A behavioral paradigm for the evaluation of narcotic antagonists.

We have developed an experimental paradigm for the behavioral evaluation of narcotic antagonists. The study specifically examined the heroin-seeking behavior of hard-core narcotic addicts on a research ward under blocked and unblocked conditions. Each patient served as his own control. A long-term follow-up program in the community, with aftercare services, was utilized to determine the relationship between behavior observed on the research ward and behavior that occurred in the community. While preliminary one-month follow-up data offered some cause for an optimistic view of narcotic antagonist treatment, behavioral data observed on the research ward raised serious doubts about the possibility of extinguishing heroin self-administration with antagonists. The behavioral data were not consistent with laboratory descriptions of extinction. Rather, the data suggested that narcotic antagonist programs should emphasize the development of contingencies for the reinforcement of narcotic antagonist self-administration to ensure an opiate-free state, instead of focusing on an extinction approach.

Partial opioids. Medications for the treatment of pain and drug abuse.

Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug-abuse problems. Cyclazocine is a low-liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the mu opioid receptor and as kappa agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying kappa agonist and partial mu agonist properties, a series of 8-amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the mu, delta, and kappa opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the mu, delta and kappa receptors.

Effects of cyclazocine on cocaine self-administration in rats.

Cyclazocine is a kappa-opioid receptor agonist and mu-opioid receptor antagonist that was studied in the 1960s as a potential treatment for heroin addicts. Based on the evidence that opioid mechanisms modulate the reinforcing effects of cocaine, it has been suggested that cyclazocine be reconsidered for use in treating cocaine dependence. In the present study, the effects of orally administered (+/-)-cyclazocine, (+)-cyclazocine and (-)-cyclazocine on intravenous cocaine self-administration were assessed in rats. (+/-)-Cyclazocine produced a dose-related (2-8 mg/kg) decrease in cocaine intake without affecting bar-press responding for water. Neither enantiomer significantly altered responding for either cocaine or water. The efficacy of orally administered (+/-)-cyclazocine on cocaine self-administration was comparable to that previously observed using the intraperitoneal route. Distinct actions of the enantiomers of cyclazocine that might contribute to the unique efficacy of the racemate are discussed. Although the mechanistic basis for the results are not entirely understood, the data suggest that (+/-)-cyclazocine should be considered as a potential treatment for cocaine dependence.

A laboratory study of hydromorphone and cyclazocine on smoking behavior in residential polydrug users.

The effects of cyclazocine and hydromorphone on spontaneous and laboratory cigarette smoking were compared in a double-blind, placebo-controlled, crossover study. Participants (seven men, one woman) received oral doses of placebo, cyclazocine (0.2, 0.4, and 0.8 mg) and hydromorphone (5 and 15 mg) in a randomized order on experimental days. Spontaneous smoking was recorded during two intervals on the experimental days: a 3-h period 5-8 h after drug administration (Interval 1), and the rest of the day (Interval 2). Measures of smoking topography and subjective and physiologic effects of a single cigarette were obtained on the experimental days. Neither hydromorphone nor cyclazocine significantly changed spontaneous smoking when compared to the placebo condition; however, compared to hydromorphone (5 mg), cyclazocine (0.4 and 0.8 mg) decreased spontaneous smoking during Interval 1. Hydromorphone (5 and 15 mg) and cyclazocine (0.4 and 0.8 mg) diminished smoking-induced increases in heart rate. Compared to the placebo condition, cyclazocine (0.2 and 0.4 mg) reduced exhaled carbon monoxide (CO) boost, a measure of smoke exposure. Further studies of the effects of kappa opioid agonists on smoking behavior may lead to a better understanding of the role of opiates in smoking behavior.

Analysis and modification of opiate reinforcement.

The authors describe a research protocol for the evaluation of narcotic antagonists which examines the heroin-seeking behavior of hard-core heroin addicts on a research ward under blocked and unblocked conditions. Each patient served as his own control. This paper serves as an introduction to a series of papers which follow dealing with behavioral, psychiatric, and aftercare results. It describes detailed methods and preliminary results for the first 21 subjects admitted to the study. More specific results are reported in the papers that follow.

Pharmacological approaches to the treatment of morphine-type dependence.

Of the two pharmacologically different possibilities of interfering with the processes of either tolerance or dependence of the morphine type, the so-called maintenance method commonly using methadone is predominantly a matter of tolerance, whereas the blockade with specific opiate antagonists such as cyclazocine intervenes in processes underlying dependence and withdrawal. The experimental evidence for these mechanisms is described.

A unit for delivering multiple drug treatment and prevention services.

A diverse group of drug abusers in New Haven has benefited from a multifaceted treatment program at the Connecticut Mental Health Center's drug dependence unit. The unit is also involved in research, training, and community education: Treatment approaches include methadone maintenance, long- and short-term therapeutic communities, a day program for adolescents, and a low-intervention program using narcotic antagonists. Out of approximately 2400 applicants, 1600 have entered treatment, and 550 are considered drug-free program graduates. A long-term follow-up study is in progress to validate and extend those initial results.

Cyclazocine: comparison to hydromorphone and interaction with cocaine.

Kappa-opioid agonists produce neurobiological and behavioral effects opposite to those of cocaine and may be useful for the treatment of cocaine dependence. To evaluate the kappa- and mu-agonist effects of cyclazocine and to test whether cyclazocine pretreatment would attenuate the effects of cocaine, healthy, male and female, experienced opiate and cocaine users (n = 13) were enrolled in a two-phase study. In Phase 1, placebo, cyclazocine (0.2, 0.4 and 0.8 mg) and the mu-agonist hydromorphone (5 and 15 mg) were administered orally in six 4.5-hour sessions separated by at least 72 h. In Phase 2, cocaine (100 mg intranasal) was given 2 h after oral pretreatment with cyclazocine (0, 0.1, 0.2, 0.4, 0.8 and 0 mg, in that order) in each of six sessions conducted daily Monday to Friday and the following Monday. Physiological, subjective and behavioral measures were collected in each session. Nine participants completed Phase 1; eight completed Phase 2. Hydromorphone (15 mg) produced prototypic mu-agonist effects. Cyclazocine exhibited only modest kappa-like effects. Cyclazocine also had only modest, non-dose-related effects on response to cocaine. However, cocaine effects were consistently lower on the last administration (cyclazocine 0 mg pretreatment) following 4 days of cyclazocine pretreatment, compared to the first administration (0 mg pretreatment). This finding is unlikely to be fully attributable to cocaine tolerance and is not accounted for by pharmacokinetic changes; plasma concentrations of cocaine were not altered by cyclazocine. This study is suggestive but not strongly supportive for the use of kappa-opiate drugs to diminish acute effects of cocaine administration or for the use of these kappa agonists in drug abuse treatment applications.

Cyclazocine in the treatment of opiate addiction: a review with recommendations.

The use of cyclazocine, a narcotic antagonist in the treatment of opiate addiction, is reviewed. Eleven investigations which have employed cyclazocine within addiction treatment programs have led to the conclusion that cyclazocine has yet to demonstrate its therapeutic efficacy due to low patient acceptance and the difficulty in maintaining effective blocking dosages. The use of naloxone to alleviate side effects during cyclazocine induction and technological advances in implantable sustained-release devices may facilitate the effectiveness of cyclazocine treatment of opiate addiction. Experimental designs are advocated as the best method for the evaluation of narcotic treatment programs.