morphinans and Substance-Related-Disorders

Because there are few efficacious medications for drug dependence, many clinical trials are being conducted in earnest to find such medications. Considerable evidence has shown that opioid kappa receptor agonists attenuate several behavioral responses induced by drugs of abuse. Although this raises the possibility that opioid kappa receptor agonists may be useful for the treatment of drug dependence on drugs of abuse, it has been previously reported that treatment with selective opioid kappa receptor agonists causes a psychotomimetic effect and dysphoria both in clinical studies and experimental animal models. As a result, we found the novel opioid kappa receptor agonist TRK-820, another chemical class of opioid kappa receptor agonist that has a morphinan scaffold unlike prototypical opioid kappa receptor agonists, by application of a modified message-address concept. TRK-820 showed high selectivity for an opioid kappa receptor, and strong agonistic activity in both in vitro and in vivo experiments. Like other opioid kappa receptor agonists, TRK-820 could markedly suppress the rewarding effects induced by morphine and cocaine and the discriminative stimulus effect of cocaine. Furthermore, TRK-820 attenuated the mecamylamine-precipitated nicotine-withdrawal aversion in a conditioned place preference paradigm. It is worthwhile to note that unlike prototypical opioid kappa receptor agonists, TRK-820 failed to produce a significant place aversion in rodents at doses that were sufficient to produce significant antinociception. Taken together, these findings indicate that TRK-820 may be useful for the treatment of drug dependence without any aversive effects.

Topics: Animals; Humans; Morphinans; Receptors, Opioid, kappa; Spiro Compounds; Substance-Related Disorders

Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Drug Evaluation, Preclinical; Etorphine; Humans; Hydromorphone; Ligands; Morphinans; Narcotic Antagonists; Receptors, Opioid, mu; Structure-Activity Relationship; Substance-Related Disorders

Topics: Animals; Biogenic Monoamines; Biological Transport; Carrier Proteins; Cocaine; Fluorescent Dyes; Humans; Isoquinolines; Ligands; Morphinans; Narcotic Antagonists; Piperidines; Protein Binding; Radioisotopes; Receptors, Opioid; Structure-Activity Relationship; Substance-Related Disorders

Topics: Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Drug Tolerance; Humans; Morphinans; Morphine; Narcotics; Neoplasms; Opioid-Related Disorders; Pain; Parasympatholytics; Psychotropic Drugs; Substance-Related Disorders

Topics: Animals; Humans; Morphinans; Psychiatric Status Rating Scales; Substance-Related Disorders

Nalbuphine is a potent analgesic with a low side effect and dependence profile in animals and man. Nalbuphine is distinguished from other agonist/antagonist analgesics in having greater antagonist activity and fewer behavioral effects at analgesic doses than pentazocine, butorphanol or buprenorphine. At equi-analgesic doses, nalbuphine is quantitatively similar to nalorphine in regard to its large ratio of antagonist to analgetic activity. Clinical studies have confirmed this balance of strong antagonist to analgesic activity. Nalbuphine has been shown to effectively antagonize the respiratory depressant activity of narcotic analgesics while concomitantly adding to their analgetic responses. Unlike nalorphine or pentazocine, nalbuphine produces few overt behavioral or autonomic effects in animals at doses over 300 times its analgesic range. These findings are confirmed by clinical results which show that nalbuphine produces few psychotomimetic effects, even at elevated dose levels, in contrast to nalorphine or pentazocine. Nalbuphine produces limited respiratory depression in animals and in man. Significant cardiovascular effects have not been found. Nalbuphine was found to produce significantly less inhibition of gastrointestinal activity than any of the clinically useful narcotic or agonist/antagonist analgesics tested in animals. Nalbuphine's analgetic effects are reversed by naloxone doses similar to those which reverse nalorphine's agonist effects. Results in this and other tests suggest that nalbuphine is primarily a kappa-agonist/mu-antagonist analgesic. Unlike pentazocine or buprenorphine, nalbuphine does not suppress the narcotic abstinence syndrome in partly-withdrawn morphine-dependent animals or man. Rather, due to nalbuphine's strong antagonist activity, analgesic-range doses of nalbuphine severely exacerbate the withdrawal syndrome in partly-withdrawn mice, monkeys and humans. Nalbuphine also precipitates a strong abstinence response in non-withdrawn morphine-dependent animals and man. In post-addict humans, analgesic-range doses of nalbuphine are perceived as minimally morphine-like, but higher doses are judged to be progressively more nalorphine-like (i.e. dysphoric), which further limits nalbuphine's abuse potential in drug-seeking individuals. Primary dependence studies have demonstrated that physical dependence is possible at high dose levels that produce marked side effects. Other studies show that dependence is unlikely to be of signi

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Depression, Chemical; Discrimination, Psychological; Dogs; Guinea Pigs; Haplorhini; Humans; Mice; Morphinans; Morphine; Nalbuphine; Naloxone; Rabbits; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiration; Self Administration; Sleep Stages; Substance Withdrawal Syndrome; Substance-Related Disorders

Buprenorphine is a mixed agonist-antagonist with high affinity at both mu and kappa opiate receptors. Its pharmacological profile is determined primarily by partial agonism at mu-receptors and unusually slow kinetics at these receptors. Its intrinsic activity is such that in nearly all clinical situations it is as effective an analgesic as morphine with considerably longer duration and much more favourable acute safety. In long-term dosing studies in rodents and primates buprenorphine did not produce the manifestations of physical dependence when treatment was stopped. In self-administration studies in the same species only limited levels of reinforcing efficacy were demonstrated when compared with the opiates. In human former opiate addicts the limited potential of buprenorphine to produce psychological dependence was confirmed as was the favourable physical dependence profile. Some misuse of buprenorphine has been reported in 3 of the 29 countries in which buprenorphine is marketed despite its wide clinical acceptance, particularly as the sublingual formulation.

Topics: Animals; Buprenorphine; Chemical Phenomena; Chemistry; Depression, Chemical; Discrimination, Psychological; Dose-Response Relationship, Drug; Humans; Macaca mulatta; Morphinans; Morphine; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reinforcement, Psychology; Respiration; Self Administration; Substance-Related Disorders

Butorphanol (Stadol) is a synthetic agonist-antagonist analgesic from the 14-hydroxymorphinan series. Animal studies display analgesia, antitussive effects, low gastrointestinal activity, limited respiratory depression, some cardiovascular and skeletal muscle actions, diuresis, slight miosis and opiate antagonism. Butorphanol is metabolized in the liver with renal excretion, yielding a half-life of 3-4 h. Pain relief is good to excellent with parenteral administration in 90% of patients with moderate to severe pain. Surgical anesthetic indications involve preoperative and preinduction supplementation, balanced anesthesia and postoperative pain. Side effects are sedation, nausea, elevated pulmonary vascular pressures and rarely CNS excitation. Limited respiratory depression exists. Butorphanol is a potent analgesic agent with a favorable side effect profile.

