dextromethorphan and Pain

Topics: Analgesics; Analgesics, Opioid; Animals; Binding Sites; Glycine; Humans; Ion Channel Gating; Pain; Peripheral Nervous System Diseases; Protein Subunits; Receptors, N-Methyl-D-Aspartate

Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.

Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Pain; Receptors, N-Methyl-D-Aspartate

We evaluated in a qualitative systematic review the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on reducing postoperative pain and analgesic consumption beyond the clinical duration of action of the target drug (preventive analgesia). Randomized trials examining the use of an NMDA antagonist in the perioperative period were sought by using a MEDLINE (1966-2003) and EMBASE (1985-2003) search. Reference sections of relevant articles were reviewed, and additional articles were obtained if they evaluated postoperative analgesia after the administration of NMDA antagonists. The primary outcome was a reduction in pain, analgesic consumption, or both in a time period beyond five half-lives of the drug under examination. Secondary outcomes included time to first analgesic request and adverse effects. Forty articles met the inclusion criteria (24 ketamine, 12 dextromethorphan, and 4 magnesium). The evidence in favor of preventive analgesia was strongest in the case of dextromethorphan and ketamine, with 67% and 58%, respectively, of studies demonstrating a reduction in pain, analgesic consumption, or both beyond the clinical duration of action of the drug concerned. None of the four studies examining magnesium demonstrated preventive analgesia.. We evaluated, in a qualitative systematic review, the effect of N-methyl D-aspartate antagonists on reducing postoperative pain and analgesic consumption beyond the clinical duration of action of the target drug (preventive analgesia). Dextromethorphan and ketamine were found to have significant immediate and preventive analgesic benefit in 67% and 58% of studies, respectively.

Topics: Analgesics, Opioid; Anesthetics, Dissociative; Clinical Trials as Topic; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Ketamine; Magnesium; MEDLINE; Pain; Pain, Postoperative; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Research Design

Topics: Animals; Chemistry, Pharmaceutical; Chronic Disease; Dextromethorphan; Drug Combinations; Drugs, Investigational; Humans; Morphine; Pain

Most traditional opioids and non-steroidal anti-inflammatory drugs that are used to control perioperative pain have substantial side effects. The number of choices in clinical use was recently increased by two promising groups of drugs: N-methyl-D-aspartate receptor antagonists and central alpha2 agonists. One N-methyl-D-aspartate antagonist, dextromethorphan, blocks the generation of central pain sensation that arise from peripheral nociceptive stimuli by moderating the activity of N-methyl-D-aspartate. It pre-empts the sensation of acute pain at doses of 30-90 mg without serious side effects, while reducing the amount of analgesics required perioperatively by 50%. It is available in oral form and has a confirmed lack of effect on haemodynamics and respiration. Dexmedetomidine is a relatively new, highly selective central alpha2 agonist. Its sedative, pro-anaesthetic and pro-analgesic effects at 0.5-2 microg/kg given intravenously stem mainly from its ability to blunt the central sympathetic response by as yet unknown mechanism(s) of action. It also minimises opioid-induced muscle rigidity, lessens postoperative shivering, causes minimal respiratory depression, and has haemodynamic stabilising effects.

Topics: Adrenergic alpha-Agonists; Analgesics; Animals; Dexmedetomidine; Dextromethorphan; Humans; N-Methylaspartate; Pain; Pain, Postoperative; Premedication; Receptors, Adrenergic, alpha-2; Receptors, N-Methyl-D-Aspartate

Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the excitatory amino acids, glutamate and aspartate. Only a handful of N-methyl-D-aspartate antagonists are clinically available. These include ketamine, dextromethorphan, memantine, and amantadine, as well as three clinically used opioids (methadone, dextropropoxyphene, and ketobemidone). This review summarizes the single-dose efficacy of the first two compounds in the treatment of experimental and neuropathic pain. In all examples presented here, NMDA-receptor antagonists with affinity at the phencyclidine site have been shown to modulate pain and hyperalgesia but are limited by dose-limiting side effects. Thus, provided their therapeutic ratio is favorable, NMDA-receptor antagonists may be effective in the treatment of some types of chronic pain.

Topics: Analgesics; Clinical Trials as Topic; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Ketamine; Nervous System Diseases; Pain; Receptors, N-Methyl-D-Aspartate; Research Design

To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties.. A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywords nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan.. The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM in acute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt with chronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation of acute pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types of chronic pain showed DM to be associated with unsatisfactory pain relief.. DM attenuates acute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.

Topics: Animals; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Pain; Receptors, N-Methyl-D-Aspartate

Topics: Chronic Disease; Dextromethorphan; Humans; Pain; Receptors, N-Methyl-D-Aspartate

This review has covered the five potential causes for opioid poorly responsive pain, namely (a) a loss of opioid receptors on the spinal terminals of C-fibres as a result of peripheral nerve damage, (b) an accumulation of morphine-3-glucuronide, (c) changes in the non-opioid peptides, F8Fa or CCK, either spinally or supraspinally, (d) actions of the opioid peptide dynorphin and (e) spinally generated hypersensitive states via activation of the NMDA receptor. The loss of opioid receptors is likely to be important where peripheral nerve pathology or compression occurs, but the evidence suggests that increasing the dose will overcome the reduced opioid response. Morphine-3-glucuronide is unlikely to be a factor, nor is dynorphin, but the endogenous peptides CCK and F8Fa may be important. Finally, there is an association between the NMDA receptor and hyperalgesia/allodynia and reduced opioid sensitivity. Dextrorphan and ketamine reduce NMDA mediated events and so are available to test this hypothesis.

Topics: Analgesics, Opioid; Animals; Central Nervous System; Clonidine; Dextromethorphan; Dextrorphan; Dynorphins; Humans; Morphine; N-Methylaspartate; Neoplasms; Neurophysiology; Neuroprotective Agents; Pain; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Sympatholytics

To evaluate efficacy and satisfaction of dextromethorphan as a non-narcotic adjuvant to current analgesic regimens for medication abortion.. We conducted a randomized, double-blinded, placebo-controlled trial. We randomized eligible participants (N = 156) 1:1 to adjunctively take dextromethorphan (loading dose 60 mg and two subsequent 30 mg doses at 2 and 5 hours after misoprostol administration) or placebo combined with usual-care nonsteroidal anti-inflammatory medications ± opioids for pain. Participants reported pain scores and satisfaction using a secure texting application at 2, 5, 8, and 24 hours after misoprostol administration. Our primary outcome was worst pain score and total analgesic use.. Baseline demographics of enrolled participants were similar between randomization arms. Worst pain scores for participants receiving dextromethorphan versus placebo (8.0 vs 7.0, p = 0.06) did not differ. Total milligram usage of ibuprofen (800 mg vs 610 mg, p =.62), acetaminophen (1000 mg vs 1300 mg, p = 0.62), and opioids (10 mg vs 15 mg, p = 0.51) did not differ between the randomization groups. Participants randomized to placebo were significantly more likely to be satisfied with their pain control (91% vs 75%, p = 0.02).. Dextromethorphan used adjunctively with standard analgesics did not reduce pain associated with medication abortion. Participants who received dextromethorphan reported decreased satisfaction with their pain control.. Dextromethorphan used adjunctively with commonly used analgesic regimens did not reduce medication abortion associated pain. Many participants did not use analgesics as counseled, and nearly 25% used no analgesia during medication abortion.

