dextrorphan and Substance-Withdrawal-Syndrome

Consistent with their antagonistic actions at N-methyl-D-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM. Administration of 30 mg/kg of DXM resulted in higher brain levels of DXM and DXT than administration of 10 mg/kg of DXM, but much lower DXT levels than that produced by 30 mg/kg of DXT. Co-treatment with QND resulted in higher brain levels of DXM (but not DXT) suggesting that QND produces an increase in the brain availability of DXM. In summary, brain levels of DXM were inversely correlated with the intensity of opioid withdrawal syndrome. QND induced increased brain levels of DXM tend to attenuate the intensity of opioid withdrawal syndrome. We suggest that it is DXM, rather than DXT, that is responsible for the attenuating effect on the intensity of opioid withdrawal syndrome, and that the beneficial action of QND on the effect of DXM should be more pronounced in humans.

Topics: Animals; Brain; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Drug Synergism; Male; Mastication; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Quinidine; Stereotyped Behavior; Substance Withdrawal Syndrome

As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966-present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.

Topics: Adult; Analgesics, Opioid; Antitussive Agents; Delusions; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Drug Tolerance; Female; Hallucinations; Humans; Nonprescription Drugs; Psychoses, Substance-Induced; Receptors, sigma; Recurrence; Substance Withdrawal Syndrome; Substance-Related Disorders

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

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