dextromethorphan has been researched along with Substance-Withdrawal-Syndrome* in 24 studies
7 trial(s) available for dextromethorphan and Substance-Withdrawal-Syndrome
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Lack of efficacy of dextromethorphan in managing alcohol withdrawal: a preliminary report of a randomized, double-blind, placebo-controlled trial.
Alcohol withdrawal syndrome is associated with increased central N-methyl-D-aspartate (NMDA) glutamate transmission. Medications that reduce glutamate release or block NMDA overactivation have shown efficacy for treating alcohol withdrawal syndrome. Dextromethorphan (DXM), a widely used antitussive drug, is a low-affinity, noncompetitive NMDA antagonist with potential neuroprotective properties. This study, using a randomized, double-blind, placebo-controlled study design, examined the benefit of DXM in the management of acute alcohol withdrawal. Alcohol-dependent patients admitted for detoxification treatment and experiencing moderate alcohol withdrawal, as measured by a score greater than 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), were randomly assigned to receive either DXM 360 mg/d or an identical placebo for 7 days in a double-blind manner. All subjects received a concurrent dose of lorazepam 2 mg along with the initial administration of DXM or placebo and were given additional lorazepam (1 mg) as a rescue medication according to the symptom-triggered detoxification protocol. Outcome measures consisted of the mean total dose of lorazepam received, the sequential scores on the CIWA-Ar, and craving assessed by the Obsessive-Compulsive Drinking Scale. Forty subjects completed the study, 18 in the DXM group and 22 in the placebo group. We found that compared with placebo, DXM use was not associated with lower lorazepam doses to control alcohol withdrawal symptoms. The progression in CIWA-Ar and Obsessive-Compulsive Drinking Scale scores was also comparable between the 2 groups. Our preliminary results do not support the efficacy of high-dose DXM in reducing the need of benzodiazepines to treat withdrawal symptoms in alcohol-dependent patients. Topics: Adult; Alcohol Abstinence; Alcohol Drinking; Alcoholism; Brain; Dextromethorphan; Double-Blind Method; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Humans; Lorazepam; Middle Aged; Psychiatric Status Rating Scales; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Taiwan; Time Factors; Treatment Failure | 2014 |
A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal.
Dextromethorphan has been reported to ameliorate opioid withdrawal symptoms in both animal and human subjects. In the present study, we investigated the efficacy of dextromethorphan as an add-on medication in heroin detoxification treatment in a double-blind, placebo-controlled design. Sixty-five heroin-dependent patients (male, 63; female, 2) participated in this inpatient detoxification trial after giving informed consent. Clonidine 0.075 mg 4 times a day was given as an antiwithdrawal medication at baseline. Each patient was then randomly assigned to treatment with either dextromethorphan 60 mg or placebo 4 times a day as additional medication. Flurazepam 30 mg was given before bedtime for insomnia. Other medications that were allowed included loperamide for diarrhea and lorazepam for agitation. Participants were monitored using the Objective Opioid Withdrawal Scale 3 times a day as the primary outcome to compare drug efficacy between groups. Generalized estimating equation model analysis revealed that the Objective Opioid Withdrawal Scale had no group difference between dextromethorphan and placebo group overall (P = 0.29), whereas a significant difference between groups was found during day 3 to day 6 (P = 0.04) by post hoc analysis. There was no difference in the Clinical Global Impression Scale, patient's impression of treatment, and use of ancillary medications between groups. No severe adverse effects were noticed. We suggest that dextromethorphan has some beneficial effect in attenuating the severity of opioid withdrawal symptoms and can be used as an adjunction medication in the treatment of opioid withdrawal, whereas the exact efficacy needs further investigation. Topics: Adult; Clonidine; Dextromethorphan; Double-Blind Method; Drug Therapy, Combination; Female; Heroin Dependence; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Treatment Outcome | 2014 |
The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans.
