morphinans and Heroin-Dependence

Buprenorphine is an opioid mixed agonist-antagonist that has potential usefulness as a pharmacotherapy for opiate addiction. Buprenorphine significantly suppressed opiate self-administration by heroin addicts. Buprenorphine also suppressed opiate self-administration in a primate model. Although buprenorphine is a positive reinforcer in rhesus monkey, it is less reinforcing than other opioids and some opioid mixed agonist-antagonists as evaluated in progressive ratio and drug substitution procedures. These data suggest that the abuse liability of buprenorphine should be less than that of other opioid drugs. The safety and potential therapeutic benefits of buprenorphine relative to other currently available pharmacotherapies probably overweigh the possible risks of abuse.

Topics: Adult; Animals; Buprenorphine; Conditioning, Operant; Eating; Heroin Dependence; Humans; Macaca; Male; Methadone; Morphinans; Naltrexone; Opioid-Related Disorders; Reinforcement, Psychology; Self Administration

Heroin-dependent out-patients who had been prescribed buprenorphine by general practitioners took part in a controlled study in which 2 mg or 4 mg of buprenorphine were administered by the sublingual route to assess its acceptability as a maintenance opiate and to determine the effects of its abrupt withdrawal and reintroduction a week later. Subjects who received 4 mg of buprenorphine reported being more intoxicated and having fewer symptoms of opiate withdrawal than did the subjects who received the 2-mg dose. Subjects who received the higher dose also abused opiate and benzodiazepine drugs less frequently. When buprenorphine was ceased abruptly, the subjects reported mild withdrawal discomfort for which many requested symptomatic treatment. The reintroduction of buprenorphine caused their condition to restabilize. The subjects' use of opiate drugs, as shown by urine assay, rose from a prevalence of around 15% of specimens at the beginning to about 50% of specimens at the end of the five-week study period. Sublingual buprenorphine was acceptable to opiate-addicted outpatients as a maintenance treatment. However, daily doses of greater than 4 mg will probably be required to suppress concurrent opiate abuse, and detoxification will need to be undertaken gradually.

Topics: Administration, Oral; Adult; Buprenorphine; Dose-Response Relationship, Drug; Female; Heroin Dependence; Humans; Male; Morphinans; Narcotics; Patient Dropouts; Random Allocation; Substance Withdrawal Syndrome; Surveys and Questionnaires

Cigarette smoking increased during administration of buprenorphine, an opioid mixed agonist-antagonist, in comparison to drug-free baseline in seven heroin addicts maintained on buprenorphine for 24 days (P less than 0.01-0.001). Ascending buprenorphine doses (0.5 - 8.0 mg/day) were associated with significant increases in cigarette smoking at doses of 2.0 mg/day sc and above. Cigarette smoking during 10 days of buprenorphine maintenance at 8 mg/day was significantly higher than during the buprenorphine induction phase (P less than 0.01). Six subjects given placebo buprenorphine over 14 days showed no change in cigarette smoking. The placebo group self-administered heroin for 10 days, and cigarette smoking increased significantly during heroin use (P less than 0.001). The rate of cigarette smoking defined by intercigarette intervals was highest during the 10 days of high-dose buprenorphine maintenance or placebo plus heroin self-administration. Both groups requested significantly more cigarettes at intervals of 0-10, 11-20, and 21-30 min than during the drug-free baseline. These data confirmed previous findings that opioid agonist administration is associated with increased cigarette smoking and suggest that buprenorphine has primarily agonist effects on cigarette smoking.

Topics: Adult; Buprenorphine; Dextroamphetamine; Dose-Response Relationship, Drug; Endorphins; Ethanol; Heroin; Heroin Dependence; Humans; Male; Methadone; Morphinans; Smoking; Time Factors

We previously reported that the κ agonists with mixed μ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and μ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and μ agonist/antagonist may have utility for the treatment of drug dependence.

Topics: Analgesics, Opioid; Animals; Conditioning, Psychological; Drug-Seeking Behavior; Heroin Dependence; Male; Mice; Morphinans; Morphine; Narcotic Antagonists; Pain; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdominal Muscles; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Heroin Dependence; Hot Temperature; Male; Mice; Morphinans; Morphine; Pain Measurement; Postural Balance; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Self Administration

This study aimed to describe the short term follow-up of a cohort of 198 i.v. heroin users by 44 highly motivated General Practitioners (GPs). The study showed that for these GPs, the work-load linked with the care of these patients was heavy. Nearly half of them saw at least one drug-addict every day. These GPs work within a network and stated they benefit from a regular training on drug addiction topics. The profile of i.v. heroin users, followed by these GPs, is different from the ones usually described in other health care structures (higher percentage of women and better social insertion). The two main motives to consult a GP are the demand of drugs concerning their addiction and medical concern (due to infectious diseases especially). The answer of GPs, concerning the demand of drugs, divide physicians into two groups: those who never prescribe morphine like drugs as substitution and those who do so. In addition, both of them often prescribe psychotropic drugs to some of their patients. Nevertheless, these prescriptions are just one of the elements of a follow-up contract between a GP and his patients. Morphine like prescription is more frequently described among long term drug-addicts already well-known by GPs. This selection prohibits a straight comparison of the results of two groups of patients (with and without morphine like substitution). But the main fact is that patients under morphine like substitution are followed better (in terms of continuity) after 4 months of observation.

