Opioids, commonly used for pain management, have been associated with a variety of cardiac complications, including QT prolongation, which is a critical marker of increased risk for cardiac rhythm abnormalities. QT prolongation represents a delay in the heart’s electrical system, increasing the risk of potentially fatal arrhythmias such as torsades de pointes. Several opioids, including methadone, buprenorphine, and tramadol, have been implicated in prolonged QT interval due to their complex pharmacological interactions with cardiac ion channels, particularly potassium channels involved in cardiac repolarization (1).
Methadone, a synthetic opioid commonly used in opioid substitution therapy, is most commonly associated with QT prolongation. Methadone’s effect on the heart is primarily attributed to its inhibition of hERG potassium channels, which are critical for the cardiac repolarization process. This inhibition can lead to delayed ventricular repolarization, impacting cardiac rhythm (2). The degree of QT prolongation with methadone is dose-dependent, and higher doses are associated with a greater increase in QT interval. Clinical guidelines recommend regular electrocardiogram (ECG) monitoring for patients receiving high doses of methadone or those with additional risk factors for QT prolongation, such as electrolyte imbalances or concomitant use of other QT-prolonging medications (3).
Buprenorphine, another opioid used in the treatment of addiction, has a lower risk of QT prolongation compared to methadone. However, it still poses a risk, especially when used in combination with other drugs that prolong the QT interval or in patients with predisposing conditions. Buprenorphine’s partial agonist activity at the opioid receptor and antagonist effects at the kappa receptor may lessen its impact on the QT interval compared to full agonists, such as methadone (4). Therefore, understanding individual patient profiles and medication regimens is critical to reducing the risk of arrhythmias when prescribing opioids.
Opium and its derivatives, including natural opioids such as morphine and codeine, can also lead to prolonged QT, although to a lesser extent than synthetic opioids such as methadone. In a study comparing opium users to those taking synthetic opioids, the natural opioids were found to produce less significant changes in the QT interval. However, the exact mechanisms behind these differences are still under investigation (1).
The risk of QT prolongation in opioid users is compounded by the presence of additional risk factors such as HIV, where interactions with antiretroviral drugs, particularly those that inhibit cytochrome P450 enzymes such as CYP3A4, may exacerbate the effect. This highlights the importance of a comprehensive patient evaluation that includes assessment of drug interactions and careful consideration of the cardiovascular implications of opioid therapy (5).
In conclusion, opioids carry a significant risk for prolonged QT, with synthetic opioids such as methadone being particularly implicated. Regular ECG monitoring, dose adjustment, and careful management of drug interactions are essential strategies to minimize the cardiac risks associated with opioid therapy. As opioid use continues to be a cornerstone of pain management and addiction treatment, further research is needed to elucidate the precise mechanisms and develop safer therapeutic strategies to mitigate the cardiovascular risks associated with these drugs.
References
- Golibkhon A, Akbar Gafur Ugli B, Makhamadjonov Farkhod Ugli M. Opioid Agents and Cardiac Arrhythmia: A Literature Review. Cureus. 2023;15(4):e38007. Published 2023 Apr 23. doi:10.7759/cureus.38007
- Isbister GK, Brown AL, Gill A, Scott AJ, Calver L, Dunlop AJ. QT interval prolongation in opioid agonist treatment: analysis of continuous 12-lead electrocardiogram recordings. Br J Clin Pharmacol. 2017;83(10):2274-2282. doi:10.1111/bcp.13326
- Chen A, Ashburn MA. Cardiac Effects of Opioid Therapy. Pain Med. 2015;16 Suppl 1:S27-S31. doi:10.1111/pme.12915
- Klivinyi C, Bornemann-Cimenti H. Pain medication and long QT syndrome. Korean J Pain. 2018;31(1):3-9. doi:10.3344/kjp.2018.31.1.3
- Liu J, Shah SK, Basu-Ray I, Garcia-Diaz J, Khalid K, Saeed M. QT prolongation in HIV-positive patients: Review article. Indian Heart J. 2019;71(6):434-439. doi:10.1016/j.ihj.2019.11.259