Current Opinion in Investigational Drugs

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32 Current Opinion in Investigational Drugs 2006 Vol 7 No 1 70. Acadia Pharmaceuticals Inc: ACADIA Pharmaceuticals announces encouraging interim results from ongoing phase II trial of ACP-103 for treatment-induced psychosis in patients with Parkinson's disease. Press Release (2005): June 22. http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irolnews 71. Acadia Pharmaceuticals Inc: ACADIA Pharmaceuticals announces encouraging interim results from phase II study of ACP-103 in schizophrenia patients with haloperidol-induced akathisia. Press Release (2004):January 12. http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irolnews 72. Eisai Co Ltd: Eisai annual report 2004 describing clinical trial status of E2007. Annual Report (2004). http://www.eisai.co.jp/pdf/eannual/epdf2004an.pdf 73. Oh JD, Bibbiani F, Chase TN: Quetiapine attenuates levodopainduced motor complications in rodent and primate parkinsonian models. Exp Neurol (2002) 177(2):557-564. 74. Katzenschlager R, Manson AJ, Evans A, Watt H, Lees AJ: Low dose quetiapine for drug induced dyskinesias in Parkinson's disease: A double blind cross over study. J Neurol Neurosurg Psychiatry (2004) 75(2):295-297. 75. Panacea Pharmaceuticals Inc: Panacea describe pre-clinical status of PAN-408 and PAN-527. Company Web Site (2005). http://www.panaceapharma.com/technology/parkinson.aspx 76. Dass B, Iravani MM, Huang C, Barsoum J, Engber TM, Galdes A, Jenner P: Sonic hedgehog delivered by an adeno-associated virus protects dopaminergic neurones against 6-OHDA toxicity in the rat. J Neural Transm (2005) 112(6):763-778. 77. IVAX Inc: IVAX laboratories pipeline. A pipeline that spans a wide spectrum. Company Web Site (2005). http://www.ivaxlaboratories.com/jsps/pipeline.jsp 78. Iwashita A, Yamazaki S, Mihara K, Hattori K, Yamamoto H, Ishida J, Matsuoka N, Mutoh S: Neuroprotective effects of a novel poly(ADPribose) polymerase-1 inhibitor, 2-[3-[4-(4-chlorophenyl)-1-piperazinyl] propyl]-4( 3 H)-quinazolinone (FR255595), in an in vitro model of cell death and in mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Pharmacol Exp Ther (2004) 309(3):1067-1078. 79. Ceregene Inc: Ceregene reports initiation of phase 1 clinical trial of novel gene therapy for patients with Parkinson's disease. PRESS RELEASE (2005):September 21. 80. Migenix Inc: Migenix receives approval to initiate MX-4509 phase I/II study. Press Release (2005): April 28. http://www.migenix.com/newsreleases/042805.pdf 81. Kato H, Araki T, Imai Y, Takahashi A, Itoyama Y: Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease. J Neurol Sci (2003) 208(1-2):9-15. 82. Ono Pharmaceutical Co Ltd: Development status of ONO-2506 for injection/PROGLIA. Press Release (2005):May 26. 83. Phytopharm plc: Commences phase II proof of principle study in Alzheimer's disease. Press Release (2003):December 09. 84. NINDS: NINDS Parkinson's disease neuroprotection trial of CoQ10 and GPI 1485. Press Release (2005):August 01. http://www.clinicaltrials.gov/ct/gui/show/NCT00076492?order=1 85. sanofi-aventis Inc: Molecules of tomorrow: sanofi-aventis describe the clinical trial status of SR 57667. Press Release (2005):November 15. http://en.sanofi-aventis.com/rd/molecules/p_rd_molecules.asp 86. NINDS: A multi-center, double-blind, pilot study of minocycline and creatine in subjects with early untreated Parkinson's disease. NINDS Parkinson's disease neuroprotection trial (2003):May. http://www.clinicaltrials.gov/ct/show/NCT00063193?order=1 87. Novartis AG: Novartis shows dynamic momentum in industryleading pipeline. Press Release (2005):January 20.
