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Ketamine and MDARs in the treatment of neuropathic pain

Pain and NMDA and ketamine

Chronic pain hypersensitivity and neuropathic pain depends partly on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino targeted for the NMDA receptor were low affinity channel blockers of the NMDA multimeric receptor complex, including the anesthetic agent ketamine and the Alzheimer's drug memantine. These drugs have been developed in many indications during a great many years, without clear succes in stroke and head trauma. Ketamine, however, is a highly succesful anesthetic drug. Its use in neuropathic pain is emerging.

Direct NMDA receptor antagonists such as selfotel (Novartis AG) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being developed for the treatment of neuropathic pain in the antagonist dose range. [1] 

Ketamine as a neuropathic pain reliever

Pain increases by stress, and recently was foudn that stress also exacerbates neuropathic pain via (Glucocorticoid and) NMDA Receptor Activation. [2] Non-oral administered low-dose ketamine is being used increasingly to treat neuropathic painsyndromes. A lozenge containing 25 mg of ketamine was evaluated in six patients with chronic neuropathic pain. Oral and sublingual bioavailability was 25%.

Incidently cases have been described of  opioid-refractory pain that responded to a low-dose IV infusion of ketamine in the inpatient setting. The patient was then successfully transitioned to oral memantine for long-term outpatient management, in a novel use of this oral NMDA receptor antagonist. [3]

Ketamine transdermal in neuropathic pain

An oral gel of ketamine has been developed for the treatment of neuropathic pain. [4] The metabolite of ketamine, norketamine, which is also an NMDA receptor antagonist, is identified as an potential important contributar to ketamine’s cinical efficacy. 

Currently our centre developes a cream with ketamine and amitriptyline.

Ketamine Intra nasal application

The following is quite interesting:

Ketamine, a non-opiate, is an N-methyl-D-aspartate (“NMDA”), receptor antagonist that has been in clinical use for over 30 years as a general anesthetic.

Since its approval by the FDA, ketamine has been safely used as an anesthetic in tens of thousands of patients. NMDA receptors are located in the central nervous system and play a role in the perception of acute and chronic pain. Ketamine blocks NMDA receptors and therefore is a logical drug candidate for use as an analgesic for syndromes associated with acute pain, as well as breakthrough pain.

Ketamine, at lower doses than that approved for use as an anesthetic, has been reported in the medical literature to be an effective medication for the treatment of postoperative pain, neuropathic pain and pain during emergency medical procedures.

Javelin has a developed Ereska, a proprietary nasal formulation of ketamine which is currently under development for treatment of acute moderate-to-severe pain. The Company believes that Ereska is optimized for use as a pain medication and may offer a safe, non-opioid alternative for the treatment of moderate-to-severe pain.

Previous randomized, double-blinded, placebo-controlled phase II clinical studies have demonstrated statistically significant (p<0.05) relief of moderate to severe post-operative and breakthrough pain. Ereska was fast-acting, with statistically significant (p<0.05) pain relief occurring as early as 4 minutes post administration of Ereska. Ereska also appeared to be safe and well-tolerated by patients.

These results were presented at the American Society for Clinical Pharmacology and Therapeutics in Atlanta, Georgia in April 2002 and the American Society of Clinical Oncology in Orlando, Florida in May 2002.

In May 2003, following the presentation of clinical data at the plenary session of the Advanced Technology Application for Combat Casualty Care conference in Orlando, Florida, the U.S. Department of Defense awarded a $4 million funding extension to Javelin to aid in the development of Ereska. This award is based on the need of the military for a fast-acting, non-invasive, and non-sedating alternative to the intravenous and oral medications commonly used for treatment of combat-related injuries.

In June 2004, the company attended the End-of-Phase II meeting with representatives of the U.S. Food and Drug Administration (FDA).

In August 2005, Javelin presented a meta-analysis of three randomized, placebo-controlled studies involving ketamine analgesia for patients with acute moderate-to-severe pain.

The results of the meta-analysis demonstrated that intranasal ketamine was effective at relieving moderate-to-severe pain over the 10 to 50 mg dose range with no statistically significant changes to vital signs or arterial oxygen saturation levels.

Other NMDA receptor ligands for neuropathic pain

Perzinfotel is a potent, selective, competitive NMDA receptor antagonist, and this drug showed ito be efficacious in inflammatory and neuropathic pain models. [5] This drug is developed in the laboratories of Whyeth. [6] Wyeth develops more of these ligands at the moment, like N-methyl-d-aspartate (NMDA) antagonists with different chemical structures, such as EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) for neuroptrotection and neuropathic pain. [7]

Gabapentin, a new analgasic drug and an older ‘brother’of Pregabeline (Lyrica) has been shown to exert a neuro-protective effects against glutamate-induced neuronal injury at least in part by inhibiting the NMDA receptor-activated ion current. [8]

Mixed NMDA receptor ligands and MOA-inhibitors

Treating neuropathic pain probably needs polypharmacy. Mixed drugs targeting multiple receptors are therefore interesting new inroads in the treatment if this chronic painstate. Indantadol is a new kid on the block based on these two pharmacological mechanisms (NMDA and MOA-I). [9] Antidepressants are widely used to treat neuropathic pain. Influencing the NA and serotonin system cearly reduces pain. This would be the mechanism of the reversible MAO-A inhibition.

