Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes.

Abstract

Importance\nAlthough tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids.\n\n\nObjective\nTo assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings.\n\n\nDesign, Setting, and Participants\nRetrospective, population-based, propensity score-matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (≈6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017.\n\n\nExposures\nNew prescription dispensation of tramadol or codeine (no dispensation in the previous year).\n\n\nMain Outcomes and Measures\nOutcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models.\n\n\nResults\nOf the 1\u202f093\u202f064 patients with a tramadol or codeine dispensation during the study period (326\u202f921 for tramadol, 762\u202f492 for codeine, 3651 for both drugs concomitantly), a total of 368\u202f960 patients (184\u202f480 propensity score-matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders.\n\n\nConclusions and Relevance\nIn this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders. The findings should be interpreted cautiously, given the potential for residual confounding.