This is an important topic. (The week my pain dr. tried me out on 30 mg./day of Methadone, in a cold switch from Oxycontin/oxycodone, I picked up a hernia for the experience.)
I was controlling nicely with oral Nalaxone HCL (f.k.a. Narcan) a powerful "mu-"opioid antagonist which, although available only as a serious drug injectable for use in emergency room for overdoses, when taken 1 ml. at a time via an oral syringe with each Oxycontin or oxycodone - the drug being previously transferred with a 10 ml. hypodermic needle from a 10 ml. vial into bottle from which the oral syringe could then be drawn - the effect was to neutralize the opioid receptors that would otherwise shut down the bowel without significantly impacting (at that dose) the opioids analgesic/pain killing effect.
For an abstract of a small study on the practice, see, Hawkes ND, Richardson C, Evans BK, et al, Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine.
Aliment Pharmacol Ther. 2001 May;15(5):625-30:
INTRODUCTION: Constipation is a common side-effect of opioid therapy; in addition to their analgesic effect, opioids reduce intestinal secretion and motility with an increase in whole-gut transit time. Naloxone, a specific opioid antagonist, reverses these effects but may also cause symptoms of opioid withdrawal in patients on long-term therapy.
AIM: To use an enteric-release formulation, designed to produce a topical effect in the gut, with minimum systemic effects.
METHODS: Naloxone 10 mg b.d. and codeine 30 mg b.d. were used with identical placebo capsules in four sets of studies; 12 male volunteers were given the drugs alone and in combination, with a control study involving double placebo, during each of four study periods. Whole-gut transit time was calculated and compared for each treatment period. RESULTS: Naloxone, both alone and with codeine, significantly shortened the mean whole-gut transit time compared with the control period, respectively, from 53.1 to 42.1 h (P=0.005) and to 40.7 h (P=0.024). Urgency to defecate was reported by two volunteers on naloxone alone and by three on combination therapy.
CONCLUSIONS: The results show that the naloxone formulation counteracts the effect of codeine on intestinal transit, suggesting that it may have useful clinical applications.
PMID: 11328255 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/11328255
I was one this for years. Insurance didn't cover it, but it was generic and not too bad. A case of 25 10 cc. vials cost about $132 and lasted six weeks. That is, until the manufacturer apparently realized that as the sole generic producer, it would take a competitor something one the order of 2 years to secure FDA approval to get another generic on the market and in that time - hey, it had a monopoly, so why not price it accordingly. And figuring that the product - marketed to keep people from dying of a heroin OD - had what an economist would call "price inelastic demand" (which is to say, whatever it costs, ERs had to have it - the priice went up in stages every six weeks or so, as I recall first to $400 a case or so, and then more, maybe $600. That's the last time I bought it in any event. When next I looked my pharmacist was telling me that his cost was roughly $900 and I was out of the market,
the price having gone up by over six-fold in under a year. (Since the price started climbing he had been selling it to me at his cost, where he made his money on my account through compounding a ketamine/lidocaine/gabapentin gel for my feet, which is covered by insurance.)
I just checked tonight, another pharmacist I know told me that the wholesale price for a case of 25 10 ml injectable vials is still around $900, so I’m guessing the manufacturer must have found a stable monopoly price.
The only good news in all of this is that clinical trials appear to be fairly well advanced on the development of an "an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation." Specifically, a successful report of Phase II testing was reported in December, 2008. While the drug will doubtlessly be priced higher than you would pay for the privilege of taking generic oxycodone along with a ml of the liquid (.4 mg) Naloxone, the good news is that it should at least be covered by insurance. See, Simpson K, Leyendecker P, Hopp M, et al, Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain,
Curr Med Res Opin. 2008 Dec;24(12):3503-12:
OBJECTIVE: Opioid therapy is frequently associated with treatment-limiting constipation. Naloxone is an opioid antagonist with low oral systemic bioavailability. This Phase III clinical trial assessed the safety and efficacy of an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation.
STUDY DESIGN: This double-blind, multicenter trial was conducted in specialist and primary care centers in four European countries in an out-patients setting. The study included 322 adult patients with moderate-to-severe, noncancer pain requiring opioid therapy in a range of >or=20 mg/day and <or=50 mg/day oxycodone. Following a run-in phase patients were randomized to receive oxycodone PR/naloxone PR or oxycodone PR for 12 weeks. The primary outcome was improvement in constipation as measured using the Bowel Function Index (BFI). Secondary/exploratory assessments focused on pain intensity and additional bowel parameters. Trial registration: NCT00412152.
RESULTS: A significant improvement in BFI scores occurred with oxycodone PR/naloxone PR compared with oxycodone PR after 4 weeks of double-blind treatment (-26.9 vs. -9.4, respectively; p < 0.0001), observed after only 1 week of treatment and continued until study end. A significant increase in the number of complete spontaneous bowel movements and decrease in laxative use were also reported. This improvement in bowel function was achieved without compromising the analgesic efficacy of the oxycodone component; pain intensity remained constant throughout the study. The incidence of adverse events was comparable in both groups and consistent with those expected of opioid analgesics. As the study was limited to a dose range of up to 50 mg oxycodone equivalent per day, further research on higher doses would be recommended.
CONCLUSION: The fixed-ratio combination of oxycodone PR/naloxone PR is superior to oxycodone PR alone, offering patients effective analgesia while significantly improving opioid-induced constipation.
PMID: 19032132 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/19032132
An FDA summary of the status of the trial is at
http://clinicaltrials.gov/ct2/show/NCT00412152 and from the same manufacturer, the European firm Mundipharma Research GmbH & Co KG ,
the next drug in the pipeline hopes to do the same thing with Dilaudid (Hydromorphone). See,
http://clinicaltrials.gov/ct2/show/NCT00992576
FINALLY, the Pain Research page of Mundipharma is interesting in its own right:
One example of our successful development work is an innovative agonist/antagonist combination. This analgesic differs fundamentally from previous opioid preparations due to its considerably improved tolerability. As the only medications of its kind, it possesses the strong, pain-relieving effect of opioids and simultaneously prevents the most frequent undesired effect of this active ingredient to date – gastro-intestinal dysfunction, with opioid-induced constipation as the main symptom. In addition, we are working on developing further agonist/antagonist combinations. And we even have a series of other promising substances in the pipeline. In total, there are currently 11 projects in the field of analgesia at various phases of development. [Emphasis added.]
http://www.mundipharma-research.com/...reas/pain.html
I imagine that the first patents in this area that make it to FDA approval will prove to be lucrative. For more on this area, I refer back to my post on February 11th in the
which path will you choose? thread [post #8]
http://neurotalk.psychcentral.com/sh...879#post620879
Mike