Topics: Anesthesia; Animals; Antitussive Agents; Butorphanol; Chemical Phenomena; Chemistry; Depression, Chemical; Diuretics; Dose-Response Relationship, Drug; Humans; Morphinans; Morphine; Naloxone; Nausea; Oxymorphone; Pain; Pulmonary Wedge Pressure; Rats; Respiration; Substance-Related Disorders

Nalbuphine is an agonist/antagonist analgesic. After parenteral administration of 'usual' doses it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies in patients with moderate to severe pain, usually following surgery, the characteristics of analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anaesthesia when used as a component of a 'balanced' anaesthesia technique, although a relatively low 'ceiling' effect for reduction of anaesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other agonist/antagonist analgesics, a 'ceiling' effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important haemodynamic changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist/antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. Thus, nalbuphine appears to offer a useful alternative to morphine in patients with moderate to severe pain.

Topics: Administration, Oral; Analgesics, Opioid; Anesthesia; Animals; Hemodynamics; Humans; Kinetics; Morphinans; Nalbuphine; Narcotic Antagonists; Respiration; Substance-Related Disorders

The chemical properties, animal and human pharmacology, analgesic efficacy, relative potency, administration, and adverse effects of nalbuphine, a recently marketed, parenteral, strong analgesic with narcotic antagonist properties, are reviewed. Acute, subacute, and chronic toxicity studies in animals revealed no unusual adverse effects. The abuse potential of nalbuphine in man is probably similar to pentazocine. Respiratory depression produced by usual therapeutic doses of nalbuphine is equivalent to that of morphine; at higher than usual doses, nalbuphine produces less respiratory depression. Nalbuphine has few effects on cardiovascular hemodynamics in patients without cardiac disease or with stable ischemic disease. In patients with acute myocardial infarction, nalbuphine has an advantage over morphine, pentazocine, and butorphanol of not producing hypotension. Nalbuphine is as effective and has the same potency as morphine as an analgesic, with about the same onset, peak, and duration of action. Sedation is the most common adverse effect and occurs about as often as with other strong analgesics. Nausea and vomiting occur less often. In contrast to pentazocine, the frequency of psychotomimetic reactions apparently is very low. On the basis of presently available evidence, nalbuphine appears to have fewer disadvantages than any other parenteral strong analgesic.

Topics: Analgesics; Animals; Hemodynamics; Humans; Morphinans; Nalbuphine; Respiration; Substance-Related Disorders

Buprenorphine, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine-like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine's respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine-like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug's dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time.

Topics: Animals; Buprenorphine; Hemodynamics; Humans; Intestinal Absorption; Kinetics; Morphinans; Narcotic Antagonists; Narcotics; Respiration; Substance-Related Disorders; Tissue Distribution

The chemistry, pharmacology, uses, side effects, pharmacokinetics and dosage of butorphanol tartrate, a narcotic analgesic with antagonist properties, are reviewed. When administered intramuscularly or intravenously, butorphanol tartrate appears to be as effective for relieving moderate to severe pain as are pentazocine, meperidine and morphine. Butorphanol produces sedation more commonly and, at therapeutic dosages, depresses respiration as much as these other narcotic analgesics. A limited number of long-term clinical studies suggest a lower physical dependence liability with butorphanol than with other narcotic analgesics. Butorphanol is more expensive than morphine and, for most patients, offers no significant advantages over morphine for short-term use. Because butorphanol's cardiovascular effects are not completely understood, morphine also remains the drug of choice for pain associated with myocardial infarction.

Topics: Butorphanol; Clinical Trials as Topic; Drug Evaluation; Hemodynamics; Humans; Kinetics; Morphinans; Respiration; Substance-Related Disorders; Time Factors

Topics: Animals; Benzomorphans; Chemical Phenomena; Chemistry; Cyclazocine; Humans; In Vitro Techniques; Models, Biological; Morphinans; Morphine Derivatives; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pentazocine; Receptors, Opioid; Structure-Activity Relationship; Substance-Related Disorders; Thebaine

Topics: Autoanalysis; Body Fluids; Chromatography; Chromatography, Gas; Chromatography, Thin Layer; Evaluation Studies as Topic; Hemagglutination Inhibition Tests; Humans; Hypnotics and Sedatives; Immunoassay; Mass Spectrometry; Morphinans; Morphine; Muramidase; Narcotics; Spectrometry, Fluorescence; Spectrum Analysis; Substance-Related Disorders

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Codeine; Drug Tolerance; Guinea Pigs; Half-Life; Haplorhini; Humans; Ileum; In Vitro Techniques; Meperidine; Mice; Molecular Conformation; Morphinans; Nalorphine; Narcotic Antagonists; Pentazocine; Rats; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders; Tail

Topics: Animals; Chlorpromazine; Codeine; Cyclazocine; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Lysergic Acid Diethylamide; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentobarbital; Rats; Receptors, Drug; Species Specificity; Substance Withdrawal Syndrome; Substance-Related Disorders; Surveys and Questionnaires

Topics: Analgesics; Blood Circulation; Fentanyl; Humans; Intestines; Levallorphan; Meperidine; Methadone; Methotrimeprazine; Morphinans; Morphine; Nalorphine; Narcotic Antagonists; Nausea; Pain; Pentazocine; Psychopharmacology; Respiration; Substance-Related Disorders; Urinary Tract; Vomiting

Topics: Alkaloids; Analgesics; Animals; Drug Tolerance; Heroin; Humans; Models, Chemical; Morphinans; Narcotic Antagonists; Piperidines; Pyrrolidines; Structure-Activity Relationship; Substance-Related Disorders

Topics: Animals; Azepines; Brain; Drug Tolerance; Humans; Methadone; Morphinans; Morphine; Opium; Phenazocine; Piperidines; Receptors, Drug; Substance-Related Disorders; Synapses; Synaptic Transmission

In this report-the fourth of a series on codeine and its alternates for pain and cough relief-an attempt is made to evaluate, on the basis of experimental and clinical data, and wherever possible in comparison with codeine, the effectiveness of a number of antitussive substances currently in clinical use. In the discussion of the undesired side-effects particular attention is paid to the risk of dependence and abuse.

