Response of chronic neuropathic pain syndromes to ketamine: a preliminary study

Bačkonja, Miroslav; Arndt, George A.; Gombar, Kathy A.; Check, Bill; Zimmermann, Marco

doi:10.1016/0304-3959(94)90149-x

Cited by 284 publications

(115 citation statements)

References 14 publications

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“…It has been clearly shown in animal studies that various NMDA antagonists [4,12], including memantine [42], if administered in a manner that blocks NMDA receptors, can relieve neuropathic pain. In a clinical trial [59] in which memantine was administered to neuropathic pain patients for 9 weeks at doses titrated to the individual patient's level of tolerance, the maximum tolerated dose was 55 mg/day.…”

Section: Discussionmentioning

confidence: 99%

“…To test for irreversible neuronal degeneration, rats were sacrificed 24 or 48 h following treatment with saline, memantine alone (20, 30 or 50 mg/kg), donepezil alone (2.5, 5 or 10 mg/kg), or memantine (20 or 30 mg/kg) + donepezil (2.5, 5 or 10 mg/kg). Memantine was tested in a dose range from 10 to 50 mg/kg because the dose of memantine reportedly required to exert an antiexcitotoxic neuroprotective effect is 20 mg/kg [4,35,58]. Donepezil was tested at doses from 2.5 to 10 mg/kg because this dose range is reportedly well tolerated and reversibly inhibits cholinesterase activity in the adult rat brain by about 20% to 70% [31].…”

Section: Dosing Regimensmentioning

confidence: 99%

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Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg ip), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5 to 10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

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Section: Discussionmentioning

confidence: 99%

Section: Dosing Regimensmentioning

confidence: 99%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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“…This interpretation is consistent with data from human clinical trials of memantine as a drug for relieving neuropathic pain. It has been shown repeatedly in animal studies that various NMDA antagonists (Davar et al, 1991;Backonja et al, 1994), including memantine (Neugebauer et al, 1993;Eisenberg et al, 1995), if administered at a dose that blocks NMDA receptors, can relieve neuropathic pain. In a clinical trial in which memantine was administered to neuropathic pain patients for 9 weeks at doses titrated to the individual patient's level of tolerance, the maximum tolerated dose was 55 mg/d (Sang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Low Doses of Memantine Disrupt Memory in Adult Rats

Creeley¹,

Wozniak²,

Labruyere³

et al. 2006

J. Neurosci.

121

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Memantine, a drug recently approved for treatment of Alzheimer's disease, has been characterized as a unique NMDA antagonist that confers protection against excitotoxic neurodegeneration without the serious side effects that other NMDA antagonists are known to cause. In the present study, we determined what dose of memantine is required to protect the adult rat brain against an NMDA receptormediated excitotoxic process and then tested that dose and a range of lower doses to determine whether the drug in this dose range is associated with significant side effects. Consistent with previous research, we found that memantine confers a neuroprotective effect beginning at an intraperitoneal dose of 20 mg/kg, a dose that we found, contrary to previous reports, produces locomotor disturbances severe enough to preclude testing for learning and memory effects. We then determined that, at intraperitoneal doses of 10 and 5 mg/kg, memantine disrupts both memory and locomotor behaviors. Rats treated with these doses performed at control-like levels in learning a hole-board task but were significantly impaired in demonstrating what they had learned when tested 24 h later. This impairment of memory retention was not state dependent in that it was demonstrable regardless of whether the rats were or were not exposed to memantine on the day of retention testing. We conclude that, in the adult rat, memantine behaves like other NMDA antagonists in that it is neuroprotective only at doses that produce intolerable side effects, including memory impairment.

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“…NMDA receptor antagonists block pain transmission in dorsal horn spinal neurons (Dickenson & Sullivan, 1987;Seltzer et al, 1991) and reduce pain-related behaviour in neuropathic animal models (Davar et al, 1991;Mao et al, 1993). Despite their e cacy in clinical trials (Backonja et al, 1994;Eide et al, 1994;Pud et al, 1998) human use of NMDA receptor antagonists has been limited by potentially serious neurotoxic side e ects.…”

Section: Introductionmentioning

confidence: 99%

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

Christensen

Idänpään-Heikkilä

Guilbaud

et al. 1998

British J Pharmacology

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1 We evaluated the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966), to modulate the antinociceptive action of systemic morphine in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) and thermal (struggle latency to hindpaw immersion into a water bath) stimuli were used. 2 In the mechanical test, morphine (0.05, 0.1 and 0.3 mg kg 71 , i.v.) alone produced dose-dependent e ects in both neuropathic and uninjured rats. Likewise, morphine (0.1, 0.3 and 1 mg kg 71 , i.v.) dosedependently increased struggle latencies of the nerve-injured hindpaw in the hot noxious (468C) test but was ine ective in the non-noxious warm (448C) and cold (108C) test. 3 Pretreatment with (+)-HA966 (2.5 mg kg 71 , s.c.) dose-dependently enhanced the e ect of morphine in the mechanical test with the relative potency being nerve-injured hindpaw4contralateral hindpaw4uninjured rat. 4 Likewise, (+)-HA966 dose-dependently enhanced the e ect of morphine against a hot (468C) stimulus and produced, in combination with morphine, a dose-dependent e ect against a warm (448C) stimulus. In the cold (108C) test, (+)-HA966 reversed the ine ectiveness of the highest dose of morphine. 5 Naloxone blocked the e ect of the combination of (+)-HA966 with morphine in all tests. The drug combination produced no motor de®cits in animals using the rotarod test. 6 These ®ndings suggest that combined administration of antagonists, acting at the glycine site of the NMDA receptor complex and morphine may be a promising approach in the treatment of neuropathic and acute pain.

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Response of chronic neuropathic pain syndromes to ketamine: a preliminary study

Cited by 284 publications

References 14 publications

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Low Doses of Memantine Disrupt Memory in Adult Rats

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

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