levorphanol and Substance-Withdrawal-Syndrome

Topics: Administration, Oral; Animals; Biotransformation; Body Weight; Codeine; Dealkylation; Dextropropoxyphene; Dogs; Guinea Pigs; Humans; Injections, Subcutaneous; Levorphanol; Meperidine; Methadyl Acetate; Morphine; Narcotics; Rabbits; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Acetylcholine; Animals; Atropine; Binding Sites; Brain; Chromatography; Drug Tolerance; Electric Stimulation; Haplorhini; Humans; Kinetics; Levorphanol; Methadone; Mice; Molecular Conformation; Morphine; Naloxone; Narcotic Antagonists; Rats; Receptors, Drug; Structure-Activity Relationship; Substance Withdrawal Syndrome; Time Factors

According to the hypothesis that the development of physical dependence on and tolerance to opiates depends on the inhibition by opiates of L-asparaginase and L-glutaminase activities in the brain, and the blockade by opiates of the aspartatergic/glutamatergic receptors especially NMDA, four female and fourty-four male heroin addicts were included in a double-blind clinical trial. Four mg chlorpromazine (CPZ) was administered every hour and 10 mg diazepam (DIA) every 6 hours to a group consisting of two female and nineteen male inpatients. The remaining subjects received 15 mg non-opioid antitussive dextromethorphan (DM) instead of CPZ. The withdrawn addicts were controlled twice a day and yawning, lacrimation, rhinorrhoea, perspiration, goose flesh, muscle tremor, dilated pupils, anorexia, joint and muscle aches, restlessness, insomnia, emesis, diarrhea, craving and rejection of smoking as abstinence syndrome signs were observed and rated on a scale of 1, 2 and 3 points according to their intensity. All signs, except perspiration and emesis, were significantly less intense in the group given DM + DIA than CPZ + DIA. The other plus points included the immediate stop of craving and the early onset of smoking in DM + DIA group. The results are considered to be supporting evidence for the hypothesis emphasizing the blockade of NMDA receptors by opiates in opiate addiction. Furthermore, the decrease caused by non-opioid NMDA antagonists in the responsiveness of NMDA receptors appears very promising for the treatment of opiate addicts.

Topics: Adult; Chlorpromazine; Dextromethorphan; Diazepam; Double-Blind Method; Female; Heroin Dependence; Humans; Levorphanol; Male; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome

Topics: Animals; Aspirin; Brain; Cyclazocine; Drug Tolerance; Fenclonine; Humans; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Pargyline; Pentazocine; Phenylalanine; Physostigmine; Placebos; Serotonin; Substance Withdrawal Syndrome

The dual antagonist effects of the mixed-action μ-opioid partial agonist/κ-opioid antagonist buprenorphine have not been previously compared in behavioral studies, and it is unknown whether they are comparably modified by chronic exposure. To address this question, the dose-related effects of levorphanol, trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50,488), heroin, and naltrexone on food-maintained behavior in rhesus monkeys were studied after acute and chronic treatment with buprenorphine (0.3 mg/kg/day). In acute studies, the effects of levorphanol and U50,488 were determined at differing times after buprenorphine (0.003-10.0 mg/kg i.m.). Results show that buprenorphine produced similar, dose-dependent rightward shifts of the levorphanol and U50,488 dose-response curves that persisted for ≥ 24 h after doses larger than 0.1 mg/kg buprenorphine. During chronic treatment with buprenorphine, the effects of levorphanol, U50,488, heroin, and naltrexone were similarly determined at differing times (10 min to 48 h) after intramuscular injection. Overall, results show that buprenorphine produced comparable 3- to 10-fold rightward shifts in the U50,488 dose-response curve under both acute and chronic conditions, but that chronic buprenorphine produced larger (10- to ≥ 30-fold) rightward shifts in the heroin dose-effect function than observed acutely. Naltrexone decreased operant responding in buprenorphine-treated monkeys, and the position of the naltrexone dose-effect curve shifted increasingly to the left as the time after daily buprenorphine treatment increased from 10 min to 48 h. These results suggest that the μ-antagonist, but not the κ-antagonist, effects of buprenorphine are augmented during chronic treatment. In addition, the leftward shift of the naltrexone dose-effect function suggests that daily administration of 0.3 mg/kg buprenorphine is adequate to produce opioid dependence.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Buprenorphine; Dose-Response Relationship, Drug; Drug Tolerance; Female; Levorphanol; Macaca mulatta; Male; Naltrexone; Narcotic Antagonists; Substance Withdrawal Syndrome

The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats. OBJECTIVE. The purpose of this study was to extend observations to a non-human primate.. Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR-->NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL-->NTX).. Seven subjects acquired the discrimination in an average of 108+/-14 sessions. MOR-->NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56-1.7 mg/kg) and of naltrexone (0.01-10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR-->NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR-->NTX-appropriate responding.. This is the first non-rodent study of the discriminative effects of MOR-->NTX. MOR-->NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs.

