Elsevier

Heart & Lung

Volume 40, Issue 5, September–October 2011, Pages 448-453
Heart & Lung

Care of the Critically Ill
Methadone-induced torsades de pointes: A twist of fate

https://doi.org/10.1016/j.hrtlng.2010.12.008Get rights and content

Abstract

A case of methadone-induced torsades de pointes is presented to demonstrate clinical features that predispose patients to this serious cardiac arrhythmia. A patient who was receiving methadone maintenance treatment for heroin addiction presented to the hospital with dizziness and near-syncope. He was taking a relatively high dose of methadone but was not taking any concomitant cytochrome P450 inhibitor or QT-prolonging drugs. He had prolonged corrected QT interval, hypokalemia, and hypomagnesemia on admission and was later found to have severe left ventricular dysfunction. On admission to a telemetry unit, the patient experienced chest discomfort and palpitations with corresponding torsades de pointes that was terminated with correction of hypokalemia and hypomagnesemia. The corrected QT interval became shorter but remained profoundly prolonged until methadone was substituted with buprenorphine.

Section snippets

Case Presentation

A 61-year-old man had a history of smoking, diabetes mellitus, hypertension, anemia, posttraumatic stress disorder, and anxiety. He was a previous heroin user and had been receiving maintenance methadone of 110 mg/day. He presented to the emergency department after 2 episodes of dizziness and near-syncope. The first episode occurred the night before hospital admission and lasted less than 1 minute without chest pain, shortness of breath, shaking movements, neurologic deficits, or bladder

Incidence

Oral methadone significantly increases the QTc interval, and more than 80% of patients in MMT programs have some degree of QTc prolongation.7, 10, 17 However, profound QTc prolongation is less common, and its reported incidence in the literatures varies from 2.4% to 16.7%.9, 17, 18 Data on methadone-induced TdP are limited, and prior publications presented a small series of patients or individual case reports.6, 7, 9 Twenty-two percent of all Food and Drug Administration (FDA) Adverse Event

Cause

The QT interval represents ventricular depolarization and repolarization. Methadone acts by inhibiting rectifier potassium ion flux IKr, which leads to an increased action potential duration and a prolonged QTc interval.20, 21 It has been reported that increases in QTc interval are dose dependent.7, 22, 23, 24 Most of the fatal cases of TdP in the FDA MedWatch system involved patients taking more than 100 mg/day of methadone.25 Two studies of 5 and 17 patients with methadone-induced TdP

Diagnosis

Most patients with methadone-induced QTc prolongation remain asymptomatic, and the diagnosis depends on the documentation of a long QTc.9, 10 The QT interval is measured from the beginning of Q wave to the end of T wave on the ECG (Figure 4). This interval is affected by heart rate and needs to be corrected accordingly. Multiple acceptable formulas have been described, such as Bazett’s correction, Fridericia’s correction, and Framingham correction.11, 13, 29, 30, 31 Bazett’s correction is the

Treatment

In the presence of QTc prolongation, methadone dose should be adjusted or switched to an alternative drug and the ECG should be repeated.35 Methadone is recommended to be promptly substituted by another drug if the patient’s QTc is ≥ 500 msec, and the patient should also be referred to a cardiologist.35 In patients with nonsustained TdP, electrolyte abnormalities need to be promptly corrected, and methadone and other concomitant CYP450 inhibitors or QT prolonging drugs need to be discontinued.