Topics: Alkaloids; Animals; Antitussive Agents; Cats; Codeine; Cough; Dogs; Guinea Pigs; Histamine H1 Antagonists; Humans; Isoquinolines; Meperidine; Methadone; Mice; Morphinans; Phenanthrenes; Phenothiazines; Rats; Substance-Related Disorders

This report-the second of a series on codeine and its alternates for pain and cough relief-contains a detailed evaluation of experimental and clinical data on newer substances having analgesic properties comparable to and in approximately the same range as those of codeine. The data are discussed under the headings: analgesic effects in animals; clinical usefulness; side-effects with particular reference to dependence and abuse liability.

Topics: Amides; Analgesics; Animals; Antitussive Agents; Azepines; Carisoprodol; Cats; Chickens; Codeine; Cough; Cyclazocine; Dextropropoxyphene; Diphenylacetic Acids; Dogs; Ducks; Guinea Pigs; Humans; Indenes; Indoles; Isoquinolines; Mice; Morphinans; Nalorphine; Narcotic Antagonists; Pain; Pentazocine; Phenethylamines; Pyrrolidines; Rats; Substance-Related Disorders; Thalidomide

Nalfurafine (nalfurafine hydrochloride, TRK-820, Remitch®) was launched as an anti-pruritic for uremic pruritus in hemodialysis patients in Japan in 2009. Since the drug is an opioid that mainly binds to κ-receptors and possesses κ-agonistic pharmacological properties and also binds partially, but very weakly, to μ-receptors, the abuse liability of the drug was assessed by using questionnaires in patients enrolled in a clinical trial evaluating the efficacy and safety of the drug. The clinical trial was conducted for up to 52 weeks in patients subjected to regular hemodialysis. End-stage renal disease (ESRD) patients with uremic pruritus (n = 146) were administered nalfurafine 5 μg intravenously after each hemodialysis session. 81 ESRD patients without uremic pruritus served as non-treatment controls. All pruritus patients answered the 3 questionnaires of "the Addiction Research Centre Inventory (ARCI)", "modified Short Opiate Withdrawal Scale (SOWS)", which provides a range of signs and symptoms of opiate withdrawal, and Severity of Dependence Scale (SDS), which measures the dependence potential of the drug. The control patients were tested with the ARCI and modified SOWS questionnaires. There were no significant differences between the nalfurafine group and control group in the ARCI and modified SOWS scales. Thus, no evidence of abuse liability was indicated in the results. Also, no significant differences in the blood pressure, respiratory rate, body temperature and pupil diameter were shown between the two groups.

Topics: Antipruritics; Female; Humans; Male; Middle Aged; Morphinans; Renal Dialysis; Spiro Compounds; Substance-Related Disorders; Surveys and Questionnaires; Time Factors; Uremia

The chemistry, pharmacology, uses, side effects, pharmacokinetics and dosage of butorphanol tartrate, a narcotic analgesic with antagonist properties, are reviewed. When administered intramuscularly or intravenously, butorphanol tartrate appears to be as effective for relieving moderate to severe pain as are pentazocine, meperidine and morphine. Butorphanol produces sedation more commonly and, at therapeutic dosages, depresses respiration as much as these other narcotic analgesics. A limited number of long-term clinical studies suggest a lower physical dependence liability with butorphanol than with other narcotic analgesics. Butorphanol is more expensive than morphine and, for most patients, offers no significant advantages over morphine for short-term use. Because butorphanol's cardiovascular effects are not completely understood, morphine also remains the drug of choice for pain associated with myocardial infarction.

Topics: Butorphanol; Clinical Trials as Topic; Drug Evaluation; Hemodynamics; Humans; Kinetics; Morphinans; Respiration; Substance-Related Disorders; Time Factors

Buprenorphine was evaluated for its abuse potential and utility in treating narcotic addiction. The drug was morphine-like but was 25 to 50 times more potent than morphine and was longer-acting. Little if any physical dependence of clinical significance was produced by buprenorphine. The effects of morphine to 120-mg doses were blocked by buprenorphine, a blockade that persisted for 29 1/2 hours. In man, buprenorphine has less intrinsic activity than morphine, and as such, as a low abuse potential. Moreover, the drug has potential for treating narcotic addiction since it is acceptable to addicts, is long-acting, produces a low level of physical dependence such that patients may be easily detoxified, is less toxic than drugs used for maintenance therapy, and blocks the effects of narcotics.

Topics: Adult; Blood Pressure; Buprenorphine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Euphoria; Humans; Male; Methadone; Middle Aged; Morphinans; Morphine; Naloxone; Narcotics; Pulse; Pupil; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Administration, Oral; Adult; Aged; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Tolerance; Female; Heroin; Humans; Infusions, Parenteral; Male; Middle Aged; Morphinans; Neoplasms; Pain; Substance-Related Disorders; Terminal Care; Time Factors

Topics: Animals; Clinical Trials as Topic; Conditioning, Psychological; Cyclazocine; Extinction, Psychological; Heroin; Humans; Morphinans; Narcotic Antagonists; New York City; Substance-Related Disorders

Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including if the combination will function as a reinforcer in drug-naïve rats, and if the combination produces aversive effects that could explain nalfurafine's ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine's ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male Sprague-Dawley rats received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13% of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.

Topics: Analgesics, Opioid; Animals; Conditioning, Classical; Dose-Response Relationship, Drug; Male; Morphinans; Opioid-Related Disorders; Oxycodone; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, kappa; Reinforcement, Psychology; Reward; Self Administration; Spiro Compounds; Substance-Related Disorders

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.

Topics: Analgesics, Opioid; Animals; Blood-Brain Barrier; Caco-2 Cells; Dose-Response Relationship, Drug; Drug Compounding; Humans; Male; Morphinans; Permeability; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Substance-Related Disorders; Time Factors

Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6'-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations>1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

Topics: Analgesics, Opioid; Animals; Arrestins; beta-Arrestins; CHO Cells; Computer Simulation; Cricetulus; Drug Evaluation, Preclinical; Dynorphins; GTP-Binding Proteins; Humans; Ibogaine; Mesencephalon; Mice; Models, Molecular; Morphinans; Rats; Receptors, Opioid, kappa; Receptors, Opioid, mu; Signal Transduction; Substance-Related Disorders

The intent of this study was to review fatalities involving oxycodone in the west of Scotland using a liquid chromatography-electrospray ionization-tandem mass spectrometry method developed for the determination of oxycodone and N- and O-demethylated metabolites in unhydrolyzed postmortem specimens. Ten oxycodone positive postmortem cases were detected, and nine were drug-related fatalities. Five cases were attributed solely to oxycodone intoxication and four to polydrug intoxication. Although there was overlap between blood oxycodone levels in deaths attributed to oxycodone only and those due to polydrug intoxication, lower oxycodone levels (< 1 mg/L) were associated with polydrug intoxication when compared with cases due to oxycodone alone (> 1 mg/L). The role of the parent drug in oxycodone fatalities has been fully studied, but the role of oxycodone metabolites (noroxycodone and oxymorphone) was investigated in this report for the first time. Oxycodone was more commonly detected in blood, urine, and vitreous humor followed by noroxycodone. The ratio between oxycodone and its N-demethylated metabolite was evaluated and found to be useful in determining whether death occurred shortly after drug administration or if there was a significant delay. High parent/metabolite ratios were correlated with short survival times after ingestion. The median ratio of oxycodone/noroxycodone was 2.4 and ranged from 0.7 to 49. Oxycodone prescriptions have risen sharply in Scotland in recent years, and the identification of 10 oxycodone-related deaths in the past 18 months highlights the importance of including this drug in routine laboratory screening and confirmation procedures.