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Dextromethorphan; Double-Blind Method; Female; Humans; Misoprostol; Pain; Pain, Postoperative; Pregnancy

We investigated co-analgesic effect of dextromethorphan in adolescent post-operative patients with idiopathic scoliosis. In a double-blind study, 60 patients with ASA physical status I-II were randomised into two groups. Group dextromethorphan (n = 30; age: 15.9 +/- 2.4 years) was given oral dextromethorphan 30 or 45 mg 1 hr before surgery and 8, 20 and 32 hr after operation. Group placebo (n = 30; age: 16.5 +/- 2.7 years) received placebo at identical times. Post-operative analgesic requirements were assessed using nurse-controlled analgesia system. Pain was assessed using numeric rating scale before first administration of morphine and at 2, 3, 4, 6, 24 and 48 hr after operation. Blood samples were taken 20 min. after the first use of morphine (within 1 hr after operation). The total use of analgesics during surgery was lower in the dextromethorphan group. The dose of morphine providing relief immediately after surgery, as well as total analgesic requirements in the first and second day after surgery did not differ between groups. Subjectively evaluated pain intensity score (numeric rating scale) was lower for the dextromethorphan patients in the first 4 hr, but not later after surgery. Plasma levels of morphine, morphine-6-glucuronide and morphine-3-glucuronide did not differ between groups. Dextromethorphan did not influence morphine glucuronidation, in terms of promotion of formation of any morphine glucuronides. In conclusion, in young patients subjected to spine surgery, addition of dextromethorphan to morphine reduced pain only in early post-operative period. In such patients, co-analgesic action of dextromethorphan was not associated with significant changes in plasma levels of morphine metabolites.

Topics: Administration, Oral; Adolescent; Analgesics, Opioid; Dextromethorphan; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Morphine; Nurse's Role; Pain; Pain Measurement; Pain, Postoperative; Scoliosis; Spine

In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain.. Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.

Topics: Adult; Analgesics, Opioid; Capsaicin; Dextromethorphan; Double-Blind Method; Drug Combinations; Drug Synergism; Female; Forearm; Hot Temperature; Humans; Hyperalgesia; Male; Middle Aged; Morphine; Pain; Thigh

Pain associated with diabetic peripheral neuropathy (DPN) has a substantial negative impact on patients' quality of life.. The primary objective of this study was to evaluate the tolerability of capsules containing dextromethorphan (DM) and quinidine (Q) in patients with painful DPN. A secondary objective was to perform a preliminary assessment of the efficacy of DM/Q in this patient population.. This was a multicenter, open-label, dose-escalation study. Eligible patients were aged between 18 and 80 years, had a confirmed diagnosis of diabetes with acceptable glycemic control, had been receiving established diabetic therapy for at least 3 months, and had a clinical diagnosis of distal symmetric sensory neuropathy with daily DPN-associated pain for the previous 3 months. On study entry, patient-rated diabetic pain had to be moderate or greater. Patients who met the inclusion criteria underwent a 2-week washout period during which all analgesics were discontinued, followed by 29 days of treatment with capsules containing DM 30 mg and Q 30 mg (DM30/Q30), beginning with 1 capsule/d and escalating at approximately 1-week intervals, as tolerated, to a maximum dose of 4 capsules/d (DM120/Q120). Tolerability was assessed based on adverse events and changes in clinical and laboratory parameters and nerve conduction velocity. Preliminary efficacy assessments included changes from baseline in scores on the pain intensity rating scale (PIRS), pain relief rating scale (PRRS), peripheral neuropathy quality-of-life instrument, and patients' diary assessments of sleep, present pain intensity, pain, and activity.. The study included 36 men and women (mean age, 58 years; mean body mass index, 32.8 kg/m(2)). Of the 33 subjects who completed the study, 23 (69.7%) did so at the highest permitted dose (DM120/Q120). The most commonly reported adverse events (occurring in > or =5% of subjects) were nausea (27.8%), dizziness (25.0%), and headache (25.0%). Three patients experienced 5 serious adverse events, only 1 of which was considered possibly related to study drug. The most commonly occurring laboratory abnormalities (involving glycosylated hemoglobin, serum glucose, triglycerides, and cholesterol) were considered typical of a population with diabetes. Improvements from baseline in scores on the PIRS, PRRS, and other exploratory efficacy measures were noted (P < 0.001).. The results of this open-label study indicated that the combination of DMIQ (dose range, DM30/Q30-DM120/Q120) was well tolerated in patients with pain associated with DPN. Based on the preliminary efficacy results, a randomized, controlled, double-blind trial is warranted to assess the tolerability and efficacy of this combination in patients with DPN.

Topics: Adult; Aged; Analgesics, Opioid; Chromatography, Liquid; Dextromethorphan; Diabetic Neuropathies; Dose-Response Relationship, Drug; Female; Humans; Male; Mass Spectrometry; Middle Aged; Pain; Quinidine

The aim of this study was to investigate the effect of dextromethorphan (DM) 0.5 mg/kg administered intravenously (i.v.) on hyperalgesia and pain after a tissue injury in human volunteers, and to describe the relationship between pharmacokinetic and pharmacodynamic data. The heat-capsaicin sensitisation model, a well-established experimental hyperalgesia model was induced in 24 healthy, male volunteers aged 21-35 years. The subjects received i.v. DM 0.5 mg/kg or isotonic saline on two separate study sessions. The primary outcome measure from 0 to 3 h was reduction in area of established secondary hyperalgesia. Secondary outcome measures were reduction in area of secondary hyperalgesia in response to brief thermal stimulation, heat pain detection thresholds and painfulness after tonic heat pain. Blood samples were collected throughout the study to describe the relationship between pharmacokinetic and pharmacodynamic data. Intravenous DM 0.5 mg/kg significantly reduced areas of established secondary hyperalgesia with an average of 39% (P<0.05). Development of secondary hyperalgesia was substantially prevented by DM (P<0.05). No significant effect was seen on either heat pain detection thresholds or after tonic heat pain. The pharmacokinetic-pharmacodynamic relationship showed a large inter-subject variation with a mean delay in effect of nearly 2 h in relation to peak serum concentration. The results strongly indicate that DM is an anti-hyperalgesic drug. The delay in effect may be explained by several mechanisms and suggests that timing of DM administration is an essential factor for using the drug in clinical settings.

