Prescription of tramadol is associated with higher rates of adverse clinical outcomes compared to codeine in patients with chronic non-cancer pain


1. A retrospective population-based cohort study found that the prescription of tramadol was significantly associated with all-cause mortality, cardiovascular events and fractures at higher rates than the prescription of codeine.

2. No difference in event rates for constipation, falls, delirium, opioid use disorder, or sleep disturbance was noted between tramadol and codeine users.

Level of Evidence Assessment: 2 (Good)

Study overview: Chronic non-cancer pain is very common in the general population and can significantly reduce quality of life. Opioid drugs are commonly prescribed for the management of chronic pain despite their extensive side effect profile. Tramadol and codeine are two widely prescribed weak opioids; this study aimed to compare the adverse events associated with tramadol versus codeine used to treat a range of pain presentations in adult patients. Xie et al. conducted a retrospective cohort study of the population in Catalonia, Spain, using the database of the System for the Development of Research in Primary Care (SIDIAP). A total of 368,960 patients who received tramadol or codeine between January 1, 2007 and December 31, 2017 were included in the final propensity matched cohort. The cumulative incidence over one year of all-cause mortality for patients who received tramadol was 12.86 per 1000 participants compared to 5.59 per 1000 in the codeine group. The incidence at 1 year of cardiovascular disease was 9.97 / 1000 participants in the tramadol group versus 8.62 / 1000 in the codeine group; finally, the incidence of fractures was 12.07 / 1000 for tramadol and 8.08 / 1000 for codeine. There was no significant difference in the rates of constipation, delirium, falls, opioid abuse / dependence, and sleep disturbance between the two groups. This study found that tramadol is associated with a higher risk of specific adverse events over a period of one year compared to codeine in the Spanish population studied. It contributes important data to our understanding of the safety profile of weak opioids in chronic non-cancer pain, which is very important given the frequency with which they are prescribed. A main limitation of this study was its retrospective design, which does not control for potential confounders. In addition, the use of a single database makes the data subject to information bias. Likewise, the measurement of exposure by prescription of tramadol or codeine may not represent actual drug use (i.e. a prescription is dispensed but may be partially or totally unused), therefore, the incidence values ​​of adverse reactions reported here should be interpreted with caution. Despite these drawbacks, Xie et al. collected data from a strong cohort and explored in depth the safety of common pain relievers.

Click here to read the study in JAMA

Click here to read an accompanying editorial in JAMA

Relevant reading: Opioids for chronic non-cancer pain: a meta-analysis of efficacy and side effects

In depth [retrospective cohort study]: SIDIAP was the main source of data in this study; this database is based on electronic health records, socio-demographic factors and pharmacy declarations from the region of Catalonia. It has been previously validated. New prescriptions of tramadol or codeine were taken into account in a 12-month retrospective window. Patients were excluded if they had been prescribed opioids for a history of trauma or major surgery, or if they had a current opioid prescription within 12 months of the referral date. Propensity score matching was used to control for possible confusion in this study, calculated using logistic regression including all baseline patient characteristics. Study results were assessed using the International Classification of Diseases (ICD-10) code for the following events known to be associated with opioid use: all-cause mortality, cardiovascular event (accident cerebrovascular, arrhythmia, myocardial infarction, heart failure), fracture, falls, delirium, constipation, sleep disturbances, opioid abuse / dependence. Kaplan Meier survival curves and hazard ratios were used to summarize event rates since the index date. The most frequent indications for the prescription of opioids in the tramadol and codeine groups were respectively: back pain (47.5%, 48.5%), neck / shoulder (28.6%, 29.5%) and osteoarthritis. (15.3%, 15.5%). The incidence of all-cause mortality, cardiovascular disease and fractures in 1 year per 1000 participants is listed as follows for the tramadol cohort versus the codeine cohort, with 95% confidence intervals: 12.86 (12, 34-13.38) versus 5.59 (5.25-5.94) for mortality, 9.97 (9.50-10.43) versus 8.62 (8.19-9.05) for cardiovascular disease, 12.07 (11.56-12.57) versus 8.08 (7.67-8.50) for fractures. The risk ratios for each adverse event in the tramadol group versus codeine group are as follows, with 95% confidence intervals listed: mortality 2.31 (2.08-2.56), cardiovascular events 1.15 (1.05-1.27) and fractures 1.50 (1.37-1.65). The sensitivity analysis demonstrated that the higher risk of mortality associated with the prescription of tramadol compared to codeine was significantly associated with a younger age (hazard ratio 3.14, 95% confidence interval [1.82-5.41]) compared to the elderly. Cardiovascular events were more likely to occur in women (1.32, [1.19-1.46]) compared to men.

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