Topics: Adult; Aged; Cause of Death; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Morphinans; Mortality; Narcotics; Oxycodone; Reproducibility of Results; Scotland; Spectrometry, Mass, Electrospray Ionization; Substance Abuse Detection; Substance-Related Disorders; Tandem Mass Spectrometry

A case of opioid withdrawal precipitated in an opioid-dependent person by low plasma levels of naloxone is presented. In this patient, changes were observed in the hypothalamic-pituitary-adrenal (HPA) axis that preceded the clinical symptoms and adrenergic signs of withdrawal. Plasma naloxone levels were strongly correlated with plasma cortisol levels (P < .0001, R2 = .73, r = .85). In addition, these neuroendocrine changes persisted after adrenergic changes and clinical symptoms had been ameliorated by administration of a short-acting opioid agonist. It is suggested that the HPA axis is a more sensitive indicator of opioid withdrawal than the adrenergic system.

Topics: Drug Hypersensitivity; Female; Humans; Hypothalamo-Hypophyseal System; Middle Aged; Morphinans; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Substance Withdrawal Syndrome; Substance-Related Disorders

Recently, we demonstrated that delta opioid binding sites are involved in the development of morphine tolerance and dependence. In our present work, we studied the effect of the potent and selective delta antagonist, naltrindole (NTI), and its nonequilibrium analog, naltrindole 5'-isothiocyanate (5'-NTII), on the development of morphine tolerance and dependence in mice. In the acute model, mice injected with 100 mg/kg of morphine sulfate s.c. displayed acute tolerance 4 hr later as evidenced by a greater than 3-fold increase of the ED50 of morphine sulfate when compared to that of control mice. The acute tolerance was accompanied by the development of acute physical dependence as seen by the dramatic decrease in the amount of naloxone required to precipitate withdrawal jumping. Likewise, in the chronic model s.c. implantation of morphine pellets (75 mg free base) for 3 days produced tolerance and physical dependence. The ED50 of morphine sulfate in this case was increased by about 19-fold and the amount of naloxone needed to precipitate withdrawal jumping was 40 times lower than that required for acutely dependent mice. The development of acute tolerance and dependence was suppressed markedly in mice pretreated with NTI before induction of tolerance and dependence with 100 mg/kg of morphine sulfate. Multiple administration of either NTI or 5'-NTII before and during implantation with morphine base pellets also inhibited substantially the development of morphine tolerance and dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Drug Implants; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Indoles; Isothiocyanates; Male; Mice; Morphinans; Morphine; Naltrexone; Narcotic Antagonists; Nociceptors; Receptors, Opioid; Receptors, Opioid, delta; Substance-Related Disorders; Thiocyanates

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.

Topics: Animals; Body Weight; Indoles; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Back Pain; Humans; Injections; Morphinans; Nalbuphine; Substance-Related Disorders

The kappa opioid agonists, Mr 2033 and U-50, 488, or the mu opioid agonist, morphine, were administered chronically to three separate groups of rhesus monkeys. Tolerance developed to the overt signs of intoxication produced by each compound. Monkeys receiving morphine were not cross-tolerant to Mr 2033 or to U-50, 488, and monkeys receiving U-50, 488 were not cross-tolerant to morphine. Monkeys given Mr 2033 chronically were, however, cross-tolerant to morphine. When administration of U-50,488 was interrupted, or the monkeys receiving this compound were given an opioid antagonist, withdrawal behaviors were displayed that were qualitatively different from deprivation or antagonist-induced morphine withdrawal. These signs were suppressed by kappa agonists but not by morphine. Deprivation-induced withdrawal from Mr 2033 resulted in signs similar to those shown by U-50,488-dependent monkeys and some signs were observed in withdrawn morphine-dependent monkeys. Several antagonists, including the mu-selective antagonist beta-funaltrexamine, precipitated signs of withdrawal normally associated with morphine dependence in Mr 2033-dependent monkeys. Withdrawal from Mr 2033 was suppressed by kappa agonists in a stereoselective manner, and by morphine. The asymmetrical cross-tolerance and cross-dependence between Mr 2033 and morphine, and the appearance of morphine-like signs during precipitated withdrawal, suggest that Mr 2033 is kappa receptor selective but not specific. Dependence to U-50,488, however, was qualitatively and pharmacologically distinct from morphine-dependence and is apparently a consequence of specific activity at kappa receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Cyclazocine; Drug Tolerance; Endorphins; Ethylketocyclazocine; Macaca mulatta; Morphinans; Morphine; Narcotic Antagonists; Pentobarbital; Pyrrolidines; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Buprenorphine; Humans; Morphinans; Substance-Related Disorders

Reinforcing thresholds for rewarding brain stimulation to the medial forebrain bundle-lateral hypothalamus were determined in rats by means of a rate-free psychophysical method. Nalbuphine, a mixed agonist-antagonist opioid, alone caused a significant, but modest, dose-dependent lowering of the threshold for reinforcing stimulation. Concomitant administration of an ineffective dose of tripelennamine, an antihistamine, with nalbuphine potentiated the threshold lowering effect of nalbuphine. These results are similar to previous results obtained with tripelennamine and pentazocine suggesting that nalbuphine may have abuse potential if combined with tripelennamine.

Topics: Animals; Drug Interactions; Male; Morphinans; Nalbuphine; Rats; Reinforcement, Psychology; Reward; Self Stimulation; Substance-Related Disorders; Tripelennamine

Topics: Buprenorphine; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Humans; Hydrolysis; Morphinans; Substance-Related Disorders

A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.

