Drug-related mortality associated with gabapentinoid/Z-drug co-prescribing among opioid-agonist treatment recipients

Background

The protective effect of opioid-agonist treatment (OAT) in preventing drug-related deaths (DRD) among people with opioid dependence is widely reported. Over the past decade, DRD rates among people receiving OAT in Scotland have increased. Co-prescribing of sedative medications with OAT may increase the risk of DRD during treatment. The aim of this study was to estimate the risk of DRD during periods of co-prescription of OAT with gabapentinoids or Z-drugs.

Methods

We conducted a retrospective cohort study of individuals prescribed OAT between 2011 and 2020. Records were linked to mortality data (from National Records of Scotland), sociodemographic, comorbidity and prescribing data (from Public Health Scotland). We used multivariable quasi-Poisson regression to determine whether exposure to OAT with co-prescription of gabapentinoids or Z-drugs was associated with risk of DRD, compared to periods without co-prescription. Models were adjusted for potential confounders.

Results

Among 46,602 individuals with around 305,000 person-years of follow-up, we found that co-prescription was common, with 25% and 34% of the cohort ever being co-prescribed gabapentinoids or Z-drugs, respectively. Gabapentinoids are increasingly being prescribed to OAT recipients in Scotland.

Crude DRD rates among OAT recipients have increased over time. DRD rates were higher during periods of co-prescription with each medication type, compared with periods without. 

In adjusted analyses, we found a strong association between co-prescribed gabapentinoid exposure and DRD (adjusted hazard ratio = 2.18, 95% CI = 1.92-2.46), compared to periods without. Exposure to co-prescribed Z-drugs was more weakly associated with an increased risk of DRD (adjusted hazard ratio = 1.39, 95% CI = 1.15-1.66).

Conclusions 

This large nationwide record linkage study includes the majority of people prescribed OAT in Scotland between 2011 and 2020. It is the first study to our knowledge to examine the risk associated with co-prescribing among OAT patients during a period where Scotland's DRD rate trebled, and is among the highest internationally. Our findings strengthen evidence from UK research that was not powered to find an association between gabapentinoids and DRD; but we found weaker evidence for Z-drugs.

Complex health needs among people with opioid use disorder may necessitate prescribing of gabapentinoids and/or Z-drugs. The increased risk of DRD identified suggests caution and close monitoring is required when co-prescribing such medications to patients receiving OAT.