Long-Term Pharmacotherapy for Opiate (Primarily Heroin) Addiction: Opioid Antagonists and Partial Agonists

Abstract

The action of a specific opioid antagonist is to bind to specific opioid receptors and thus prevent the action of exogenous opioids. Use of such an antagonist will prevent the normal physiological action of the endogenous opioids at their receptors. The first pure specific opioid antagonist which was successfully synthesized, characterized, and patented in 1960 by Dr. J. Fishman with M.J. Lewenstein was naloxone, an alkyl derivative of nor-oxymorphone (BLUMBERG et al. 1961; BLUMBERG and DAYTON 1974). Naloxone was thus the first specific opioid antagonist used clinically and remains extremely useful in the management of accidental or medical opioid overdose. Naloxone has very limited systemic bioavailability, with less than 3% reaching the systemic circulation after oral administration; when it is used for management of narcotic overdose (or when the attempt was made to use it in the more chronic management of opiate dependency) by direct receptor blockade of opiate agonist action in the central nervous system, naloxone must be administered parenterally, and ideally, intravenously (KREEK 1973c; KREEK et al. 1983a,b,c, 1984). Although brief sporadic attempts were made to use naloxone in the maintenance treatment of addiction, it was clear that this use would not be suitable because of the need for a parenteral route of administration. However, studies using naloxone showed that a specific opioid antagonist could block all exogenous opioid effects, and moreover, could reverse the effects of both exogenous and endogenous opioids (KOSTERLITZ and WATT 1968; VEREBEY and MULE 1975; VOLAVKA et al. 1979a,b; MENDELSON et al. 1980; NABER et al. 1981; KREEK and HARTMAN 1982; KREEK et al. 1983a,b,c, 1984; COHEN et al. 1983; KREEK and CULPEPPER-MORGAN 1991.