Tricyclic Antidepressants: Intoxication in Man

Effects of Acute Overdose Most of the numerous publications on acute intoxication with tricyclic antidepressants deal with attempted suicide in adults or with accidental selfpoisoning in children. Taking into account the difficulty in establishing the dose ingested – particularly in the case of children and of successful suicides – it is not surprising that it is difficult to predict the severity of an acute intoxication from the dose apparently taken. In children, fatalities have occurred with doses below 500 mg and survival with doses as high as approximately 1,700 mg. In adults, doses below 1,000 mg may already prove fatal but survival has been reported with doses up to 4,000 mg or higher (). In children, the critical dose level for imipramine seems to lie around 500 mg. Of a survey comprising 34 cases, only two children who had ingested less died whereas only three with larger doses survived (). Adults, who have ingested 1,000 – 2,000 mg still have a good chance of recovery whereas the risk of a fatality becomes far greater at levels of over 2,000 mg (). In relation to body weight, an LD50 value for imipramine has been determined for children at 40 – 50 mg/kg and for adults at 30 – 50 mg/ kg (). The symptoms Read more […]

The Theoretical Basis of Narcotic Addiction Treatment with Narcotic Antagonists

The theoretical basis of narcotic addiction treatment with narcotic antagonists was well stated by Martin et al. (). Briefly, outpatient maintenance of a previously detoxified opioid addict on a daily oral opioid-blocking dose of a narcotic antagonist is expected to accomplish two objectives: (a) to remove the incentive for seeking and using opioid drugs; and (b), to extinguish conditioned abstinence (including “craving”) should this phenomenon occur as a response to environmental stimuli to which unconditioned abstinence had previously become conditioned (). Needless to add, such a period of out-patient maintenance on a narcotic antagonist should be used to “rehabilitate” the patient – i.e., to train him in the skills necessary for holding a socially useful job. to form new, mutually supportive relationships with non-drug using persons, and to persuade him to give up the illegal “hustling” activities which had become self-reinforcing during previous periods of opioid addiction. Such a period of out-patient maintenance on a narcotic antagonist would have advantages over detoxification followed by enforced abstention from opioids (by prison sentences with or without a subsequent probationary period) in Read more […]

Measurement and Extinction of Conditioned Withdrawal-Like Responses in Opiate-Dependent Patients

As O’Brien has reviewed elsewhere in this volume (), there has been much experimental work on opiates and Pavlovian conditioning processes since Wikler’s original observations of withdrawal-like responses in drug-free patients (). Several studies have found evidence of conditioned withdrawal-like and opiate-like responses in rats, monkeys, and humans (). Addict patients viewing slides or videotapes of drug-related stimuli () or handling drug objects in a preparation ritual () experience subjective craving and withdrawal-like changes in physiological measures of skin temperature, heart rate, pupillary dilation, etc. Research from our own laboratory has demonstrated that opiate withdrawallike responses in humans can be conditioned to an arbitrary conditioned stimulus (). These studies leave little doubt that conditioned withdrawal-like phenomena exist and can be both reliably elicited and measured. They do not, however, address the clinical significance of these responses. Though Wikler (1948) proposed conditioned withdrawal as the primary cause of relapse in drug-free patients, this link has not been clinically tested and is still controversial. Based on interviews with Baltimore street addicts, McAuliffe () had recently Read more […]

Buprenorphine, Heroin, and Methadone: Comparison of Relative’ Reinforcing Properties

Buprenorphine is a partial agonist of the morphine type. It is both a long-acting opiate antagonist, like naltrexone, and a potent opiate agonist with respect to analgesia, physiological and subjective reactions in man (). However, buprenorphine does not induce physical dependence in several species and appears to produce only minimal physical dependence in man (). Buprenorphine’s positive morphine-like agonist effects combined with its antagonist potency, low toxicity, and minimal capacity for producing physical dependence, suggested that it should be valuable for the treatment of opiate addiction (). Clinical studies have shown that buprenorphine maintenance (8 mg/ day s.c.) significantly suppressed self-administration of heroin (21 to 40.5 mg/day) by male heroin addicts over 10 days of heroin availability in comparison to buprenorphine placebo (). Buprenorphine (0.282 to 0.789 mg/kg/day i.v.) also significantly suppressed opiate self-administration in the rhesus monkey drug self-administration model (). Recent clinical studies have shown that sublingual administration of buprenorphine (1-2 mg) should be suitable for daily maintenance for the treatment of narcotic addiction (). The opiate agonist effects of Read more […]

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 […]

Classically Conditioned Phenomena in Human Opiate Addiction

Classical and operant conditioning factors are both potentially significant in the maintenance of opiate use. Analysis from the perspective of the operant conditioning paradigm emphasizes the importance of discriminative stimulus control and the efficacy of opiates as reinforcers (). In the context of the classical conditioning paradigm, emphasis is placed on environmental correlates of drug effects and withdrawal symptoms as elicitors of overt behavioral and physiological responses. Concurrently it must be recognized that a model based on integration of both paradigms probably reflects most accurately the reality of human opiate dependence (). In the context of either the operant or classical conditioning paradigms, seemingly contradictory and diverse effects of stimuli and events may be identified. However, careful analysis leads to the conclusion that systematic results prevail and that findings parallel those involving other behaviors and reinforcers. As has been discussed in a recent review (), the primary problems appear to arise in delineating the phase of opiate action (e.g., onset, termination, withdrawal) with which stimulus events are associated. A secondary problem arises in differentiating patterns of 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 […]

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 […]