Topics: Adolescent; Adult; Area Under Curve; Capsaicin; Cross-Over Studies; Dextromethorphan; Dextrorphan; Double-Blind Method; Excitatory Amino Acid Antagonists; Humans; Hyperalgesia; Infusions, Intravenous; Male; Pain; Pain Measurement; Pain Threshold; Reaction Time; Time Factors; Treatment Outcome

Temporal summation of second pain at least partly reflects temporal summation of dorsal horn neuronal responses, and both have been termed windup (WU), a form of nociception-dependent central sensitization. Animal and human experiments have shown that both forms of WU depend on N-methyl-D-aspartate (NMDA) and substance P receptor systems. WU of second pain (WU(SP)) in patients with fibromyalgia (FM) is enhanced compared with normal control (NC) subjects and is followed by exaggerated WU(SP) aftersensations and prolonged WU(SP) maintenance at low stimulus frequencies. Because the enhanced WU(SP) of FM patients could be related to abnormal endogenous modulation of NDMA receptors, we tested the effects of the NMDA receptor antagonist dextromethorphan (DEX) on WU(SP) in FM and NC subjects in a double-blind, placebo-controlled, crossover study. WU(SP) was elicited by trains of 0.7-second duration thermal pulses applied to the glabrous surface of the hands or by 1-second mechanical stimuli to the adductor pollicis muscle of the hands at a frequency of 0.33 Hz. In comparison to baseline and placebo conditions, single oral doses of DEX 60 and 90 mg reduced thermal and mechanical WU(SP) in NC and FM subjects, with DEX 90 mg being most effective. These effects did not differ for male and female NC subjects. FM subjects required less thermal and mechanical stimulus intensity than NC to achieve maximal WU(SP), but the extent of WU(SP) reduction by DEX did not statistically differ between NC and FM subjects for all study conditions. Thus, central pain processing of FM subjects is not different from NC in at least one important aspect, namely their NMDA receptor system responsiveness to pharmacologic inhibition by DEX.. Results of this study demonstrate that FM patients show abnormal WU(SP) during thermal and mechanical stimulation compared with NC. Because oral doses of the NMDA receptor antagonist DEX attenuated thermal and mechanical WU(SP) similarly in FM patients and NC, other mechanisms than WU(SP) need to be considered for the widespread pain of FM patients. These mechanisms might include tonic nociceptive input from peripheral tissues and/or enhanced descending facilitation.

Topics: Adult; Chronic Disease; Cross-Over Studies; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Fibromyalgia; Hot Temperature; Humans; Hyperalgesia; Male; Middle Aged; Motor Activity; Nociceptors; Pain; Receptors, N-Methyl-D-Aspartate

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), may enhance the analgesic effects and prevent the tolerance that may result from chronic opioid administration, others have not. The potential for reduced doses, enhanced opioid analgesia, and decreased analgesic tolerance associated with the MS/DM combination were evaluated in a series of three large, randomized, double-blind, parallel group, phase 3, multicenter trials each of 3 months duration in patients with chronic, non-malignant, non-neuropathic pain. To evaluate these unique endpoints, novel study designs were employed. In Study A, patients received fixed doses of MS or MS/DM, based on the stable dose of MS/DM attained during a Run-in period; changes from baseline in average daily pain intensity were compared. In Studies B and C, patients self-titrated doses of MS or MS/DM, based on stable doses of MS or other opioids attained during Run-in periods, to maintain pain relief; percentage changes from baseline in MS (or MS-equivalent) doses were compared. No statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated in any trial. These results suggest that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Dextromethorphan; Double-Blind Method; Drug Combinations; Drug Tolerance; Female; Humans; Male; Middle Aged; Morphine; Pain; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

IV infusion tests performed to predict subsequent response to oral analgesics are an increasingly popular method used to enhance medical care and conserve resources. Because no infusion test is completely accurate, the potential benefits of these tests must be weighed against the frustration and waste in resources encountered with false-positive results, and the failure to use a potentially beneficial treatment with false-negative results. In recent years, drugs that act antagonistically at N-methyl-d-aspartate receptors have been shown to be valuable adjuncts in the treatment of pain. To determine the predictive value of small-dose (0.1 mg/kg) IV ketamine on an oral dextromethorphan (DX) treatment regimen, we analyzed the analgesic response to these drugs in 25 patients at 2 tertiary care military treatment facilities, institutions at which DX is not readily accessible. When >/=50% response for both drugs was used as the outcome measure for success, the positive predictive value of the ketamine test was 64%, the negative predictive value 73%, and the observed agreement 68%. However, when >/=67% relief with ketamine was used as an outcome measure (as determined by a receiver operating characteristic curve), the positive predictive value was 90%, the negative predictive value 80%, and the observed agreement increased to 84%. Based on these results, we conclude that an IV ketamine test may be useful in predicting response to oral DX. More research is needed to determine the ideal candidates for such a test, and the optimal dose and cutoff value for the response to ketamine.

Topics: Administration, Oral; Adult; Anesthetics, Local; Databases, Factual; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Humans; Injections, Intravenous; Ketamine; Lidocaine; Male; Middle Aged; Pain; Pain Measurement; Peripheral Nervous System Diseases; Predictive Value of Tests; Receptors, N-Methyl-D-Aspartate; ROC Curve

N-methyl-aspartate (NMDA) receptor antagonists have been shown to improve opioid analgesia in the animal model. The cough suppressant dextromethorphan is a clinically available NMDA-receptor antagonist. In this randomised, double-blind, placebo-controlled study 20 patients with chronic pain of several years duration were given 100 mg of oral dextromethorphan or matching placebo 4 h prior to an intravenous infusion of morphine 15 mg. Pain intensity and adverse effects were assessed at 0, 4, 5 and 7 h. Dextromethorphan had no effect on morphine analgesia: the mean (+/-SEM) visual analogue scores for pain relief (VAS, 0-100 mm) at the end of the morphine infusion were 38 (+/-6) for dextromethorphan+morphine and 38 (+/-7) for placebo+morphine. VAS scores for pain intensity were comparable both at rest and at movement at all time points. The most common adverse effects reported were dizziness, nausea and sedation. There were no significant differences in either the incidence or severity of adverse effects. In conclusion, oral dextromethorphan 100 mg had no effect on pain relief by intravenous morphine 15 mg in patients with chronic pain.

