Tuesday, February 19, 2008

Genetics and morphine toxicity; Prognosis articles

A rather academic post: genetics and some prognostically relevant papers.

has a study on genetic variations and response to morphine in cancer patients. The data comes from a prospective study of ~220 advanced cancer patients who were receiving morphine for pain. They were treated per a palliative care team's protocol and about 60 of them were rotated off morphine due to inadequate analgesia +/- intolerable side effects. This analysis compares rates of certain genetic polymorphisms between patients who 'did well' with morphine with those required rotation (it is unclear from this paper if the clinicians treating these patients were blinded to the genetic analysis or even when those analyses were done in relation to the patients rotating off morphine). They were looking at certain (known) variations in the multidrug resistance (MDR-1; it is implicated in penetration of drugs across the blood brain barrier amongst many other things) and catechol-O-methyltransferase (COMT; involved with monamine metabolism and implicated in pain modulation) genes.

Responders and switchers were were matched demographically at baseline. Before we get to the genetics the differences and similarities between the groups are worth noting. Obviously switchers reported less pain relief and more side effects and particularly drowsiness, confusion, and hallucinations were associated with switching in regression analysis. Morphine doses however were similar between groups however morphine serum levels were lower in the switchers. There were no correlations between morphine dose, analgesic response, or morphine/morphine metabolite serum levels. All of this reinforces the long-held observation that analgesia (or for that matter dose limiting side effects) don't per se have much to do with morphine dose, serum levels, etc. (The one exception here is that myoclonus was associated with total morphine level).

I'll be the first to admit here that I am not qualified to judge the genetic analysis segment of the article (please comment though if you've read the article and have the requisite background to comment intelligently on it). I think it's safe to say the results are intriguing and hypothesis generating. Essentially they found that certain COMT polymorphisms were associated with the need to switch; MDR-1 variations weren't; however certain MDR-1 variations (as well as COMT ones) were strongly associated with CNS toxicities like drowsiness, confusion, and hallucinations. A few things to note here: all switchers were changed to oxycodone and they (off-handedly) mention that most of these patients did well with the switch (suggesting that this is a morphine and not an opioid-class effect; which is not to say that oxycodone is 'better').

The astonishing individual variation in response to opioids is a fascinating thing and a clinical challenge, and maybe one day we will be able to rationalize it. One patient can be crippled (literally) by painful bone mets and fractures and have their pain well controlled with 25mcg/hr of transdermal fentanyl with a few doses of 15mg of morphine for breakthrough; the next patient with a similar clinical picture is on 5mg/hr of intravenous hydromorphone. I had a patient once who was on ~2 grams a day of oral oxycodone (with pretty good analgesia); the moment he got into the hospital and got a whiff of intravenous hydromorphone he would be delirious (and didn't get much pain relief). I am hopeful that in the next couple decades why this happens will be much clearer, and research like this (and this) will help clarify things further; it seems that pretty soon all our patients will be getting shot-gun genomic analyses anyway and maybe this will provide our profession some useful information regarding drug selection and toxicity.

Ross, J.R., Riley, J., Taegetmeyer, A.B., Sato, H., Gretton, S., du Bois, R.M., Welsh, K.I. (2008). Genetic variation and response to morphine in cancer patients. Cancer DOI: 10.1002/cncr.23292

[Cancer also has a study on symptom burden after autologous stem-cell transplants for myeloma: things get bad really fast, then get better, and pre-existing symptom burden was the best predictor of symptom burden 30 days post transplant.]

Lancet Oncology has a study relevant to prognosis in pancreatic cancer. It looks at the prognostic utility of CA 19-9 response in patients with advanced pancreatic cancer (did those whose 19-9's dropped dramatically do better than those whose didn't). The data come from a prospective chemotherapy trial involving ~350 patients (~250 of whom had CA 19-9 elevations at baseline). Median overall survival was 7.7 months and which was similar between those with baseline normal and baseline elevated 19-9's. 19-9 drop, neither velocity nor magnitude, was not associated with improved survival. However, those patients whose 19-9's were above the median 19-9 level of those with elevated 19-9's had significantly worse survival (6 month 50% survival vs. ~11 months). Let me clarify that sentence: looking only at those with elevated CA 19-9's, the median elevation was 59 times the upper limit of normal (~2000U/mL); those patients whose 19-9's were higher than that median elevation had a worse prognosis (despite, intriguingly, having a similar response to chemotherapy). This was a large trial with prospectively gathered data and it is good supporting evidence that very high CA 19-9 elevations predict worse survival (average ~6 months) in pancreatic cancer.

Mayo Clinic Proceedings has a small study about a single center's (the Jacksonville Mayo) experience with liver transplantation (its focus is on what happens to those patients who the transplant committee declines to list). It mentions the outcomes of those who were initially listed including the number who die while listed: 5% (the mean time to transplant was 46 days which seems really short to me). Frustratingly it doesn't mention what happened to the patients who were denied transplants due to significant comorbid medical illness.

BMJ has an article relevant for long-term prognosis in stroke. It is based on data from 3 large cohort studies on the natural history of ischemic stroke in patients in the UK (involving over 7000 people; overall survival at 6 months was ~75%). This study looks at those patients who were alive at 6 months and sees if their functional status at that point predicts prognosis. Not surprisingly, it does: the most disabled patients who made it 6 months had a median survival of 2.5 years; those patients who weren't functionally dependent had a median survival about 6 years; functionally independent patients lived ~10 years. (They used Rankin Scores to define disability).

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