Methadone prolongs cardiac conduction in young patients with cancer-related pain
DOI:
https://doi.org/10.5055/jom.2016.0325Keywords:
methadone, complex pain, cardiac conduction, pediatric oncologyAbstract
Objective: Methadone prolongs cardiac conduction, from mild corrected QT (QTc) prolongation to torsades de pointes and ventricular fibrillation, in adults. However, methadone use for pain and its effects on cardiac conduction have not been investigated in pediatric populations.
Methods: A retrospective review of QTc intervals in patients receiving methadone analgesia was conducted. Medical records from a 4-year period (September 2006 to October 2010) at a pediatric oncology institution were reviewed, and correlations were tested between cardiac conduction and methadone dosage and duration of therapy, electrolyte levels, renal and hepatic dysfunction, and concurrent medications.
Results: Of the 61 patients who received methadone, 37 met our inclusion criteria and underwent 137 electrocardiograms (ECGs). During methadone treatment, the mean QTc was longer than that at baseline (446.5 vs 437.55 ms). The mean methadone dose was 27.0 ± 24.3 mg/d (range, 5-125 mg/d; median, 20 mg/d) or 0.47 ± 0.45 mg/kg per day (range, 0.05-2.25 mg/kg per day; median, 0.37 mg/kg per day), and the mean duration of therapy was 49 days. The authors identified a correlation between automated and manual ECG readings by two cardiologists (Pearson r = 0.649; p < 0.0001), but the authors found no correlations between methadone dose or duration and concurrent QTc-prolonging medications, sex, age, electrolyte abnormalities, or renal or hepatic dysfunction.
Conclusion: At a clinically effective analgesic dose, methadone dosage and duration were not correlated with QTc prolongation, even in the presence of other risk factors, suggesting that methadone use may be safe in pediatric populations. The correlation between automated and manual ECG readings suggests that automated ECG readings are reliable for monitoring cardiac conductivity during the reported methadone-dosage regimens.
References
Anghelescu D, Faughnan L, Hankins G, et al.: Methadone use in children and young adults at a cancer center: A retrospective study. J Opioid Manag. 2011; 7(5): 353-361.
Krantz MJ, Mehler PS: QTc prolongation: methadone's efficacy-safety paradox. Lancet. 2006; 368(9535): 556-557.
Krantz MJ, Lewkowiez L, Hays H, et al.: Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002; 137(6): 501-504.
Reddy S, Hui D, El Osta B, 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): 33-38.
Shaiova L, Berger A, Blinderman CD, et al.: Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008; 6(2): 165-176.
Gorman AL, Elliott KJ, Inturrisi CE: The d- and l-isomers of methadone bind to the non-competitive site on the N-methyld-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997; 223(1): 5-8.
Andrews CM, Krantz MJ, Wedam EF, et al.: Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation. Cardiol J. 2009; 16(3): 210-217.
Bryson J, Tamber A, Seccareccia D, et al.: Methadone for treatment of cancer pain. Curr Oncol Rep. 2006; 8(4): 282-288.
Gourlay G, Cherry D, Cousins M: A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986; 25: 297-312.
Ventafridda V, Ripamonti C, Bianchi M, et al.: A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom Manage. 1986; 1(4): 203-207.
Bruera E, Watanabe S, Fainsinger R, et al.: Custom-made capsules and suppositories of methadone for patients on high-dose opioids for cancer pain. Pain. 1995; 62(2): 141-146.
De Conno F, Groff L, Brunelli C, et al.: Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol. 1996; 14: 2836-2842.
Ripamonti C, Zecca E, Bruera E: An update on the clinical use of methadone for cancer pain. Pain. 1997; 70(2-3): 109-115.
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): 638-639.
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): 747-753.
Sekine R, Obbens EA, Coyle N, et al.: The successful use of parenteral methadone in a patient with a prolonged QTc interval. J Pain Symptom Manage. 2007; 34(5): 566-569.
Anchersen K, Clausen T, Gossop M, et al.: Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: A mortality assessment study. Addiction. 2009; 104(6): 993-999.