Topics: Analgesics, Opioid; Chronic Disease; Dextromethorphan; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Morphine; Pain; Treatment Outcome

There are few repeated dose-controlled trials of N-methyl-d-aspartate glutamate receptor antagonists in patients with neuropathic pain. The authors sought to evaluate two low-affinity N-methyl-d-aspartate antagonists using a novel two-stage design.. The authors studied patients with painful diabetic neuropathy (DN) and postherpetic neuralgia (PHN) in two crossover trials: (1) efficacy trial (dextromethorphan vs. memantine vs. active placebo [lorazepam]) and (2) dose-response trial of the preferred active drug in responders from the first study (0% vs. 25% vs. 50% vs. 100% of each patient's maximally tolerated dose). Pain intensity was measured on a 20-point scale.. Nineteen of 23 DN patients and 17 of 21 PHN patients completed the efficacy trial. Median doses for DN and PHN were 400 and 400 mg/day dextromethorphan, 55 and 35 mg/day memantine, and 1.8 and 1.2 mg/day lorazepam. In the efficacy trial, among patients with DN, dextromethorphan reduced pain intensity by a mean of 33% from baseline, memantine reduced pain intensity by a mean of 17%, and lorazepam reduced pain intensity by a mean of 16%; the proportions of subjects achieving greater than moderate pain relief were 68% with dextromethorphan, 47% with memantine, and 37% with lorazepam. Mean reductions in pain intensity in patients with PHN were 6% with dextromethorphan, 2% with memantine, and 0% with lorazepam. No comparison with placebo reached statistical significance in the efficacy trial. In the 10 DN subjects who responded to dextromethorphan, there was a significant dose-response effect on pain intensity (P = 0.035), with the highest dose significantly better than that of lorazepam (P = 0.03).. Dextromethorphan is effective in a dose-related fashion in selected patients with DN. This was not true of PHN, suggesting a difference in pain mechanisms. Selective approaches to pain-relevant N-methyl-d-aspartate receptors are warranted.

Topics: Adult; Aged; Dextromethorphan; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Excitatory Amino Acid Antagonists; Female; Herpesviridae Infections; Humans; Male; Memantine; Middle Aged; Neuralgia; Pain; Pain Measurement; Quality of Life; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers.. The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.. Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively.. Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.

Topics: Acute Disease; Adult; Analgesics; Cross-Over Studies; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Humans; Injections, Intravenous; Ketamine; Male; Middle Aged; Nociceptors; Pain; Pain Threshold; Receptors, N-Methyl-D-Aspartate

Previous studies have shown that N-methyl-D-aspartate receptor antagonists provide a preemptive analgesic effect in humans. This study was designed to examine whether premedication with dextromethorphan, an N-methyl-D-aspartate antagonist, also provided a preemptive analgesic effect that improved postoperative pain management.. Sixty patients who were American Society of Anesthesiologists status I and II scheduled for hemorrhoidectomy (modified Whitehead procedure) were included in the study. Patients were randomly assigned to the control and study groups. For the control group patients received chlorpheniramine maleate (20 mg), a component of the injection form of dextromethorphan, intramuscular injection 30 minutes before skin incision. In the study group dextromethorphan 40 mg containing 20 mg chlorpheniramine maleate (intramuscular) was given as premedication 30 minutes before skin incision. Pethidine (1 mg/kg, intramuscular) was given for pain relief as required postoperatively. The time to first pethidine injection, total pethidine consumption, worst pain score, and pethidine-related side effects were recorded for 48 hours postoperatively.. The times to first pethidine injection (mean +/- standard error of the mean) were 5.2 +/- 3 and 19.6 +/- 6 hours in the control and study groups, respectively. Total pethidine consumption was 140 +/- 11.3 and 63.5 +/- 11.8 mg in the control and study groups. The worst visual analog scale pain scores were 7.4 +/- 0.2 and 5.6 +/- 0.3 in the control and study groups during the two-day observation. The numbers of patients who required pethidine injection were 29 and 20 in the control and study groups, respectively. Two patients suffered pethidine-related side effects, such as nausea, vomiting, dizziness, and headache, in the control group, and no patient complained of any side effect in the study group.. We found that dextromethorphan premedication provided a preemptive analgesic effect, thus producing reduced postoperative pain and pethidine requirement and improved recovery from hemorrhoidectomy.

Topics: Adult; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Hemorrhoids; Humans; Injections, Intramuscular; Male; Middle Aged; Pain; Postoperative Complications; Preoperative Care

N-methyl-D-aspartate-receptor antagonists may be useful in pain management. The aim of this study was to evaluate dextromethorphan (DEX), a commonly used oral antitussive drug with NMDA-receptor antagonistic properties, in respect of its analgesic properties as single drug and co-administered with morphine (MO) on experimental ischemic pain. In addition, the analgesic effects of another clinically available NMDA-receptor antagonist, ketamine (KET) as well as of morphine (MO) were tested as active controls.. Nineteen healthy volunteers were included in the study. Experimental ischemic pain was induced using the forearm tourniquet test. Placebo (PLAC), oral DEX (30 and 90 mg, respectively), KET (9 microg kg(-1) min(-1) i.v.), MO (0.1 mg kg(-1), i.v.) and the DEX+MO and KET+MO combinations were evaluated during eight separate experiments. Development of ischemic pain was rated by visual analog scale (VAS) every minute over 30 min and ratings were summed as sum of pain scores (SPS).. DEX by itself did not influence SPS compared to PLAC. The DEX+MO co-administration did not enhance MO-induced analgesia. MO and KET reduced pain ratings by 27% and 39%, respectively. The KET+MO combination showed no enhancement of the analgesic effect in comparison with the respective drugs in monotherapy.. DEX in clinical doses has no effect on the present acute ischemic pain model and does not influence MO-induced analgesia. Further studies on other pain modalities are needed in order to evaluate the potential use of DEX in pain treatment.

Topics: Adult; Analgesics; Analgesics, Opioid; Dextromethorphan; Drug Combinations; Female; Humans; Ischemia; Isotonic Contraction; Male; Morphine; Pain; Pain Measurement; Receptors, N-Methyl-D-Aspartate

N-methyl-D-aspartate (NMDA) receptor antagonists relieve neuropathic pain in animal models, but side effects of dissociative anesthetic channel blockers, such as ketamine, have discouraged clinical application. Based on the hypothesis that low-affinity NMDA channel blockers might have a better therapeutic ratio, we carried out two randomized, double-blind, crossover trials comparing six weeks of oral dextromethorphan to placebo in two groups, made up of 14 patients with painful distal symmetrical diabetic neuropathy and 18 with postherpetic neuralgia. Thirteen patients with each diagnosis completed the comparison. Dosage was titrated in each patient to the highest level reached without disrupting normal activities; mean doses were 381 mg/day in diabetics and 439 mg/day in postherpetic neuralgia patients. In diabetic neuropathy, dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.01), relative to placebo. In postherpetic neuralgia, dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72). Five of 31 patients who took dextromethorphan dropped out due to sedation or ataxia during dose escalation, but the remaining patients all reached a reasonably well-tolerated maintenance dose. We conclude that dextromethorphan or other low-affinity NMDA channel blockers may have promise in the treatment of painful diabetic neuropathy.

