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Original Investigation
October 19, 2021

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

Author Affiliations
  • 1Centre for Statistics in Medicine and NIHR Biomedical Research Centre Oxford, NDORMS, University of Oxford, Oxford, United Kingdom
  • 2Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFes), Instituto Carlos III, Madrid, Spain
  • 3Gerència Territorial de Barcelona, Institut Català de la Salut, Barcelona, Spain
  • 4Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain
  • 5Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
  • 6Musculoskeletal Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
  • 7Internal Medicine Department, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
  • 8National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
  • 9Department of Clinical Sciences Lund, Orthopedics, Clinical Epidemiology Unit, Faculty of Medicine, Lund University, Lund, Sweden
  • 10Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
  • 11Women’s College Hospital Research Institute, Toronto, Toronto, Ontario, Canada
  • 12Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 13Universitat de Barcelona, Barcelona, Spain
JAMA. 2021;326(15):1504-1515. doi:10.1001/jama.2021.15255
Key Points

Question  Is tramadol compared with codeine prescription dispensation associated with differences in the risk of mortality and other clinical outcomes?

Findings  In this retrospective cohort study that used propensity score matching and included 368 960 participants, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of all-cause mortality (HR, 2.31), cardiovascular events (HR, 1.15), and fractures (HR, 1.50), but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders.

Meaning  New prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of mortality, cardiovascular events, and fractures, although the findings should be interpreted cautiously, given the potential for residual confounding.

Abstract

Importance  Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids.

Objective  To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings.

Design, Setting, and Participants  Retrospective, 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.

Exposures  New prescription dispensation of tramadol or codeine (no dispensation in the previous year).

Main Outcomes and Measures  Outcomes 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.

Results  Of the 1 093 064 patients with a tramadol or codeine dispensation during the study period (326 921 for tramadol, 762 492 for codeine, 3651 for both drugs concomitantly), a total of 368 960 patients (184 480 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.

Conclusions and Relevance  In 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.

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