From: ghost@alpha.c2.org (Graham Host) Subject: Buprenorphine Date: 1995/10/30 newsgroups: alt.drugs.hard In article <46mcu2$g8e@park.interport.net>, G@O.M (Sir William Osler) wrote: >>In article , >> sis@boom.bah (President Newt) wrote: >>As for "true fiends" on bupe...what I meant was, as far as I'm aware in order >>to take bupe or other agonist/antagonists without being kicked into instant >>withdrawal it's necessary to be completely clean of agonist opioids, hence >>"not a fiend".... IME, someone with a large tolerance will indeed be thrown into abrupt withdrawal by bupe, but someone with a small tolerance will not be. "Large tolerance" in this case refers to someone who had unlimited access to a pure agonist for over 15 years before trying bupe. >>>>Sup My last post was wrong in classifying buprenorphine as a >>>mixed agonist/antagonist; it is classified as a partial agonist, due to >>>its relatively weak mu stimulation. It actually inhibits the "bad" >>>receptors. Interestingly morphine, the prototypical pure agonist, is a >>>partial kappa agonist as well (though a much stronger mu agonist). >>Hmmmm...the only ref I have super handy, the British layman-intended but very >>reliable "Handbook of Psychoactive Medicines" describes buprenorphine as a >>"partial _antagonist_" and states that concommitant use of opioid agonists is >>"inadvisable" but doesn't refer to direct provoking of withdrawal. Also >states that "unlike other partial antagonists" >>buprenorphine _cannot_ be antagonized by naloxone. >Well, I'm still confused. Seems like I have nothing but out of date references >on hand (my Goodman and Gilman is from 1967 (!)). Also, in my original >response I apparently confused a characteristic described in above handbook of >pent with bupe. This ref made _no_ ref to bupe inducing withdrawal. I found a Believe it, it will if you have a "large" tolerance. >only adds to my confusion. This article >(http://www.nida.nih.gov/NIDA_Notes/NNVol10N1/Bupren.html) describes the stuff >as a partial mu agonist but says nothing about antagonist properties. To add >to the confusion, note this paragraph re planned combos of bupe and naloxone: >As a partial mu agonist, buprenorphine has some potential for misuse, making >it subject to diversion--being sold by patients to >other addicts. This characteristic makes it unsuitable to use as a take-home >medication. As if a potential downside effect makes take-home out of the question. Have these folks ever heard of cost-benefit analysis? To be fair, they are probably well aware of the concept, but also aware of what is politically palatable in the USA. >I'm doing a search of the net as I write this, and just read an archived >article at Paranoia which describes bupe as a mixed ag/antag, but says it >doesn't "seem" to induce withdrawal in the opioid dependent. What really As I said before, it depends on the level of tolerance. If it's high enough bupe _will_ cause withdrawal. It's an experience not easily forgotten. The gradual development of withdrawal symptoms is one thing, but the abrupt change brought about by an antagonist is quite another. >struck me though is this articles claim that bupe is only schedule 5 (!) as of >Feb 1995. Anyone with an up to date PDR who can confirm this??? Did you check the available formulations? When I had a pressing need for bupe to aid withdrawal, the only formulation available in the USA was an injectable. As someone who had unlimited access to a pure agonist with a potency about 500X morphine for more than 15 years and chose to not inject, I found this ironic. To facilitate my withdrawal, I had to take up the needle I had avoided for 15 years? Not. With the help of someone to whom I am very grateful, I obtained a few hundred Temgesic tablets. As it happened, the literature I had depended upon to decide bupe would be of great benefit was (understandably) not based upon subjects who had unlimited access to a very potent agonist for many years. Temgesic threw me into withdrawal, and was useless until I was nearly over the agony. The web page pointer was interesting, and I hope the "expedited" approval by the FDA actually happens, as it did for LAAM. However, as one who has been around a while, it is hard to ignore the facts that LAMM was recognized as safe and efficacious as early as 1976 (Blaine, J.D. and P. Renault, Eds., RX = 3X/Week LAAM Alternative to Methadone. NIDA monograph 8, 1977) and buprenorphine was proposed as a detox/maintenance agent in 1978 (Jasinski, et al, Arch. Gen. Psychiatry 35:501-516, 1978). Clearly, the scientific facts are not the important factors in the USA, at least. Given that, and the grave prognosis of the Clinton administration, bupe needs to be used soon, or it may not be used at all in the foreseeable