(331) Comparative risk of mortality in new users of prescription opioids for non-cancer pain: results from the International Pharmacosurveillence Study

Background: Opioids comprise of several drugs with differences in pharmacological action and potency. Evidence to date on the comparative safety of opioids is sparse and conflicting, with recommended daily dose thresholds that vary considerably between countries.

Objectives: To examine the comparative risk of all-cause mortality in patients newly initiated on opioids for non-cancer pain, across three jurisdictions in the UK, US and Canada.

Methods: A multi-centre retrospective cohort study was conducted between 2006-2016. Data sources included UK national primary care electronic health records from Clinical Practice Research Datalink, 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 on 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 experienced a higher risk 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]). 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 MME/day, patients on higher doses experienced 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].

Conclusions: Compared to codeine, in opioid new users, 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.