Although most cancer pain can be controlled with dose titration of first-line opioids, some cancer pain, in particular neuropathic pain, remains a significant challenge, despite the addition of adjuvant drugs such as anticonvulsants and antidepressants. Preclinical and in vitro studies have identified properties of methadone that are not found in most clinically-used opioids. Methadone potentiates the analgesic effects of morphine,4
has antagonist activity at NMDA receptors,5, 6
and inhibitory effects at catecholamine uptake transporters.7
Although it remains to be determined whether any of these effects occur in patients with pain, an increasing number of case reports describe improved pain relief after rotation to methadone.8–13
These potential advantages of methadone must be weighed against relative risk of QTc prolongation and the development of TdP as a consequence of methadone therapy.14
Recent case reports have associated methadone with the development of TdP.14–16
In a retrospective report, Krantz et al.14
describe 17 patients who developed TdP while taking high doses (average equal to approximately 400 mg/day) of oral methadone for chronic pain or methadone maintenance. Most of the patients in these case series had a predisposing risk factor other than methadone for arrhythmia.14–16
As with other non-antiarrhythmic drugs, the effect of methadone on cardiac repolarization appears to be mediated through blockade of the human ether-a-go-go (HERG) potassium channel.17
However, the extrapolation to a clinically relevant methadone concentration from in vitro data17
failed to account for the extensive protein binding of methadone in human plasma18
and, therefore, overestimated the in vivo QT prolongation potency of methadone.
A prospective study by Krantz et al. 19
evaluated 180 methadone maintenance patients at entry to the program and at six months after the start of methadone therapy. The ECG evaluation included a measure of QT dispersion, a predictor of drug-induced TdP. No occurrences of TdP were observed. Methadone modestly increased both QTc interval and QT dispersion. The authors concluded that the magnitude of this effect appears to be substantially less with methadone than with antiarrhythmic drugs known to produce TdP. Three additional recent prospective studies that included follow-up at two weeks to 12 months did not observe TdP and concluded that chronic oral methadone poses little risk of serious QTc prolongation except when other predisposing factors are present.20–22
A retrospective study by Kornick et al 2
compared the ECG of inpatients who had received IV methadone or IV morphine by continuous infusion. In this selected group of patients, the QTc prolongation in IV methadone patients was significantly greater than in IV morphine patients. The association was complicated by the in vitro observation that chlorobutanol, the preservative in parenteral methadone preparations, blocks the HERG potassium channel at relevant concentrations and potentiates the blocking action of methadone in vitro. Thus, the QTc prolongation in these patients may have been caused by a direct cardiotoxic effect of either methadone or chlorobutanol, or by a synergistic interaction of the two compounds. None of the 47 patients who received iv methadone developed TdP.2
When, as in this report, a patient has a history of a significant QTc prolongation (>500 ms) and parenteral methadone is the most effective means of controlling the patient’s pain, the following considerations will reduce the potential for the development of life threatening TdP:
- Awareness of non-drug-related causes of QTc prolongation, including hypokalemia, hypomagnesemia or hypocalcemia, or underlying cardiac disease.
- Avoidance of other drugs that can prolong QTc.19
- Avoidance of other drugs that can inhibit the biotransformation of methadone such as CYP3A4 inhibitors.23
- Availability of preservative-free parenteral methadone. Since the current standard practice does not mandate the use of preservative-free methadone, this preparation is not yet generally available and must be ordered from and outside source. This limits our ability to use this preparation to manage a pain crisis. In this case, parenteral methadone (with preservative) was rapidly titrated and then converted to the oral route before we were able to obtain the preservative-free methadone. However, based on a growing concern about the potential contribution of the chlorobutanol preservative to QTc prolongation with parenteral methadone, we recommend that preservative-free methadone be available for patients with a predisposition to or higher risk of QTc prolongation.
- Determination of the patient’s QTc at specified time intervals during parenteral methadone therapy.
- The goals of care, including the risk and consequences of TdP, should be discussed.
Given the limited data on the risk of QTc prolongation and TdP associated with methadone infusions, there is no definitive answer that is adequate for all patients. The decision must be tailored to the individual clinical situation and goals of care. Good communication among the patient, family and providers is a critical component of the decision process. For the patient in this case report, initiating and continuing a methadone infusion during the patient’s pain crisis and then converting to the oral route of drug administration when the pain had been brought under control was a reasonable decision. In retrospect the benefit far outweighed the risk.