New Study Assesses Tramadol, Codeine, and the Risk of Cardiovascular Events

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Tramadol is examined alongside codeine to determine if it puts patients at a higher risk of adverse cardiovascular events.

In this study, investigators found that tramadol was not associated with short-term increased risk of cardiac events including: myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, cardiovascular deaths, and all-cause mortality, when compared with codeine.

According to the study, tramadol is used for the treatment of moderate to moderately severe pain and is considered a synthetic weak opioid. It’s most similarly compared to codeine but marketed with a lower risk of abuse and misuse than other opioid medications.

It’s been the preferred prescription over codeine for the last decade. In the US from 2007-2011, prescriptions for tramadol have increased by 65%, ranking third among all opioid prescriptions. Tramadol is excluded from the controlled and narcotic drug schedule which could explain the increased rate of use.


Tramadol’s effect on the cardiovascular system is mostly unknown. By increasing the body’s serotonin and norepinephrine levels, the risk of arterial ischemia and cardiovascular events could increase.

The team of investigators, including Kristian Filion, PhD, FAHA, Associate Professor and William Dawson Scholar, McGill University, examined the short-term risk of cardiovascular events with the use of tramadol and compared it with the effect codeine had on the cardiovascular system among patients with non-cancer pain.

Codeine and tramadol seem similar as weaker opioids but their pharmacologic profiles are substantially different. Tramadol inhibits the reuptake of serotonin and norepinephrine, which contributes to its ability to relieve pain but may also lead to adverse effects when compared with classic opioids.

Higher serotonin levels could provoke autonomic hyperactivity which can lead to cardiac adverse events like tachycardia, hypertension, and cardiac arrhythmia. In addition to that, high serotonin levels are also connected to increased risk of coronary artery disease.


Compared with codeine, short-term use of tramadol was not associated with an increased risk of cardiac events among patients with non-cancer pain. There was no evidence of higher risk of unstable angina, ischemic stroke, coronary revascularization, cardiovascular death, or all-cause mortality when compared with codeine.

In the subgroup analysis, investigators found no difference in the prevalence of myocardial infarction in patients with or without a history of cardiovascular disease.

There were 2 recent studies that associated tramadol with an elevated risk of mortality in the adult population compared to NSAIDs or non-use. Investigators pointed out that both study results were limited.

Patients with multiple comorbidities, including cardiovascular, renal, or bleeding disorders, who were at higher risk of mortality, could have been prescribed tramadol in order to avoid NSAIDs.

Consistent with the current study results, these recent studies found that when compared with codeine, tramadol did not show increased risk of mortality.

The Study

In this retrospective population-based cohort study, investigators used data from the Clinical Practice Research Datalink (CPRD). The individuals examined were new users of tramadol or codeine from April 1998-March 2017.

There were 123,394 tramadol users and 914,333 codeine users included in the final cohort. Investigators defined exposure  by using a comparable approach to an intention-to-treat, with a maximum follow-up of 30 days.

Myocardial infarction was the primary endpoint, with the secondary endpoints being unstable angina, ischemic stroke, coronary revascularization, cardiovascular death, and all-cause mortality.

The study, “Tramadol versus Codeine and the Short-term Risk of Cardiovascular Events in Patients with Non-Cancer Pain: A Population-Based Cohort Study” was published in The British Journal of Clinical Pharmacology.