methylnaltrexone and Heroin-Dependence

One of the most common undesired effects of analgesic opioid use and addiction is constipation. Numerous pharmacologic agents have been used to treat opioid-induced bowel hypomotility with limited success. Methylnaltrexone bromide (MNTX) selectively targets the peripheral adverse effects of opioids while preserving the central analgesic effects of opioid agonist treatment.. While it is indicated for use in nonsurgical patients in the palliative care setting, here we report the use of MNTX for the alleviation of postoperative ileus in a heroin user with recurrent cervical cancer undergoing diverting colostomy and urinary conduit placement.. Results suggest that MNTX may accelerate postoperative gastrointestinal recovery in opioid-dependent patients. Further studies are warranted to evaluate its role in the pharmacologic management of postoperative ileus.

Topics: Analgesics, Opioid; Female; Heroin Dependence; Humans; Ileus; Injections, Subcutaneous; Middle Aged; Naltrexone; Narcotic Antagonists; Postoperative Complications; Quaternary Ammonium Compounds

3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-beta-d-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of micro-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at micro-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.

Topics: Adenylyl Cyclases; Animals; Cocaine; Discrimination Learning; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Heroin; Heroin Dependence; Macaca mulatta; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotics; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Self Administration