Background: Opioids have contributed to an epidemic in several Western countries, and have been associated with a multitude of adverse outcomes and unintentional deaths. Despite increased awareness of potential harms, they remain commonly prescribed in most countries internationally for non-cancer pain due to limited therapeutic options. As a drug class, opioids comprise of several drugs with differences in pharmacological action and potency. Evidence to date on the comparative safety of different opioids is sparse and conflicting. Additionally currently recommended daily dose thresholds vary considerably between countries.

Objectives: The aim of this study was to examine the comparative risk of all-cause mortality in patients newly initiated on opioids for non-cancer pain, across three jurisdictions in the United Kingdom (UK), United States (US) and Canada.

Methods: A multi-centre retrospective, population-based cohort study was conducted between 2006-2016. Data sources included UK national primary care electronic health records from the Clinical Practice Research Datalink, The Partners HealthCare Research Patient Data Registry in Boston (US), and The Montreal Population Health Record data (Canada). New users of opioids aged ≥18 years, without a previous history of cancer were included. Patients with a diagnosis of a pain condition and with known backpain were analysed separately. The main outcome was all-cause mortality within two years after initial opioid prescription, with codeine as the referent. Fully adjusted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using Cox-proportional models and adjusted for confounders.

Results: In total 1,066,216 patients were included (UK: n= 996,857; Boston, US: n= 43,243; Montreal, Canada: n= 26,116). Compared to codeine, patients using morphine had a significantly higher adjusted risk in the UK (HR: 12.57 [95% CI, 11.87, 13.31]), US (HR: 8.67 [95% CI, 3.36; 22.35]) and Canadian cohorts (HR: 6.54; [95% CI, 1.32, 32.45]). A higher risk of death with morphine was observed across patient subgroups of any pain diagnosis (HR: 10.25 [95% CI, 9.06; 11.60]) and back pain (HR: 9.08 [95% CI: 7.63; 10.80]). Fentanyl-treated patients also experienced a higher risk of death in all three groups in the UK (All patients HR, 11.39 [95% CI, 10.73, 12.08]); any pain diagnosis: HR 8.11 [95% CI, 7.12; 9.24]; backpain: HR, 6.47; 95% CI, 5.37, 7.80]) and across all patients in the Canadian cohort (HR: 5.83 [95% CI, 1.21, 28.13]). In addition, other factors associated with higher mortality were being on combination opioids (HR, 11.39 [95% CI, 10.73, 12.08]), buprenorphine (HR, 5.66 [95% CI, 5.33; 6.02]) and oxycodone (HR, 3.54 [95% CI, 2.93, 4.28]). Compared to those on <50 morphine milligram equivalents (MME)/day, patients on higher doses experience an incremental increase in risk: 50-120 MME/day: HR, 1.92, [95% CI, 1.18; 3.11], 120-200 MME/day: HR: 5.68, [95% CI, 2.45; 13.18]; ≥200 MME/day: HR: 10.05 [95% CI, 3.99; 25.31; US cohort]. The use of concomitant antipsychotics was associated with a higher mortality risk in both the UK (HR, 2.67 [95% CI, 2.56, 2.78]) and the US cohorts (HR: 2.72 [95% CI, 2.01; 3.70)].

Conclusion: In new users of opioids, compared to codeine, strong opioids including morphine, fentanyl, buprenorphine, oxycodone, and combination opioids were associated with a higher subsequent risk of all-cause mortality. Doses higher than 50MME/day were also associated with an increased risk of death.

Acknowledgements: NIL.

Disclosure of Interests: Meghna Jani: None declared, Nadyne Girad: None declared, David Bates EarlySense, David Buckeridge: None declared, William Dixon: None declared, Robyn Tamblyn: None declared