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PubMed1995

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)

Adult↗
PubMed1994

Cognitive deterioration from long-term abuse of dextromethorphan: a case report.

Dextromethorphan (DM), the dextrorotatory isomer of 3-hydroxy-N-methylmorphinan, is the main ingredient in a number of widely available, over-the-counter antitussives. Initial studies (Bornstein 1968) showed that it possessed no respiratory suppressant effects and no addiction liability. Subsequently, however, several articles reporting abuse of this drug have appeared in the literature. The drug is known to cause a variety of acute toxic effects, ranging from nausea, restlessness, insomnia, ataxia, slurred speech and nystagmus to mood changes, perceptual alterations, inattention, disorientation and aggressive behavior (Rammer et al 1988; Katona and Watson 1986; Isbell and Fraser 1953; Devlin et al 1985; McCarthy 1971; Dodds and Revai 1967; Degkwitz 1964; Hildebrand et al 1989). There have also been two reported fatalities from DM overdoses (Fleming 1986). However, there are no reports describing the effects of chronic abuse. This report describes a case of cognitive deterioration resulting from prolonged use of DM.

Adult↗
PubMed1995

Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan.

Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p-chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Novel anticonvulsant analogs of dextromethorphan: improved efficacy, potency, duration and side-effect profile.

The anticonvulsant and neuroprotective activity of dextromethorphan (DM, [+]-3-methyl-17-methylmorphinan) may be, in part, due to its metabolism to the phencyclidine hydrochloride-like compound dextrorphan (DX). We evaluated the anticonvulsant activity and neurological impairing effects in rats of three novel analogs of DM which, based upon their position-3 substituents, would either not be expected to be metabolized to DX or might do so at a reduced rate. The DM analogs were determined to be more potent and more efficacious than DM against maximal electroshock convulsions; two of the analogs, namely [(+)-3-ethoxy-17-methylmorphinan] and [(+)-3-(2-propoxy)-17-methyl-morphinan], were equipotent to DX. [(+)-3-(Ethoxy-17-methylmorphinan], and [(+)-3-(2-propoxy)-17-methylmorphinan) exhibited a duration of action (1-2 hr) slightly longer than DX (0.5-1 hr) and similar to DM (2-4 hr). The anticonvulsant effect of [(+)-3-amino-17-methylmorphinan] persisted 4-6 hr. Against flurothyl convulsions DM was proconvulsant, DX was anticonvulsant and the DM analogs were inactive. In contrast, N-methyl-D-aspartate convulsions were antagonized by i.c.v. pretreatment with DM and the DM analogs, albeit with a potency approximately 10 times less than that of DX. Results of rotarod performance testing further distinguished the analogs from DM, DX or the anticonvulsant drug diazepam. No behavioral impairment was observed at the highest doses tested of each of the DM analogs, resulting in protective indices (i.e., rotarod TD50/maximal electroshock anticonvulsant ED50) greatly exceeding DM, DX or clinical anticonvulsant drugs. The results of this study establish these 3-substituted DM analogs as novel anticonvulsants exhibiting improved potency, efficacy, duration and side-effect profiles.

Animals↗
PubMed1993

Dextromethorphan O-demethylation and dextrorphan glucuronidation in a French population.

The dextromethorphan (DMP) O-demethylation and the dextrorphan (DRP) glucuronidation distributions were studied in 120 French Caucasian subjects. After a single 25 mg DMP oral administration, DMP, free and total DRP concentrations were measured in 8h-urine collection, using an HPLC technique with fluorescent detection. The DMP and free DRP concentrations ratio, in log form, was used to estimate the oxidative demethylation phenotype of the subjects. Two different populations were found. The first one consisted of the extensive metabolizers (90.8%, 95% confidence interval from 85.6 to 95.9%) and the second one consisted of poor metabolizers (9.2%, 95% confidence interval from 4.0 to 14.4%). The antimode value of the distribution was estimated at approximately 0.7 corresponding to a ratio of 5. Moreover, this ratio was compared to the DMP and total DRP concentrations ratio, usually defined to DMP O-demethylation phenotyping. On the other hand, the glucuronide DRP concentration was calculated by subtracting the free DRP concentration from the total DRP concentration. Consequently, the free DRP and glucuronide DRP concentrations ratio was also used to estimate the DRP glucuronidation in the present population. This ratio in log form reflected the UDP-glucuronyltransferase(s) capacity(ies). This log ratio appeared to be normally distributed in the population studied. These results show that log DMP/free DRP ratio can be used, as well as log DMP/total DRP ratio, to determine the oxidative phenotype of subjects and that the DRP conjugation does not exhibit any apparent genetic polymorphism.