Topics: Animals; Benzeneacetamides; Conditioning, Operant; Dextrorphan; Discrimination Learning; Dose-Response Relationship, Drug; Generalization, Psychological; Levorphanol; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pyrrolidines; Receptors, Opioid; Saimiri; Substance Withdrawal Syndrome

The development of physical dependence on opiates appears to involve an inhibition by opiates of L-asparaginase and glutaminase, and the blockade by opiates of aspartatergic (ASPergic)/glutamatergic (GLUergic) receptors. Ketamine (K) (0.5 or 1 mg/kg) or dextromethorphan (DM) (1 or 2 mg/kg), both of which are known to decrease the responsiveness of ASPergic/GLUergic receptors, were administered to the three morphine (M)-containing pellets implanted rats prior to 2 mg/kg naloxone (NL) injection. Whereas 0.5 mg/kg K showed no significant effect on abstinence syndrome signs, 1 mg/kg K and 1 mg/kg DM significantly attenuated some of the signs. The attenuation or prevention of all the signs were observed after 2 mg/kg DM administration. Almost complete prevention was seen from the second minute on during the ten-minute observation period. As ASP and GLU antagonists K and DM have this antagonizing effect on the precipitated abstinence syndrome signs, the manifestation of abstinence syndrome may mainly result from the normalization of ASP and GLU production because of the disinhibition by NL of the enzymes and the stronger stimulation of ASPergic/GLUergic receptors which have no opiate blockade after NL injection.

Topics: Animals; Dextromethorphan; Ketamine; Levorphanol; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Earlier studies have suggested that the acute administration of an opiate can result in the development of supersensitive dopamine receptors. The present study was undertaken to determine whether the supersensitive dopamine receptors can modify the development of opiate tolerance and dependence. Administration of morphine (100 mg/kg s.c.) 6 or 24 hr before apomorphine (i.p.) potentiated apomorphine-induced climbing behavior in mice. Administration of levorphanol (12 mg/kg s.c.) 3 or 6 hr, but not 24 hr, before apomorphine also potentiated apomorphine-induced climbing behavior. Coadministration of 5 mEq/kg of LiCl with morphine or levorphanol attenuated the increased sensitivity developed to apomorphine after either opiate. Acute tolerance and dependence was induced by administration of 100 mg/kg of morphine or 12 mg/kg of levorphanol. Lithium enhanced the development of acute tolerance when coadministered with morphine 3, 6 or 24 hr before test doses of morphine, or with levorphanol 3 hr before test doses of levorphanol. Administration of apomorphine 5 min before naloxone significantly decreased the naloxone ED50 for inducing withdrawal jumping in mice that had been pretreated with morphine or levorphanol. Although coadministration of lithium with morphine or levorphanol had no significant effect on naloxone-induced withdrawal jumping, it attenuated the ability of apomorphine to decrease naloxone ED50. Morphine (100 mg/kg s.c.) increased the number of whole brain [3H]spiroperidol binding sites 3 and 6 hr after administration of morphine. This increase was no longer present 24 hr after morphine administration. Levorphanol (12 mg/kg s.c.) also increased the number of binding sites 3 hr after administration. Coadministration of lithium with morphine attenuated the increase in [3H]spiroperidol binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Apomorphine; Behavior, Animal; Drug Interactions; Drug Tolerance; Levorphanol; Lithium; Male; Mice; Morphine; Naloxone; Narcotics; Opioid-Related Disorders; Receptors, Dopamine; Spiperone; Substance Withdrawal Syndrome

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered by an intracerebroventricular (i.c.v.) injection did not affect levorphanol analgesia, but PLG at higher doses (10 and 100 micrograms/mouse) and alpha-melanocyte-stimulating hormone (alpha-MSH) (10 ng/mouse) antagonized levorphanol analgesia. Development of levorphanol tolerance was facilitated by 10 ng/mouse of PLG, unaffected by 10 micrograms/mouse of PLG, but antagonized by 100 micrograms/mouse of PLG and 10 ng/mouse of alpha-MSH. The effect of PLG on levorphanol dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) facilitated the development of levorphanol dependence, but 10 micrograms/mouse of PLG had no effect. PLG (100 micrograms/mouse) antagonized development of levorphanol dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in levorphanol-dependent mice. alpha-MSH (10 ng/mouse) antagonized development of levorphanol dependence as evidenced by an increase in the ED50 of naloxone required to induce withdrawal jumping. These results indicate that PLG and alpha-MSH affected levorphanol-induced analgesia, tolerance and dependence in a qualitatively similar manner to their effect on morphine-induced analgesia, tolerance and dependence.