Topics: Analgesia; Animals; Chemical Phenomena; Chemistry; Codeine; Humans; Levorphanol; Magnetic Resonance Spectroscopy; Morphinans; Morphine; Rats; Receptors, Opioid; Substance-Related Disorders

Topics: Buprenorphine; England; Humans; Injections, Intravenous; Morphinans; Substance-Related Disorders; Tablets

The agonist/antagonist analgesics, butorphanol (Stadol) and nalbuphine (Nubain), are being increasingly employed as intravenous sedation agents; nalbuphine will be available in the future as an oral analgesic. The drugs possess numerous pharmacologic similarities and some dissimilarities. Both are equianalgesic (and nalbuphine is equipotent) with morphine parenterally and codeine orally. Their pharmacokinetics are similar; nalbuphine has a longer duration of action. Both may precipitate an abstinence syndrome in narcotic-dependent persons and will probably be associated with low-level drug abuse potential. They are both agonists of the kappa opioid receptor and partial agonists of the mu receptor. Butorphanol is a partial agonist of the sigma receptor responsible for psychotomimetic effects. The incidence of adverse effects is low, sedation being the most common. In cardiac-risk patients, nalbuphine does not increase cardiac work or oxygen requirements; nor do increasing doses of nalbuphine increase the duration of respiratory depression. Both drugs possess plateau respiratory depressant actions.

Topics: Anesthesia, Dental; Butorphanol; Codeine; Drug Interactions; Heart; Humans; Kinetics; Morphinans; Nalbuphine; Preanesthetic Medication; Receptors, Opioid; Respiration; Substance-Related Disorders; Therapeutic Equivalency

Topics: Butorphanol; Drug and Narcotic Control; Humans; Male; Morphinans; Personnel, Hospital; Substance-Related Disorders

Topics: Analgesics; Azepines; Buprenorphine; Female; Humans; Male; Meptazinol; Morphinans; Nalbuphine; Pregnancy; Substance-Related Disorders

Topics: Butorphanol; Humans; Male; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Xorphanol is a new mixed agonist-antagonist from the morphinan class of analgesics. On the basis of animal experiments, the physical dependence liability of xorphanol is predicted to be of a low order in man. Conceptually, xorphanol is of interest since in vitro experiments have revealed anti-naloxone properties and resistance to antagonism by opioid antagonists. At the practical level, xorphanol is a well tolerated, orally active analgesic that provides effective pain relief clinically.

Topics: Animals; Chemical Phenomena; Chemistry; Humans; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine; Pain; Rats; Rats, Inbred Strains; Substance-Related Disorders; Time Factors; Urination

The racemate and optical isomers of the C-homobenzomorphans, 1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzaz onine, were evaluated in a number of assays sensitive to narcotics of different types. All three C-homobenzomorphans were active in vitro in guinea pig ileum, mouse vas deferens, and rat brain membrane binding assays, but were of low potency. These C-homobenzomorphans showed different profiles of in vivo activity. The (+)-isomer and racemate were active as agonists in the tail-flick assay, whereas the (-)-isomer was inactive. At higher doses, the (-)-isomer and the racemate behaved as antagonists of morphine in the tail-flick assay. All three compounds were active in the phenylquinone test, but naloxone did not block this effect. In addition, all three were potent in the hot-plate test. Neither of the isomers substituted for morphine in dependent rats or monkeys. However, the (+)-isomer precipitated withdrawal in these monkeys. The (-)-isomer produced opioid-like physical dependence in both rats and monkeys. Some of the implications regarding the results with these remarkable homobenzomorphans are discussed.

Topics: Analgesics; Animals; Benzomorphans; Benzoquinones; Binding, Competitive; Body Weight; Etorphine; Guinea Pigs; In Vitro Techniques; Macaca mulatta; Male; Mice; Morphinans; Muscle Contraction; Muscle, Smooth; Quinones; Rats; Rats, Inbred Strains; Reaction Time; Stereoisomerism; Substance-Related Disorders

Topics: Animals; Benzomorphans; Chemical Phenomena; Chemistry; Discrimination Learning; Haplorhini; Histamine H1 Antagonists; Mice; Morphinans; Pain; Papio; Rats; Substance-Related Disorders

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.

Topics: Analgesics; Animals; Benzomorphans; Catatonia; Constipation; Dose-Response Relationship, Drug; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Etorphine; Gastrointestinal Motility; Humans; Male; Morphinans; Morphine; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Adult; Buprenorphine; Humans; Male; Morphinans; Substance-Related Disorders

Topics: Australia; Buprenorphine; Drug and Narcotic Control; Humans; Morphinans; Substance-Related Disorders

Topics: Buprenorphine; Humans; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Buprenorphine is a powerful new analgesic agent with agonist and antagonist opiate receptor activity. Its withdrawal symptoms have been reported as being mild; however, its potential for abuse is not known. A case of buprenorphine abuse is reported, in which the patient's history and his response to naloxone suggest that important underlying factors were physical tolerance and dependence.

Topics: Adult; Buprenorphine; Humans; Male; Morphinans; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Administration, Oral; Analgesics; Analgesics, Opioid; Animals; Haplorhini; Humans; Mice; Morphinans; Morphine; Narcotic Antagonists; Rats; Substance-Related Disorders; Time Factors

Topics: Adult; Buprenorphine; Humans; Male; Middle Aged; Morphinans; Pain; Substance-Related Disorders

Topics: Adult; Buprenorphine; Humans; Morphinans; Substance-Related Disorders

Topics: Butorphanol; Drug and Narcotic Control; Humans; Morphinans; Substance-Related Disorders

After the intravenous injection of butorphanol or norbutorphanol in rats every 1 hr for 3 days, naloxone-induced body weight loss and withdrawal syndrome were observed to some degree. A slow-released emulsion containing each of the test drugs was injected subcutaneously in guinea-pigs, and naloxone was administered after 2 or 3 days. BT caused little jumping response even at a dose of 600 mg/kg, and the reaction was significantly weaker than that of pentazocine. No jumping responses were recognized in the cases of NB (600 mg/kg). In morphinized rats, the injection of BT or HB caused potent body weight loss, and these rats exhibited withdrawal syndrome which was more potent than that by pentazocine at the same dose. The body weight losses by the injection of NB and pentazocine were to the same degree, and these changes were significantly different from that of the saline control. BT inhibited the adenylate cyclase activity of the rat caudate nuclei, and the effect was weaker than that of pentazocine. NB showed a slight inhibition, and HB had no effect on the activity. These results suggest that the physical dependence liability of butorphanol is less than that of pentazocine, and the potent mu-antagonistic character of butorphanol is based on the liability. NB, a mu-agonist, makes dependence production possible. The ability of HB is negligible.

Topics: Animals; Behavior, Animal; Butorphanol; Humans; Injections, Intravenous; Male; Morphinans; Morphine; Narcotics; Rats; Rats, Inbred Strains; Substance-Related Disorders

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

Topics: Animals; Behavior, Animal; Buprenorphine; Drug Tolerance; Humans; Macaca mulatta; Morphinans; Self Administration; Substance-Related Disorders

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment or upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor - which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine - in comparison to pure agonists is limited, like that of other partial agonists.

