Pharmacotherapies for Treatment of Opioid Dependence

109 Presentation PHARMACOTHERAPIES FOR TREATMENT OF OPIOID DEPENDENCE FRANK J. VOCCI, Ph.D. Deputy Director HEINZ SORER, Ph.D. Pharmacologist Medications Development Division National Institute on Drug Abuse 5600 Fishers Lane, Room 11A-55 Rockville, MD 20857 THIS PAPER is a review of various pharmacotherapies currently in use and under development for treatment of opioid addiction. When a compound is first synthesized by chemists, usually in very small quantities (100 mg or less), the first in vitro test to which it is subjected measures binding to opioid receptors. A brief overview of the concept of multiple opioid receptors would be useful at this point. Studies of the binding of various ligands in the brain and other organs suggest the existence of a multitude of distinct types of receptors that can interact with opioid drugs or endogenous peptides. There is reasonably firm evidence for three major categories of opioid receptors in the central nervous system (CNS), designated μ (mu), κ (kappa), and δ (sigma); investigators have also tentatively identified two subtypes of each category. Molecular cloning and expression of individual receptors will greatly facilitate the unraveling of this complex issue in the near future. The antagonist, naloxone, binds with high but variable affinity to all of these receptors, and the term "naloxone-sensitive" is often (but perhaps incorrectly) used synonymously with "opioid" in describing the actions of a given drug. Inferences from these data attempt to relate pharmacological effects of opioid drugs to interactions with a particular constellation of receptors. For example, analgesia is thought to involve activation of μ receptors (largely at supraspinal sites) and κ receptors (principally within the spinal cord); ¿recepJournal of Health Care for the Poor and Underserved, Vol. 3, No. 1, Summer 1992 110 Treatment of Opioid Dependence tors may also be involved, but the relative contribution of spinal and supraspinal sites is controversial. Moreover, a given opioid drug may interact variably with all three types of receptors and act as an agonist, a partial agonist, or an antagonist at each.1 The profile of interactions of receptors and opioid drugs in humans is inferred both from clinical observations and from guarded extrapolation of pharmacological actions in animals. The opioids may be divided into three groups: morphine-like opioid agonists (compounds that act at various receptors, primarily at μ and perhaps at xrand ¿receptors); opioid antagonists (agents such as naloxone that either block the effects of antagonists or are essentially devoid of agonist activity at any receptor); and opioids with mixed actions. The last category includes the agonist/antagonists (substances such as nalorphine or pentazocine that appear to be agonists at some receptors and antagonists or very weak agonists at others) and the partial agonists (such as buprenorphine). In addition, certain opioid drugs (e.g., nalorphine, pentazocine) produce dysphoric or psychotomimetic effects in humans that are poorly antagonized by naloxone. Although initially postulated to be mediated by δ "opioid" receptors, the status of these sites is now uncertain. Even though the affinity of morphine for μ receptors is only about tenfold that for ¿and κ receptors, it is likely that morphine and other morphine-like opioid agonists produce analgesia primarily through interaction with μ-opioid receptors. This is best judged from the properties of sufentanil, a potent analgesic that binds about 200-fold more tightly to μ than to fror ¿receptors and exhibits a high degree of cross-tolerance with morphine-like agonists. Other consequences of μ-receptor activation include respiratory depression, miosis, reduced gastrointestinal motility, and feelings of well-being or euphoria. Two apparently distinct types of μ receptors have been detected based on their relative affinities for agonists: μ, (higher affinity), postulated to mediate supraspinal analgesic actions; and μ2 (lower affinity), postulated to medicate respiratory depression and gastrointestinal actions, among others.2 Certain benzomorphan relatives of pentazocine interact quite selectively with κ receptors. These agonists produce analgesia that is undiminished in animals made tolerant to μ agonists and that results from actions primarily in the spinal cord; they cause less intense miosis and respiratory depression than do μ agonists. Instead of euphoria, »cagonists produce dysphoric, psychotomimetic effects (disoriented or depersonalized feelings).3 The consequences of stimulating ¿opioid receptors in humans are uncertain because of the lack of selective agonists that can traverse the blood-brain barrier. In animals, relatively specific ¿agonists...