Wednesday, January 27, 2010

Methadone Analgesia Cardiac Concerns Unfounded

Some past reports have suggested that methadone may negatively affect cardiac function, potentially leading to the serious arrhythmia known as torsades de pointes. A recently-reported study in patients with cancer finds that methadone analgesia has little detrimental effect on the QTc interval and can be safely used even in very ill patients.

Researchers at the M.D. Anderson Cancer Center, Houston, Texas, enrolled 100 patients with cancer in a prospective observational study [Reddy et al. 2010]. Subjects were followed clinically and via serial ECGs for QTc changes at baseline prior to initiating methadone analgesia and at 2, 4, and 8 weeks thereafter. QTc prolongation was defined on ECG tracings as >430 milliseconds (ms) in males and >450 ms in females, and clinically significant effects were defined as a QTc interval >25% from baseline or ≥500 ms. All patients had a cancer diagnosis, with most having a limited prognosis of less than 3 months. ECG assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-weeks follow-up, respectively. Reasons for discontinuation were primarily due to hospice transfers or return to the local community and 11 patients discontinued methadone due to typical opioid-related side effects; no dropouts were cardiac related.

At baseline prior to methadone induction, 28 patients (28%) had QTc prolongation and by weeks 2, 4, and 8 after beginning methadone 5 (8%), 3 (8%), and 3 (11%) patients, respectively, still exhibited QTc prolongation. None of the patients had a >25% increase in QTc and only 1 patient had a QTc >500 ms; this person had a QTc of 498 ms at baseline and after increasing to 509 ms without adverse effect at week 2 the QTc resolved by week 4. There was no clinical evidence in any patients of torsades de pointes, ventricular fibrillation, or sudden cardiac death. The researchers conclude that their study supports the safety of methadone analgesia and that it can be“… prescribed without reservation in the palliative care population.”

Commentary: Most publications discussing methadone these days — as well as the ‘black box’ caution on labeling in the U.S. [PI here] — prominently note concerns about its alleged cardiotoxicity, specifically prolongation of the QTc interval that might incur serious arrhythmia including torsade de pointes. However, we have previously discussed controversies surrounding these allegations and limitations of the evidence behind them [see prior blogpost 8/8/09]. This present study by Reddy et al. is of some importance in this ongoing debate about methadone’s cardiac safety for several reasons…

  1. These were quite ill patients who might be considered at high risk for cardiac stress and, indeed, more than a quarter of them had prolonged QTc intervals prior to methadone treatment.

  2. Of the 28 patients with baseline QTc prolongation, almost all (79%) had one or more risk factors that might have been viewed as a further contraindication for methadone therapy, including: medications known to prolong QTc or invoke torsade de pointes, structural cardiac disease, electrolyte abnormalities, and/or female sex.

  3. Despite these many risks, there was only 1 instance of clinically significant QTc prolongation (>500 ms), which was asymptomatic and occurred in a patient with excessive prolongation at baseline; this prolongation became apparent at week 2 and resolved by the week 4 ECG tracing. Remarkably, there was a slight trend toward decreasing median QTc measures in all patients at 4 and 8 weeks, which is worthy of further investigation.

  4. QTc prolongation during methadone therapy was more frequent among patients with QTc interval prolongation at baseline; however, there was no significant association between QTc interval and methadone dose (p=0.45).
A limitation of this study was its observational format with lack of a control group and the relatively small numbers of patients by week 8, making it more of a large case series report. However, reports in the past that originally raised concerns about methadone-related arrhythmia were much smaller case series, and included patients on methadone maintenance for addiction. Also, compared with the very much larger dosages reported in studies involving methadone as addiction therapy, the doses of methadone in this study of palliative-care patients with cancer were relatively low but typical of doses used for pain management — median at 2 weeks 23 mg/day, maximum 90 mg/day. Therefore, it would probably be prudent in the future to consider supposed cardiotoxic effects of methadone separately regarding its use for analgesia versus as maintenance therapy for addiction. Reddy and colleagues assert, “To date, all the studies on methadone for pain control have consistently shown that the risk of methadone-induced QTc prolongation and arrhythmia is minimal.” However, they do recommend that, “For patients with significant risk factors for QTc prolongation or on high doses of methadone (>100 mg/day), monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”

Reference: 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 Palliative Med. 2010,13(1):33-38 [abstract here].
Our thanks also to Andrew Byrne, MD, Redfern, Australia for bringing this article to our attention.

ADDENDUM: Also from M.D Anderson Cancer Center recently, an article on methadone analgesia initiation and rotation in outpatient settings for patients with cancer. The authors note that methadone was safe, with high success rates (ie, relatively few discontinuations) and low side effect profiles. See: Parsons HA, de la Cruz M, El Osta B. Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer. 2010;116(2):520-526. Full article PDF [here]. Insightful discussion by palliative care specialists at the Pallimed weblog [here].