Preclinical observations suggest that NMDA receptor-mediated glutamatergic neurotransmission is involved in the expression and maintenance of opioid dependence.. The present study evaluated whether memantine, the clinically available non-competitive NMDA receptor antagonist, decreases naloxone-precipitated withdrawal in morphine-dependent humans.. Eight heroin-dependent, non-treatment seeking, inpatient participants were stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, they received a series of challenges with naloxone (0.4 mg, IM) and the severity of opioid withdrawal was monitored. Either placebo or memantine (60 mg PO) was given 6 h before each naloxone challenge. A modified multiple baseline, across-participants design was used to evaluate the effects of memantine on the severity of naloxone-precipitated opioid withdrawal.. Naloxone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as assessed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withdrawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine. Medication effects, assessed 5 h after memantine administration and before naloxone administration, included significant increases in ratings of "strong" and "good" drug effect, and "I feel sedated", "mellow", and "high".. Memantine attenuated the expression of opioid physical dependence in humans, indicating that glutamatergic neurotransmission at the NMDA receptor site contributes to the maintenance of opioid dependence. This finding suggests that memantine may be a useful adjunct in the treatment of opioid dependence. Topics: Adult; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Humans; Male; Memantine; Morphine; Naloxone; Opioid-Related Disorders; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 2001 |
NMDA receptor challenge with dextromethorphan - subjective response, neuroendocrinological findings and possible clinical implications.
Glutamatergic NMDA receptors are believed to play a major role in the pathophysiology of numerous neuropsychiatric disorders including substance use and schizophrenia. Neuropharmacological studies measuring subjective response, psychopathology and biological parameters are helpful in studying pathophysiology of these disorders. We report preliminary data of a placebo-controlled double-blind challenge study in recently detoxified alcoholics (n = 20) and healthy controls (n = 10) using the non-competitive NMDA antagonist dextromethorphan. Findings suggest that dextrometorphan can produce ethanol-like subjective effects in both alcoholics and controls and induce a mild form of craving in alcoholics only. The results of this study give further support to the hypothesis of glutamatergic NMDA receptors mediating much of ethanol's psychotropic effects. Possible clinical implications of these findings are discussed. Topics: Adult; Alcoholism; Dextromethorphan; Double-Blind Method; Excitatory Amino Acid Antagonists; Humans; Hydrocortisone; Male; Middle Aged; Neurosecretory Systems; Prolactin; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 2000 |
Opiate withdrawal with dextromethorphan.
Topics: Adult; Aged; Dextromethorphan; Heroin Dependence; Humans; Male; Methadone; Middle Aged; Patient Satisfaction; Substance Withdrawal Syndrome; Treatment Outcome | 1997 |
A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal.
Dextromethorphan and its metabolite dextrophan antagonize N-methyl-D-aspartate (NMDA)-mediated activity in pre-clinical studies. We examined dextromethorphan's effects on naloxone-precipitated opiate withdrawal in opiate-dependent subjects stabilized on 25 mg of methadone. Subjects received challenges on three different days with 0.4 mg of intramuscular naloxone. Pretreatment 1 h before naloxone was with dextromethorphan in a double-blind, balanced, randomized design with either placebo, dextromethorphan 60 mg, or dextromethorphan 120 mg for six subjects; and placebo, dextromethorphan 120 mg, or dextromethorphan 240 mg for five subjects. There was considerable inter-individual variability in the response to dextromethorphan, but no net attenuation by dextromethorphan on any withdrawal measure assessed. Two of three subjects detoxified from methadone with dextromethorphan 60 mg orally every 4 h demonstrated considerable withdrawal. Topics: Adult; Dextromethorphan; Double-Blind Method; Female; Humans; Male; Naloxone; Pilot Projects; Substance Withdrawal Syndrome | 1996 |
The treatment of heroin addicts with dextromethorphan: a double-blind comparison of dextromethorphan with chlorpromazine.
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 | 1990 |
17 other study(ies) available for dextromethorphan and Substance-Withdrawal-Syndrome
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Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats.
Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence.. Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC).. Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS.. The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.. Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. Topics: Animals; Dextromethorphan; Dopamine; Nicotine; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reward; Substance Withdrawal Syndrome; Tobacco Use Disorder | 2023 |
You Abused What? Getting High with Unique Medications.
Topics: Amines; Anticonvulsants; Antidiarrheals; Antipsychotic Agents; Antitussive Agents; Cyclohexanecarboxylic Acids; Dextromethorphan; Drug Misuse; Gabapentin; gamma-Aminobutyric Acid; Humans; Loperamide; Pregabalin; Quetiapine Fumarate; Substance Withdrawal Syndrome; Substance-Related Disorders | 2017 |
Dextromethorphan abuse.
Topics: Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Substance Withdrawal Syndrome; Substance-Related Disorders | 2014 |
Dextromethorphan withdrawal and dependence syndrome.
The N-methyl-D-aspartate (NMDA) antagonist dextromethorphan has been available in pharmacies without a prescription since 1954 as an antitussive agent. There is an alarming increase in reports of its abuse. Dextromethorphan is avidly taken, mainly by young people, as a psychoactive drug. The currently available data yield incomplete information about the extent of the problem and its significance for addiction medicine in Germany.. We report the case of a 44-year-old man who became dependent on dextromethorphan through years of abuse, buying the substance for himself without a prescription in German pharmacies. He told us he had taken it regularly for six years. He had become dependent on dextromethorphan, ultimately taking it in a dose of 1800 mg daily. This led him to overt neglect of his work and leisure activities. A urine sample taken on admission to the hospital was found to contain dextromethorphan. During inpatient detoxification, he developed an vegetative withdrawal syndrome consisting of craving, diaphoresis, nausea, hypertension, and tachycardia. He was treated on our ward for three weeks, and a stay in a residential detoxification facility was planned thereafter.. Dextromethorphan is a psychotropic substance that carries a potential for abuse and dependence. On the basis of the currently available data, its reclassification as a prescription drug should be considered. Topics: Adult; Alcoholism; Antitussive Agents; Cross-Sectional Studies; Dextromethorphan; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Humans; Male; Patient Admission; Rehabilitation Centers; Substance Abuse Detection; Substance Withdrawal Syndrome; Substance-Related Disorders; Temperance | 2010 |
Brain levels of dextromethorphan and the intensity of opioid withdrawal in mice.
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 | 2008 |
Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?
18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block alpha3beta4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective alpha3beta4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5-40 mg/kg, s.c.), mecamylamine (0.25-4 mg/kg, i.p.) and bupropion (10-30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that alpha3beta4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal. Topics: Acute Disease; Animals; Bupropion; Dextromethorphan; Drug Therapy, Combination; Female; Mecamylamine; Morphine Dependence; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Substance Withdrawal Syndrome | 2005 |
Coricidin HBP cough and cold addiction.
Topics: Acetaminophen; Adolescent; Animals; Antitussive Agents; Chlorpheniramine; Dextromethorphan; Drug Combinations; Humans; Male; Nonprescription Drugs; Phenylpropanolamine; Substance Abuse Detection; Substance Withdrawal Syndrome; Substance-Related Disorders | 2005 |
Dextromethorphan psychosis, dependence and physical withdrawal.
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 | 2005 |
The clinically available NMDA receptor antagonist dextromethorphan attenuates acute morphine withdrawal in the neonatal rat.
We investigated the ability of dextromethorphan, a clinically available NMDA receptor antagonist, to attenuate the behaviors and the expression of c-fos mRNA associated with acute morphine withdrawal in the 7-day-old rat. The intensity of the acute morphine withdrawal behaviors and the elevation in c-fos mRNA expression in the brain induced by acute morphine withdrawal were reduced by dextromethorphan. Thus, dextromethorphan can attenuate acute morphine withdrawal in the developing organism. Topics: Acute Disease; Animals; Animals, Newborn; Brain; Dextromethorphan; Drug Interactions; Excitatory Amino Acid Antagonists; Gene Expression; Male; Morphine; Morphine Dependence; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Substance Withdrawal Syndrome | 2003 |
Dextromethorphan attenuates morphine withdrawal syndrome in neonatal rats passively exposed to morphine.
