Tramadol as First-Line Therapy for OA May Be Associated With Greater Mortality

woman suffering from pain in knees
Senior woman suffering from pain in knees at home. Holding her knee and massaging with hands, feeling exhausted, sitting on sofa in living room. Close-up. Medications and pills on table
Treating osteoarthritis in older patients with tramadol vs nonsteroidal anti-inflammatory drugs may be associated with an increased mortality rate during the year following treatment initiation.

Treating osteoarthritis (OA) in older patients with tramadol, which binds µ-, δ-, and κ- opioid receptors with low affinity and acts as an inhibitor of norepinephrine and serotonin reuptake, may be associated with an increased mortality rate during the year following treatment initiation compared with nonsteroidal anti-inflammatory drugs (NSAIDs), according to a study published in JAMA.1

In its most recent guideline, dated 2012, the American College of Rheumatology “conditionally” recommends the use of tramadol, acetaminophens, NSAIDs (oral and topical), and intra-articular injections of corticosteroids as first-line therapy for the management of knee OA-associated pain.2 Similar recommendations regarding the use of tramadol and NSAIDs as first-line treatment for knee OA were formulated by the American Academy of Orthopaedic Surgeons in its 2013 guideline.3

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For this cohort study, investigators examined the data of patients (n=88,902; mean age, 70.1±9.5; 61.2% women) age ≥50 who were treated for OA of the knee, hand, or hip at general practices in the United Kingdom between 2000 and 2015 and were followed for ≥1 year. In this cohort, patients were prescribed tramadol (n=44,451), codeine (n=16,922), diclofenac (n=6512), naproxen (n=12,397), celecoxib (n=5674), or etoricoxib (n=2946) as first-line therapy. The study’s primary outcome was all-cause mortality during the year after initial prescription of tramadol compared with the five other drugs examined determined with propensity score-matched studies for each cohort.

The prevalence of patients treated with tramadol for OA of the knee, hand, or hip was 3.4% in 2000, 11.1% in 2013, and 9.8% in 2015. Mean treatment duration for all drugs examined were: tramadol, 22 days; naproxen and diclofenac, 24 days; codeine, 25 days; etoricoxib, 27 days; and celecoxib, 31 days. Patients treated with tramadol vs the other drugs were older; had OA for longer periods; higher body mass index; and greater prevalence of comorbidities, additional prescriptions, and healthcare utilization.

During the 1-year follow-up, mortality was found to be higher in patients treated with tramadol vs naproxen (278 deaths; 23.5 per 1000 person-years vs 164 deaths; 13.8 per 1000 person-years, respectively) with a rate difference in mortality of 9.7 per 1000 person-years (95% CI, 6.3-13.2). Similar results were found when tramadol was compared with diclofenac (rate difference in mortality, 17.0 per 1000 person-years; 95% CI, 11.2-22.8) and celecoxib (rate difference in mortality, 12.8 per 1000 person-years; 95% CI, 6.9-18.7). Mortality during the year after treatment initiation was comparable in patients treated with tramadol vs codeine (519 deaths; 32.3 per 1000 person-years vs 552 deaths; 34.6 per 1000 person-years, respectively).

Study limitations include the uncertainty regarding the cause of death in a large percentage of the cohort and the possibility that tramadol was administered to patients for undiagnosed cancer- vs OA-related pain.

“[B]ased on the results reported in the current study, non-opioid therapy could be preferred for [the] management of chronic pain (eg, [OA]),” concluded the study authors.


  1. Zeng C, Dubreuil M, LaRochelle MR, Lu N, Wei J, Choi HK, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019;321(10):969-982. doi:10.1001/jama.2019.1347
  2. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-474.
  3. Jevsevar DS, Brown GA, Jones DL, et al. The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition. J Bone Joint Surg Am. 2013;95(20):1885-1886.

This article originally appeared on Clinical Pain Advisor