Relationship between Corrected-QT Intervals and Other ECG Characteristics with Methadone Dose in Methadone Maintenance Treatment (MMT) Patients and Healthy Subjects: A Case- Control Study


1 School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

2 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IR Iran

3 Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

4 Endocrinology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran


Abstract Background: In this study we assessed the relationship between corrected-QT intervals and other ECG characteristics with methadone dose and other parameters in MMT patients and healthy subjects. Methods: This was a case-control study which was carried out on patients underwent MMT and healthy control group who had been referred to Ebne-Sina academic hospital, Mashhad during 2014 - 2015. At the time of the study, 40 patients who received MMT therapy for at least 6 months and 40 voluntary healthy subjects who matched on age and sex enrolled in the study. 12-lead ECG was performed for all the patients. Mean QT interval, PR interval and QRS duration in every 12 leads were documented for each patient in maximum. Results: To evaluate the patients, we divided 80 patients into two groups: 40 patients under treatment with Methadone and 40 voluntary participants as control group. There were 20 males and 20 females in each group. Duration of addiction was 214.80  126.99 months in MMT group. Significant differences were observed in PRi between the patient and control groups (P = 0.007), and also between methadone dose and PRi (r = 0.468, P = 0.038) in males. QTc prolongation was reported in 4 patients of addicted group (10%). All of the QTc prolongation patients were female (P = 0.037). There was significant relationship between PRi and weight (P = 0.015), addiction period (P = 0.011), methadone treatment period (P = 0.018) as well as methadone dosage (P = 0.14). Methadone cut off point of 65 mg had a significant relationship with systolic blood pressure (P = 0.002), diastolic blood pressure (P = 0.013), QTCi (P = 0.016) and QRS (P = 0.044); however, no significant relationship was reported with PRi (P = 0.451). Conclusions:We found that there is no exact dosage of methadone in which the side effects such as TdP (Torsade de pointes) or QTc prolongation can be predicted. Female gender and methadone dosage 65 mg were risk factors of our study for QTc prolongation which may result in subsequent deteriorated conditions.


  1. 1.Lan T, Yuan LJ, Hu XX, Zhou Q, Wang J, Huang XX, et al. Effects of CYP2C19 variants on methadone metabolism in vitro. Drug Test Anal. 2017;9(4):634–9. doi: 10.1002/dta.1997. [PubMed: 27199033]. 4 Razavi Int J Med. 2017; 5(2):e13642. Akbari Rad M et al.