Ehret GB, Voide C, Gex-Fabry M, et al.: Drug-induced long QT syndrome in injection drug users receiving methadone: High frequency in hospitalized patients and risk factors. Arch Intern Med. 2006; 166(12): 1280-1287.
Krantz MJ, Lowery CM, Martell BA, et al.: Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005; 25(11): 1523-1529.
Krantz MJ, Martell BA, Arnsten JH, et al.: Medications that prolong the QT interval. JAMA. 2003; 290(8): 1025; author reply 1026.
Krantz MJ, Martin J, Stimmel B, et al.: QTc interval screening in methadone treatment. Ann Intern Med. 2009; 150(6): 387-395.
Zeltser D, Justo D, Halkin A, et al.: Torsade de pointes due to noncardiac drugs: Most patients have easily identifiable risk factors. Medicine (Baltimore). 2003; 28(4): 282-290.
Peles E, Bodner G, Kreek MJ, et al.: 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.
Kay GN, Plumb VJ, Arciniegas JG, et al.: Torsade de pointes: The long-short initiating sequence and other clinical features: Observations in 32 patients. J Am Coll Cardiol. 1983; 2(5): 806-817.
Makkar RR, Fromm BS, Steinman RT, et al.: Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993; 270(21): 2590-2597.
Martell BA, Arnsten JH, Ray B, et al.: The impact of methadone induction on cardiac conduction in opiate users. Ann Intern Med. 2003; 139(2): 154-155.
Lexicomp Online: Drug Index. Hudson, OH: Wolters Kluwer Health, 2012. Available at http://www.crlonline.com/lco/action/home/switch. Accessed July 2, 2012.
Davies D, DeVlaming D, Haines C: Methadone analgesia for children with advanced cancer. Pediatr Blood Cancer. 2008; 51(3): 393-397.
Friedrichsdorf SJ, Kang TI: The management of pain in children with life-limiting illnesses. Pediatr Clin North Am. 2007; 54(5): 645-672, x.
Fredheim OM, Borchgrevink PC, Hegrenaes L, et al.: Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: A prospective 9-month follow-up study. J Pain Symptom Manage. 2006; 32(2): 180-185.
Martell BA, Arnsten JH, Krantz MJ, et al.: Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005; 95(7): 915-918.
Amos LB, D’Andrea LA: Severe central sleep apnea in a child with leukemia on chronic methadone therapy. Pediatr Pulmonol. 2013; 48(1): 85-87.
Boyer EW, McCance-Katz EF, Marcus S: Methadone and buprenorphine toxicity in children. Am J Addict. 2010; 19(1): 89-95.
Grodofsky S, Edson E, Huang S, et al.: The QTc effect of low-dose methadone for chronic pain: A prospective pilot study. Pain Med. 2015; 16(6): 1112-1121.
Wheeler AD, Tobias JD: Bradycardia during methadone therapy in an infant. Pediatr Crit Care Med. 2006; 7(1): 83-85.
Roth M, Davies D, Friebert S, et al.: Attitudes and practices of pediatric oncologists regarding methadone use in the treatment of cancer-related pain: Results of a North American Survey. J Pediatr Hematol Oncol. 2013; 35(2): 103-107.
Ebert SN, Liu XK, Woosley RL: Female gender as a risk factor for drug-induced cardiac arrhythmias: Evaluation of clinical and experimental evidence. J Womens Health. 1998; 7(5): 547-557.
Rautaharju PM, Surawicz B, Gettes LS, et al.: AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009; 53(11): 982-991.
Tyl B, Azzam S, Blanco N, et al.: Improvement and limitation of the reliability of automated QT measurement by recent algorithms. J Electrocardiol. 2011; 44(3): 320-325.
Moulin D, Palma D, Watling C, et al.: Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci. 2005; 32(3): 340-343.
Published
How to Cite
Issue
Section
License
Copyright 2005-2024, Weston Medical Publishing, LLC
All Rights Reserved