Topics: Animals; Buprenorphine; Drug Tolerance; Humans; Male; Methadone; Morphinans; Morphine; Naloxone; Rats; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Animals; Butorphanol; Female; Humans; Morphinans; Morphine; Nalbuphine; Pentazocine; Rats; Self Administration; Sleep, REM; Substance-Related Disorders

Topics: Analgesics; Animals; Benzomorphans; Chemical Phenomena; Chemistry; Chromatography, Thin Layer; Drug Evaluation; Guinea Pigs; Humans; Meperidine; Methadone; Morphinans; Morphine; National Institutes of Health (U.S.); Rats; Research Support as Topic; Spectrophotometry, Infrared; Substance-Related Disorders; United States

Intravenous injections of buprenorphine, a partial opiate agonist and antagonist, maintained operant responding under second order schedule control (FR 3 VR 16:S) across a dose range of 0.005 to 0.10 mg/kg/inj. A drug naive monkey and four monkeys with a history of morphine self-administration all self-administered buprenorphine at all doses studied. Four monkeys showed dose-related increases in the total amount of buprenorphine (mg/kg) self-administered each day as the available dose increased from 0.01 to 0.10 mg/kg/inj. Injections per day remained equivalent to the number of injections at the lowest dose studied or increased significantly (p less than 0.05, 0.01), as the dose per injection increased in three monkeys. Even at high buprenorphine doses, there was no evidence of sedation. Monkeys consistently self-administered significantly more buprenorphine than saline in control studies (p less than 0.01). Buprenorphine's agonistic effects appear to persist for 24 to 48 hours. When saline and buprenorphine were available on alternate days, monkeys did not distinguish between them, but when 3 days of saline were alternated with 1 day of buprenorphine (0.03 mg/kg/inj), monkeys took significantly more buprenorphine than saline (p less than 0.02--0.001). Abrupt discontinuation of buprenorphine (0.10 mg/kg/inj) did not result in discernible withdrawal signs. The effects of buprenorphine on food intake were inconsistent, but there were no significant changes in body weight as a function of chronic buprenorphine self-administration or withdrawal. These data indicate that buprenorphine is a positive reinforcer in rhesus monkeys and maintains behavior leading to its administration on second order schedules over a wide dose range. Despite its opiate agonist properties, there was no evidence of physical dependence.

Topics: Animals; Buprenorphine; Drug Interactions; Food; Humans; Macaca mulatta; Morphinans; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome; Substance-Related Disorders

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Topics: Acetates; Analgesics; Animals; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Butorphanol; Hemodynamics; Humans; Morphinans; Neoplasms; Pain, Postoperative; Respiration; Substance-Related Disorders

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

Racemic 1,4-dimethyl- (1), 1,4,12 alpha-trimethyl- (2), and 1,4,12 beta-trimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine (3) have been optically resolved. The analgesic potency and physical-dependence capacity of the optical isomers and their racemic parents were determined. The levo isomers of compounds 2 and 3 were analgesically much more potent than the dextro isomers and were equipotent with morphine. Optical resolution gave no effect on the activity of compound 1. None of the optical isomers and the racemates suppressed the morphine-withdrawal syndrome in the monkey.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Macaca mulatta; Mice; Morphinans; Self Administration; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.

Topics: Analgesics; Animals; Catalepsy; Drug Tolerance; Erythrocebus patas; Haplorhini; Humans; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine Dependence; Narcotic Antagonists; Papio; Rats; Reaction Time; Substance-Related Disorders

Topics: Analgesics, Opioid; Anesthesia; Benzomorphans; Chemical Phenomena; Chemistry; Depression, Chemical; Humans; Morphinans; Naloxone; Narcotic Antagonists; Narcotics; Pentazocine; Respiration; Substance-Related Disorders; Tilidine

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.

Topics: Analgesics; Animals; Behavior, Animal; Cyclobutanes; Dogs; Drug Tolerance; Female; Haplorhini; Hemodynamics; Histamine Release; Humans; Male; Mice; Morphinans; Motor Skills; Narcotic Antagonists; Oxymorphone; Pentylenetetrazole; Pupil; Rats; Reaction Time; Respiration; Saimiri; Substance Withdrawal Syndrome; Substance-Related Disorders

The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9beta-propyl levo isomer was considerably more potent subcutaneously and equipotent orally. None of the optical isomers suppressed the withdrawal syndrome; the 9beta-propyl levo isomer exacerbated the withdrawal syndrome.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Optical Rotation; Stereoisomerism; Substance-Related Disorders

2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereochemical assignments of 9, 10 (and thus 7 and 8), and 18 follow from analogy and from NMR data of 9, 10, 17, and 18. Compound 18 and the deoxy analog 16 are as potent as morphine and codeine, respectively, as analgetics (mice) and are without physical dependence capacity (monkeys).

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Hot Temperature; Humans; Macaca mulatta; Magnetic Resonance Spectroscopy; Morphinans; Morphine Dependence; Reaction Time; Stereoisomerism; Substance-Related Disorders

Topics: Amphetamines; Barbiturates; Benzodiazepines; Benztropine; Cocaine; Drug and Narcotic Control; Forecasting; Hallucinogens; Humans; Morphinans; Morphine Derivatives; Nonprescription Drugs; Phencyclidine; Substance-Related Disorders; United States

Topics: Adult; Alcoholism; Barbiturates; Cannabis; Diazepam; Drug Combinations; Drug Therapy, Combination; Female; Germany, West; Hospitals, General; Humans; Male; Methadone; Morphinans; Opium; Promethazine; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders; Thiazines

Topics: Analgesics; Animals; Humans; Lethal Dose 50; Macaca mulatta; Male; Mice; Morphinans; Optical Rotation; Phenols; Seizures; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Biological Assay; Cyclopropanes; Delayed-Action Preparations; Dogs; Half-Life; Humans; Injections, Intramuscular; Injections, Intravenous; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Pharmaceutical Vehicles; Plastics; Pulse; Pupil; Reflex; Substance-Related Disorders; Suspensions

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

Topics: Adult; Amphetamine; Autopsy; Barbiturates; Body Fluids; Forensic Medicine; Hallucinogens; Humans; Hypnotics and Sedatives; Levallorphan; Male; Meperidine; Methadone; Methaqualone; Morphinans; Morphine; Pharmaceutical Preparations; Poisoning; Substance-Related Disorders; Tissue Extracts

Topics: Analgesics; Codeine; Drug Prescriptions; Humans; Infusions, Parenteral; Meperidine; Morphinans; Morphine; Pain; Substance-Related Disorders; Time Factors

