Thursday, May 29, 2008

Making Sh*t Happen: Methylnaltrexone

Methylnatrexone has hit the big time with a very timely publication of a industry funded double-blinded RCT in the New England Journal of Medicine. If you have been in palliative care for the past few years, methylnatrexone has been one of the drugs with some 'buzz' around it at conferences and in publications. We have touched on MNTX a few times here at Pallimed before.

This new study does not add much to previous knowledge about the medicine, but the study is the largest and most comprehensive one to date. Other double-blinded RCT's have already been published (JPSM 2008, Clin Pharm Ther 2000, J Pharmacol Exp Ther 2002, JAMA 2000) showing efficacy versus placebo without affecting analgesia from opioids. The patients were from nursing homes, hospices or palliative care centers and 60-70% were ECOG/WHO 3 or 4 (confined to bed more than 50%)

The participants were already on stable opioid doses, and stable laxative regimens with less then 3 reported BM's in the past week. More than 50% rated their 'constipation related distress' as moderate to severe. This seems to be a somewhat broad inclusion criteria. Constipation can be a very distressing symptom, but there are two types of distress from constipation: psychological distress of not 'being regular' and physical distress from GI discomfort. Many patients with advanced illness may have decreased number of stools for many reasons besides just opioid constipation, and I would propose that a regular number of stools for those with anorexia-cachexia syndrome and decreased functional status may be less then 3 per week. In assessing constipation related distress, managing expectations is part of good clinical care.

Interestingly less then 30% were on stool softeners, but most were on 2 laxatives of some category (stool softener, enema, bulk producer, contact laxative, or osmotic agent). I thought the percentage would be much higher in this population.

Of interest to some will be the oral morphine equivalent doses (OMED) these patients were on. I always find this interesting when seeing studies about hospice and palliative care patients, because opioids have a wide range of therapeutic dosing. The mean OMED was 339mg (+/-1214 )(placebo) and 417mg(+/-787)(MNTX) with a wide range in the study (9-10,160mg of morphine equivalents per day). For those readers who have not worked in palliative care you did read that number right. 10,160mg of morphine equivalents per day. If you ask anyone in palliative care they will probably tell you about the one or two patients they have seen up in that range. Now that would be a case-series to figure out how someone is tolerating those doses.

As far as drug names go, I find 'Relistor' pretty uninspiring. Methylnaltrexone is fun to say, MNTX is easy to write, To me it sounds like a drug to get you back on a transplant list-> Re-listor=Re-lister. Or was Wyeth going for being 'realistic' about your constipation or advanced illness. Maybe they were trying to stay away from names that were too scatological or associated with OTC meds. Relistor just is uninspiring. (Sorry for the sidetrack, I find drug names fascinating.)

BTW the logo is pretty bland too. Come on now another circular logo? Are they trying to replicate the millions of hospice logos with 'embracing circles/hugs?' I would think something coming out of something else would be more representative. Any graphic designers or wordsmiths want to help Wyeth out?
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I am sure many in palliative care are glad this medication is available and we will probably go through the next few months trying to figure out where it fits in the bowel toolbox. Thomas and the rest of the authors (and Progenics) should be commended for a well-designed research study in a hospice-oriented patient population. It would be a good article to review in a journal club to see how the study was designed and carried out, especially with so many institutions.

Overall the study is a good one, but it should be noted it was industry funded, which is notably very transparent in the article: "Progenics Pharmaceuticals designed the protocol and collected and analyzed the data." Is this part of the beginning of more pharmaceutical industry-palliative care/hospice collaborations? I would be interested to hear from Pallimed readers about their thoughts on the field's collaboration with industry. Is this a new source for funding and advancement of our field? Or is this a 'bogeyman' that is relatively absent from our small but growing field?

Of note there are two good editorials (here and here - sub required) in the issue regarding opioids and constipation.

(Disclaimer: I get nothing from Wyeth. Neither does Pallimed.)

(Advanced apology for the near-swear in the title for those who might be offended)

(Image from same issue of NEJM - not Opioid Induced Constipation)

(I like parentheses.)


Thomas, J., Karver, S., Cooney, G.A., Chamberlin, B.H., Watt, C.K., Slatkin, N., Stambler, N., Kremer, A., Israel, R. (2008). Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. New England Journal of Medicine, 358(22), 2232-2343.

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