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

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

Junqing Xie  1 , Victoria Y Strauss  1 , Daniel Martinez-Laguna  2   3   4   5 , Cristina Carbonell-Abella  2   3   4   6 , Adolfo Diez-Perez  2   3   4   5   7 , Xavier Nogues  2   5   7   8 , Gary S Collins  1   9 , Sara Khalid  1 , Antonella Delmestri  1 , Aleksandra Turkiewicz  10 , Martin Englund  10 , Mina Tadrous  11   12 , Carlen Reyes  2   4 , Daniel Prieto-Alhambra  1   13
Affiliations
Comparative Study

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

Junqing Xie et al. JAMA. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Strauss reported receiving grants from Amgen. Dr Martinez-Laguna reported receiving personal fees from Amgen, Italfarmaco, Ferrer, Novartis, and Rubio. Dr Carbonell-Abella reported receiving fees for lectures/classes from Amgen, Theramex, Stada, and Gebro. Dr Diez-Perez reported receiving personal fees from Amgen, Lilly, and Theramex; receiving grants from Instituto Carlos III; and owning shares of Active Life Scientific. Dr Nogues reported receiving personal fees from Amgen, UCB, and Lilly and a grant from the Foundation for Advanced Education in the Sciences. Dr Turkiewicz reported serving as associate editor for Osteoarthritis and Cartilage. Dr Englund reported receiving personal fees from Pfizer for serving as a 1-day advisory board panel member (Tanezumab; November 26, 2019). Dr Prieto-Alhambra reported receiving grant support from Les Laboratoires Servier; that his research group has received grants and advisory or speaker fees from Amgen, Astellas, AstraZeneca, Chiesi-Taylor, Johnson & Johnson, and UCB; and that Janssen, on behalf of Innovative Medicines Initiative–funded European Health Data Evidence Network and European Medical Information Framework consortiums and Synapse Management Partners, have supported training programs, open to external participants, organized by his department. No other authors reported disclosures.

Figures

Figure 1.
Figure 1.. Selection Process of Participants for the Study
aPatients could be excluded for more than 1 reason.
Figure 2.
Figure 2.. Kaplan-Meier Cumulative Incidence Plots for All Study Outcomes Within 1 Year in the Matched Cohort
Most patients in each group were observed for the whole year. There were no primary or secondary outcomes; all study outcomes were prespecified and treated equally. Cumulative incidence (95% CI) per 1000 participants, tramadol vs codeine: A, 12.86 (12.34-13.38) vs 5.59 (5.25-5.94). B, 9.97 (9.50-10.43) vs 8.62 (8.19-9.05). C, 6.92 (6.54-7.31) vs 6.39 (6.02-6.76). D, 12.07 (11.56-12.57) vs 8.08 (7.67-8.50). E, 2.75 (2.50-2.99) vs 2.32 (2.09-2.54). F, 2.22 (2.00-2.44) vs 2.08 (1.87-2.29). G, 0.21 (0.14-0.2) vs 0.20% (0.14-0.27). H, 0.12 (0.07-0.18) vs 0.06 (0.02-0.10).
Figure 3.
Figure 3.. Event Counts, Incidence Rates, Absolute Rate Differences, and Adjusted Hazard Ratios for 8 Study Outcomes Within 1 Year in the Matched Cohort
Figure 4.
Figure 4.. Subgroup-Specific Associations of Tramadol vs Codeine With All-Cause Mortality
Sizes of data markers reflect the sample size in each subanalysis. CCI indicates Charlson Comorbidity Index; NSAID, nonsteroidal anti-inflammatory drug.
Figure 5.
Figure 5.. Subgroup-Specific Associations of Tramadol vs Codeine With Cardiovascular Events
Sizes of data markers reflect the sample size in each subanalysis. CCI indicates Charlson Comorbidity Index; NSAID, nonsteroidal anti-inflammatory drug.
Figure 6.
Figure 6.. Subgroup-Specific Associations of Tramadol vs Codeine With Fractures
Sizes of data markers reflect the sample size in each subanalysis. CCI indicates Charlson Comorbidity Index; NSAID, nonsteroidal anti-inflammatory drug.
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