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Tramadol Linked to Higher Mortality Rates in Older Patients With OA
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An initial prescription of tramadol for osteoarthritis among patients aged 50 years and older is associated with a significantly increased risk for mortality over 1 year, compared with commonly used NSAIDs, but not codeine, according to data published in JAMA.
However, the researchers cautioned that their findings “may be susceptible to confounding by indication” and that further research is required to determine whether the association is causal.
“This study is important because American Academy of Orthopedic 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,” Yuqing Zhang, DSc, of Massachusetts General Hospital, and Guanghua Lei, MD, PhD, of Xiangya Hospital, told Healio Rheumatology.
“Prescriptions of tramadol have been increasing rapidly around the world, making tramadol one of the most widely used weak opioids,” they noted. “However, there is paucity of information on its safety profile, e.g., risk of all-cause mortality.”
To analyze the links between tramadol and all-cause mortality in patients with OA, the researchers studied the Health Improvement Network (THIN), an electronic medical record database that contains information on 11.1 million patients from 580 general practices in the United Kingdom. They included 88,902 patients in their final analysis, all of whom were aged 50 years or older and had a history of knee, hip or hand OA. In addition, all included participants had visited their general practitioner’s office between January 2000 and December 2015, and had at least 1 year of follow-up.
The researchers conducted five sequential propensity score-matched cohort studies to compare all-cause mortality among participants initially treated with tramadol with those treated with other medications. These included naproxen, diclofenac, celecoxib, etoricoxib and codeine. Among the participants, 44,451 initially received tramadol, 12,397 were treated with naproxen, 6,512 received diclofenac, 5,674 received celecoxib, 2,946 were treated with etoricoxib and 16,922 received codeine. The primary outcome was all-cause mortality within 1 year following initial tramadol treatment, compared with other medications.
According to the researchers, there were 278 deaths during the 1-year follow-up in the tramadol group, for a rate of 23.5 per 1,000 person-years, compared with the naproxen cohort, in which 164 participants died during the follow-up, producing a rate of 13.8 per 1,000 person-years (HR = 1.71; 95% CI, 1.41-2.07). Mortality was also higher among patients treated with tramadol compared with diclofenac (HR = 1.88; 95% CI, 1.51-2.35).
In addition, tramadol was associated with a higher all-cause mortality rate compared with celecoxib (HR = 1.7; 95% CI, 1.33-2.17) and etoricoxib (HR = 2.04; 95% CI, 1.37-3.03). However, there were no statistically significant differences between all-cause mortality rates for tramadol and codeine (HR = 0.94; 95% CI, 0.83-1.05).
“Tramadol prescription may be associated with increased all-cause mortality compared with commonly prescribed nonsteroidal anti-inflammatory drugs among patients with osteoarthritis, but further research is needed to determine if this relationship is causal,” Zhang and Lei said. “This study may point to a need to consider tramadol’s potentially increased risk of all-cause mortality in several osteoarthritis guidelines as well as in clinical practice.” – by Jason Laday
Disclosure: Zeng reports no relevant financial disclosures. Please see the study for all other relevant financial disclosures.
Perspective
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Kamran Chaudhary, MD
Several guidelines for knee osteoarthritis currently recommend tramadol including for use as a first-line agent along with a non-steroidal anti-inflammatory drugs (NSAIDs), but there is minimal data on the safety of tramadol in terms of mortality rates in comparison with other agents.
Zeng and colleagues set to examine the association of tramadol use with all-cause mortality within 1 year among patients 50 years and older with a history of OA of the knee, hip or hand in comparison with four NSAIDs, including naproxen, diclofenac, celecoxib and etoricoxib, or codeine.
The study revealed higher rates of mortality for tramadol compared with the four NSAIDs but no difference between tramadol and codeine which could have important implications for how we approach treatment for OA. However, the authors correctly point out that the results need to be interpreted with caution due to limitations of this study, such as a high percentage of causes of death that could not be determined, and an inability to determine cause-specific mortality because of a small number of cause-specific deaths.
In addition, due to the tramadol cohort having a higher and possibly more severe comorbidity burden (i.e., a higher BMI and higher prevalence of conditions, such as diabetes and cardiovascular disease) prior to propensity score matching, residual confounding by indication may have occurred even though adjustments for those factors were made. Future studies need to assess this potential important finding across a range of different indications as well as a sub-analysis based on duration of exposure to the agent and a longer assessment period.
Regardless, this study highlights the potential need for more safe and effective strategies for treatment of OA including a change in how we might approach this condition as its prevalence continues to rise. Until further studies are done, consideration to safety first should be prioritized including assessment of interventions with less systemic side effects earlier in treatment guidelines.
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