Opiates and Opiate Antagonists

ADVANCES in knowledge of the clinical and these are considered both from the neuro-- uses of the recently discovered opiate an- physiological and psychological viewpoints. tagonists nalorphine and levallorphan in the The distinction between "positive" and treatment of opiate and opioid poisoning, and "negative" euphoria is discussed, and the lat- the use of these drugs in the diagnosis of nar- ter is considered mainly from the standpoint of cotic addiction, are reviewed in this monograph. mechanisms involved in the production of Also discussed is the abuse of narcotic drugs, morphine analgesia. including the neurophysiological and psycho- Neurophysiological data obtained chiefly in logical mechanisms of intoxication, pharma- studies on "analgesic-test" reflexes in animals; cogenic dependence, and relapse after cure. indicate that morphine exerts selective depres- sant actions on interneuronal activity in thee forma- Clinical Uses of Opiate Antagonists spinal cord, medulla, midbrain reticular In human subjects, nalorphine produces autonomic effects resembling those of morphine, but often it also produces hallucinatory and other mental disturbances,. particularly after repeated doses or large single doses. In man, nalorphine has analgesic properties, and re- peated doses do not produce addiction (physi- cal dependence), but its "side effects" impair No. 52 its clinical usefulness in the management of The accompanying summary covers the pain. In medical practice, nalorphine has been principal findings presented in Public Health used primarily for resuscitation of patients Monograph No. 52, published concurrently poisoned by overdoses of morphine, heroin, with this issue of Public Health Reports. The methadone, dihydromorphinone, pantopon, le- author is with the National Institute of Mental vorphan, meperidine, or alphaprodine. In Health Addiction Research Center, National such cases, the most prominent narcotic antag- Institutes of Health, Public Health Service, onistic effects are those exerted on respiratory Lexington, Ky. depression. In subjects addicted to morphine, Readers wishing the report in full may pur- methadone, heroin, and many other opiates and chase copies of the monograph from the Super- intendent of Documents, Government Printing opioids (except possibly meperidine), nalor- Office, Washington 25, D. C. A limited phine precipitates acute "abstinence syn- number of free copies are available to official dromes" and has therefore been used clinically agencies and others directly concerned on in the diagnosis of active addictions. Analysis specific request to the Public Health Service. of dose-effect relationships both in man and Copies will be found also in the libraries of in animals suggests that nalorphine and its an- professional schools and of the major uni- alogs exert their "specific" narcotic-antagonis- versities and in selected public libraries. tic actions by (a) "molecular competition" and 0 0 0 (b) "unmasking" of the processes responsible for the opiate and opioid abstinence syn- Wikler, Abraham: Opiates and opiate an- tagonists. A review- of their mechanisms dromes. of action in relation to clinical problems. Public Health Monograph No. 52 (PHS Pub. No. 589). 39 pages. U. S. Govern- Narcotic Drug Abuse ment Printing Office, Washington, D. C., The problems of narcotic drug abuse include 1958. Price 30 cents. "euphoria," "addiction," and "habituation," Vol. 73, No. 11, November 1958 1033 tion, lateral posteroventral, and certain of the drug may serve some addicts as a means of ex- medial thalamic nuclei and cerebral cortex, piating guilt. while also exerting excitant actions at all levels The role of "conditioning" in the genesis of and augmenting supraspinal inhibition. relapse (habituation) is discussed from both Evidence acquired in studies on both man "classical" and "instrumental" theoretical view- and animals indicates that one of the important points. A number of suggestive, but not con- psychological actions of morphine is reduction clusive, observations indicate that the opiate of pain-anticipatory anxiety. Other actions of abstinence syndrome may become "conditioned" morphine that may be involved in the produc- to regularly associated environmental stimuli. tion of euphoria are discussed with particular If verified, such a process could account, in part, reference to personality factors. for the motivation to relapse under certain cir- The neurophysiological effects on the mor- cumstances long after the "unconditioned" phine abstinence syndrome of bilateral frontal morphine abstinence syndrome has subsided. lobotomy and physiological "transection" of Data more strongly supported by experimental the spinal cord in man (due to disease), and of evidence, obtained in rats, indicate that the re- decortication and spinal transection in the dog, current reduction of abstinence distress during indicate that the processes responsible for ad- maintained morphine addiction can result in diction operate at cellular (neuronal) levels reinforcement of such of the organism's activi- throughout the neuraxis and appear to involve ties as culminated regularly in administration "counter-adaptations" to the depressant effects of the drug, and that in consequence, "drug- of morphine on interneuronal activity. While seeking" behavior may persist beyond the dura- data obtained in frontal lobotomized patients tion of the "unconditioned" abstinence syn- and in monkeys subjected to bilateral frontal drome. lobectomy, bilateral cingulumotomy, or bi- It appears likely, therefore, that the probabil- lateral ablation of the cingulate gyri are con- ity of relapse is not only a function of the initial flicting in some respects, it appears that al- "euphoric" effects of opiates, which diminish though the integrity of the cerebral cortex and rapidly as tolerance develops, but also of the its connections with subcortical structures is cyclic actions of these agents in generating de- necessary for the expression of "purposive" pendence and in relieving abstinence symptoms. abstinence phenomena, the "nonpurposive" These actions persist as long as the opiates are features of the morphine abstinence syndrome administered at sufficiently high dose levels and are integrated to a very large extent subcorti- at sufficiently frequent intervals. The prob- cally. In addition, studies on man indicate that ability of relapse is also related to the extent during morphine addiction, adrenal and gon- to which the administration of these drugs is adal activities are depressed, probably through brought about by actions of the organism upon an indirect effect on the pituitary gland, and its environment. In addition, theoretical con- that transient "rebound" adrenal hyperactivity siderations suggest that "secondary rein- occurs on withdrawal of the drug. forcers," or stimuli regularly associated with In considering the psychological aspects of reduction of abstinence distress during main- addiction, it is stressed that with the develop- tained addiction, may serve as incentives for ment of tolerance the "euphoric" effects of subsequent relapse. morphine become progressively attenuated, but that new sources of gratification are developed Although practically nothing is known about as a consequence of the progressively intensi- the neurophysiological mechanisms operating fied "need" for the drug. The "rewarding" ef- in relapse, progress in that direction, as well as fects of morphine include the periodic relief of in the further elucidation of the psychological "craving," the sense of achievement engendered processes involved, may become possible with by successful pursuit of drug supplies ("hus- continued improvement of recently developed tling"), and social acceptance of the user by techniques for demonstrating in animals a other addicts. Also, the suffering attendant "model" of this most important of all problems upon abrupt and complete withdrawal of the of drug abuse.

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