How Safe Are Pregabalin and “Z-Drugs” During Opioid Maintenance?

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How Safe Are Pregabalin and “Z-Drugs” During Opioid Maintenance?

They are associated with more overdose deaths than benzodiazepines in individuals being treated with buprenorphine or methadone for opioid use disorder.

Although opioid replacement therapy (ORT) reduces risks for all-cause and overdose death in individuals with opioid use disorder, mortality in individuals on ORT is still elevated. Benzodiazepines, pregabalin, and z-drugs (e.g., zolpidem, zopiclone) are misused by and prescribed for individuals on ORT, but only benzodiazepines have been linked to overdose risk. To learn more about the safety of these medications, researchers examined Swedish registry data on 4501 individuals dispensed methadone or buprenorphine.

During 7 years, 32% of the patients were prescribed a benzodiazepine, 41% a z-drug, and 22% pregabalin; 356 individuals died, more than half from overdose. The investigators compared risks during periods in which patients were prescribed pregabalin, z-drugs, or benzodiazepines versus periods without such prescriptions.

In analyses controlling for sex, age, previous overdoses, suicide attempts, psychiatric care, and use of ORT at the time of death, z-drugs and pregabalin were significantly associated with death by overdose; pregabalin had the highest hazard ratio (2.82). Benzodiazepines were associated with nonoverdose death. Benzodiazepines and pregabalin were associated with all-cause mortality. All-cause mortality and risk for overdose were associated with only z-drugs during buprenorphine treatment and with only pregabalin during methadone treatment.


Contrary to assumptions that z-drugs and pregabalin are safer than benzodiazepines for anxiety and insomnia in individuals on ORT, these findings indicate that they may be just as dangerous, if not more so. The higher risk of overdose during periods of pregabalin use may have occurred in part because clinicians prescribed an apparently safer drug to higher-risk patients. Nonetheless, clinicians should try and exhaust other options (selective serotonin reuptake inhibitors, melatonin, etc.) before prescribing any of these medications. Clinicians who do prescribe them should have heightened vigilance, should frequently monitor patients for overuse, and should issue strong warnings about the risks for death.

Claire Wilcox, MD reviewing Abrahamsson T et al. Drug Alcohol Depend 2017 Feb 28.

Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.


Abrahamsson T et al. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment — a nation-wide register-based open cohort study. Drug Alcohol Depend 2017 Feb 28; [e-pub].
[Free full-text Drug Alcohol Depend article]

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