Gabapentin, opioids and the risk of opioid-related death: a population-based nested case-control study

Background — Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although widely perceived as safe, gabapentin-induced respiratory depression has been described when used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.

Methods and Findings — We conducted a population-based nested case-control study among opioid users who were residents of Ontario, Canada between August 1, 1997 and December 31, 2013 using administrative databases. Cases, defined as opioid users who died of an opioid-related cause were matched with up to four controls who also used opioids on age, sex, year, history of chronic kidney disease and a disease risk score. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900mg daily), moderate (900 to 1799mg daily) or high (>1800mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio (OR) 1.99, 95% confidence interval [CI] 1.61 to 2.47, p<0.0001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p=0.0009) compared to opioid prescription alone. In the dose-response analysis, moderate (OR 2.05, 95% CI 1.46 to 2.87, p<0.0001; aOR 1.56; 95% CI 1.06 to 2.28, p=0.0235) and high dose (OR 2.20, 95% CI 1.58 to 3.08, p<0.0001; aOR 1.58, 95% CI 1.09 to 2.27, p=0.0149) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p=0.1131; aOR 1.14, 95% CI 0.98 to 1.32, p=0.0831). In an exploratory analysis of patients at risk of this drug combination, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least one concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias.

Conclusions — In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin is associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products, and when deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.