We had previously found that co-injection of dextromethorphan, an antitussive drug and a non-competitive NMDA receptor antagonist, with morphine into dam rats throughout the pregnancy period could attenuate the naloxone-precipitated morphine withdrawal syndrome in their offspring. In the present study, we further tested whether postnatal injection of dextromethorphan into the neonatal rats or a 3-day co-injection of dextromethorphan with morphine into the dam rats before delivery is also effective. Female Sprague-Dawley rats were bi-daily injected with escalating doses of morphine from a week before mating till the first postnatal week. Withdrawal syndrome of morphine in the offspring, manifested mainly as abdominal stretching, was generated by injection of naloxone on postnatal day 5. Direct injection of dextromethorphan into the offspring effectively reduced the severity of naloxone-precipitated abdominal stretching in a dose-dependent manner. A 3-day co-treatment with dextromethorphan given to the dam rat before delivery also had a similar attenuating effect, but the efficacy was lower than that produced by postnatal injection. Thus, the results from the present study support that dextromethorphan is of potential in treating or preventing neonatal morphine withdrawal syndrome. Topics: Animals; Animals, Newborn; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Injections, Subcutaneous; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome | 2002 |
Dextromethorphan attenuates ethanol withdrawal syndrome in rats.
The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal. Topics: Acoustic Stimulation; Animals; Antitussive Agents; Central Nervous System Depressants; Dextromethorphan; Ethanol; Male; Motor Activity; Rats; Rats, Wistar; Seizures; Substance Withdrawal Syndrome | 1999 |
Modification of naloxone-induced withdrawal signs by dextromethorphan in morphine-dependent mice.
In the present study the effect of dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice was examined. In addition, the modulatory role of dopaminergic mechanisms upon the effect of dextromethorphan was investigated. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate three times a day for 3 days, and withdrawal signs were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulfate on day 4. Dextromethorphan (20-50 mg/kg, i.p.) caused a significant decrease in withdrawal jumping, paw-shakes, grooming, burrows, writhing and diarrhea in morphine-dependent mice. The mixed dopamine D1/D2 receptor agonist apomorphine (0.5 and 1 mg/kg, s.c.) reduced the response induced by dextromethorphan. The effect of apomorphine was blocked by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol maleate) (0.5 and 1 mg/kg, i.p.) but not by the dopamine D2 receptor antagonist sulpiride (25 and 50 mg/kg, s.c.) nor the peripheral dopamine receptor antagonist domperidone (5 and 10 mg/kg, s.c.). These results suggest that the dopaminergic system(s) may in part mediate the suppressive action of the NMDA receptor antagonist dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice. Topics: Animals; Apomorphine; Behavior, Animal; Benzazepines; Dextromethorphan; Domperidone; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Grooming; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; Sulpiride | 1999 |
Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance.
N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents. Topics: Animals; Dextromethorphan; Dizocilpine Maleate; Drug Combinations; Drug Tolerance; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome | 1996 |
The combination of tizanidine markedly improves the treatment with dextromethorphan of heroin addicted outpatients.