Administration, Oral↗
PubMed1993

[Column switching HPLC method for determination of dextrorphan, an active metabolite of dextromethorphan, in plasma].

An HPLC method for the determination of dextrorphan, an active metabolite of dextromethorphan, in plasma was established using column switching technique. The column switching system was equipped with a per-column of 30 mm x 5 mm ID, packed with mu Bondapak C18, 37-50 microns, and an analytical column of 150 mm x 5 mm ID, packed with YWG-C18, 5 microns. A 0.2% acetic acid solution was used as the pretreating mobile phase to wash out impurities from the per-column. The analytical mobile phase consisted of acetonitrile-water-acetic acid-triethylamine-dichloromethane (17:82:1:0.05:0.025). The plasma samples were directly injected into the HPLC system after enzymatic hydrolysis of dextrorphan glucuronide ester conjugate to free form with beta-glucuronidase. The dextrorphan was monitored with a fluorescence detector at 290 nm (excitation) and 315 nm (emission). The method was linear within the plasma concentration range of 20-640 ng/ml (r = 0.9987), and the detection limit was 4 ng/ml. The mean recoveries of the method averaged 103.8%. The relative standard deviations of the assay were less than 10% for both within-day and between-days.

Chromatography, High Pressure Liquid↗
PubMed1977

Dextromethorphan toxicity: reversal by naloxone.

Naloxone has been shown to be effective in antagonizing the effects of a number of narcotic and related drugs. Its successful use in managing a patient with an overdose of dextromethorphan extends its application as a specific antidote.

Dextromethorphan↗
PubMed1995

[Dextromethorphan maintains the function of the detached retina].

In order to evaluate the effect of dextromethorphan (DEX), an antagonist of N-methyl-D-aspartate receptors, on ischemic damage in the detached retina, transretinal electrical responses (trans-retinal electroretinogram: TR-ERG) to photic stimulation were recorded from the detached retina of rabbit eyes in vitro. In experiment 1, 0.1 ml of 0.1% DEX was injected into the subretinal space to produce retinal detachment (RD) of 8 mm diameter (DEX group). For the control, the same volume of Hanks' solution was injected instead of DEX (control group). In experiment 2, 0.1 ml of 0.1% DEX was dropped onto retina, and RD was produced by injecting 0.1 ml of Hanks' solution into the subretinal space (DEX group). For the control, the same volume of saline was dropped onto the retina instead of DEX (control group). In experiment 1, the averaged b-wave amplitude of the TR-ERG decreased significantly (p < 0.01) at 3 hrs after RD in the control group, but it was almost stable and did not show significant decrease in the DEX group. In experiment 2, the averaged b-wave amplitude of the ERG decreased significantly (p < 0.05) at 2 hrs after the RD in the control, but showed no significant decrease even at 3 hrs after RD in the DEX group. These results indicate that DEX injected into the subretinal space and dropped onto the retina before producing RD may reduce ischemic damage in the detached retina.

Animals↗
PubMed1996

Efficacy of low-dose dextromethorphan in the treatment of nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is an inborn error of glycine degradation causing muscular hypotonia, seizures, apnea, and lethargy; it has a poor prognosis. Accumulation of glycine in the brain is thought to cause excessive stimulation of the N-methyl-D-aspartate receptor. Dextromethorphan (DM), an N-methyl-D-aspartate receptor antagonist, in doses of 5 to 35 mg/kg per day has been shown to have beneficial therapeutic effects in some patients with NKH. We report the case of a 1-year-old infant with NKH, seizure disorder, and psychomotor delay who was clinically seizure free during treatment with sodium benzoate, arginine, benzodiazepam, and phenobarbital. Although sodium benzoate normalized serum glycine levels (103 to 125 mumol/L), cerebrospinal fluid glycine levels remained elevated (42 to 47 mumol/L), with epileptiform activity on electroencephalography. The addition of low-dose DM (0.25 mg/kg per day) to the treatment led to improvement of electroencephalographic activity, resolution of nystagmus with increased eye contact, and modest progression of developmental milestones. These data suggest that DM at doses significantly lower than previously reported may be beneficial in some patients with NKH. Treatment with low-dose DM needs further evaluation.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

[Analgesic effect of dextromethorphan for postherpetic neuralgia].