Topics: Administration, Oral; Adult; Aged; Cross-Over Studies; Dextromethorphan; Diabetic Neuropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Herpesviridae Infections; Humans; Male; Middle Aged; Neuralgia; Pain; Palliative Care; Placebos

The analgesic properties of the noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan, available for clinical use as an antitussive, have been studied in the human capsaicin pain model to determine a possible clinical effect on pain due to central sensitization. Ninety milligrams dextromethorphan or vehicle was given orally to ten volunteers, each at two different occasions in a double-blind fashion, prior to an intradermal injection of 300 micrograms capsaicin. Ongoing pain, pain evoked by von Frey filament stimulation, and pressure pain thresholds were assessed before and after the capsaicin injection. The area in which von Frey filament stimulation evoked pain was mapped after the capsaicin injection. There were no significant group effects on ongoing pain, or on von Frey or pressure hypersensitivity. There was also no significant effect on the area of mechanical hypersensitivity. These results show that clinical doses of dextromethorphan do not effect ongoing or mechanically evoked pain after capsaicin injection.

Topics: Adult; Analgesics; Capsaicin; Dextromethorphan; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Humans; Hypersensitivity; Male; Middle Aged; Pain; Stress, Mechanical

The aim was to compare the analgesic effectiveness and adverse effect incidence of oral dextromethorphan (DM) with placebo in patients with neuropathic pain. The first 10-day treatment period was a multiple-dose double-blind randomised controlled cross-over comparison of 13.5 mg of DM 3 times a day (t.d.s.) with placebo t.d.s.: 5 treatment pairs, each pair 1 day DM and 1 day placebo. The second 10-day treatment period used 27 mg of DM t.d.s. vs. placebo, with the same design. The study incorporated a 5 pair n-of-1 design for each of the 2 doses of DM. Patients took the study medication in addition to any pre-existing analgesic regime. Patients who reported benefit could continue with DM after the study. Nineteen patients with chronic neuropathic pain were studied over two 10-day treatment periods. Outcome measures were pain intensity, pain relief, adverse effects, mood, sleep and global rating of treatment. These were recorded by daily patient diaries and by clinic assessments before and after each treatment period. There were no significant differences between DM and placebo on any of the clinic assessment outcome measures. Two patients had significantly better analgesia on more than one outcome measure on within-patient testing. One had better analgesia with DM. The other had better analgesia with placebo. Ten patients had no adverse effects on either dose of DM. Two patients withdrew during the first treatment period because of adverse effects (which included increased pain intensity), and 5 during the second period. Five patients continued with DM after the study for 1-3 months. No long-term clinical benefit was apparent in those who continued with open DM. Dextromethorphan at either 40.5 or 81 mg daily did not relieve neuropathic pain.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Cross-Over Studies; Dextromethorphan; Double-Blind Method; Female; Humans; Male; Middle Aged; Pain; Pain Measurement

Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up.

Topics: Adult; Dextromethorphan; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Electrophysiology; Hot Temperature; Humans; Male; Middle Aged; Nerve Fibers; Nociceptors; Pain; Pain Measurement; Receptors, N-Methyl-D-Aspartate

Topics: Analgesia; Central Nervous System Sensitization; Dextromethorphan; Drug Development; Humans; Hyperalgesia; Models, Theoretical; Pain; Receptors, N-Methyl-D-Aspartate

Develop a burn injury model in young age rats.. Management of pain after burn injury in pediatric patients is an unresolved clinical issue.. A burn injury model in young rats of 3-4 weeks old was developed by briefly immersing the dorsal part of the right hindpaw in a hot water bath (85°C) for 12 seconds under pentobarbital anesthesia.. Burn injury, but not sham control, induced nociceptive behaviors (mechanical allodynia, thermal hyperalgesia) when examined on post-injury day 2, 4, and 7. In burn-injured rats, there was the upregulated expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor, Akt1, Akt2, and protein kinase C γ (PKCγ), but downregulated expression of neuronal nitric oxide synthase (NOS), inducible NOS, and glycogen synthase kinase-3β, within the spinal cord dorsal horn ipsilateral to burn injury. Moreover, intraperitoneal administration of a clinically available NMDA receptor antagonist dextromethorphan (30 mg/kg, once daily × 7 days beginning on day 7 after burn injury) attenuated mechanical allodynia and thermal hyperalgesia in burn-injured rats. Different from our previous finding in adult burn-injured rats; however, burn injury in young rats of this age did not spontaneously shift the morphine antinociceptive response curve to the right within the dose range used in the study when exposed to morphine for the first time, suggesting that the development of intrinsic tolerance to morphine antinociception may be different from adult rats following burn injury.. Our data suggest that this model may be used to explore the mechanisms of burn injury-induced nociception in young rats and to differentiate the sequelae from burn injury between adult and young rats under certain experimental conditions.

Topics: Aging; Analgesics, Opioid; Animals; Behavior, Animal; Blotting, Western; Burns; Dextromethorphan; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hindlimb; Hyperalgesia; Immunohistochemistry; Male; Morphine; Nitric Oxide Synthase Type II; Pain; Pain Measurement; Posterior Horn Cells; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

In the present study we assessed by LC/MS method the influence of amantadine and dextromethorphan on morphine metabolism in humans in order to explain clinically observed phenomenon of amplification of analgesic action of morphine by these drugs. Neither dextromethorphan nor amantadine influenced the rate of morphine degradation and concentration of morphine metabolites. Thus, our results suggest pharmacodynamical, not pharmacokinetic mechanism of interaction.