future. I think that bupe is very promising for someone who needs maintenance, but prefers not to be liable to the withdrawal associated with methadone or LAAM. The literature I have claims there is no withdrawal when stopping bupe. There was in my case, but it may have been prolonged withdrawal from the long term agonist that was suppressed by the bupe. In any case, it was easy compared to the withdrawal from the 500XM agonist. That was a *horrible* 11 day ordeal of writhing in misery about 23.5 hours per day and sleeping the other 1/2 hour. It was impossible to lie still for more than a few seconds, and it was impossible get warm - I was wearing a down jacket and in a down sleeping bag - and my spine felt like it had a copper pipe running its full length with ice-cold water flowing through it. The hallucinations from lack of sleep provided some diversion from the continual, and often repetitive, thought process. I ate a total of about 1000 calories during the 11 days. Clonidine had no noticeable beneficial effect. "Like the flu" it was not. It has been almost 5 years now, and I am still "not right". I fatigue easily, have limited temperature tolerance (hot weather prostrates me, and cold is very like pain), and I have moderate depression. Anti-depressants have had limited effectiveness. Since I have never used street drugs, they do not tempt me at all. I've never experienced methadone, and while it might provide some relief for my condition, I am unwilling to face the specter of withdrawal at the whim of a program administrator. Bupe offers some hope, and if it doesn't work the withdrawal would be mild. Getting loaded isn't the objective; getting well is. Graham ==================================================================== From: ghost@alpha.c2.org Subject: Re: Buprenorphine Date: 1995/11/14 newsgroups: alt.drugs.hard In article , user@host.category (Givenname Surname) wrote: >In article <199511131221.EAA20986@infinity.c2.org>, ghost@alpha.c2.org wrote: >> control. I'd be much more inclined to try bupe if it were available, >> mainly because withdrawal would be easier if I changed my mind. >bupe - because of other cases like his - and he describes the withdrawal >as worse than h withdrawal in every respect, and longer. (Not much of a >I imagine the move to add naloxone to the buprenorphine to be used in US >MT's is motivated by stories like these. Anyway, even if cases like these >are exceptions to the rule (I mean the withdrawal), I do not think bupe >should be any great leap forward from methadone. My experience was brief, and only a few hundred tablets at the end of my last withdrawal. There was definitely some withdrawal, but it was relatively mild, and may have been largely due to supressed withdrawal from the primary opioid. You're probably right about it not being any great leap. Such things are rare in reality, if not in the media. Still, the papers I have, while admittedly old, indicate bupe is promising in a way that methadone is not. I scanned in a paper with some interesting contrasts between bupe and methadone. Some of it is below. Ghost NIDA Research Monograph 41 p. 67-73 1981. Comparison of the Effects of Buprenorphine and Methadone on Opiate Self-Administration in Primates N. K. Mello, M. P. Bree, and J. H. Mendelson [much elided] Buprenorphine is a new mixed opiate agonist-antagonist drug which significantly suppressed heroin self-administration by heroin addicts in controlled clinical studies (Mello and Mendelson, 1980). Buprenorphine has 25 to 40 times the analgesic potency of morphine and similar subjective effects, but it does not produce significant physical dependence after prolonged administration (Houde, 1979; Jasinski et al. 1978; Lewis et al. 1981). Bupre- norphine's antagonistic properties can effectively block the ef- fects of high doses of morphine for 24 to 36 hours (Jasinski et al. 1978). The antagonistic component appears to preclude bupre- norphine overdose (Lewis et al. 1981). Methadone, an opiate agonist, has been used to treat heroin addiction for over 15 years. It induces cross-tolerance to the euphoric effects of other opiates and after abrupt termination, a protracted morphine-like withdrawal syndrome occurs. Despite its demonstrated clinical utility, methadone abuse has been associated with overdose deaths (Kreek, 1978). Clinical studies have consistently shown that methadone reduces but seldom com- pletely eliminates opiate use (Martin et al. 1973; Jones and Prada, 1975). Moreover, some methadone-maintained patients en- gage in a diverse pattern of polydrug use. RESULTS AND DISCUSSION Buprenorphine and methadone had divergent effects on both opiate and food self-administration over a dose range shown to be clini- cally effective in suppressing opiate use in