Internal Stimulus Control and Subjective Effects of Drugs

For many years psychotropic drugs have been characterized and classified using methods designed to measure their subjective effects in humans (). This research approach has two principal purposes: 1) to investigate the efficacy of a drug in attenuating unwanted subjective states in patients (e.g., pain, anxiety, depression), 2) to investigate the abuse potential of new drugs by comparing their subjective effects in experienced drug abusers to those produced by known drugs of abuse. In regard to the latter, such methods have been used to determine whether there are any common subjective states produced by all drugs of abuse (e.g., euphoria). Systematic studies of subjective methods for drug classification have been conducted at the Addiction Research Center (ARC) in Lexington, Kentucky, now part of the National Institute on Drug Abuse. A major mission of the ARC has been to evaluate new analgesic compounds to determine whether they produced morphine-like effects. The subjective effects of morphine and related compounds were an important aspect of this evaluation. The research demonstrated that morphine and related narcotic analgesics produced a unique spectrum of subjective effects that can be reliably discriminated Read more […]

History of Drug Exposure as a Determinant of Drug Self-Administration

The purpose of this paper is to review how a drug’s effectiveness in initiating and maintaining self-administration can be influenced by a subject’s past experience with drugs. Drug self-administration by humans and laboratory animals is considered an instance of operant behavior (), controlled by the subject’s genetic constitution, past history, and the current circumstances of drug availability (of Skinner, 1938). The influence of history of drug exposure on current drug-maintained behavior may be controlled, in turn, by the particular drugs and doses employed and the conditions under which the drug is administered. This discussion will focus on the ways in which a history of drug exposure can control later drug self-administration in laboratory animals. Effects of history of drug exposure on initiation of drug self-administration In order to study drug self-administration by laboratory animals, an experimenter must set up a situation in which subjects are exposed to some contingency between the occurrence of a specific response and delivery of a particular drug. For many drugs, no explicit behavioral or pharmacologioal history is necessary for the drug to maintain behavior. In one initial study, for example, Read more […]

The development of sustained action preparations of narcotic antagonists

The use of narcotic antagonists in the treatment of opiate addiction is based on the concept of a pharmaceutical agent capable of blocking the reinforcing properties of a dose of opiate taken during an addicts rehabilitation. The rationale for use is that the antagonist blocks the opiate “high” and makes it pleasureless, thus removing the addict’s incentive for continued use. Earlier successful therapy with cyclazocine and naloxone prompted the full-scale development of new and superior antagonists. Presently naltrexone is the drug under the most intensive clinical evaluation and appears to be a promising antagonist candidate. It was felt from the outset that a most desirable component of antagonist therapy would be long-acting drug, so that the need for an addict to decide to take his medication would be minimized. Naltrexone in oral doses of 70 mg. will provide adequate blocking protection for at least 48 hours, or perhaps 72 hours in certain individuals. This is not felt to be a long enough interval between dosages to aid the addict in becoming dissociated from his drug-taking behavior. It was recognized very early that in order to achieve the desired one week, one month or longer duration between dosages, Read more […]

Nida’s Naltrexone Research Program

The current naltrexone research program sup ported by the National Institute on Drug Abuse can be traced developmentally to its embryonic beginnings in the mid-1960’s. At that time Dr. William Martin and his co-workers at the Addiction Research Center in Lexington, Kentucky initiated a series of studies into the use of narcotic antagonists for the treatment of opioid dependence (). The studies were a practical outgrowth of the theoretical formulations elaborated by Dr. Abraham Wikler over the preceding years (). The results of the studies showed that a narcotic antagonist could be effectively used to block the euphorigenic and dependence-producing properties of opioids in man. Furthermore, this chemotherapeutic agent would produce neither physical dependence nor abuse liability in the treated individual. This was important because previous treatment drugs had the liability of producing their own degree of addiction. These early clinical studies into the therapeutic use of narcotic antagonists might have faded into textbook obscurity had it not been for a number of concurrent social and political events that were rapidly developing. In the years following the tragedy of President Kennedy’s assassination on November Read more […]

Behavioral Pharmacology of Narcotic Antagonists

Narcotic antagonists are currently the major pharmacological alternative to methadone for the long-term treatment of narcotic addiction. The clinical utility of antagonist treatment is undergoing continuing evaluation (). Within the last five years, there have been several comprehensive reviews of research on narcotic antagonist drugs (). This review will focus upon some recent behavioral studies of narcotic antagonist drugs in man and in animals. It is now apparent that antagonist drugs may have a number of complex behavioral effects, in addition to antagonism of the pharmacological effects of opiate drugs (). Recent explorations of the aversive properties of some antagonists () have been complemented by studies of the positive reinforcing qualities of antagonist drugs. The finding that opiate dependent monkeys will work to produce an infusion of a narcotic antagonist under certain conditions () suggests the complexity of the process of drug-related reinforcement (). Narcotic agonists and antagonists each may maintain behavior that leads to their administration. Of the several compounds which have narcotic antagonist properties), only two appear to be relatively “pure” antagonists with minimal agonistic activity. Read more […]

