dextromethorphan and Diabetic-Neuropathies

AVANIR Pharmaceuticals Inc, under license from Irisys Research & Development, is developing AVP-923 (Zenvia, Neurodex) for the treatment of pseudobulbar affect (PBA; in collaboration with Medison Pharma Ltd) and neuropathic pain associated with diabetic peripheral neuropathy. PBA, the main indication of AVP-923, is a neurological disorder characterized by uncontrollable and unpredictable episodes of laughing and/or crying. AVP-923 consists of a combination of the NMDA antagonist/sigma1 receptor agonist dextromethorphan hydrobromide (DM) and the cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine sulfate (Q). DM has been under investigation for several years as a neuroprotective agent in stroke, neurosurgery and amyotrophic lateral sclerosis (ALS); however, it is rapidly metabolized by CYP2D6, reducing the drug's bioavailability at neuronal targets. The inclusion of Q inhibits the rapid first-pass metabolism of DM to increase systemic concentrations of the drug in the plasma and, in theory, increase the potential efficacy. The initial clinical data for AVP-923 in the treatment of PBA demonstrated the combination was effective, but exhibited significant side effects. Of particular concern to the FDA were increased QTc intervals reported in patients dosed with a 30-/30-mg dose of DM/Q. A subsequent phase III clinical trial assessing a lower dose of AVP-923 (20 or 30 mg DM/10 mg Q) for the treatment of PBA in patients with ALS or multiple sclerosis was implemented by AVANIR and demonstrated a favorable safety profile of AVP-923 while maintaining efficacy. Pending approval of the data from the FDA, AVP-923 would be the first FDA-approved treatment for PBA.

Topics: Animals; Clinical Trials as Topic; Dextromethorphan; Diabetic Neuropathies; Drug Combinations; Humans; Mood Disorders; Quinidine

Topics: Amines; Anti-Asthmatic Agents; Anticonvulsants; Antidepressive Agents; Antitussive Agents; Cyclohexanecarboxylic Acids; Dextromethorphan; Diabetic Neuropathies; Fructose; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Humans; Lamotrigine; Mexiletine; Nerve Fibers; Posterior Horn Cells; Pregabalin; Selective Serotonin Reuptake Inhibitors; Sodium Channels; Topiramate; Triazines

To review the use of dextromethorphan for the treatment of painful diabetic neuropathy.. MEDLINE and EMBASE searches for studies using dextromethorphan to manage diabetic neuropathy were conducted from 1966 to 1999 and 1980 to 1999, respectively.. Peripheral neuropathy is a common manifestation of diabetic patients. Many classes of medications have been investigated to treat this condition, including N-methyl-D-aspartate inhibitors. A review of studies using dextromethorphan to manage diabetic neuropathy was performed.. There are insufficient safety and efficacy data to justify the use of dextromethorphan for treating painful diabetic neuropathy. Further clinical trials are needed.

Topics: Dextromethorphan; Diabetic Neuropathies; Excitatory Amino Acid Antagonists; Humans; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate

To evaluate dextromethorphan coadministered with quinidine as treatment of diabetic peripheral neuropathic pain.. In a 13-week, phase 3, randomized controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain for ≥3 months received double-blind placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. Efficacy measures included four pain rating scales applied daily using patient diaries, and another two applied at five clinic visits.. On all six scales, DMQ 45/30 mg was significantly superior to placebo, including the primary efficacy analysis, which utilized mixed-effects modeling to test all scores on an 11-point numerical Pain Rating Scale (P < 0.0001). Sensitivity analyses gave consistent results. Efficacy vs placebo was also seen for diary ratings of present pain intensity, and pain interference with sleep and with activities (all P < 0.0001). Among clinic visit assessments, DMQ 45/30 mg demonstrated greater leg pain relief (P = 0.0002) and greater reduction of leg pain intensity (P = 0.0286) vs placebo. The efficacy of DMQ 30/30 mg was numerically less than for 45/30 mg but for most outcomes remained significantly greater vs placebo. Adverse events were mostly mild or moderate and of expected types. Discontinuation for adverse events in the DMQ groups was at least twice as common as placebo.. Throughout a 13-week trial, DMQ was effective, with an acceptable safety profile, for treatment of DPN pain. Other fixed-dose combinations of DMQ should be studied to improve overall tolerability while maintaining significant efficacy.

Topics: Adult; Aged; Aged, 80 and over; Dextromethorphan; Diabetic Neuropathies; Double-Blind Method; Drug Combinations; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Placebos; Quinidine

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

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

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