Guidelines for Methadone Therapy

Before initiating methadone therapy, a detailed history and physical examination are important; particular attention should be given to any symptoms or family history suggestive of heart disease or syncope.11, 39 Medication review needs to account for any concurrent drugs that may cause QTc prolongation. The Maudsley prescribing guidelines advise the clinician to avoid prescribing methadone, especially in high doses, to patients who are taking CYP450 inhibitor or QTc prolongation drugs.35 Any

Discussion

It is generally agreed that there is enough evidence to suggest that methadone may cause TdP in patients who also have coexisting risk factors for QT prolongation/TdP or in those receiving very high doses of methadone.6 The case presentation demonstrated several clinical features associated with methadone-induced TdP. The patient was taking a relatively high dose of methadone and had symptoms of dizziness and near syncope, which should arouse a strong suspicion for methadone-induced TdP. In

Conclusions

To prevent possible fatal outcome from methadone-induced TdP, healthcare providers need to be aware of this potential life-threatening adverse effect of methadone treatment and should be diligent in identifying patients who are at risk of developing TdP. The providers need to obtain careful medication and drug-use histories, screen for risk factors associated with QT prolongation, counsel patients regarding potential drug interactions, and measure the QT interval before and during methadone

References (42)

  • B. Vastag

    Methadone regulations overhauled

    JAMA

    (2001)
  • M.J. Krantz et al.

    Torsade de pointes associated with very-high dose methadone

    Ann Intern Med

    (2002)
  • C. Sticherling et al.

    Methadone-induced TdP tachycardias

    Swiss Med Wkly

    (2005)
  • Food and Drug Administration methadone alert (2006): death, narcotic overdose, and cardiac arrhythmias. Available at:...
  • G.B. Ehret et al.

    Drug-induced long QT syndrome in injection drug users receiving methadone

    Arch Intern Med

    (2006)
  • I. Maremmani et al.

    QT interval prolongation in patients on long-term methadone maintenance therapy

    Eur Addic Res

    (2005)
  • S. George et al.

    Methadone and the heart: what the clinician needs to know

    Curr Drug Abuse Rev

    (2008)
  • Y.G. Yap et al.

    Drug induced QT prolongation and torsades de pointes

    Heart

    (2003)
  • A. Chan et al.

    Drug induced QT prolongation and torsades de pointes: evaluation of a QT nomogram

    Q J Med

    (2007)
  • European Agency for the Evaluation of Medical Products (EMEA) public statement to suspend the marketing authorization...
  • M.J. Krantz et al.

    Physician awareness of the cardiac effects of methadone: results of a national survey

    J Addict Dis

    (2007)
  • Cited by (16)

    • State-of-the-art treatment of opioid use disorder

      2018, The Assessment and Treatment of Addiction: Best Practices and New Frontiers
    • Magnesium enhances opioid-induced analgesia – What we have learnt in the past decades?

      2017, European Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Magnesium has an antiarrhythmic effect on some arrhythmias (e.g. in torsades de pointes [Tdps] and atrial paroxysmal tachycardia). Tdps and prolonged QT interval were reported after methadone administration (Raina et al., 2014; Thanavaro and Thanavaro, 2011; van den Beuken-van Everdingen et al., 2013). Intravenous administration of MgSO4 as co-treatment has proven efficacious in some cases of methadone-induced Tdps (Khalesi et al., 2014; Pimentel and Mayo, 2008; Rajpal et al., 2013).

    • Opioid analgesics and narcotic antagonists

      2014, Side Effects of Drugs Annual
      Citation Excerpt :

      Presumably there are other susceptibility factors that can contribute to the risk. A man who was taking methadone maintenance treatment developed dizziness and near syncope [67A]. His QTc interval was prolonged, and there was hypokalemia, hypomagnesemia, and severe left ventricular dysfunction.

    • Management of opioid use disorders: A national clinical practice guideline

      2018, CMAJ
      Citation Excerpt :

      Conversely, methadone can increase the risk of a rare but fatal ventricular arrhythmia (torsades de pointes) because of its substantial QT-prolonging effects, especially at higher doses.47 Case series have reported that transitioning patients taking methadone who were experiencing torsades de pointes to buprenorphine corrected the condition.48,49 Long-term opioid use, including opioid agonist treatment, may lead to abnormalities in the endocrine system, mainly affecting the gonadal axis and leading to hypogonadism.50,51

    • CARDIAC EFFECTS

      2022, Karch's Drug Abuse Handbook: Third Edition
    View all citing articles on Scopus
    View full text