Topics: Adult; Cohort Studies; Family Practice; Female; Follow-Up Studies; Heroin Dependence; Humans; Infections; Male; Morphinans; Narcotics; Psychotropic Drugs; Time Factors; Workload

Dr. Jasinski suggested years ago that on the basis of some preliminary findings buprenorphine could hold promise for the treatment of heroin dependence (D. Jasinski, J.S. Pevnick and J.D. Griffith, Arch. Gen. Psychiatry, 35 (1978) 501)). No significant report has been published to confirm that assumption, and no treatment program seems to have started on that ground. Buprenorphine is now available in several countries including Belgium. We tried to devise a treatment program for heroin addicts combining chemotherapy with sublingual buprenorphine and psychotherapy. The interim results of this treatment program--initiated in 65 heroin addicts and undertaken by 34 of them for periods varying from 2 to 17 months--seem sufficiently promising to pursue our research.

Topics: Adult; Buprenorphine; Female; Heroin Dependence; Humans; Male; Morphinans; Patient Dropouts; Physician-Patient Relations; Time Factors

Topics: Buprenorphine; Heroin Dependence; Humans; Injections; Injections, Intramuscular; Morphinans; Tongue

Topics: Adult; Buprenorphine; Drug Tolerance; Heroin Dependence; Humans; Male; Morphinans; Social Facilitation; Substance-Related Disorders

Topics: Animals; Buprenorphine; Dose-Response Relationship, Drug; Eating; Heroin Dependence; Humans; Hydromorphone; Macaca mulatta; Macaca nemestrina; Male; Methadone; Morphinans; Opioid-Related Disorders; Self Administration

Buprenorphine, a mixed opiate agonist-antagonist, suppressed plasma luteinizing hormone (LH) and increased prolactin levels after 12 consecutive days of ascending dose administration (0.5-8 mg/day s.c.) in comparison to drug-free control conditions. During a subsequent 10-day period of buprenorphine maintenance at a dose of a 8 mg s.c., LH levels remained suppressed and prolactin levels continued to be elevated. Tolerance to buprenorphine effects on LH and prolactin levels did not occur during chronic drug administration. Buprenorphine-induced changes in plasma LH and prolactin after chronic administration to human males were smaller than those observed with less potent opiate agonist drugs. Effects of buprenorphine on LH and prolactin levels are more consistent with the actions of opiate agonists rather than opiate antagonists.

Topics: Adult; Buprenorphine; Double-Blind Method; Heroin Dependence; Humans; Luteinizing Hormone; Male; Morphinans; Narcotic Antagonists; Narcotics; Prolactin; Radioimmunoassay

Topics: Adult; Buprenorphine; Conditioning, Operant; Double-Blind Method; Heroin Dependence; Humans; Male; Morphinans; Reinforcement, Psychology; Self Administration; Work

Heroin-dependent men were given buprenorphine (a partial opiate agonist-antagonist) or a placebo under duoble-blind conditions on a clinical research ward where they could acquire heroin (21 to 40.5 milligrams per day, intravenously). Buprenorphine significantly (P less than .001) suppressed the self-administration of heroin over 10 days. Control subjects took between 93 and 100 percent of the available heroin. The effects of buprenorphine were dose-dependent; a dose of 8 milligrams per day reduced heroin use by 69 to 98 percent; a dose of 4 milligrams per day reduced heroin use by 45 percent. Termination of buprenorphie maintenance did not result in opiate withdrawal signs or symptoms. The subjects liked buprenorphine and indicated that it was preferable to methadone or naltrexone. Buprenorphine should be a safe and effective new pharmacotherapy for heroin dependence.

Topics: Adult; Buprenorphine; Double-Blind Method; Heroin Dependence; Humans; Informed Consent; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Oxilorphan (levo-BC-2605) is a new, long-acting, narcotic antagonist that has agonist properties. Twenty-one (21) heroin addicts in Los Angeles were detoxified and given at least one oral dose of oxilorphan. Only three (14.3%) patients took daily doses for 14 days, which was the maximal time allowed for oxilorphan administration in this study. The remainder discontinued oxilorphan because of subjective side effects or for unknown reasons. Side effects most responsible for dropouts were dysphoria, insomnia, weakness, hallucinations, nausea, drowsiness and anorexia. Oxilorphan provided 24-hour protection with a single, oral dose, but subjective side effects encountered during inductiolinical trials with oxilorphan should be attempted with other addict populations to fully determine its potential therapeutic value.

Topics: Adult; Drug Evaluation; Female; Heroin Dependence; Humans; Male; Morphinans; Narcotic Antagonists; Substance Withdrawal Syndrome

Stereospecific opiate binding has been demonstrated in human erythrocyte membranes, having a Kd of 9-10(-9) M. In most respects the binding characteristics resemble those of synaptic membranes. These included the correlation of binding affinity and pharmacological potency of opiates; competition by naloxone; inhibition by Ca2+ and Na+; and sensitivity to phospholipases and trypsin. A comparison of stereospecific opiate binding in control human subjects and heroin addicts revealed a 43% increase in the addict group.

Topics: Adult; Brain; Calcium Chloride; Dextrorphan; Erythrocyte Membrane; Erythrocytes; Female; Heroin Dependence; Humans; Hydromorphone; Kinetics; Levorphanol; Male; Morphinans; Phospholipases; Receptors, Opioid; Serine; Sodium Chloride; Stereoisomerism; Structure-Activity Relationship; Synaptic Membranes; Trypsin

Topics: Adult; Cyclopropanes; Drug Interactions; Female; Heroin Dependence; Humans; Infusions, Parenteral; Male; Methadone; Morphinans; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Administration, Oral; Adult; Cyclazocine; Cyclopropanes; Dose-Response Relationship, Drug; Headache; Heroin; Heroin Dependence; Humans; Methadone; Morphinans; Narcotic Antagonists; Reflex, Pupillary; Substance-Related Disorders; Time Factors