naloxone and dezocine

Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Cognition; Cycloparaffins; Humans; Hydromorphone; Male; Monitoring, Physiologic; Naloxone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Psychomotor Performance; Surveys and Questionnaires; Tetrahydronaphthalenes

The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine failed to antagonize dezocine's rate-decreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Columbidae; Cycloparaffins; Discrimination Learning; Female; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Receptors, Opioid, mu; Tetrahydronaphthalenes

Dezocine in equianalgesic intravenous doses depressed respiratory response to CO2 breathing of six healthy subjects to approximately the same degree as morphine but with a more rapid onset and higher peak depression. The depression was dose related up to 30 mg/70 kg but was not increased by an additional 10 mg/70 kg dose. Its duration of effect was approximately the same as that of morphine. Respiratory depression by dezocine was promptly and almost completely antagonized by 0.4 mg naloxone, but antagonism lasted less than 1 hr. Healthy subjects found dezocine less pleasant than morphine and after large doses reported sensations suggestive of psychotomimetic effects. A ceiling effect for respiratory depression has now been demonstrated for three agonist-antagonist analgesics: nalorphine, nalbuphine, and dezocine. It is not yet clear to what extent this is a general characteristic of agonist-antagonist analgesics.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Carbon Dioxide; Cycloparaffins; Dose-Response Relationship, Drug; Humans; Injections, Intravenous; Male; Morphine; Nalbuphine; Naloxone; Respiration Disorders; Tetrahydronaphthalenes

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Cycloparaffins; Discrimination Learning; Dose-Response Relationship, Drug; Female; Male; Morphine; Naloxone; Narcotic Antagonists; Pyrrolidines; Saimiri; Tetrahydronaphthalenes