Moclobemide has been described in literature as an anagesic drug.[10][11][12] But data supporting the analgesic properties of moclobemide are thin. In the only one clinical trail done the study was aborted due to modest efficacy. The conclusion was: Moclobemide appears to have limited efficacy in the treatment of neuropathic pain.[12] Furthermore, one older pharmacological paper also was sceptical about MOA-I effects in a pain model.[14]

Indantadol is an oral and nonselective monoamine oxidase inhibitor and NMDA antagonist that is being developed by Vernalis plc, for the potential treatment of neuropathic pain. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia to 67%.[15]

The tolerability profile of indantadol at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was acceptable. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol is currently in phase II clinical trials in patients with diabetic peripheral neuropathic pain. 400 mg twice daily did increase hart rate and bloodpressure, probably a MOA-I effect, as well as a decrease in alertness. In this dose-range MOA inhibition has been demonstrated. [16][17]

Given the results available to date, indantadol may have a role in the treatment of neuropathic pain if the favorable pharmacokinetic profile and efficacy of the drug are maintained in more extensive clinical trials. 

From the Centre for the study and treatment of neuropathic pain and neuropathy in Soest, the Nertherlands

This site helps patients and treating physicians, neurologists, anesthesiologists and other pain specialists to find the best and most up to date research findings related to neuropathy and neuropathic pain and the treatment thereof.

In our centre we are specialised in treating patients suffering from neuropathic pain and neuropathy following an Integrated Medicine concept. Part of our activities are within the field of consultation. We assist pharmaceutical companies in R&D strategies related to finding new drugs to treat neuropathic pain and neuropathy.

February 2010, Jan M. Keppel Hesselink, MD, PhD.


[1] Wood PL. | The NMDA receptor complex: a long and winding road to therapeutics. | IDrugs. | 2005 Mar;8(3):229-35.

[2] Alexander JK, DeVries AC, Kigerl KA, Dahlman JM, Popovich PG. | Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation. | Brain Behav Immun. | 2009 Aug;23(6):851-60. Epub 2009 Apr 8.

[3] Grande LA, O'Donnell BR, Fitzgibbon DR, Terman GW. | Ultra-low dose ketamine and memantine treatment for pain in an opioid-tolerant oncology patient. | Anesth Analg. | 2008 Oct;107(4):1380-3.

[4] Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. | Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: Preliminary findings from a three-way randomized, crossover study. | Clin Drug Investig. | 2009;29(5):317-24. doi: 10.2165/00044011-200929050-00004.

[5] Baudy RB, Butera JA, Abou-Gharbia MA, Chen H, Harrison B, Jain U, Magolda R, Sze JY, Brandt MR, Cummons TA, Kowal D, Pangalos MN, Zupan B, Hoffmann M, May M, Mugford C, Kennedy J, Childers WE Jr. | Prodrugs of perzinfotel with improved oral bioavailability. | J Med Chem. | 2009 Feb 12;52(3):771-8.

[6] Brandt MR, Cummons TA, Potestio L, Sukoff SJ, Rosenzweig-Lipson S. | Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. | J Pharmacol Exp Ther. | 2005 Jun;313(3):1379-86. Epub 2005 Mar 11.

[7] Sun L, Chiu D, Kowal D, Simon R, Smeyne M, Zukin RS, Olney J, Baudy R, Lin S. | Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride). | J Pharmacol Exp Ther. | 2004 Aug;310(2):563-70. Epub 2004 Apr 9.

[8] Kim YS, Chang HK, Lee JW, Sung YH, Kim SE, Shin MS, Yi JW, Park JH, Kim H, Kim CJ. | Protective effect of gabapentin on N-methyl-D-aspartate-induced excitotoxicity in rat hippocampal CA1 neurons. | J Pharmacol Sci. | 2009 Jan;109(1):144-7.

[9] Csajka C, Imbimbo BP, Piccinno A, Dostert P, Verotta D. | Mechanistic pharmacokinetic and pharmacodynamic modeling of CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride), a novel N-methyl-D-aspartate antagonist and monoamine oxidase-A inhibitor in healthy subjects. | J Pharmacol Exp Ther. | 2005 May;313(2):647-57. Epub 2005 Jan 25.

[10] Schreiber S, Getslev V, Weizman A, Pick CG. | The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways. | Neurosci Lett. | 1998 Sep 11;253(3):183-6.

[11] Apaydin S, Goldeli E, Uyar M, Erhan E, Yegul I, Tuglular I. | The antinociceptive effect of moclobemide on the vocalization threshold to paw pressure in a rat model of unilateral mononeuropathy. | Pharmacol Res. | 2001 Dec;44(6):503-7.

[12] Menkes DB, Fawcett JP, Busch AF, Jones D. | Moclobemide in chronic neuropathic pain: preliminary case reports. | Clin J Pain. | 1995 Jun;11(2):134-8.

[13] Menkes DB, Fawcett JP, Busch AF, Jones D. | Moclobemide in chronic neuropathic pain: preliminary case reports. | Clin J Pain. | 1995 Jun;11(2):134-8.

[14] Bianchi M, Mantegazza P, Panerai AE. | Effects of two different reversible monoamine oxidase-A inhibitors on nociceptive thresholds in the rat. | Eur J Pharmacol. | 1992 Aug 14;219(1):113-6.

[15] Mathiesen O, Imbimbo BP, Hilsted KL, Fabbri L, Dahl JB. | CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model. | J Pain. | 2006 Aug;7(8):565-74.

[16] Mattia C, Coluzzi F. | Indantadol, a novel NMDA antagonist and nonselective MAO inhibitor for the potential treatment of neuropathic pain. | IDrugs. | 2007 Sep;10(9):636-44.

[17] [No authors listed] | CHF 3381. | Drugs R D. | 2004;5(1):28-30.