According to the hypothesis implying that the main mechanism underlying opiate addiction is the blockade by opiates of NMDA receptor functions and subsequent upregulation and supersensitivity of the receptors, noncompetitive NMDA receptor blocker dextromethorphan (DM) has been successfully used in the heroin addict treatment. As the stimulation of NMDA receptors modulates the release of neurotransmitters and hormones such as NE, D, ACh, GH, LH, LSH, ACTH etc., all of which have been found responsible for the manifestation of abstinence syndrome signs including craving and neuronal death by excessive stimulation of NMDA receptors, the incomplete blockade of the NMDA receptors minimizes the intensity of the abstinence syndrome and provides the downregulation of the receptors. In the present study, tizanidine (TIZ), which inhibits the release of endogenous excitatory aminoacids by the agonistic activity on alpha 2-adrenoreceptors, was combined with DM to obtain further benefits. Forty-four male and three female heroin addicts were the subjects of the study. Their daily mean heroin intake was about 2.28 g street heroin. The main duration of heroin use was approximately 3.4 years. Two to three hours after abrupt withdrawal, the outpatients were given 15 mg DM every hour, 25 or 50 mg chlorpromazine (CPZ) + 4 mg TIZ every six hours and 10 mg diazepam + 10 mg hyoscine N-butyl Br + 250 mg dipyrone every six hours three hours following CPZ. The addicts were controlled twice a day. Yawning, rhinorrhea, perspiration, piloerection, restlessness, insomnia, emesis, diarrhea, craving, rejection of smoking and pupils were observed and/or questioned. Two of the 47 outpatients took heroin on the first days.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Adult; Ambulatory Care Facilities; Clonidine; Dextromethorphan; Drug Therapy, Combination; Female; Heroin Dependence; Hormones; Humans; Infant, Newborn; Male; Neurotransmitter Agents; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 1995 |
Effects of MK 801 on morphine physical dependence: attenuation and intensification.
It has previously been reported that the noncompetitive NMDA receptor antagonists ketamine and dextromethorphan suppressed the naloxone-induced morphine abstinence syndrome. In addition, the previous blockade by ketamine and dextromethorphan of NMDA receptors has been shown to intensify the naloxone-elicited morphine abstinence syndrome. On the basis of this information, another noncompetitive NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-a,d-cyclohepten-5,10-imine maleate (MK 801), was administered to rats in which two morphine-containing (75 x 2 morphine base) pellets had been implanted. The naloxone-precipitated abstinence syndrome in rats injected with 0.3 mg/kg MK 801 36 h after pellet implantation was found significantly more intense than controls whereas the abstinence syndrome in rats that received 0.1 mg/kg MK 801 before naloxone injection was less intense. The intensification by MK 801 given 36 h following pellet implantation was attributed to the further increase in upregulation and supersensitivity of NMDA receptors caused by morphine. The attenuation was explained by the blockade by MK 801 of NMDA receptors as occurred in the case of ketamine and dextromethorphan. Topics: Animals; Dextromethorphan; Dizocilpine Maleate; Ketamine; Male; Morphine; Morphine Dependence; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 1992 |
Previous chronic blockade of NMDA receptors intensifies morphine dependence in rats.
Chronic exposure of receptors to antagonists generally results in upregulation and/or supersensitivity. On the other hand, the noncompetitive NMDA receptor antagonists ketamine (K) and dextromethorphan (DM) suppress opiate abstinence syndrome by blocking NMDA receptors. Therefore, 40 mg/kg ketamine (K), 5 mg/kg dextromethorphan (DM), 5 mg/kg morphine (M) and 2 mg/kg naloxone (NL) alone or in combination with NL were IP administered to the rats five times during the daytime only for five days to see whether they would intensify abstinence syndrome through upregulation and/or supersensitivity of NMDA receptors. Three days following the implantation of three M-containing pellets, abstinence syndrome was brought about by 2 mg/kg NL injection. Jumping, wet dog shake, writhing, teeth chattering, diarrhoea, defecation and ptosis were observed for ten min. All drugs used alone or in combination with NL increased the intensity of abstinence syndrome. Since K and DM are noncompetitive NMDA receptor antagonists, the intensifying effect of NL or M was considered to be related to their interactions with NMDA receptors. Furthermore, on the basis of the results of the previous and present study, NL was claimed to act on NMDA receptors, like other opioids, but with higher affinity for and weaker blocking effect on NMDA receptors. Topics: Amino Acids; Analgesics; Animals; Behavior, Animal; Dextromethorphan; Dynorphins; Injections, Spinal; Kainic Acid; Male; Morphine Dependence; Naloxone; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 1991 |
Suppression by ketamine and dextromethorphan of precipitated abstinence syndrome in rats.
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 | 1990 |