Monday, August 13, 2007

Levorphanol: Another back-to-the future opioid?

Back when I was a novice nurse, in 1980, I worked at a community hospital in Washington, DC. The favorite analgesic of one of our oncologists was Levo-Dromoran (levorphanol). The reason was that it was a little more potent than morphine, but more importantly it had a longer duration of action. I have only a vague recollection of how frequently we dosed it, but I think it was every 6 hours.

I moved on from that hospital after 3 years, and haven’t seen levorphanol ordered in all those intervening years (of course, extended release morphine became available in the ‘80’s). In 2003 there was an article in NEJM titled “Oral opioid therapy for chronic peripheral and central neuropathic pain.” (Free full text of older research articles; must register) Kathy Foley had an accompanying editorial extolling the trial results for demonstrating opioid responsiveness in neuropathic pain. If you didn’t read the article, you wouldn’t know that the study drug was levorphanol. At the time I remember thinking, “Why the heck would they select levorphanol for this study? Nobody uses the stuff!” (I guess somebody must, otherwise it wouldn’t still be on the market). Recently, however, there have been 2 articles on levorphanol in major palliative care journals. Are we about to see this drug resurrected?

Eric Prommer reviewed the pharmacology of levorphanol in Supportive Care in Cancer and suggested that it shouldn’t be overlooked as a step three analgesic. McNulty presented a case series in the Journal of Palliative Medicine in which levorphanol was used successfully as a rescue analgesic when other opioids, including methadone, were ineffective or produced unacceptable side effects [McNulty’s paper has an odd title. “Intractable” and “refractory” are sometimes used interchangeably, although I tend to think of intractable as worse than refractory. I’ve never before seen one of these terms used as an adjective for the other.]

In a very small nutshell, the advantages and disadvantages of levorphanol:

  • Has been shown to be responsive in both peripheral and central neuropathic pain syndromes (small number of central pain patients, with response not much higher than would be expected from placebo); no studies comparing levorphanol with other opioids

  • Multiple analgesic mechanisms: strong affinity for mu, delta, and kappa receptors; NMDA antagonist; serotonin & norepinephrine reuptake inhibitor

  • 4-8 times more potent than morphine (per Prommer: suggested starting dose when switching from another opioid: 15:1 – 12:1, based on oral morphine equivalents [OME]); (per McNulty: 25:1 – 12:1 based on OME, using a table of decreasing ratios as OME increases, similar to methadone tables [examples here])

  • Oral to parenteral ratio of 2:1

  • Can be administered via oral, intravenous, subcutaneous, and intramuscular routes; not sublingual

  • Not metabolized via cytochrome system, so relatively smaller risk of drug-drug interactions, especially compared to methadone
  • Relatively long acting, dosing every 6 hours, possibly longer in some patients

  • Accumulates, so all the usual precautions, including waiting 3 days between dose changes
  • Anticholinergic properties similar to morphine
  • Neurotoxic 3-glucuronide metabolite with symptoms (sedation, irritability) seen in the higher dose ranges

  • Relatively slow onset, so not a good choice for breakthrough pain

I have a couple of concerns about levorphanol making a comeback, and they have little to do with the drug itself, at least directly. The first is that this is another relatively unique opioid which could be dangerous in inexperienced hands. The second is that there is a very, very small clinical research basis for using levorphanol. I suspect that widespread use could reveal additional warts as well as benefits.

I’d be interested to hear from our readers about any clinical experiences you may have with levorphanol.

Analgesic trivia:
What was the first oral sustained-release morphine product? Most people would say MS Contin, but that’s because Perdue Frederick had good marketing folks. MS Contin came out shortly after Roxane’s Oramorph, but MS Contin was color coded (all dose sizes of Oramorph are white) and quickly eclipsed Roxane’s just-as-good and less expensive product (yeah, I’m old enough to remember all that)

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