Topics: Amantadine; Analgesics, Non-Narcotic; Analgesics, Opioid; Chromatography, High Pressure Liquid; Dextromethorphan; Dose-Response Relationship, Drug; Drug Interactions; Humans; Mass Spectrometry; Morphine; Pain; Pain Threshold

Dextromethorphan, an antitussive, has a complex pharmacologic profile and has not been well studied. Our aim was to evaluate whether dextromethorphan and its metabolites, dextrorphan and 3-methoxymorphinan, have a spinal anaesthetic effect. Using a method of spinal blockade in rats, we evaluated the potencies and durations of the effects of dextromethorphan and its metabolites on spinal blockades of motor function and nociception. Bupivacaine was the active control. We found that dextromethorphan and its metabolites produced a dose-related spinal blockade of motor function and nociception. On an ED(50) basis, the ranks of potencies were bupivacaine>dextrorphan>3-methoxymorphinan>dextromethorphan (p<0.05 for the differences). On an equipotent basis, dextrorphan and bupivacaine produced similarly longer nociceptive blockades than did dextromethorphan and 3-methoxymorphinan (p<0.05 for the differences). Co-administration of dextromethorphan or its metabolites with bupivacaine produced an additive effect. In conclusion, intrathecal injections of dextromethorphan or its metabolites, dextrorphan and 3-methoxymorphinan, produced dose-related spinal blockades of motor function and nociception. The suitability of these drugs as clinical spinal anaesthetics is worth further evaluation.

Topics: Anesthesia, Spinal; Anesthetics, Local; Animals; Bupivacaine; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Motor Activity; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Time Factors

Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrome P450 (CYP) 2D6 isozyme. Methadone has been found to inhibit CYP2D6, indicating a potential for interaction with dextromethorphan.. An 83-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan.. Vulnerability to delirium was potentially caused by coadministration of methadone, which can inhibit the CYP2D6 isozyme.. Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan.

Topics: Aged; Analgesics, Opioid; Antitussive Agents; Cough; Delirium; Depressive Disorder; Dextromethorphan; Drug Interactions; Female; Humans; Methadone; Pain; Selective Serotonin Reuptake Inhibitors; Sertraline

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-d--aspartate (NMDA) receptor antagonists, such as dextromethorphan, to opioid analgesics, such as morphine may enhance the analgesic effects. The aim of the study was to assess the effect of non-competitive NMDA antagonists and paracetamol (propacetamol) on pain threshold and analgesic potency of this drugs and their combinations in formalin model for pain in rats. Intraperitoneal administration of paracetamol only in doses of 100 g/kg or higher resulted in increase of pain threshold in tail flick and paw pressure tests. The results of our study suggest that there was no significant difference in pain threshold between separate administration of dextromethorphan and in combination with paracetamol. In a formalin model for pain we have shown that paracetamol in non-analgesic doses (10 mg/kg) administered in combination with dextrometorphan, ketamine and mamantine was more effective than those drugs given separately but the best analgesic effect was obtained when combination of paracetamol and dextromethorphan was applied. The addition of higher doses of these combined drugs, that is paracetamol and all three NMDA antagonists did not result in enhancement of dose-dependant analgesia. In conclusion it should be stated that NMDA antagonists improve analgesic effect of paracetamol in the formalin model for pain. although only to a limited extend.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Behavior, Animal; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Ketamine; Male; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar

Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors can modulate morphine analgesia in experimental animals and humans. However, this literature is highly inconsistent, with NMDA receptor antagonists variously shown to potentiate, attenuate or produce no effect on morphine analgesic magnitude. A number of factors influencing this modulation have been proposed, but no one has examined such factors simultaneously, and all existing studies in mice were conducted exclusively in male subjects. Thus, the influence of systemic administration of site-specific NMDA receptor antagonists-including dextromethorphan, dextrorphan, MK-801, LY235959, L-701,324, and Ro 25-6981-on morphine analgesia (15-45 mg/kg; 15, 30 and 60 min post-injection) was studied in male and female mice using the 49 degrees C tail-withdrawal test. We found that oral and intraperitoneal dextromethorphan, a low-affinity non-competitive antagonist, dose-dependently potentiated low-dose morphine analgesia but attenuated high-dose morphine analgesia. Dextrorphan and MK-801 were found to potentiate low- but not high-dose morphine analgesia. The competitive glutamate-site antagonist, LY235959, and glycine-site antagonist, L-701,324, potentiated morphine analgesia at all doses. In contrast, the polyamine (NR2B) site antagonist, Ro 25-6981, attenuated morphine analgesia at all doses. Strikingly, the non-competitive antagonists produced no modulation of morphine analgesia whatsoever in female mice, whereas no sex differences were observed using competitive or NR2B antagonists. These findings indicate that NMDA modulation of morphine analgesia is critically influenced by sex, site of antagonism, morphine dose and time after injection. Our data suggest that NMDA antagonism via competitive or glycine site antagonism might result in more reliable clinical effects on morphine analgesia in both sexes.

Topics: Animals; Central Nervous System; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Isoquinolines; Male; Mice; Morphine; Pain; Phenols; Piperidines; Quinolones; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Time Factors

Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and alpha(3)ss(4) nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors.. We used MK-801 as a tool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats.. DM (2-20 microg) or MK-801 (5-15 microg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 microg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%-50.4%) at doses of 2 to 10 microg. Pretreatment with MK-801 (5 or 10 microg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7% vs 50.5% and 43.3%).. Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.

Topics: Analgesics, Opioid; Animals; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Morphine; Pain; Pain Measurement; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and 80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.

Topics: Animals; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Formaldehyde; Injections, Intraperitoneal; Ketamine; Male; Memantine; Mice; Nociceptors; Pain

The local, peripheral administration of antidepressants and excitatory amino acid receptor antagonists can cause analgesia in a number of conditions. The present study examined the effects of combinations of dextromethorphan and ketamine, two clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic effect. Combination of an inactive dose of dextromethorphan with amitriptyline, and vice versa, resulted in an increase of analgesia so that previously inactive doses now caused significant analgesia. Combinations of multiple doses of ketamine with amitriptyline did not modify the response to amitriptyline. Both dextromethorphan and ketamine increased the paw edema induced by formalin, and this was blocked by low doses of amitriptyline. In the absence of formalin, amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in this study exerts multiple pharmacological effects. Increased analgesia by drug combinations (amitriptyline/dextromethorphan) could show the involvement of a number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium channels, blockage of biogenic amine receptors), while a lack of intensification (amitriptyline/ketamine) could reflect occluded actions due to expression of similar actions by the other drug. Paw edema induced by dextromethorphan and ketamine involves inhibition of biogenic amine reuptake, and the ability of amitriptyline to block biogenic amine receptors likely accounts for its inhibiton of these actions. Combinations of these particular agents could represent a method for augmented analgesia and minimization of local adverse reactions.