Topics: Alcoholism; Amphetamine; Barbiturates; California; Cannabis; Cocaine; Drug Prescriptions; Ethanol; Hallucinogens; Humans; Hypnotics and Sedatives; Morphinans; Narcotics; Nicotiana; Nonprescription Drugs; Plants, Toxic; Societies, Medical; Solvents; Substance-Related Disorders; Tranquilizing Agents

Topics: California; Cannabis; Chromatography, Gas; Chromatography, Thin Layer; Cocaine; Humans; Indicators and Reagents; Lysergic Acid Diethylamide; Morphinans; Pharmaceutical Preparations; Spectrophotometry, Ultraviolet; Substance-Related Disorders

Topics: Analgesia; Analgesics; Anesthesia, Intravenous; Animals; Azides; Barbiturates; Blood Pressure; Cats; Codeine; Depression, Chemical; Drug Synergism; Drug Tolerance; Guinea Pigs; Haplorhini; Humans; In Vitro Techniques; Lethal Dose 50; Macaca; Mice; Morphinans; Morphine; Rabbits; Rats; Respiration; Substance-Related Disorders; Synaptic Transmission

Topics: Analgesics; Animals; Cyclazocine; Female; Haplorhini; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentazocine; Stereotyped Behavior; Substance Withdrawal Syndrome; Substance-Related Disorders; Thebaine; Time Factors

Topics: Acylation; Alkylation; Analgesics; Animals; Female; Furans; Haplorhini; Humans; Isomerism; Lethal Dose 50; Male; Mice; Mice, Inbred Strains; Molecular Conformation; Morphinans; Morphine; Narcotic Antagonists; Structure-Activity Relationship; Substance-Related Disorders; Tail

Topics: History, 20th Century; Humans; Levallorphan; Methylation; Morphinans; Nalorphine; Narcotic Antagonists; Substance-Related Disorders

Topics: Aspirin; Drug Combinations; Drug Synergism; Humans; Morphinans; Morphine Dependence; Substance-Related Disorders

Topics: Adolescent; Adult; Affect; Cannabis; Dose-Response Relationship, Drug; Drug Contamination; Frustration; Group Processes; Humans; Male; Morphinans; Substance-Related Disorders

Topics: Analgesia; Animals; Cardiovascular System; Digestive System; Humans; Male; Morphinans; Nalorphine; Respiration; Substance-Related Disorders; Urethra

Topics: Chromosome Aberrations; Chromosome Disorders; Female; Humans; Infant, Newborn; Lysergic Acid Diethylamide; Morphinans; Morphine Dependence; Substance-Related Disorders

Topics: Adolescent; Adult; Amphetamine; Barbiturates; Cannabis; Cocaine; Cognition Disorders; Factor Analysis, Statistical; Hallucinogens; Humans; Male; Morphinans; Perceptual Disorders; Psychological Tests; Socioeconomic Factors; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Aspirin; Caffeine; Codeine; Drug Combinations; Humans; Morphinans; Narcotics; Phenacetin; Substance-Related Disorders; Tropanes

Topics: Chemical Phenomena; Chemistry; Hallucinogens; Humans; Lysergic Acid Diethylamide; Meperidine; Methadone; Morphinans; Morphine Dependence; Pentazocine; Substance-Related Disorders

Topics: Adult; Age Factors; Amenorrhea; Endocarditis; Female; France; Gangrene; Hepatitis; Heroin; Humans; Injections; Male; Middle Aged; Morphinans; Pharmaceutic Aids; Sepsis; Sexually Transmitted Diseases; Skin Manifestations; Social Behavior Disorders; Social Conditions; Substance-Related Disorders

Topics: Acetaminophen; Acetanilides; Administration, Oral; Analgesics; Aspirin; Codeine; Dextropropoxyphene; Hemorrhage; Humans; Indomethacin; Morphinans; Pain; Phenacetin; Phenylbutazone; Substance-Related Disorders

Topics: Adolescent; Age Factors; Brain Damage, Chronic; Cannabis; Family; Female; Humans; Intelligence; Lysergic Acid Diethylamide; Male; Morphinans; Personality Disorders; Prognosis; Psychoses, Substance-Induced; Substance-Related Disorders; Time Factors

Topics: Humans; Morphinans; Naloxone; Narcotic Antagonists; Substance-Related Disorders

Topics: Administration, Oral; Cyclazocine; Euphoria; Humans; Injections; Lactates; Methadone; Morphinans; Naloxone; Naphthalenes; Narcotic Antagonists; Polyethylenes; Polymers; Substance-Related Disorders

Topics: Animals; Antibody Specificity; Carbon Isotopes; Codeine; Cross Reactions; Guinea Pigs; Heroin; Humans; Imines; Immune Sera; Lysine; Microchemistry; Morphinans; Morphine; Nalorphine; Rabbits; Radioimmunoassay; Substance-Related Disorders

Topics: Adult; Amphetamine; Black or African American; Cannabis; Ethnicity; Female; Heroin; Humans; Lysergic Acid Diethylamide; Male; Morphinans; Politics; Puerto Rico; Sex Factors; Social Conditions; Students; Substance-Related Disorders

Topics: Adolescent; Adult; Age Factors; Amphetamine; Cannabis; Female; Hallucinogens; Heroin; Humans; Lysergic Acid Diethylamide; Male; Morphinans; New York; Religion; Social Conformity; Socioeconomic Factors; Substance-Related Disorders

Topics: Age Factors; Cannabis; Criminal Psychology; Employment; Ethnicity; Family Characteristics; Heroin; Hospitalization; Humans; Length of Stay; Male; Morphinans; Occupations; Puerto Rico; Remission, Spontaneous; Socioeconomic Factors; Substance-Related Disorders

Topics: Adolescent; Adult; Age Factors; Amphetamine; Cannabis; Criminal Psychology; Denmark; Education; Female; Hospitals, Special; Humans; Male; Morphinans; Prisons; Socioeconomic Factors; Substance-Related Disorders

Topics: Antitussive Agents; Benzoates; Codeine; Cough; Drug Synergism; Ethics, Pharmacy; Expectorants; Histamine H1 Antagonists; Humans; Morphinans; Substance-Related Disorders; Vasoconstrictor Agents

Topics: Alkaloids; Amphetamine; Analgesics; Barbiturates; Chlorpheniramine; Chromatography; Chromatography, Thin Layer; Codeine; Dextropropoxyphene; Histamine H1 Antagonists; Hot Temperature; Humans; Indicators and Reagents; Isonipecotic Acids; Meperidine; Methadone; Methods; Morphinans; Morphine; Pentazocine; Phenacetin; Phenothiazines; Quinidine; Substance-Related Disorders; Ultraviolet Rays

Topics: Animals; Drug Tolerance; Humans; Injections, Intraperitoneal; Levorphanol; Male; Mice; Morphinans; Morphine; Narcotic Antagonists; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

According to a recently proposed hypothesis, physical dependence upon alcohol is due to the formation of an endogenous opiate. We tested the hypothesis by determining whether or not ethanol-dependent mice would show typical opiate-dependent behavior (withdrawal jumping syndrome) when challenged with the opiate antagonist naloxone. Our results do not support the hypothesis.

