Article of the Month

Reviewed by Dr Carla Ripamonti (Italy), an IAHPC Board Member

The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study

Reddy S, Hui D, Osta BEI, de la Cruz M, Walker P, Plamer JL, Bruera E Journal  of Palliative Medicine 2010; 13/1:33-38  

Oral methadone is considered to be a useful alternative to oral morphine in treating moderate to severe cancer pain. Methadone is a synthetic opioid analgesic displaying agonistic activity. It is characterized by a large inter-individual variation in pharmacokinetics and by a rapid and extensive distribution phases (half-life of 2-3 hours) followed by a slow elimination phase (beta half-life of 15 to 60 hours).  The latter may cause accumulation problems if doses are too large or the dosing intervals are too short over a long period of time. This is the main reason why close attention is required when using this drug in treating chronic cancer pain. Methadone has the potential to control pain that does not respond to morphine or other opioids because methadone shows incomplete cross-tolerance with other mu-opioid receptor agonist analgesics. There is also the possibility of using methadone instead of other opioids when an accumulation of active metabolites of them are the cause of side effects such as myoclonus, sedation, confusion, nausea and vomiting. Methadone is a more potent opioid than believed. The dose ratio between methadone and the other strong opioids varies significantly  (from 1:4 to 12-14:1) according to the type and doses of opioids previously administered.

For this reason, caution is recommended when switching from any opioid to methadone, especially in patients who are tolerant to high doses of other opioids.  

Some reports, which are very relevant to the methadone maintenance population in which the average methadone dose is generally high, suggest that high doses of methadone (higher risk > 300 mg/day or 600 mg/day) may prolong the QTc interval (QT interval corrected for heart rate) and occasionally cause torsades de pointes, polymorphic ventricular tachycardia and sudden death. The QT interval is the time between the beginning of the Q wave and the end of the T wave on the ECG tracing and is affected by the heart rate.  

In a prospective longitudinal study carried out to evaluate the affect of methadone on QTc  in methadone naïve cancer patients seen in the palliative care setting, the authors enrolled 100 consecutive patients with  cancer related pain who received methadone as a first opioid or after switching from other opioids. 

Patients with a history of arrhythmias, pacemaker, prior defibrillation and/or impaired cognitive function were excluded. 

Three electrocardiograms (ECGs) 5 minutes apart, were performed at baseline and at 2, 4 and 8 weeks after methadone initiation in order to determine the QTc interval; the mean of the 3 measurements was used for analysis. 

Clinically significant QTc prolongation was defined as QTc interval 500 ms or more, or a greater than a 25% increase from baseline after starting treatment with methadone. 

Follow-up assessment was available for 66 patients and only 25 patients had all 4 assessments. 

In contrast to other reports, the patients in this investigation did not receive high methadone dose (> 300 or > 600 mg/day) but received a median daily dose of 23 mg (range 3-90 mg) at 2 weeks and no significant association was found between QTc interval and methadone dose (p= 0.45).  

Before methadone was started, 28 patients had baseline QTc prolongation but not greater than 500 ms. 

13 patients had prolonged QT intervals from baseline but none of them had a QT interval increase of > 25%.  

No torsade de pointes, ventricular fibrillation or sudden death was documented. 

Patients with QTc prolongation at baseline had higher chance of developing QTc prolongation at 2 weeks compared with those without baseline QTc abnormalities (71% vs 17%) (p< 0.001).  

Why I choose this article    

1. Data in the literature show that methadone is an effective and tolerated opioid analgesic able to control pain when other strong opioids fail.  

2. Methadone is one of the most studied drugs, it is cheap in both developing and developed countries and it is easy to administer.  

3. However, there are a lot of concerns about the use of methadone for cancer pain due to the  unpredictable  pharmokinetics (PK) of the drug  (because each in patient has an individual PK) and because of the long elimination (Beta T1/2) half life.  

4. Moreover, the FDA has issued a warning box for methadone underlying its risk of QTc prolongation and sudden death. Although this adverse effect exists for patients on high methadone doses and/or with pre-existing risk factors for QTc prolongation, this study shows that methadone at the doses commonly used in routine palliative care practice does not pose a major risk for patients with cancer-related pain who are also in the advanced stages of the disease.

This review is provided by Dr. Carla Ripamonti (Italy). Dr. Ripamonti is an IAHPC Board Member and you may learn more about her by going to our website for details at:
http://www.hospicecare.com/Bio/c_ripamonti.htm