Tuesday, April 22, 2008

Morphine vs fentanyl vs methadone; More

Editor's note, evening of 4/23/08: my original post from yesterday went out garbled (a couple paragraphs were missing). I've fixed it as best I can (see the comments on this post). --Drew.

1)
The European Journal of Pain has a randomized trial comparing long acting morphine with transdermal fentanyl or methadone as the initial long-acting drug in cancer patients. This was a prospective, unblinded study of ~100 Italian cancer patients (mean age ~60 years) who had ongoing moderate to severe pain (mean baseline pain scores were 7/10) on weak opioids. (It's unclear what the baseline opioid use was in these subjects - without the paper explicitly saying so one has the impression that the group doing the study used a standard 'WHO Pain Ladder' protocol and these patients were ones who were having ongoing pain despite 'weak,' 'step 2,' opioids. Doses of at least 300mg of tramadol and 180mg a day of codeine were mentioned in the methods section.) They were randomized to 60 mg daily of morphine ER, 25 mcg/hr of TD fentanyl, or 5 mg q8hours of methadone (i.e. a methadone:morphine ratio of 1:4). Doses were then adjusted without any specific protocol (the group's own usual practice was used): for better or worse this study measures one center's 'real-life' experience after the randomization. Break through medication was morphine at about 1/6th of the 24 hour morphine equivalent dose of the long-acting med. Data were collected for a month. An 'intention to protocol' analysis was used: if you know what that means exactly please leave a comment - as far as I can tell it means an intention to treat analysis and they analyzed patients based on initial randomization even if their opioids were switched mid-study for clinical reasons. The study was powered to find a 30% difference in pain intensity.

Findings are easy to summarize:
All groups looked very similar throughout the four weeks (took 2-3 days for doses to stabilize; pain had reduced to the less than 4/10 level at week one and stayed there; side effects were similar). Fentanyl, which has found to be less constipating compared to long acting morphine in previous trials, was not found to be so in this one (although it wasn't necessarily powered to do this).

Two other findings to comment on. First the opioid escalation index was lowest for methadone (not surprising) but was highest for fentanyl (essentially those randomized to fentanyl needed a larger dose increase over the 4 weeks of the study compared to the others). The most obvious suggestion for this is that their chosen equivalent dose of fentanyl (25mcg/hr = 0.6mg fentanyl a day = 60 mg of morphine a day) was too low.

The other one is that these findings seemingly contradict another randomized trial comparing morphine ER with methadone as the initial long-acting opioid (which found that methadone was poorly tolerated compared with morphine and not a better analesic). That study used a methadone:morphine ratio of 1:2 to start off with, and was also starting patients on long-acting drugs relatively earlier - using 30 mg daily of oral morphine instead of 'waiting' until they needed 60 mg. It also used methadone as the break through drug in the methadone arm. These are sufficient differences to make comparison of the studies difficult. I have used the earlier article as a(nother)** reason not to use methadone as a first-line agent but the current study suggests that using this lower, initial ratio may improved methadone's tolerability as a first-line 'strong' opioid. I'm curious as to what others think of this.

**Other reasons for not using it as a first line drug: complex drug-drug interactions, QTc prolongation which is a particular concern in my patients with prolonged prognoses, complexities of transitioning someone off methadone onto another opioid if needed, ongoing lack of head-to-head evidence that it provides any clinical benefit over other opioids, and a general impression that the psychiatric side effects of methadone are worse than with other opioids (sleep disturbances, bad dreams, hallucinations). (That last point is completely a personal impression and not based in anything else.)

ResearchBlogging.orgMERCADANTE, S., PORZIO, G., FERRERA, P., FULFARO, F., AIELLI, F., VERNA, L., VILLARI, P., FICORELLA, C., GEBBIA, V., RIINA, S. (2008). Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain DOI: 10.1016/j.ejpain.2008.01.013

2)
Briefies:

a) The American Thoracic Society has released a policy statement on palliative and end-of-life care for patients with respiratory illnesses and in ICUs. Compared to a lot of society statements this one is somewhat of a tour-de-force in its scope and length - a good one for the teaching file. I loved these sentences:

'Families should be informed in advance of agonal breathing so they can view it is as a part of the dying process rather than a sign of patient discomfort. If one uses the term "agonal breathing," one should help the family to understand that it does not imply that the patient is in agony.'

They perhaps should have just recommended not to use the word 'agonal' in front of families altogether.

b) The latest issue of Journal of Clinical Ethics has a case discussion on Jewish law/ethics and artificial nutrition at the end of life (there are a handful of associated commentaries also - links to them are available from the PubMed citation linked-to above). This is the best commentary (from a medical perspective) on this that I've seen since I've been looking and is a good discussion of the issues involved, their history, and conflict resolution surrounding them.

c) Pain Medicine has a review about methadone's drug interactions. It's lengthy and the most comprehensive overview of the topic I've run across.

d) Pain has an editorial about efforts to get transmucosal fentanyl approved for 'breakthrough' pain for chronic non-malignant pain which is really an editorial about what is actually meant by breakthrough pain, and cautions against extrapolating from cancer pain research to CNMP.

e) BMJ has an article describing what the authors describe as the 'co-development' of palliative care and the right to euthanasia in Belgium, which is directed directly at those who worry that the growth of euthanasia would limit the development of palliative care. Their conclusion is that both 'movements' occurred together in Belgium and have shared some synergy (and common 'workers'):
Within Belgium we found few professional stances contending that palliative care and legalisation of euthanasia are antagonistic, no slippery slope effects, and no evidence for the concern of the European Association for Palliative Care that the drive to legalise euthanasia would interfere with the development of palliative care. Rather, there were many indications of reciprocity and synergistic evolution.
My assumption is that this is in BMJ as a debate-sparker as the UK considers 'assisted death' legalization.

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