Topics: Amitriptyline; Analgesics, Non-Narcotic; Animals; Behavior, Animal; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Edema; Excitatory Amino Acid Antagonists; Formaldehyde; Hindlimb; Histamine; Injections, Subcutaneous; Ketamine; Male; p-Methoxy-N-methylphenethylamine; Pain; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Receptor Agonists; Time Factors

The present study examined the effects of local peripheral and systemic administration of three clinically used excitatory amino acid receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors and edema produced by formalin (1.5% and 5%) in rats. Peripheral administration of dextromethorphan produced a locally mediated suppression of flinching behaviors induced by 1.5% and 5% formalin, but biting/licking behaviors were not affected. Memantine and ketamine had no effect on either of these behaviors. All three agents augmented edema produced by 1.5% and 5% formalin. When administered alone, dextromethorphan, memantine and ketamine produced an intrinsic paw swelling response, and this was blocked by the biogenic amine receptor antagonists mepyramine, phentolamine, methysergide and ketanserin. Following systemic administration, all three agents suppressed biting/licking behaviors, had no effect on flinching behaviors, and suppressed paw swelling induced by 5% formalin to varying degrees. These results provide evidence for a peripherally mediated antinociceptive action of dextromethorphan in the rat formalin test, but this may not necessarily be due to block of excitatory amino acid receptors as it is not observed with memantine or ketamine. All three agents produce a peripherally mediated paw swelling, which is likely due to blockade of biogenic amine reuptake. Systemic administration of all three agents produces antinociceptive and anti-inflammatory actions that may be due to block of excitatory amino acid receptors in the spinal cord.

Topics: Animals; Behavior, Animal; Dextromethorphan; Dose-Response Relationship, Drug; Edema; Excitatory Amino Acid Antagonists; Formaldehyde; Hindlimb; Injections, Intraperitoneal; Injections, Subcutaneous; Ketamine; Male; Memantine; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley

Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Area Under Curve; Benzamides; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Fentanyl; Ketamine; Male; Mice; Morphine; Pain; Pain Measurement; Piperazines; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sufentanil

The authors describe an unusual case of central pain (CP) that resulted from giant venous hemangiomas. The patient was treated with a variety of medications, including the N-methyl-D-aspartate antagonist dextromethorphan. We report the first known association between venous malformations and CP and briefly describe why the use of dextromethorphan in this disorder requires further evaluation.

Topics: Analgesics, Opioid; Dextromethorphan; Excitatory Amino Acid Antagonists; Female; Humans; Intracranial Arteriovenous Malformations; Ketamine; Magnetic Resonance Imaging; Middle Aged; Oxycodone; Pain; Pain Measurement; Receptors, N-Methyl-D-Aspartate

Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available compounds in combination with classical morphine, fentanyl-like opioids, the delta opioid agonist SNC80 and the kappa opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of clonidine, ketamine or dextromethorphan. Clonidine was also evaluated in combination with ketamine and dextromethorphan. ED50 values were calculated from the proportion of animals reaching a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED50 values for morphine, fentanyl and sufentanil but exerted no effect on SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive efficacy of morphine and sufentanil but not SNC80 or U50,488H. By contrast, clonidine potentiated all opioids tested. In addition, the potency of clonidine was found to increase with co-administration of ketamine but not dextromethorphan. The strongest opioid sparing interactions occurred between clonidine and the lipophilic mu opioids fentanyl and sufentanil and the delta opioid SNC80. In summary, these results suggest an important role for lipophilic opioids in combination therapies particularly with clonidine as well as possible advantages of specific delta or kappa opioid combinations with alpha-2 agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-Agonists; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Benzamides; Clonidine; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Fentanyl; Ketamine; Male; Mice; Morphine; N-Methylaspartate; Pain; Pain Measurement; Piperazines; Reaction Time; Receptors, Opioid

The antinociceptive effect of morphine and methadone was tested in two substrains of Sprague-Dawley (SD) rats, from B&K Universal, Sweden (BK) and Mollegård, Denmark (DK). In both sub-strains of SD rats subcutaneous morphine or methadone produced dose-dependent antinociception on the hot plate test. However, the effect of the opioids was less in DK-SD than BK-SD rats, particularly for morphine as it failed to produce maximal antinociception even at high doses. Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, potentiated the antinociceptive effect of morphine and methadone in the DK-SD rats. The potentiation of morphine by dextromethorphan was significantly greater than its effect on methadone at equipotent doses. The results showed that there is a sub-strain difference for SD rats in the response to the antinociceptive effect of opioids, which may be due to greater NMDA receptor activity in DK-SD than in BK-SD rats. The higher efficacy of methadone may be derived from its proposed NMDA receptor blocking property and/or high intrinsic activity.

Topics: Analgesics, Opioid; Animals; Catalepsy; Central Nervous System; Dextromethorphan; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Excitatory Amino Acid Antagonists; Male; Methadone; Morphine; Neurons; Nociceptors; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid

Endo (which acquired Algos in July 2000) has developed EN-3231, a combination of morphine and dextromethorphan, for the treatment of moderate-to-severe chronic pain. In October 1998, the FDA accepted for filing the company's NDA submission on EN-3231, which was submitted in August 1998. However, in August 1999, Algos received a 'non-approvable' letter from the FDA for EN-3231. In September 2000, the company met with the FDA to discuss what information the FDA required in order to approve EN-3231. The FDA requested a second pivotal trial, which Endo initiated promptly. Endo hoped to file its supplement to the NDA during 2002.

Topics: Analgesics, Opioid; Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Dextromethorphan; Drug Combinations; Humans; Morphine; Pain; Structure-Activity Relationship

We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA receptor antagonists dextromethorphan (2.5--30 mg/kg), memantine (2.5--15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25--10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.

Topics: Analgesics; Animals; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Hindlimb; Male; Morphine; Nociceptors; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tail; Time Factors

Preclinical and double-blind single-dose placebo-controlled studies demonstrated that MorphiDex (MS:DM), a 1:1 ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), provides significantly greater analgesia than an equal dose of immediate release MS, with a faster onset, and a duration of > or = 8 h. The analgesic effect of MS:DM compared to MS was evaluated in 2 double-blind, multiple-dose studies in 321 patients with cancer and other chronic pain: a crossover study that consisted of two 2-wk periods and a 4-wk parallel study. As specified in the study protocols, patients took sufficient MS or MS:DM to achieve satisfactory pain control. In the crossover study, the MS:DM group required half as much morphine as the MS group to achieve satisfactory pain control (80 mg and 162 mg, respectively). The interval between doses and the time from the last dose of the day to the first dose of the next day were significantly longer for MS:DM compared to MS. In the parallel study, MS:DM also provided pain control at a significantly lower dose. After four weeks of treatment, the mean daily dose of MS increased, while there was little change in the MS:DM mean daily dose (P = 0.025) to maintain satisfactory pain control. More patients preferred MS:DM to run-in MS than preferred MS to run-in MS (P = 0.026). The addition of DM to MS did not increase the incidence of adverse events, which were those commonly associated with opioid use. These studies confirm that MS:DM provides satisfactory pain relief but at a significantly lower morphine daily dose.

