Monday, October 30, 2006

Buccal fentanyl tablets (OraVescent technology!!); Long-acting hydromorphone as a breatkthrough analgesic?

2 from the Clinical Journal of Pain

First is a randomized, placebo-controlled trial of a buccal fentanyl tablet** for breakthrough pain in cancer patients. It looked at ~80 cancer patients who had at least 4 breakthrough pain episodes daily. They went through an open label dose-finding titration phase where they used higher doses of the fentanyl tablet until they found a dose that was effective (up to 800mcg at a time). Those that found an effective dose then were blindly given either fentanyl or placebo for subsequent episodes of breakthrough pain (patients could use their prior rescue analgesia med if they didn't receive adequate analgesia with this). They found that the fentanyl tablet provided better analgesia than the placebo and was pretty well tolerated.

A couple things about this. The study seems like it was more or less done to generate data for FDA approval of the drug, and is not very helpful clinically. I'm not knocking this, these studies have to be done, and there are still some clinically relevant aspects to this article. The patients initially went through an open-label phase to see if they found the fentanyl tablet efficacious and tolerable. Those patients who didn't find the tablet efficacious or tolerable weren't included in the placebo controlled part of this trial (these patients constituted a quarter of the initial subject population), so it's no surprise that the placebo-controlled trial found the fentanyl tablet to be, well, efficacious and tolerable. FDA-wise this is helpful: the new drug seems to be safe and it certainly works for some patients. It doesn't however help us clinicians to have a good sense of: what to expect when we start our patients on this, who to start it on, what a reasonable adverse event rate is, etc. One would like to see head-to-head trials of this (or, for that matter, Actiq) with oral short-acting opioids for breakthrough pain (I'm being hopeful here and not suggesting that the authors should have done this in this particular study).

A secondary finding of the study is that, as with Actiq (the transbuccal fentanyl lollipop), the initial breakthrough dose of the fentanyl tablet (as defined through the open label dose-finding phase) seems to have no relationship with a patient's pre-existing opioid requirement. That is, the "your breakthrough dose should be approximately 10% of your total oral opioid dose" rule doesn't seem to apply with these drugs. This could be for two reasons: one is that there's something different about transbuccal fentanyl than oral opioids. The other is that appropriate breakthrough dosing of oral opioids has never really been studied (the ~10% rule is based on expert opinion) and maybe we should be going through a formal dose-finding on all our patients. (Of course, many of us do this, albeit not necessarily formally...I assume many of us out there have patients whose breakthrough dosing varies greatly from the dose the ~10% rule suggests).

**Per the article: "The fentanyl buccal tablet (FBT) incorporates a novel drug delivery platform, OraVescent technology, which employs an effervescence reaction to enhance fentanyl absorption through the buccal mucosa...." While I'm sure this is a swell new drug delivery method "OraVescent" sounds like it should describe some sort of new breath-freshener, mouthwash, or toothpaste and not an opioid delivery system. One wonders if the Freshtastic OraVescence of this product will preclude its blinded comparison with other opioids.

Second is a prospective look at opioid rotation to long-acting hydromorphone in cancer patients. I've already blogged enough for one day so I'll keep this short.

i) They rotated ~50 patients at a morphine to hydromorphone ratio of 5:1 then decreased the dose by another 1/3 presumably for incomplete cross-tolerance.
ii) Speaking of breakthrough pain...they used long-acting hydromorphone for breakthrough pain (they didn't mention telling the patients to crush/chew it so one has to assume the patients were indeed taking an intact long-acting opioid for breakthrough).
iii) This seemed to be safe and well-tolerated overall, but across the group there weren't consistent improvements in pain or side effects (but clearly some patients did benefit).

Conclusion: if you're a student of the opioid-rotation literature this is an interesting study to think about, otherwise...I guess it's got me thinking about MS Contin as a breakthrough analgesic (ha ha).

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