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

Document Type : Original Article

Authors

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.

Keywords

Open Access Policy: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

References

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. [PubMed: 27199033]. 4 Razavi Int J Med. 2017; 5(2):e13642. Akbari Rad M et al.
https://doi.org/10.1002/dta.1997
PMid:27199033
 
2. Wolff K. Characterization of methadone overdose: clinical considerations and the scientific evidence. Ther Drug Monit. 2002;24(4):457-70. [PubMed: 12142628].
https://doi.org/10.1097/00007691-200208000-00001
PMid:12142628
 
3. 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. [PubMed: 16717269].
https://doi.org/10.1503/cmaj.051528
PMid:16717269 PMCid:PMC1459894
 
4. 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. [PubMed: 20597697].
https://doi.org/10.1089/jpm.2009.0427
PMid:20597697
 
5. 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. [PubMed: 20390695].
https://doi.org/10.1080/10550880903436044
PMid:20390695
 
6. 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. [PubMed: 23808912].
https://doi.org/10.3109/00952990.2013.804525
PMid:23808912
 
7. Buchanan D. Sinus bradycardia related to methadone in a patient with myeloma receiving thalidomide therapy. Palliat Med. 2010;24(7):742-3. [PubMed: 20921094].
https://doi.org/10.1177/0269216310373526
PMid:20921094
 
8. 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. [PubMed: 21081591].
https://doi.org/10.1136/adc.2009.181701
PMid:21081591
 
9. Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005;25(11):1523-9. [PubMed: 16232014].
https://doi.org/10.1592/phco.2005.25.11.1523
PMid:16232014
 
10. Ashwath ML, Ajjan M, Culclasure T. Methadone-induced bradycardia. J Emerg Med. 2005;29(1):73-5. [PubMed: 15961013].
https://doi.org/10.1016/j.jemermed.2004.10.022
PMid:15961013
 
11. 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.
 
12. 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].
 
13. 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. [PubMed: 19386945].
https://doi.org/10.2146/ajhp070392
PMid:19386945
 
14. Lamont P, Hunt SC. A twist on torsade: a prolonged QT interval on methadone. J Gen Intern Med. 2006;21(11):C9-C12. [PubMed: 17026725].
https://doi.org/10.1111/j.1525-1497.2006.00588.x
PMid:17026725 PMCid:PMC1831670
 
15. 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].
 
16. 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].
https://doi.org/10.1016/0304-3959(95)00017-M
PMid:8577492
 
17. Dale O, Sheffels P, Kharasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol. 2004;58(2):156- 62. [PubMed: 15255797].
https://doi.org/10.1111/j.1365-2125.2004.02116.x
PMid:15255797 PMCid:PMC1884589
 
18. Bazett HC. An Analysis of the Time-Relations of Electrocardiograms. Ann Noninvasive Electrocardiol. 1997;2(2):177-94.
https://doi.org/10.1111/j.1542-474X.1997.tb00325.x
 
19. 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 [PubMed: 23972442].
https://doi.org/10.3109/15563650.2013.830732
PMid:23972442
 
20. 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.
 
21. 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].
https://doi.org/10.1016/S0304-3959(03)00205-7
PMid:14527710
 
22. 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].
https://doi.org/10.1592/phco.23.6.802.32186
PMid:12820821
 
23. Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med. 2006;259(1):59-69. [PubMed: 16336514].
https://doi.org/10.1111/j.1365-2796.2005.01589.x
PMid:16336514
 
24. 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.[PubMed: 15918160].
https://doi.org/10.1002/pds.1112
PMid:15918160
 
25. 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. [PubMed: 15857742].
https://doi.org/10.1016/j.jpainsymman.2004.06.012
PMid:15857742
 
26. 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. [PubMed: 17222284].
https://doi.org/10.1111/j.1360-0443.2006.01668.x
PMid:17222284
 
27. 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. [PubMed: 15608471].
https://doi.org/10.1159/000081416
PMid:15608471
 
28. 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. [PubMed: 20508789].
https://doi.org/10.4097/kjae.2010.58.4.338
PMid:20508789 PMCid:PMC2876853
 
29. 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. [PubMed: 19824814].
https://doi.org/10.1089/jpm.2009.0184
PMid:19824814 PMCid:PMC2939847
 
30. Cruciani RA. Methadone: to ECG or not to ECG...That is still the question. J Pain Symptom Manage. 2008;36(5):545-52. [PubMed: 18440771].
https://doi.org/10.1016/j.jpainsymman.2007.11.003
PMid:18440771
 
31. 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].
https://doi.org/10.7326/0003-4819-150-6-200903170-00103
PMid:19153406
 
32. 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. [PubMed: 19397459].
https://doi.org/10.1592/phco.29.5.495
PMid:19397459 PMCid:PMC3150470
 
33. 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. [PubMed: 15781034].
https://doi.org/10.1016/j.amjcard.2004.11.055
PMid:15781034

Files

Share

How to cite

Statistics