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Methadone and Torsade de Pointes: How Can We Better Understand the Association?

      Methadone-associated QTc interval prolongation is used as a surrogate marker of its association with torsade de pointes, a potentially fatal arrhythmia. Unfortunately, prediction of torsade de pointes based only on QTc interval prolongation is unreliable. QTc interval prolongation beyond normal limits (≥450 msec for men and ≥470 msec for women) has been noted in up to 20% of individuals taking methadone,
      • Mayet S.
      • Gossop M.
      • Lintzeris N.
      • Markides V.
      • Strang J.
      Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?.
      but only a tiny fraction might develop torsade de pointes.
      Drugs (including methadone
      • Katchman A.N.
      • McGroary K.A.
      • Kilborn M.J.
      • et al.
      Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.
      ) inhibiting rapid delayed rectifier potassium ion current (IKr) channels or its cloned equivalent, the human Ether-à-go-go-Related Gene (hERG) channel, can delay ventricular repolarization and prolong the QT interval. However, identifying a propensity for a drug to produce hERG blockade is not, by itself, an adequate predictor of torsade de pointes liability. hERG blocking potency should be considered in the context of drug therapeutic concentrations.
      • Katchman A.N.
      • McGroary K.A.
      • Kilborn M.J.
      • et al.
      Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.
      Also, multiple ion channel blocking effects of a drug may alter potential effects of the hERG block. It is important to consider hERG blockade alongside other in vitro and in vivo data to obtain an integrated assessment of a drug's liability for QT prolongation and torsade de pointes potential.
      • Hancox J.C.
      • McPate M.J.
      • El H.A.
      • Zhang Y.H.
      The hERG potassium channel and hERG screening for drug-induced torsades de pointes.
      To understand clinical factors linking methadone with QTc prolongation and torsade de pointes, we reviewed the 32 case reports (31 adults, 1 infant) available on this topic.

      Vieweg VRW, Hasnain M, Howland RH, et al. Methadone, QTc interval prolongation and torsade de pointes: case reports offer the best understanding of this problem. Ther Adv Psychopharmacol. In press. doi 10.1177/2045125312469982.

      For the 31 adult cases, 19 were men and 12 women. Age of adults ranged from 22 to 61 years (mean 44.4 years for men and 46.3 years for women). Female sex and increasing age are risk factors for QTc interval prolongation.
      • Bednar M.M.
      • Harrigan E.P.
      • Anziano R.J.
      • Camm A.J.
      • Ruskin J.N.
      The QT interval.
      Young adults and men are much more likely than older adults and women to require methadone treatment for opiate dependence, which may explain the relatively young age and preponderance of male cases in the sample studied.
      QTc interval measurement was reported for 27 adult cases (480-710 msec). Methadone dose specified for 29 cases ranged from 40 mg/day to 700 mg/day. Ten cases (32.3%) experienced QTc interval prolongation at methadone doses ≤120 mg/day, of which 9 developed torsade de pointes. Among the 21 cases developing torsade de pointes for whom QTc interval measurements and daily methadone doses were recorded, there were insignificant correlations between QTc interval and methadone dose using both parametric and nonparametric statistics. Others have reported a dose-response association between methadone and QTc interval.
      • Mayet S.
      • Gossop M.
      • Lintzeris N.
      • Markides V.
      • Strang J.
      Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?.
      • Krantz M.J.
      • Kutinsky I.B.
      • Robertson A.D.
      • Mehler P.S.
      Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes.
      However, given the highly variable bioavailability of methadone and likely concurrent use of medications that inhibit its metabolism, any correlation between dose, per se, and QTc prolongation may be misleading. A recent study of 80 patients enrolled in an opiate maintenance treatment program
      • Stallvik M.
      • Nordstrand B.
      • Kristensen O.
      • Bathen J.
      • Skogvoll E.
      • Spigset O.
      Corrected QT interval during treatment with methadone and buprenorphine—Relation to doses and serum concentrations.
      found no association between QTc interval and methadone serum concentrations.
      Among the 31 adult cases we reviewed, major risk factors for QTc interval prolongation and torsade de pointes included female sex (n = 12), heart disease (n = 11), electrolyte imbalance (hypokalemia [n = 7] and hypomagnesemia [n = 4]), metabolic drug interactions (n = 19), concurrent use of QTc-prolonging medications (n = 14), hepatic impairment (n = 6), sinus bradycardia (n = 8), and cocaine (n = 6). Multiple risk factors besides methadone were identified in 24 of 31 adult patients (77.4%). The presence of one or more of these risk factors may drive QTc interval prolongation to torsade de pointes. Stallvik et al
      • Stallvik M.
      • Nordstrand B.
      • Kristensen O.
      • Bathen J.
      • Skogvoll E.
      • Spigset O.
      Corrected QT interval during treatment with methadone and buprenorphine—Relation to doses and serum concentrations.
      did not find an association between methadone concentration and QTc interval, but observed that low serum potassium levels increased QTc interval significantly. Similarly, in a study
      • Mayet S.
      • Gossop M.
      • Lintzeris N.
      • Markides V.
      • Strang J.
      Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?.
      reporting QTc interval prolongation in 18% of methadone users, 19.3% were co-prescribed a QTc-prolonging medication and 47% used cocaine. We need to closely monitor patients for these risk factors and correct them if possible. Serial electrocardiogram monitoring should be considered when dealing with modifiable risk factors.
      Methadone (or any other drug)-associated torsade de pointes is a rare event. We believe considering torsade de pointes merely an extension of QTc interval prolongation and using conventional statistics to study this has serious limitations in better understanding drug–torsade de pointes association. Case-report or case-series format will better identify risk factors underlying the association, allowing more systematic analysis. We plan to establish a dedicated Web site (www.qtcprolongation.com) and encourage clinicians to report cases with drug-induced QTc interval prolongation or torsade de pointes.

      Hasnain M. Report cases of drug-induced QTc prolongation with or without TdP. Available at: http://www.qtcprolongation.com. Accessed January 10, 2013.

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      1. Vieweg VRW, Hasnain M, Howland RH, et al. Methadone, QTc interval prolongation and torsade de pointes: case reports offer the best understanding of this problem. Ther Adv Psychopharmacol. In press. doi 10.1177/2045125312469982.

        • Bednar M.M.
        • Harrigan E.P.
        • Anziano R.J.
        • Camm A.J.
        • Ruskin J.N.
        The QT interval.
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        • Krantz M.J.
        • Kutinsky I.B.
        • Robertson A.D.
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        Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes.
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        • Nordstrand B.
        • Kristensen O.
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      2. Hasnain M. Report cases of drug-induced QTc prolongation with or without TdP. Available at: http://www.qtcprolongation.com. Accessed January 10, 2013.