We investigated the analgesic effect of dextromethorphan (DM), a non-selective NMDA receptor antagonist, in 25 patients with postherpetic neuralgia (PHN). We administered DM 45mg.day-1 orally for 14 days and then 90mg.day-1 for next 14 days. Decrease in pain intensity and alleviation of allodynia were observed in 9 patients (36%). Side effects with no severe cases occurred in 8 patients (32%) and these were mainly digestive symptoms. We concluded that DM might be useful to treat PHN with allodynia probably due to central sensitization.

Aged↗
PubMed1996

The effects of dextromethorphan on kainic acid-induced seizures in the rat.

Several studies have shown that dextromethorphan (DM) has both anticonvulsant and proconvulsant effects depending on the animal model. In this study, we examined the effects of DM on three parameters associated with kainic acid (KA)-induced seizures: cell loss in the hippocampus, increased AP-1 DNA binding activity and increased c-Jun and fos-related antigen (FRA) expression. KA administration (8 mg/kg, ip) produced robust behavioral convulsions lasting 4-6 hr. Pretreatment with DM (12.5-75 mg/kg, po) 15 min before KA injections reduced the seizures as well as mortality in a dose-dependent manner. Histological studies revealed a severe loss of cells in the CA1 and CA3 fields of the hippocampus in KA-treated rats. DM pretreatment also reduced this cell loss in a dose-dependent fashion. Biochemical studies showed that DM pretreatment also attenuated the KA-induced increase of AP-1 binding activity and c-Jun/FRA expression in the hippocampus. These results indicate that DM is an effective antagonist of KA.

Animals↗
PubMed1996

The abuse of dextromethorphan-based cough syrup: a pilot study of the community of Waynesboro, Pennsylvania.

Drug abuse has been a national social problem in the United States for decades and is often complicated by the emergence of new types of abused drugs or new forms of abuse. In the late 1980s, the community of Waynesboro, Pennsylvania began to detect behavior among its teenagers that suggested a new form of drug abuse and thus a new social problem. The drug was dextromethorphan, used in cough syrup-principally Robitussin DM. The form of abuse is often referred to as "roboing" or "robo-copping." This paper presents the results of the first phase of a comprehensive investigation of this phenomenon in the Waynesboro school district. Data from a survey of school personnel indicate that abuse of cough syrup (Robitussin or other brands) has increased over the years and is increasingly perceived as a problem by the community.

Adolescent↗
PubMed1996

Abuse of dextromethorphan-based cough syrup as a substitute for licit and illicit drugs: a theoretical framework.

Drug abuse has been a national social problem in the United States for decades and is often complicated by the emergence of new types of abused drugs or new forms of abuse. The forms of abuse, particularly by young persons, include the search for substitutes for better-known substances. It is unclear, however, what factors determine the choice of drug or substance for experimentation, considering the wide range of choices. This paper attempts to delineate the factors which make Dextromethorphan-based cough syrup an attractive choice.

Adolescent↗
PubMed1996

Effects of the combined oral administration of NSAIDs and dextromethorphan on behavioral symptoms indicative of arthritic pain in rats.

The effects of combined single oral treatments with non-steroidal anti-inflammatory drugs (NSAIDs) and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan (DM) on arthritic pain were examined in a rat model of adjuvant-induced arthritis. Although 12.5-100 mg/kg doses of DM alone produced no reliable effects, treatments with ibuprofen (IB, 50 and 100 mg/kg but not 12.5 or 25 mg/kg) produced mild analgesia in arthritic rats as determined using the Randall-Sellito test. IB showed a dose-response relationship which appeared to plateau at doses of 50 and 100 mg/kg. Adding 50 mg/kg DM to each IB dose resulted in significantly greater analgesic activity than IB alone at doses of 25, 50 and 100 mg/kg. A similar interaction between 50 mg/kg DM and 50 mg/kg IB occurred with respect to spontaneous pain behavior. Adding 25 mg/kg DM to 25 mg/kg IB likewise increased analgesia as measured by both the Randall-Sellito and spontaneous pain behavior tests (both P < 0.05). Five more NSAIDs were evaluated using the Randall-Sellito test, which included naproxen (NP), piroxicam (PIR), etodolac (ET), diclofenac (DC), and ketorolac (KE). For all six NSAIDS, the addition of 50 mg/kg DM reliably increased their analgesic potency, as indicated by reliable increases in previously effective NSAID doses (all six NSAIDs) as well as previously ineffective NSAID doses (IB, NP, DC, and PIR). These data demonstrate that DM greatly potentiates the analgesic activity of IB, DC, NP, PIR, ET, and KT and increases the peak effect over the NSAIDs alone. Similiar to DM's previously demonstrated enhancement of opioid analgesia in acute pain, the combination of DM and an NSAID may represent a novel analgesic approach to improved management of arthritic pain.