Topics: Analgesia; Animals; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Drug Tolerance; Humans; Levorphanol; Male; Melanocyte-Stimulating Hormones; Mice; MSH Release-Inhibiting Hormone; Naloxone; Substance Withdrawal Syndrome; Substance-Related Disorders

The use of clonidine in the management of opiate abstinence is presented in a patient dependent upon levorphanol tartrate given for chronic pain. Use of levorphanol was abruptly discontinued, and the patient was monitored for signs and symptoms of opiate withdrawal. He manifested a significant increase in pulse and blood pressure and had perspiration, agitation, and opiate-seeking behavior. Clonidine effectively abolished these signs and symptoms. The mechanism by which clonidine prevents the opiate abstinence syndrome is discussed. Clonidine is a safe and inexpensive means of achieving rapid opiate withdrawal.

Topics: Adult; Chronic Disease; Clonidine; Humans; Levorphanol; Male; Opioid-Related Disorders; Pain; Substance Withdrawal Syndrome

Topics: Animals; Corticosterone; Humans; Levorphanol; Male; Morphine; Naloxone; Narcotics; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesics; Animals; Corpus Striatum; Dextrorphan; Drug Implants; Humans; Levorphanol; Male; Mice; Morphine; Morphine Dependence; Naloxone; Rats; Reaction Time; Receptors, Opioid; Substance Withdrawal Syndrome; Time Factors

Effects of in vitro methadone and several other narcotics were investigated on 3H-5-HT uptake in rat hypothalamus slices. The results indicated that d, l-methadone and levorphanol had slightly greater inhibitory action on the uptake than the isomers, d-methadone and dextrorphan, respectively. Morphine, diacetylmorphine and the narcotic antagonist naloxone produced a considerably weaker inhibitory effect. After an acute injection of methadone, but not morphine, the uptake of 5-HT by hypothalamic slices of treated animals was inhibited. The chronic treatment of rats with methadone for 18 days had no significant effect on the uptake, but following the withdrawal of this treatment for 2 weeks the 5-HT uptake was significantly elevated. The inhibitory effects of in vitro methadone in the hypothalamus slices were not modified by the chronic drug treatment.

Topics: Animals; Dextrorphan; Female; Heroin; Humans; Hypothalamus; In Vitro Techniques; Levorphanol; Methadone; Morphine; Naloxone; Rats; Serotonin; Substance Withdrawal Syndrome; Time Factors

Topics: Alcohol Drinking; Animals; Animals, Newborn; Dextrorphan; Drug Interactions; Ethanol; Humans; Levorphanol; Male; Methadone; Methadyl Acetate; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

By subcutaneous implantation of 2 or 13 morphine pellets (75 mg morphine/pellet), rats were made tolerant to, and dependent on narcotic analgesics. Occipital cortex slices from dependent animals and placebo-implanted controls were incubated with (-)-3H-noradrenaline and subsequently superfused with physiological salt solution. The accumulation of 3H-noradrenaline was not changed by pretreatment with 2, but was slightly decreased by pretreatment with 13 morphine pellets. The overflow of tritium evoked by electrical field stimulation was higher in slices from morphine-implanted rats than in those from placebo controls. Morphine and levorphanol, added in vitro, inhibited the stimulation-induced overflow of tritium at similar concentrations and to a similar degree in slices from morphineand placebo-pretreated animals.--It is concluded that, during chronic treatment with morphine, an adaptation takes place in the brain to compensate for the acute effect of narcotic analgesics, i.e. inhibition of the release of noradrenaline by nerve impulses. The chain of events from the drug-receptor interaction to the depression of the release process can be escluded as substrate of this adaptation. During withdrawal, the compensatory changes provoke an enhanced increase of extracellular noradrenaline during nerve impulses.

Topics: Animals; Cerebral Cortex; Drug Implants; Drug Tolerance; Electric Stimulation; Humans; Levorphanol; Male; Morphine; Morphine Dependence; Naloxone; Neurons; Norepinephrine; Occipital Lobe; Rats; Substance Withdrawal Syndrome

Topics: Aminopyrine; Analgesics; Animals; Behavior, Animal; Humans; Isonipecotic Acids; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Animals; Brain Chemistry; Chromatography, Thin Layer; Drug Interactions; Humans; Lethal Dose 50; Levorphanol; Male; Mice; Mice, Inbred Strains; Morphinans; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome; Tartrates; Time Factors; Tritium

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

Topics: Adrenal Glands; Animals; Body Weight; Brain; Drug Tolerance; Epinephrine; Female; Growth; Humans; Levorphanol; Methadone; Monoamine Oxidase Inhibitors; Morphine; Morphine Dependence; Norepinephrine; Organ Size; Rats; Stimulation, Chemical; Substance Withdrawal Syndrome; Substance-Related Disorders; Thebaine; Time Factors

Topics: Drug Therapy; Humans; Levallorphan; Levorphanol; Methadone; Neoplasms; Osteoarthritis; Pain; Substance Withdrawal Syndrome; Toxicology