Opioids are drugs used to treat pain. Opioids are addictive and can result in abuse. Tramadol is a unique opioid drug that is increasingly used because it has a lower risk of addiction and abuse than other opioids. It decreases pain, in part, by increasing the body's serotonin levels. This process may increase or decrease the risk of having heart-related problems. With no high-quality studies examining the effect of tramadol on the risk of having heart problems, there is an urgent need to do so. We will answer this question in the UK's Clinical Practice Research Datalink (CPRD). We will compare the chances of having heart problems between patients who use tramadol and those who use another opioid, codeine. The main outcome of our study will be heart attacks. Other outcomes will be chest pain, surgery to open blocked arteries in the heart, strokes, irregular heartbeats, excessive bleeding from blood clotting problems, blood clots in the vein, bleeding, and death. If we find that tramadol changes the risk of having heart problems, we will alert regulatory agencies, doctors, and patients to this risk or benefit. If not, our study will provide reassurance regarding the safety of this drug.
With increasing concerns about opioid abuse and opioid-related deaths, the use of tramadol, a weak opioid with a low potential for abuse, has increased dramatically. Its mechanism of action involves binding to the mu-opioid receptor and inhibiting serotonin and norepinephrine reuptake. Because of its unique effect on serotonin, tramadol may lead to serotonin syndrome, a potentially life-threatening condition linked to hypertension, tachycardia, and cardiac arrhythmia. Conversely, serotonin reuptake inhibitors commonly lower platelet serotonin levels, potentially conferring cardioprotective abilities to tramadol. To date, there have been only three observational studies examining the cardiovascular effects of tramadol, all of which had major limitations. For additional insight, we will conduct a retrospective, population-based cohort study. In the CPRD linked to the Hospital Episode Statistics (HES) and Office for National Statistics (ONS) databases, we will identify a study cohort of patients initiating tramadol or the active comparator codeine for non-cancer pain. Patients will be followed for myocardial infarction (MI; primary outcome), unstable angina, cardiac revascularization, major haemorrhage, ischaemic stroke, arrhythmia, venous thromboembolism (VTE), bleeding, and death (cardiovascular, sudden death, and all-cause). We will compare the risk of outcomes between tramadol and codeine users with marginal structural Cox models weighted by inverse probability of treatment.
Myocardial infarction (primary)
- Ischaemic stroke
- Sudden cardiac death
- Unstable angina
- Arrhythmia
- All-cause mortality
- Cardiac revascularization
- Major haemorrhage
- Cardiovascular death
- Drug utilization
- Venous thromboembolism
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Christopher Filliter - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Jacques LeLorier - Collaborator - Centre Hospitalier de l'Universite de Montreal
Josselin Cabaussel - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Collaborator - McGill University
Linda Ou - Collaborator - McGill University
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University
Roland Grad - Collaborator - McGill University
Sarah Yoon - Collaborator - McGill University
YA-HUI YU - Collaborator - Georgia State University
Ya-Hui Yu - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data