Topics: Analgesics; Analgesics, Opioid; Chronic Disease; Dextromethorphan; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Excitatory Amino Acid Antagonists; Humans; Morphine; Pain; Randomized Controlled Trials as Topic

The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan on morphine-induced antinociception was studied with the hot plate test in Sprague-Dawley (SD), Wistar-Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA) rats. Subcutaneous morphine at 5 mg/kg induced significant antinociception in all four rats strains. Subcutaneous dextromethorphan at 15 and 45 mg/kg, but not 5 mg/kg, significantly and dose-dependently potentiated morphine-induced antinociception in SDs, WKs and SHRs, but not in DAs. In SHRs and DAs the antinociceptive effect of morphine was followed by prolonged hyperalgesia, which was reduced (SHRs) or abolished (DAs) by dextromethorphan. These results suggest that there are significant differences among rat strains in their response to morphine and in the ability of dextromethorphan to potentiate morphine-induced antinociception. These differences are possibly of genetic origin. Moreover, these data show that morphine, at least in some strains of rats, induced a delayed and NMDA receptor-dependent hyperalgesic response, supporting the notion that administration of opiates may activate NMDA receptors, leading to reduced antinociceptive effect and the development of hyperalgesia.

Topics: Animals; Dextromethorphan; Drug Synergism; Hot Temperature; Hyperalgesia; Male; Morphine; Nociceptors; Pain; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Rats, Sprague-Dawley; Species Specificity

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

Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect +/- S.E.), at the maximum dose not yielding motor impairment, was memantine (96 +/- 5%) = AP5 (91 +/- 7%) > dextrorphan (64 +/- 11%) = dextromethorphan (65 +/- 22%) > MK801 (34 +/- 8%) > ketamine (18 +/- 6%). For the formalin test, the order of efficacy was AP5 (86 +/- 9%) > memantine (74 +/- 5%) > or = MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%) > dextromethorphan (31 +/- 12%) > ketamine (17 +/- 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.

Topics: 2-Amino-5-phosphonovalerate; Analgesics; Animals; Dextromethorphan; Dextrorphan; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Formaldehyde; Hyperalgesia; Injections, Spinal; Ketamine; Male; Memantine; Morphine; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Nerves; Touch

In this study, we investigated whether selective activation of nociceptive primary afferent fibers by capsaicin would induce modulations on tooth-pulp-evoked sensory or inhibitory masseter reflex responses in healthy human subjects. The contribution of central N-methyl-D-aspartate (NMDA) receptor mechanisms in capsaicin-induced effects on sensory or reflex responses was evaluated by dextromethorphan, an NMDA-receptor antagonist. The inhibitory masseter reflex was evoked by electrical stimulation (constant current, single pulses) of the upper incisor while the subject was biting at 10% of his maximal force. The sensation of the tooth pulp stimulation was evaluated by visual analogue scale (VAS). The magnitude, duration, and the the latency of the reflex were determined by bite force measurements. The inhibitor masseter reflex could be induced by non-painful tooth pulp stimulation, and the inhibition was enhanced as a function of increasing stimulus intensity. Capsaicin (1%) applied topically to the skin of the cheek produced a spontaneous burning pain sensation. During capsaicin treatment, the VAS ratings for the sensation induced by tooth pulp stimulation were significantly reduced, whereas no significant changes were found in the tooth-pulp-induced masseter reflex responses. Double-blind treatment with dextromethorphan at a dose of 100 mg (= the highest does without side-effects) had no effect on sensory or reflex responses. These data indicate that noxious stimulation of the facial skin by capsaicin induces differential effects on tooth-pulp-evoked sensory and inhibitory masseter reflex responses: Sensory responses are strongly attenuated, while masseter reflex responses are not significantly changed. Dextromethorphan at a clinically applicable dose does not influence tooth-pulp-evoked sensory or reflex responses or their modulation by capsaicin. Furthermore, the lack of modulation of the masseter reflex response by capsaicin differs from the capsaicin-induced enhancement of a nocifensive limb flexion reflex described earlier.

Topics: Administration, Cutaneous; Adult; Bite Force; Capsaicin; Cheek; Dental Pulp; Dextromethorphan; Differential Threshold; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Evoked Potentials; Humans; Irritants; Male; Masseter Muscle; Middle Aged; Muscle Contraction; Neurons, Afferent; Nociceptors; Pain; Pain Measurement; Reaction Time; Receptors, N-Methyl-D-Aspartate; Reflex; Sensation; Skin

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.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Behavior, Animal; Dextromethorphan; Diclofenac; Drug Interactions; Drug Therapy, Combination; Etodolac; Ibuprofen; Injections, Intraperitoneal; Male; Naproxen; Pain; Piroxicam; Rats; Rats, Sprague-Dawley

The injection of dilute formalin results in a stereotyped nociceptive behavioral response. Administration of dextromethorphan (s.c.) but not saline, 30 min prior to intraplantar formalin injection prevents this nociceptive response in a dose-dependent manner. In addition, intraplantar formalin reliably induces c-fos mRNA in the ipsilateral spinal dorsal horn as assessed with quantitative solution hybridization at 30 min postinjection. No change in c-fos mRNA was detected in the contralateral spinal dorsal horn, nucleus raphe magnus, periaqueductal grey, medial thalamus, or sensorimotor cortex. Pretreatment with dextromethorphan at 60 mg/kg s.c., 30 min prior to formalin resulted in a suppression of c-fos induction, so that c-fos mRNA levels in the ipsilateral spinal dorsal horn of animals receiving dextromethorphan prior to formalin did not differ from controls. These data indicate that dextromethorphan suppresses formalin nociceptive behavior and one of the biochemical consequences of formalin nociception, i.e., induction of c-fos mRNA.

Topics: Animals; Behavior, Animal; Depression, Chemical; Dextromethorphan; Formaldehyde; Male; Mice; Mice, Inbred BALB C; Pain; Proto-Oncogene Proteins c-fos; RNA, Messenger; Spinal Cord

The oral antitussive dextromethorphan is a clinically available N-methyl-D-aspartate receptor antagonist. Dextromethorphan has analgesic efficacy in the experimental formalin test, blocks the nociceptive activation of the immediate-early gene, c-fos proto-oncogene, and prevents and reverses the development of opiate analgesic tolerance in experimental models. These data suggest that dextromethorphan should be evaluated in a controlled clinical trial for analgesic efficacy in zoster-associated neuralgia.

Topics: Dextromethorphan; Drug Tolerance; Humans; Narcotics; Nociceptors; Pain; Proto-Oncogene Mas

Topics: Adult; Anorexia; Bone Neoplasms; Carcinoma, Renal Cell; Codeine; Cough; Dextromethorphan; Humans; Kidney Neoplasms; Male; Pain; Sweating