Administration, Oral↗
PubMed1997

Dextromethorphan alters the reinforcing effect of cocaine in the rat.

Dextromethorphan (DM) at supra-antitussive doses produces psychotomimetic effects in humans. In order to achieve a better understanding of the pharmacological mechanisms responsible for the behaviors induced by DM, we examined the effects of DM on the intravenous self-administration of cocaine in the rat. The effects of DM (40 mg/kg, p.o.) on responding for 0.5, 0.25, 0.125, 0.06 and 0.03 mg/kg/infusion of cocaine was assessed. DM decreased the rate of responding for higher doses of cocaine (0.5, 0.25 and 0.125 mg/kg/infusion), and increased the rate of responding for lower doses of cocaine (0.06 and 0.03 mg/kg/infusion), suggesting that DM shifted the dose-response curve for cocaine self-administration to the left. Therefore, our results indicate that the sensitivity to cocaine's behavioral effects appears to be enhanced by DM.

Animals↗
PubMed1998

Ineffectiveness of dextromethorphan in cancer pain.

Experimental studies have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists may be effective analgesics in a wide variety of chronic pain states. The mechanism is presumed to be related to decreased firing of dorsal horn neurons after constant repeated C-fiber stimulation. Dextromethorphan (DM), a potent NMDA antagonist with a good safety profile, may be a promising agent for the treatment of persistent pain. An open-label randomized trial was designed to examine the effects of combining DM with NSAIDs, dextropropoxyphene, or morphine in cancer patients with pain. Patients who required a change in the step of the World Health Organization's (WHO) analgesic ladder because of a pain level of 4 or more on a numerical pain scale were randomly allocated to receive DM 30 mg three times a day (30 patients) or conventional treatment (30 patients). There were 20 patients randomized for each step of the analgesic ladder. Pain mechanisms, pain intensity (numerical 0-10 scale), symptoms more frequently present in advanced cancer patients or associated with opioid therapy (graded on a 0-3 scale--not at all, slight, a lot, awful), opioid escalation index, days on opioid treatment, and adverse effects were recorded. After 2 days 75%, 80%, and 100% of patients treated with DM in steps 1, 2, and 3, respectively, required conventional treatment, because adequate pain relief had not been achieved (pain scale > 4). Failure of this treatment was equally observed in neuropathic pain or nociceptive pain syndromes. Four patients treated with DM who did not require the conventional treatment immediately did require this change after some days, due to poor pain control. A highly significant reduction in pain was observed in patients directly treated with the conventional treatment in all the three steps of the analgesic ladder. No significant analgesic effects could be found when DM at this dose was combined with NSAIDs, dextropropoxyphene, or morphine.

Analgesics, Opioid↗
PubMed1996

Inhibitory effects of dextromethorphan on c-fos protein expression during focal cerebral ischemia in rats.

AIM: To study the effect of dextromethorphan (DM) in focal cerebral ischemia. METHODS: The c-fos protein was detected immunohistochemically in the brain of rats after focal cerebral ischemia (induced by placing a nylon thread in the lumen of the internal carotid artery) with and without treatment with DM. RESULTS: Focal cerebral ischemia induced c-fos protein expression outside the core territory of the middle cerebral artery (MCA) and neuronal damage in the core territory of the MCA. There was an evident expression of c-fos protein in the ipsilateral regions outside the MCA territory (e.g. cingulate cortices, piriform cortices and entorhinal cortices), and in the contralateral regions of hippocampus after 4-h reperfusion following 1-h MCA occlusion. But morphological results showed severe edema and neuronal damage in the core territory and the ipsilateral hippocampus. DM blocked both the c-fos protein induction and neuronal damage in all regions. CONCLUSION: DM reduced c-fos protein expression and blocked the neuronal damage after focal cerebral ischemia.

Animals↗
PubMed1999

Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan.

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.

Adult↗