The mechanism of action of gabapentin in neuropathic pain J Kenneth Baillie* & Ian Power Address Department of Anaesthesia, Critical Care and Pain Medicine University of Edinburgh Royal Infirmary of Edinburgh 51 Little France Street Edinburgh EH16 4SA UK Email: j.k.baillie@doctors.org.uk *To whom correspondence should be addressed Current Opinion in Investigational Drugs 2006 7(1):33-39 © The Thomson Corporation ISSN 1472-4472 Neuropathic pain is a common and potentially treatable cause of considerable lifelong morbidity. Effective pharmacological treatments are scarce, but one group of drugs that has shown promise is the antiepileptics. Gabapentin has become popular as a first-line treatment for neuropathic pain because of its efficacy as an antineuropathic agent and relatively benign sideeffect profile. However, its mechanism of action is far from clear. This review discusses the available evidence for the postulated mechanisms of action of gabapentin. Understanding the mechanism of action of this agent may well lead to the development of safer and more effective antineuropathic drugs. Keywords Allodynia, hyperalgesia, gabapentin, γ-aminobutyric acid, mechanism of action, neuropathic pain, voltage-gated calcium channel Introduction Neuropathic pain results from abnormal firing of damaged peripheral nerves, often associated with direct nerve injury or nerve damage from diabetic, post-herpetic or alcoholic neuropathy. It has a considerable socioeconomic impact [1], affecting more than 500,000 people in the UK alone [2], the great majority of whom will require lifelong drug treatment to control otherwise intolerable suffering. There has been much recent interest in novel anti-epileptic agents as potentially useful treatments for neuropathic pain. This review will summarize the available evidence regarding the mechanism of action of one such anti-epileptic drug, gabapentin (Figure 1). The etiologies of neuropathic pain are distinct from nociceptive pain, and several drugs that are effective for one type of pain are relatively ineffective for the other. Neuropathic pain may be entirely independent of any peripheral nerve stimulus, or it may be manifest as an abnormal sensation of pain in response to stimulation of other sensory modalities. A series of gene transcription factors are activated leading to a wide range of phenotypic alterations, including a reduction in the inhibitory neurotransmitter γ-aminobutyric acid (GABA), downregulation of GABA receptors [3••], and loss of GABAergic neurons [4]. At a cellular level, there are many physiological and biochemical similarities with epilepsy. Direct injury to the peripheral nerves leads to recurrent abnormal ectopic 33 discharges [5,6], and many of the excitatory neurotransmitters released in neuropathic pain are also implicated in the propagation of seizure activity. Alterations in membrane ion channels can be found in both conditions, predisposing the membranes to abnormal depolarization [7••]. Furthermore, anti-epileptic medications are often also effective in the treatment of neuropathic pain [8]. Designed as an analog of GABA that would cross the bloodbrain barrier [9], gabapentin (1-(aminomethyl)-cyclohexane acetic acid) was originally marketed worldwide as an antiepileptic. Other anti-epileptics, such as carbamazepine and phenytoin, have also been effective treatments for neuropathic pain [8]. The main problem with the use of these older antiepileptics is the wide range of side effects. When gabapentin was also found to have antineuropathic activity, it quickly became popular because of its relatively mild and dosedependent side-effect profile, and annual worldwide sales are now in excess of US $2 billion [10•]. Other new anticonvulsants, such as pregabalin (Figure 1), a structural analog of gabapentin, may also prove to be useful treatments in neuropathic pain [11]. Figure 1. The structures of gabapentin and pregabalin. NH 2 O OH C H 3 N H 2 CH 3 gabapentin pregabalin Efficacy, safety and pharmacokinetics Gabapentin is effective in reducing pain-related behavior patterns in a variety of animal models of neuropathic pain, including static allodynia [12], mechanical hyperalgesia [13], thermal hyperalgesia [13], mechanical allodynia [14,15] and thermal allodynia [16]. In humans, gabapentin reduces neuropathic pain caused by diabetes mellitus [17], postherpetic neuralgia [18], cancer [19] and a variety of other neuropathic pain syndromes [20]. Gabapentin is ineffective in acute post-operative pain following mastectomy [21] and, interestingly, the analgesic efficacy of this agent is dependent on the presence of some pathological state, such as nerve injury or inflammation [22]. A recent systematic meta analysis of randomized, controlled trials of gabapentin yielded a combined number of patients needed to treat (NNT) with the drug for an improvement in neuropathic pain of 4.3 [10•], comparable with those for carbamazepine and phenytoin [8]. There is also encouraging evidence of an additive effect of gabapentin with other antineuropathic and analgesic agents in rat models of neuropathic pain [12,23,24] and healthy human volunteers [25]. Furthermore, gabapentin prevents the development of opiate tolerance in rats [26]. In an elegantly designed clinical trial, Gilron et al showed that the O OH
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