Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis

Abstract

Importance: An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs.

Objective: To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis.

Design, setting, and participants: Sequential, propensity score-matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016.

Exposures: Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922).

Main outcomes and measures: All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications.

Results: After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05]).

Conclusions and relevance: Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.

Figure 1.. Prevalence of Tramadol, Naproxen, Diclofenac, Celecoxib, Etoricoxib, and Codeine Prescriptions Among Patients With Knee, Hip, or Hand Osteoarthritis in The Health Improvement Network Database From 2000 to 2015

Of the matched participants, 12 397 were included in the naproxen cohort, 6512 in the diclofenac cohort, 5674 in the celecoxib cohort, 2946 in the etoricoxib cohort, and 16 922 in the codeine cohort.

Figure 2.. Time to Death for Propensity Score–Matched Cohorts of Patients With Osteoarthritis and Initial Prescription of Tramadol Compared With Other Drugs

Each patient can only be counted once in a category; however, the same patient could be selected multiple times in 5 categories. Each category represents a specific sequential propensity score–matched cohort study (ie, tramadol vs naproxen, tramadol vs diclofenac, tramadol vs celecoxib, tramadol vs etoricoxib, or tramadol vs codeine). The median (interquartile range) follow-up time for all drugs was 12.0 (0.0) months.