We read with great interest the comments of Daniell on our article showing a QTc interval reduction after substitution of (R,S)-methadone by (R)-methadone in opioid-dependent patients.1 Based on the hypothesis of a prolongation of the QTc interval through a depletion of testosterone levels induced by methadone (1.7- to 2.6-fold lower testosterone plasma levels were measured in patients receiving opiates compared with controls2), Daniell suggests that the reduction of QTc interval observed in our study could be due to an increase of testosterone levels. We believe that this is an unlikely mechanism for several reasons. First, methadone, mainly (S)-methadone, is a potent inhibitor of the cardiac human ether-à-go-go–related gene (hERG) voltage-gated potassium channel, which is implicated in the repolarization of the cardiac action potential, directly related to the QTc interval.3 In addition, morphine strongly decreases testosterone levels in men4 and should therefore increase the QTc interval, which is not the case,5 and which is in agreement with the fact that morphine is not an hERG channel inhibitor.3
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