neramexane and Pain

Topics: Alcoholism; Animals; Cyclopentanes; Humans; Neuroprotective Agents; Pain; Receptors, N-Methyl-D-Aspartate

NMDA-receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti-hyperalgesic (prevention of central sensitization) properties of the NMDA-receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40 mg p.o.), flupirtine (100 mg) or placebo in a double-blind, randomized, cross-over study. Pain evoked by intradermal capsaicin injection as well as pain evoked by pinpricks was significantly reduced by neramexane (-22% to -30% vs. placebo) in the non-sensitized skin indicating a marked analgesic effect. Moreover, dynamic mechanical allodynia (pain to light touch) was also significantly attenuated by neramexane (-28% vs. placebo). However, static secondary hyperalgesia to pinprick stimuli after capsaicin injection was not significantly reduced (-9% vs. placebo). Flupirtine showed no analgesic or anti-hyperalgesic effect. Mechanically-evoked wind up of pain sensation was not affected by any treatment. The results suggests that in a human surrogate model of neurogenic hyperalgesia a single low-dose of neramexane had a marked analgesic effect in the sensitized and in the non-sensitized state and thus may be a useful drug to treat the enhanced pain sensitivity in neuropathic pain patients. Its efficacy may be based on analgesia rather than anti-hyperalgesia or anti-windup. In contrast, flupirtine showed neither an analgesic nor an anti-hyperalgesic effect at a dose used for the treatment of postoperative pain.

Topics: Aminopyridines; Analgesics; Capsaicin; Cross-Over Studies; Cyclopentanes; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hyperalgesia; Injections, Intradermal; Nervous System Diseases; Pain; Physical Stimulation; Receptors, N-Methyl-D-Aspartate; Treatment Outcome

Diabetic neuropathic pain remains an unmet clinical problem and is poorly relieved by conventional analgesics. N-methyl-D-aspartate (NMDA) receptors play an important role in central sensitization in neuropathic pain. Although NMDA antagonists are highly effective in reducing neuropathic pain, these agents cause severe side effects at therapeutic doses, which limit their clinical uses. Neramexane and memantine are uncompetitive NMDA antagonists with minimal side effects at therapeutic doses. Here we determined the antinociceptive effect of chronic administration of neramexane and compared its effect with that of memantine and gabapentin in a rat model of diabetic neuropathic pain. Mechanical hyperalgesia was measured with a noxious pressure stimulus, and tactile allodynia was assessed with von Frey filaments in diabetic rats induced by streptozotocin. Compared with vehicle-treated rats, treatment with neramexane (12.3, 24.6, and 49.2 mg/kg/day) for 2 weeks via an osmotic minipump produced dose-dependent and sustained effects on mechanical hyperalgesia and allodynia. Administration of memantine (20 mg/kg/day) or gabapentin (50 mg/kg/day) for 2 weeks also produced significant and persistent antinociceptive effects on mechanical hyperalgesia and allodynia. The magnitude of the antinociceptive effect produced by the intermediate and high doses of neramexane was comparable to that of gabapentin and memantine. The plasma level achieved by neramexane at 12.3, 24.6, and 49.2 mg/kg/day was 0.26 +/- 0.04, 0.50 +/- 0.05, and 1.21 +/- 0.16 microM, respectively. These data suggest that neramexane at therapeutically relevant doses attenuates diabetic neuropathic pain. Our study provides valuable information about the therapeutic potential of chronic administration of neramexane and memantine for painful diabetic neuropathy.

Topics: Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Cyclopentanes; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Male; Memantine; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Streptozocin; Time Factors

The purpose of the present study was to investigate whether uncompetitive NMDA antagonists with fast channel blocking kinetics, which show fewer side effects in man than compounds such as ketamine, affect the development of tolerance to continuous exposure to morphine. Rats were trained on the Randall--Selitto apparatus before being implanted, under halothane anaesthesia, with primed mini-osmotic pumps (240 microl/day). Six rats were implanted with a vehicle filled pump, seven with a morphine filled pump (28.8 mg/kg/day), and eight with a pair of pumps, one containing morphine and the other Mrz 2/579, a new NMDA antagonist (40 mg/kg/day). A fourth group was implanted with a morphine filled pump followed 25 h later by a Mrz 2/579 filled pump. Paw withdrawal tests were undertaken immediately before, and at 2, 4, 6, 8, 10, 12, 24, 48 and 72 h after the first pump was implanted. Before pump implantation, withdrawal thresholds were 120+/-7 g (mean+/-SEM, n=30). Vehicle infusion had no effect on withdrawal thresholds, whereas morphine infusion increased them significantly at 2 and 4 h after pump implantation (+2 h: 208+/-14 g; P<0.001 vs. control). From 6 h the antinociception elicited by morphine declined progressively; at 10 h withdrawal thresholds were significantly lower than the 2 h post-treatment value (P<0.001). In rats treated with morphine plus Mrz 2/579, thresholds remained significantly higher between 10--72 h post-implantation than with morphine alone (P<0.05). In contrast, infusion of the same level of Mrz 2/579 once tolerance had developed did not reverse tolerance. These results indicate that fast NMDA channel blockers such as Mrz 2/579 may prove to be useful in enhancing analgesia to continuous morphine administration.

Topics: Analgesics, Opioid; Animals; Cyclopentanes; Drug Tolerance; Male; Morphine; Neuroprotective Agents; Pain; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Sodium Chloride; Substance Withdrawal Syndrome; Wakefulness