Topics: Alcoholism; Animals; Dopamine; Ethanol; Humans; Isoquinolines; Male; Mice; Morphinans; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Animals; Bridged-Ring Compounds; Humans; Methods; Mice; Morphinans; Motor Activity; Nalorphine; Narcotics; Substance-Related Disorders

Topics: Administration, Oral; Adult; Age Factors; Central Nervous System; Electroencephalography; Heroin; Humans; Injections, Intravenous; Male; Methadone; Middle Aged; Morphinans; Substance-Related Disorders; Time Factors

Topics: Adolescent; Adult; Analgesics; Cyclazocine; Family Characteristics; Heroin; Hospitalization; Humans; Interpersonal Relations; Male; Methadone; Morphinans; Narcotic Antagonists; Prognosis; Substance-Related Disorders

Topics: Analgesics; Animals; Cyclopropanes; Humans; Injections, Intraperitoneal; Mice; Morphinans; Morphine; Nalorphine; Pentazocine; Rats; Substance-Related Disorders

Topics: Amphetamine; Analgesics; Barbiturates; Chromatography, Gas; Chromatography, Thin Layer; Fluorometry; Glutethimide; Humans; Hydrogen-Ion Concentration; Hypnotics and Sedatives; Indicators and Reagents; Morphinans; Morphine; Phenothiazines; Phenytoin; Psychopharmacology; Quinine; Substance-Related Disorders; Tranquilizing Agents

Topics: Adolescent; Adult; Child, Preschool; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Maternal-Fetal Exchange; Methadone; Morphinans; Poisoning; Pregnancy; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics; Azocines; Cyclazocine; Drug and Narcotic Control; Heroin; Hospitals; Hospitals, Psychiatric; Humans; Mental Health Services; Morphinans; Narcotic Antagonists; Psychotherapy; Research Support as Topic; Substance-Related Disorders; United States

Topics: Animals; Haplorhini; Humans; Hydromorphone; Mice; Morphinans; Morphine; Nalorphine; Substance-Related Disorders

Topics: Adult; Cerebral Cortex; Electroencephalography; Heroin; Humans; Male; Middle Aged; Morphinans; Substance-Related Disorders

Topics: Adult; Azocines; Bridged-Ring Compounds; Drug Antagonism; Heroin; Humans; Male; Morphinans; Narcotic Antagonists; Substance-Related Disorders

Topics: Analgesics; Azocines; Cyclazocine; Evaluation Studies as Topic; Heroin; Hospitalization; Hospitals, General; Hospitals, Teaching; Humans; Methadone; Morphinans; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; New York City; Outpatient Clinics, Hospital; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesia; Animals; Chemical Phenomena; Chemistry; Codeine; Haplorhini; Humans; Mandelic Acids; Morphinans; Morphine; Nalorphine; Optical Rotatory Dispersion; Stereoisomerism; Substance-Related Disorders; Sulfonic Acids

Topics: Animals; Behavior, Animal; Caffeine; Catheterization; Chlorpromazine; Cocaine; Codeine; Dextroamphetamine; Ethanol; Haplorhini; Humans; Mescaline; Morphinans; Morphine; Morphine Dependence; Pentobarbital; Substance-Related Disorders

1. Morphine-like analgesic drugs caused depression of twitches of the isolated guinea-pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine-N-oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine and the analgesic narcotic antagonists nalorphine and pentazocine.2. With the first application of one of these drugs the extent of depression of twitches was proportional to concentration. Except in the case of pethidine, there was no further depression when additional drug was added to the organ bath. With the second application of a drug after washing out the first dose, the depressant effect was less; that is, tolerance developed. With pethidine, the depression of twitches was proportional to concentration and tolerance could not be observed.3. When tolerance had been produced by cumulative addition of these drugs, a concentration was reached at which further addition resulted in increased activity of the ileum.4. With codeine, morphine and normorphine, the twitches were increased in height and regular.5. With diamorphine, fentanyl, oxymorphone, pentazocine, phenazocine and phenoperidine there were increased but irregular responses to transmural stimulation.6. Having reached the concentration at which these effects were observed, washout of the drug resulted in reduction of activity; the twitches became smaller or the irregular responses ceased.7. Readministration of a drug after activity of the ileum had been depressed by withdrawal of that drug resulted in restoration of activity, the ileum being dependent on the presence of the drug for its activity.8. Codeine and nalorphine did not produce as great an increase in activity on readministration to a dependent ileum as did morphine: they seem to act as partial agonists in producing this effect.9. In similar experiments with the isolated urinary bladder of the rat and guinea-pig, morphine was less active in depressing responses to stimulation than it was on the ileum, and tolerance to the drug and dependence on it did not occur.10. These observations have been discussed in relation to analgesic activity, tolerance and dependence in man.

Topics: Analgesics; Animals; Codeine; Cyclic N-Oxides; Drug Tolerance; Electric Stimulation; Female; Fentanyl; Guinea Pigs; Heroin; Humans; Ileum; In Vitro Techniques; Male; Meperidine; Morphinans; Morphine; Muscle Contraction; Muscle, Smooth; Nalorphine; Oxymorphone; Pentazocine; Phenazocine; Phenoperidine; Rats; Substance-Related Disorders; Urinary Bladder

Topics: Adolescent; Adult; Aged; Alcoholism; Amphetamine; Analgesics; Barbiturates; Cannabis; Cocaine; Female; Hallucinogens; Heroin; Humans; Hypnotics and Sedatives; Male; Middle Aged; Morphinans; Opium; Phytotherapy; Prognosis; Substance-Related Disorders; Tranquilizing Agents

Topics: Amphetamine; Barbiturates; Dextromoramide; Female; Hospitals, Psychiatric; Humans; Male; Methadone; Morphinans; Morphine; Narcotics; Phenmetrazine; Substance-Related Disorders

Topics: Analgesics; Bridged-Ring Compounds; Chemical Phenomena; Chemistry; Cyclazocine; Humans; Levallorphan; Levorphanol; Morphinans; Morphine; Nalorphine; Naphthoquinones; Pentazocine; Substance-Related Disorders

Topics: Alcohols; Amphetamine; Barbiturates; Hallucinogens; Humans; Morphinans; Substance-Related Disorders

Topics: Humans; Morphinans; National Academy of Sciences, U.S.; Substance-Related Disorders; United States