5 Questions on Tramadol and Mortality in Osteoarthritis Patients

The weak opioid agonist tramadol is often prescribed based on one or both of 2 beliefs: It is as effective as other opioids, but with a more benign side effect profile or, because it is a US DEA schedule IV drug, it is easier to prescribe. For knee osteoarthritis (OA), tramadol has not been found more effective for pain relief vs nonsteroidal anti-inflammatory drugs (NSAIDs), but has caused a range of opioid-related side effects. Can tramadol also be fatal?

In a population of patients aged ≥50 years with a history of knee OA, researchers of a recent study in the UK compared all-cause mortality between patients who received an initial prescription of tramadol vs those who received one of the following commonly prescribed analgesics: Naproxen or diclofenac (NSAIDS); celecoxib or etoricoxib (COX-2 inhibitors); or codeine.

The 5 questions that follow are based on this study.

1. First things first: Treatment guidelines from the American Academy of Orthopedic Surgeons and the American College of Rheumatology (ACR) recommend tramadol for the management of knee OA.

A. True
B. False

Please click here for answer and next question.

Answer: A. True. Both professional societies have recommended the use of tramadol for the management of knee OA; the ACR conditionally recommends its use as first-line therapy for patients with knee OA, along with NSAIDs.

2. In the current study, during the 1-year follow-up period, the all-cause mortality rate in the tramadol cohort compared to the rate in the non-selective NSAIDs cohort was:

A. Lower
B. Higher
C. About the same

Please click here for answer and next question.

Answer: B. Higher. During the follow-up period, the mortality rate in the tramadol cohort was higher vs the rate in the naproxen cohort (23.5/1000 vs 13.8/1000 person-years, respectively) AND in the diclofenac cohort (36.2/1000 vs 19.2/1000 person-years, respectively).

3. During the 1-year follow-up period, the all-cause mortality rate was lower in the tramadol cohort vs in the selective COX-2 inhibitor cohort.

A. True
B. False

Please click here for answer and next question.

Answer: B. False. Tramadol was associated with a higher all-cause mortality rate vs celecoxib (31.2/1000 vs 18.4/1000 person-years, respectively) AND etoricoxib (25.7/1000 vs 12.8/1000 person-years, respectively).

4. Comparison of all-cause mortality rates in the codeine and tramadol cohorts found the rate in the tramadol cohort was:

A. Lower vs codeine
B. Higher vs codeine
C. About the same as codeine

Please click here for answer and next question.

Answer: C. About the same as codeine. There was no statically significant difference in all-cause mortality rate between the tramadol cohort and codeine cohort (32.2/1000 vs 34.6/1000 person-years, respectively).

5. All-cause mortality in which of the following disease state/s was higher in the tramadol cohort vs NSAIDs cohort?

A. Cardiovascular disease
B. Gastrointestinal disease
C. Infection
D. Cancer
E. A and D
F. All of the above

Please click here for answer and a note from the quiz author.

Answer: F. All of the above. The number of deaths due to cardiovascular disease, gastrointestinal disease, infection, and cancer was higher in the tramadol cohort vs NSAIDs cohort. Study authors note, however, that because the number of deaths from each cause was relatively small, most associations were not statistically significant.

Note from the quiz author

Results of the study suggest that the view of tramadol as a medication that is safer vs other opioids or vs NSAIDs may not be true. At least for the study population, patients aged ≥50 years with OA, tramadol carried a higher mortality risk vs NSAIDs and the same level of risk as codeine.

The authors note that it is unclear exactly why tramadol is associated with a higher mortality rate. They conjecture that it may somehow be related to its primary mode of analgesic action (MOA) as a µ-opioid receptor agonist and serotonin-norepinephrine reuptake inhibitor.

This MOA, they point out, may increase mortality from causes such as an increase in postoperative delirium; increased risk of falls; and other conditions associated with tramadol including hypoglycemia, hyponatremia, and potentially toxic interactions with alcohol or other central nervous system depressants.

References:

Zeng C, Dubreuil M, LaRochelle MR, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019;321:969-982.