    1. Wolff K. Characterization of methadone overdose: clinical considerations and the scientific evidence. Ther Drug Monit. 2002;24(4):457–70. [PubMed: 12142628].
    2. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006;174(11):1589–94. doi: 10.1503/cmaj.051528. [PubMed: 16717269].
    3. Heppe DB, Haigney MC, Krantz MJ. The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study. J Palliat Med. 2010;13(6):638–9. doi: 10.1089/jpm.2009.0427. [PubMed: 20597697].
    4. Fareed A, Vayalapalli S, Byrd-Sellers J, Casarella J, Drexler K, Amar R, et al. Onsite QTc interval screening for patients in methadone maintenance treatment. J Addict Dis. 2010;29(1):15–22. doi: 10.1080/10550880903436044. [PubMed: 20390695].
    5. Fareed A, Vayalapalli S, Scheinberg K, Gale R, Casarella J, Drexler K. QTc interval prolongation for patients in methadone maintenance treatment: a five years follow-up study. Am J Drug Alcohol Abuse. 2013;39(4):235–40. doi: 10.3109/00952990.2013.804525. [PubMed: 23808912].
    6. Buchanan D. Sinus bradycardia related to methadone in a patient with myeloma receiving thalidomide therapy. Palliat Med. 2010;24(7):742–3. doi: 10.1177/0269216310373526. [PubMed: 20921094].
    7. Parikh R, Hussain T, Holder G, Bhoyar A, Ewer AK. Maternal methadone therapy increases QTc interval in newborn infants. Arch Dis Child Fetal Neonatal Ed. 2011;96(2):F141–3. doi: 10.1136/adc.2009.181701. [PubMed: 21081591].
    8. Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005;25(11):1523–9. doi: 10.1592/phco.2005.25.11.1523. [PubMed: 16232014].
    9. Ashwath ML, Ajjan M, Culclasure T. Methadone-induced bradycardia. J Emerg Med. 2005;29(1):73–5. doi: 10.1016/j.jemermed.2004.10.022. [PubMed: 15961013].
    10. Salimi A, Okazi A, Sangsefidi J. Electrocardiographic Findings in Patients with Acute Methadone Poisoning. Int J Med Toxicol Forensic Med. 2014;4(1 (Winter)):11–6.
    11. Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de pointes tachycardias. Swiss Med Wkly. 2005;135(19-20):282–5. [PubMed: 15986265].
    12. Stringer J, Welsh C, Tommasello A. Methadone-associated Q-T interval prolongation and torsades de pointes. Am J Health Syst Pharm. 2009;66(9):825–33. doi: 10.2146/ajhp070392. [PubMed: 19386945].
    13. Lamont P, Hunt SC. A twist on torsade: a prolonged QT interval on methadone. J Gen Intern Med. 2006;21(11):C9–C12. doi: 10.1111/j.1525- 1497.2006.00588.x. [PubMed: 17026725].
    14. Mantelli L, Corti V, Bini R, Cerbai E, Ledda F. Effects of dl-methadone on the response to physiological transmitters and on several functional parameters of the isolated guinea-pig heart. Arch Int Pharmacodyn Ther. 1986;282(2):298–313. [PubMed: 2876691].
    15. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995;63(1):65–76. [PubMed: 8577492].
    16. Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol. 2004;58(2):156– 62. doi: 10.1111/j.1365-2125.2004.02116.x. [PubMed: 15255797].
    17. Bazett HC. An Analysis of the Time-Relations of Electrocardiograms. Ann Noninvasive Electrocardiol. 1997;2(2):177–94. doi: 10.1111/j.1542- 474X.1997.tb00325.x.
    18. Shadnia S, Rahimi M, Hassanian-Moghaddam H, Soltaninejad K, Noroozi A. Methadone toxicity: comparing tablet and syrup formulations during a decade in an academic poison center of Iran. Clin Toxicol (Phila). 2013;51(8):777–82. doi: 10.3109/15563650.2013.830732. [PubMed: 23972442].
    19. Shirinbayan P, Rafiey H, Roshan AV, Narenjiha H, Farhoudian A. Predictors of retention in methadone maintenance therapy: a prospective multi-center study. Sci Res Essays. 2010;5(21):3231–6.
    20. Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler HT, Keefe DL, et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003;105(3):499–506. [PubMed: 14527710].
    21. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23(6):802–5. [PubMed: 12820821].
    22. Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med. 2006;259(1):59–69. doi: 10.1111/j.1365- 2796.2005.01589.x. [PubMed: 16336514].
    23. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14(11):747–53. doi: 10.1002/pds.1112. [PubMed: 15918160].
    24. Cruciani RA, Sekine R, Homel P, Lussier D, Yap Y, Suzuki Y, et al. Measurement of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage. 2005;29(4):385–91. doi: 10.1016/j.jpainsymman.2004.06.012. [PubMed: 15857742].
    25. Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction. 2007;102(2):289–300. doi: 10.1111/j.1360-0443.2006.01668.x. [PubMed: 17222284].
    26. Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res. 2005;11(1):44–9. doi: 10.1159/000081416. [PubMed: 15608471].
    27. Huh B, Park CH. Retrospective analysis of low-dose methadone and QTc prolongation in chronic pain patients. Korean J Anesthesiol. 2010;58(4):338–43. doi: 10.4097/kjae.2010.58.4.338. [PubMed: 20508789].
    28. Reddy S, Hui D, El Osta B, de la Cruz M, Walker P, Palmer JL, et al. The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study. J Palliat Med. 2010;13(1):33–8. doi: 10.1089/jpm.2009.0184. [PubMed: 19824814].
    29. Cruciani RA. Methadone: to ECG or not to ECG...That is still the question. J Pain Symptom Manage. 2008;36(5):545–52. doi: 10.1016/j.jpainsymman.2007.11.003. [PubMed: 18440771].
    30. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387– 95. [PubMed: 19153406].
    31. Schmittner J, Schroeder JR, Epstein DH, Krantz MJ, Eid NC, Preston KL. Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study. Pharmacotherapy. 2009;29(5):495–502. doi: 10.1592/phco.29.5.495. [PubMed: 19397459].
    32. Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95(7):915–8. doi: 10.1016/j.amjcard.2004.11.055. [PubMed: 15781034].