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

JAMA. 2021 Oct 19;326(15):1504-1515. doi: 10.1001/jama.2021.15255.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Accidental Falls / statistics & numerical data
  • Ambulatory Care
  • Analgesics, Opioid / adverse effects*
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / epidemiology
  • Cause of Death*
  • Codeine / adverse effects*
  • Databases, Factual
  • Delirium / epidemiology
  • Drug Prescriptions / statistics & numerical data
  • Female
  • Fractures, Bone / chemically induced
  • Fractures, Bone / epidemiology
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Opioid-Related Disorders / epidemiology
  • Propensity Score
  • Proportional Hazards Models
  • Retrospective Studies
  • Sleep Wake Disorders / epidemiology
  • Tramadol / adverse effects*


  • Analgesics, Opioid
  • Tramadol
  • Codeine