Effects of antagonists of opiate self-administration

Clinical Studies Since narcotic antagonists can block the effects of opiates, proponents of narcotic antagonist maintenance for the treatment of heroin addiction argue that pharmacological blockade will eventually eliminate opiate self-administration (). However, recent studies of the efficacy of naltrexone maintenance in modulating heroin self-administration on a clinical research ward have shown that some addicts may continue to sample heroin during antagonist blockade (). The frequency of heroin self-administration during antagonist blockade was influenced by a number of factors, including whether or not the heroin addict was told that he was given naltrexone. When subjects were not told who was receiving naltrexone and who was receiving naltrexone placebo, seven of the nine subjects maintained on naltrexone blockade (75 mg/day PO) sampled heroin an average of 13 times (range: 2-46) over a ten-day period of heroin availability. Assessments of temperature, blood pressure, pulse, respiration and pupil diameter revealed no physiological effect of heroin during naltrexone blockade. Although all subjects took less heroin during naltrexone blockade than under unblocked conditions (X occasions = 55.07; range: 32-78), the Read more […]

Naltrexone in the Treatment of Opiate Dependence

At the Division of Drug Abuse Research and Treatment of New York Medical College, we began using naltrexone early in 1973, and studies are continuing at the present time. Over the past four years, more than 400 opiate addicts have been detoxified and inducted onto naltrexone by members of our staff. Our clinic is located in the East Harlem section of New York City, where the incidence of opiate addiction is exceptionally high. The clinic’s patient population is comprised of individuals from all levels of society, although most are of low socioeconomic status and have a high incidence of unemployment and use of public assistance. On the average, 38 percent are black, 38 percent are Puerto Rican, and 24 percent are white. Heroin and/or illicit methadone are the drugs primarily abused. Patients are referred to us by community service agencies, by nearby ambulatory detoxification facilities, and by expatients or those continuing in treatment. The clinic’s staff includes psychiatrists, internists, psychologists, nurses, social workers, vocational and recreational therapists, students in the mental health professions, and paraprofessional counselors. This report summarizes the results of four years’ clinical experience Read more […]

Naltrexone in the Treatment of Opiate Dependence: Clinical Efficacy

Predictive Variables Our evaluation of naltrexone’s clinical efficacy focused primarily upon identifying opiate users most likely to benefit from naltrexone treatment (). This focus emerged from earlier work with cyclazocine () which presented a typological classification of opiate users based upon patients’ self-ratings of the role opiates play in their lives. Briefly, two major groups were identified and shown to have a differential response to cyclazocine treatment. One group appeared to use opiates as a form of “self-medication” to relieve chronic emotional symptoms or stress. They indicated that the drug reduced their inhibitions, anxieties, and painful affects, and perceived themselves to function better with opiates in their system as compared with periods when they were opiate-free. In general, such individuals discontinued cyclazocine treatment prematurely. By contrast, the other group seemed to use heroin as a result of environmental influences: in these individuals disorders of feeling and impaired capacity to function without opiates did not predominate. In general, such individuals remained in cyclazocine treatment for longer periods of time. Based upon these earlier findings with cyclazocine Read more […]

Historical Trends in Naltrexone Research

The development of the narcotic antagonist, naltrexone, has related to and reflected in a fascinating way various medical and psychiatric research trends as well as an array of social and political trends. It has involved innovative cooperation between the clinical community, multiple research groups, various Federal Government agencies, and private industry. Through this cooperative interest in the project, and of course due to the pressing social need to devise new treatment approaches to the problem of heroin abuse, the research effort has yielded what seems to be a most promising and safe chemotherapeutic addition to opiate dependence therapy. The existence of narcotic antagonist agents has been known since the early twentieth century. Initially, the primary interest in this class of drugs focused on their ability to counteract the effects of opiates in man and on their consequent use in the treatment of acute opiate overdose. This application, of course, was of direct medical life-saving use in hospital emergency rooms across the country. The main agent used for this purpose has become naloxone, which is a potent narcotic antagonist with a short duration of action. However, concurrent laboratory research within Read more […]

Multimodality Treatment of Narcotic Addiction: Pharmacologic Therapies

Narcotic substitution The single therapy that has had the greatest impact on narcotic addiction appears to be methadone maintenance. Unlike drug-free approaches, it is acceptable to a large number of addicts (). It is medically safe, has minimal side effects and no toxicity when given to tolerant individuals, even for long periods of time (). Though the results of methadone treatment vary among programs, there is strong evidence that it provides a way to control narcotic addiction. Most patients who remain in methadone treatment have a marked decrease in heroin use, an increase in employment rates, and demonstrate improved personal adjustment (). At present there are approximately 80,000 people being treated with methadone in the United States (), but despite methadone’s wide applicability and effectiveness, it leaves much to be desired. It has been controversial since the beginning, and many aspects of methadone programs have been criticized (). One problem has been an inability to demonstrate that methadone treatment increases the long term cure rate for addiction. This is a disappointment, as many had hoped that the social rehabilitation obtained via methadone maintenance would lay the groundwork for successful Read more […]