opiate addicts. Bu- prenorphine significantly suppressed opiate self-administration, whereas methadone was associated with increased opiate self-ad- ministration at doses equivalent to 130 to 240 mg/day in man. Considerably higher doses of buprenorphine were required to suppress opiate self administration in monkey than in man. A daily buprenorphine dose of 8 mg sc suppressed heroin self-admin- istration by 95% to 98% in 4 subjects and by 69% to 84% in 2 subjects, whereas placebo maintenance subjects took between 93% and 100% of all the heroin available (Mello and Mendelson, 1980). In contrast to buprenorphine, which produced dose-related decre- ments in opiate self-administration, maintenance on methadone was associated with increased heroin self-administration (Table 2). At methadone doses equivalent to 120 to 240 mg/day in man heroin self-administration increased by 14% to 87%. At methadone doses equivalent to 260 to 330 mg/day in man, heroin self-administration remained higher (A319) or equivalent to baseline levels (A105). The most parsimonious interpretation of these data appears to be that methadone over a dose range of .179 to 4.73 mg/kg/day did not induce sufficient cross tolerance to significantly attenuate the reinforcing properties of heroin. Analysis of the distribution of heroin injections across daily drug sessions, 2 1/2 to 13 1/2 hours after methadone administration, showed no significant differences in number of drug injections taken during the first two and last two sessions each day. This suggests that possible differences in the duration of action of methadone in monkey and man did not sig- nificantly influence data obtained. In conclusion, these data suggest that buprenorphine may be more effective than methadone in suppressing heroin self-administra- tion. However, controlled clinical comparisons of these drugs remain to be done. These data are consistent with a clinical evaluation of buprenorphine in heroin addicts (Mello and Mendelson, 1980). Persistence of heroin self-administration during methadone maintenance is consistent with the composite clinical experience (Martin et al. 1973; Jones and Prada, 1975) as well as animal studies (Griffiths,1976; Jones and Prada, 1977). REFERENCES Downs, D.A. and Harrigan, S. Preclinical pharmacologic and toxi- cologic evaluation of compounds used in the treatment of narcotic addiction. Section I: Pharmacologic evaluation of antagonists. Contract Report: NIDA 271-77,3421, Personal Communication, 1978. Griffiths, R.R., Bigelow, G. and Henningfield, J.E. Similarities in animal and human drug taking behavior. In: Mello, N.K., ed. Advances in Substance Abuse, Behavioral and Biologic Research, Vol. 1, Greenwich: JAI Press, Inc., pp. 1-90, 1980. Griffiths, R.R., Wurster, R.M. and Brady, J.V. Discrete trial choice procedure: Effects of naloxone and methadone on choice be- tween food and heroin. Pharmacological Reviews, 27(3) :357-365 1976. Houde, R.W. Analgesic effectiveness of the narcotic agonist- antagonists. Br J Clin Pharmac, (Suppl No 3) 297-308, 1979. Jasinski, D.R., Pevnick, J.S. and Griffith, J.D. Human pharmacol- ogy and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry, 35:601-616, 1978. Jones, B.E. and Prada, J.A. Drug seeking behavior during metha- done maintenance. Psychopharmacologia (Berl.), 41:7-10, 1975. Jones, B.E. and Prada, J.A. Effects of methadone and morphine maintenance on drug seeking behavior in the dog. Psychopharmacol- ogy, 54:109-112, 1977. Kreek, M.J. Medical complications in methadone patients. In: Kissin, B., Lowinson, J. and Millman, R., eds. Recent Develop- ments in Chemotherapy of Narcotic Addiction, Ann New York Acad Sci,311:110-134, 1978. Lewis, J., Rance, M.J. and Sanger, D.J. The pharmacology and abuse potential of buprenorphine, a new antagonist analgesic. In: Mello, N.K., ed. Advances in Substance Abuse, Behavioral and Biological Research, Vol. 3, Greenwich: JAI Press, Inc., (in press), 1981. Martin, W.R., Jasinski, D.R., Haertzen, C.A., Kay, D.C., Jones, B. E., Mansky, P.A. and Carpenter, R.W. Methadone - a re-evaluation. Arch Gen Psychiatry, 28:286-295, 1973. Mello, N.K. and Mendelson, J.H. Buprenorphine suppresses heroin use by heroin addicts. Science, 207-657-659, 1980. Mello, N.K., Bree, M.P. and Mendelson, J.H. Buprenorphine self- administration by rhesus monkeys. Pharmac Biochem Behav, (in press), 1981. ACKNOWLEDGMENTS These studies were supported in part by grants from the Committee on Problems of Drug Dependence and the National Institute on Drug Abuse (DA02419 and DA00064). We thank Dr. Prabhat Sehgal for veterinary consultation. AUTHORS Nancy K. Mello, Ph.D. , Mark P. Bree, Jack H. Mendelson, M.D. Alcohol and Drug Abuse Research Center Harvard Medical School-McLean Hospital, Belmont, MA. 02178