Tramadol Linked to Higher Risk of Mortality Compared to Codeine

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant differences in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather — such as from randomized controlled trials — clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona, Spain.

Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published October 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019-2020 show that tramadol was the most prescribed opioid in the UK, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20% to 50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007-2017 and were followed up to December 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs 48.5%), neck/shoulder pain (28.6% vs 29.5%), and osteoarthritis (15.3% vs 15.5%). The most commonly used drugs were ibuprofen (34.4% vs 34.3%) and paracetamol/acetaminophen (37.1% vs 36.8%)

Higher Risk of Adverse Outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08 to 2.56]; absolute rate differences [ARD], 7.37 per 1000 person-years [95% CI, 6.09 to 8.78]), cardiovascular events (10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05 to 1.27]; ARD, 1.36 per 1000 person-years [95% CI, 0.45 to 2.36]), and fractures (12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37 to 1.65]; ARD, 4.10 per 1000 person-years [95% CI, 3.02 to 5.29]).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs older ones (HR, 3.14 [95% CI, 1.82 to 5.41] vs 2.39 [95% CI, 2.20 to 2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events vs men (HR,1.32 [95% CI, 1.19 to 1.46] vs 1.03 [95% CI, 0.93 to 1.13]; P < .001 for interaction).

Potential for Confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, Division of Rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, Massachusetts, noted that since it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set ─ blood pressure, pain, physical activity, tobacco use, body mass index ─ may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived Safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, Illinois, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAP Jordi Gol Foundation; grant 4R18/060-1). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Reyes has disclosed no relevant financial relationships. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and NIH; and royalties from UpToDate. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality (AHRQ) (R01HS027426.

J Am Med Assoc. 2021;326(15):1504-1515, 1483-1484. Abstract, Editorial

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