Among patients receiving opioids for nonmalignant pain, the daily dose is strongly associated with opioid-related mortality, particularly at doses exceeding thresholds recommended in recent clinical guidelines.

Among adults undergoing hip fracture surgery, increased wait time was associated with a greater risk of 30-day mortality and other complications. A wait time of 24 hours may represent a threshold defining higher risk.

Key Points Question What has been the burden of opioid-related deaths in the United States over a recent 15-year period? Findings In this serial cross-sectional study, we found that the percentage of all deaths attributable to opioids increased 292% (from 0.4% to 1.5%) between 2001 and 2016, resulting in approximately 1.68 million person-years of life lost in 2016 alone (5.2 per 1000 population). The burden was particularly high among adults aged 24 to 35 years; in 2016, 20% of deaths in this age group involved opioids. Meaning Premature death from opioids imposes an enormous and growing public health burden across the United States.

BackgroundPrescription 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 gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is 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 findingsWe 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 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. 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 (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg 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% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose–response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) 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 = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 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 b...