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Thursday, January 10, 2008

Alvimopam; Prognosis in GBM

Blogging on Peer-Reviewed Research
1) Pain has early e-pub'd a randomized, controlled trial of alvimopam for opioid-induced constipation. (Alvimopam is a peripherally acting mu-opioid antagonist - it counteracts opioid effects in the periphery such as constipation without blocking central effects like analgesia or sedation.) This is an industry-funded study. ~520 patients were randomized to placebo or 3 different dosing regimens of alvimopam for 6 weeks (.5mg big, 1mg daily, 1mg bid). These were adult patients, from 9 different countries, all taking opioids for chronic non-malignant pain (mean age ~50 years, almost all were white, mean opioid usage was ~6 years, mean daily oral morphine equivalent doses were in the 200-300mg range, most had chronic back pain & the rest an assortment of other chronic pain syndromes). Subjects had to have 2 or fewer spontaneous (not laxative induced) bowel movements in a two week run in period prior to the study and were 'asked' to discontinue other laxatives during the study but were given rescue bisacodyl. The primary outcome was increase in spontaneous bowel movements (SBMs) through week 3, although they followed patients for 6 weeks.

SBMs increased significantly more in all treatment groups compared with placebo (baseline was ~1/week, placebo increased to ~3/week, alvimopam groups increased to 4-5/week). This difference was despite notably increased use of rescue bisacodyl in the placebo group. There were a bunch of other secondary outcomes looked at - all related to improvements in stool frequency, consistency, and overall constipation symptoms: alvimopam globally did better than placebo, and there weren't much differences between the different alvimopam dosing regimens. Side effects & drop outs were similar between all groups, with a little more abdominal pain and diarrhea in the high dose alvimopam group, although not statistically significant. Pain and opioid use were stable in all groups. The improvements in bowel function were sustained for the full 6 weeks in the treatment groups, without attenuating. Due to similar efficacy and better tolerance, the authors' conclusion is that 0.5mg bid is the recommended dosage.

So, more good evidence that alvimopam is effective for opioid induced constipation, without any causing withdrawal or worsening analgesia. The question really is, is it a better (more effective, better tolerated) agent than the traditional mainstay of opioid induced constipation - stimulant laxatives such as sennasides and bisacodyl? My experience has been that these are quite effective for most patients...although it's a perennial problem educating patients sufficiently in how to effectively use/titrate them. I'm looking forward to using this, and methylnaltrexone, but will likely reserve them for the minority of patients who 'fail' stimulants. (On the other hand, since these will be prescription drugs if approved they may actually be cheaper for patients since high dose over the counter senna & bisacodyl can be really expensive). Anyway, one doubts that Industry is going to be funding such a study anytime soon. Final comment: I have it in the back of my head that alvimopam was encountering regulatory issues in the US regarding its approval due to toxicities (?cardiac) - I can't find my reference on that though - does anyone know or did I hallucinate this?

WEBSTER, L. (2007). Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain DOI: 10.1016/j.pain.2007.11.008

Briefly, Lancet recently published a blinded, randomized, controlled trial of haloperidol, risperidone, or placebo for aggressive behaviors in patients with intellectual disabilities. Basically all groups improved equally (placebo actually did a little better) in the study and the authors conclude antipsychotics are overused for this indication. A reasonable conclusion, however the doses used were small-ish (mean of less than
2mg for risperidone, 3mg for haloperidol), and there was such a dramatic (and presumably spontaneous) improvement in all groups that it's tough to judge anything. Either way, I'm watching with interest how the research on the use of antipsychotics for 'behaviors' (in dementia or in this case intellectual disabilities) is catching up with practice, and practice doesn't seem all that evidence-based anymore. I don't know what exactly this has to do with palliative care, other than we use these agents frequently (although for different indications), and it's interesting to see this scrutiny of them.

And even more briefly - and this one is really for prognosis 'completists' - Lancet Oncology has a paper about a prognostic nomogram for newly diagnosed glioblastoma. I'm not particularly qualified to judge the merits of this (it was developed using 'recursive partitioning analysis' and other things that I long to understand but know I'll never devote the energy to actually doing it) but it uses routinely available patient characteristics (at least in one of its iterations) to predict median survival and 2 year survival (calculator here).

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