests that, at least in those who have been receiving stable long-term treatment, risk of mortality appears to be higher in those individuals who have the benzodiazepine prescription stopped."
"I think the findings speak to the importance of carefully considering the risk/benefit balance of continuing a benzodiazepine prescription," he added.
Clinicians should be careful about letting their patients become long-term benzodiazepine users, especially if they plan to follow the standard of tapering those patients at some point, Maust added.
"I think it is important to revisit the assumption that tapering stable long-term users should be the default and instead, perhaps, focus on those with clearly elevated risk of harms," he said.
Philip Muskin, MD, of Columbia University, who was not involved in the study, agreed that the results suggest clinicians should be even more deliberate about starting patients on benzodiazepines.
While the absolute risk shown in the study is small, Muskin said, "it's real, and I think we need to respect that."
Some people need and benefit from benzodiazepines, and they appear to be better off remaining on these drugs long-term, Muskin said. Based on these results, clinicians also likely need to diligently monitor any patient who begins to taper off benzodiazepines, even long after they discontinue the treatment, he added.
Increases in overdose deaths involving benzodiazepines have risen over the past several years, leading to a number of FDA actions including a 2016 warning related to co-prescribing with opioids and a 2020 class-wide boxed warning about the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions.
The FDA is also developing an evidence-based clinical practice guideline for the safe tapering of benzodiazepines, Maust and colleagues wrote. However, no studies have looked at the risks of discontinuation, they said. Stopping benzodiazepines may be "particularly fraught" as it can have both physiological and psychological implications, they added.
For their study, Maust and colleagues assessed claims data from Optum on patients with a benzodiazepine prescription from 2013 through 2019, totaling 213,011 without concomitant opioids and 140,565 with opioids. Mean age was about 62 and nearly two-thirds in each group were women.
Discontinuation was defined as having no benzodiazepine prescription for 31 consecutive days during a 6-month period after baseline. Patients were followed for about 1 year after baseline benzodiazepine prescriptions.
The researchers also found the risks of secondary outcomes including nonfatal overdose, suicidal ideation, and emergency department use were higher among those who stopped benzodiazepines, whether or not they also used opioids (relative risk 1.2, 1.4, and 1.2, respectively).
The study was limited in that it wasn't a randomized controlled trial and couldn't account for all possible confounders. Also, risks may vary by the speed of tapering, which the researchers did not investigate, Maust said. Finally, his team used a strict definition for stable long-term use of benzodiazepines, so this population may have been more likely to experience discontinuation-related distress and adverse effects.
Still, the researchers concluded that the findings are "at odds with the assumption underlying ongoing policy efforts that reducing benzodiazepine prescribing to long-term users will decrease harms," adding that future work should examine possible mechanisms underlying these findings.
"It is possible that, having become physiologically dependent on benzodiazepines, patients experience adverse outcomes from withdrawal," they wrote. "Alternatively, patients may experience adverse consequences if they seek alternative sedating substances (e.g., cannabis or alcohol) following benzodiazepine discontinuation."
Disclosures
The study was funded by the National Institute on Drug Abuse.
The authors reported no relevant financial disclosures.
Primary Source
JAMA Network Open
Source Reference: Maust DT, et al "Benzodiazepine discontinuation and mortality among patients receiving long-term benzodiazepine therapy" JAMA Netw Open 2023; DOI: 10.1001/jamanetworkopen.2023.48557.
https://www.medpagetoday.com/psychiatry/generalpsychiatry/107959
