Kuo YF, Liaw V, Yu X, et al. Opioid and benzodiazepine substitutes: Impact on drug overdose mortality in Medicare population. Am J Med. 2022 Mar 24. pii: S0002-9343(22)00191-7. doi: 10.1016/j.amjmed.2022.02.039. (Original study)

INTRODUCTION: Gabapentinoids (GABAs) and serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]/serotonin and norepinephrine reuptake inhibitors [SNRIs]) are increasingly being prescribed as potential substitutes to opioids and benzodiazepines (benzos), respectively, to treat co-occurring pain and anxiety disorders. The toxicities of these drug classes and their combinations are not well understood.

METHODS: We conducted a matched case-control study using 2013-2016 Medicare files linked to the National Death Index. Cases were enrollees who died from drug overdose. Controls were enrollees who died from other causes. Cases and controls were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzos, and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death.

RESULTS: Among 4323 matches, benzo possession was associated with twice the risk for drug overdose death in cases vs controls. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs). Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations.

CONCLUSIONS: Benzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death. SSRIs/SNRIs were associated with lower risk of overdose death vs benzodiazepines. GABAs were not associated with decreased risk compared with opioids, raising concerns for GABAs' perceived relative safety.

Discipline Area Score
Special Interest - Pain -- Physician 7 / 7
Psychiatry 6 / 7
FM/GP/Mental Health 5 / 7
General Internal Medicine-Primary Care(US) 5 / 7
Internal Medicine 5 / 7
Neurology 5 / 7
Family Medicine (FM)/General Practice (GP) 5 / 7
Comments from MORE raters

FM/GP/Mental Health rater

Practice-altering article confirming dangers of co-prescribing gabapentinoids, benzos, and opiates.

General Internal Medicine-Primary Care(US) rater

Very interesting.

Neurology rater

I think my colleagues and I are not aware of this information because we did not encounter a case like this during our psychiatry training.

Psychiatry rater

This study examined which drugs people on Medicare were taking at the time of death compared with matched controls who died from other causes. As expected from previous studies, patients who took benzodiazepines as well as opioid drugs had a higher death rate, whereas patients who took SSRI/SNRI drugs together with opioids had decreased risk for death. However, fatal drug overdose risk was similar in users of gabapentinoids (GABA) when combined with opioids, also when used with benzodiazepines, as well as opioid-benzo combinations. This surprising finding illustrating that GABAs were not associated with decreased risk combined with opioids, suggests that GABAs are not as safe as previously thought. An association between alcohol use and SSRI/SNRI use and increased risk for death was also found, but this may be an incidental finding.
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