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Ion Channel Targets and Treatment Efficacy in Neuropathic Pain

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Ion Channel Targets and Treatment Efficacy in Neuropathic Pain The Journal of Pain, Vol 7, No 1S (January), Supplement 1, 2006: pp S38-S47 Available online at www.sciencedirect.com Ion Channel Targets and Treatment Efficacy in Neuropathic Pain John D. Markman and Robert H. Dworkin Departments of Anesthesiology and Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York. Abstract: Chronic neuropathic pain due to injury or dysfunction of the nervous system remains a formidable treatment challenge in spite of a growing range of medication choices. We review current clinical research supporting the use of ion channel modulators for neuropathic pain states. New modes of local drug delivery, novel Ca2؉ channel targets, and increased choices for drugs with activity at Na؉channels are transforming this longstanding therapeutic strategy. Clinical decision making is increasingly informed by a more nuanced understanding of the role of voltage-gated Na؉channels VGSCs) and Ca2؉ channels (VGCCs) in the pathophysiology of nerve injury. Although holding great) promise for the future, mechanism-based approaches to treatment will require greater understanding of the analgesic mechanisms of drug action and of the relationships between pathophysiologic mechanisms and clinical presentation. Perspective: Treatment options for neuropathic pain targeting ion channels have grown rapidly in the past decade. An evolving body of clinical research supports the widespread use of this longstand- ing therapeutic strategy. Improved efficacy of ion channel modulators hinges upon further elucidation of the relationship between signs and symptoms of pain and underlying pathophysiology. © 2006 by the American Pain Society Key words: Neuropathic pain, hyperexcitability, postherpetic neuralgia, diabetic peripheral neuro- pathy, anticonvulsants, efficacy, sodium channels, calcium channels. iverse types of injury to the peripheral and central neuropathic pain were not developed as analgesic nervous system cause neuropathic pain. The neu- agents. Classifying these agents as antidepressants, anti- Dronal hyperexcitability observed in animal models epileptics, and antiarrhythmic medications can be con- may have as its clinical correlate in humans the sponta- fusing and limit their clinical use as analgesic agents act- neous and evoked pains of diseases such as postherpetic ing at a common set of channels in neural tissue. neuralgia (PHN) and diabetic polyneuropathy. Recent Although a growing number of these agents from dif- scientific advances offer refined descriptions of the ferent medication classes have become available for changes in membrane channels that culminate in neuro- the treatment of neuropathic conditions, alleviation nal hyperexcitability. Because of their activity at poten- of pain associated with nerve injury continues to pose tially critical sites of membrane channels, medications a significant clinical challenge. A common finding has that target ion channels are a mainstay of treatment for been that each agent provides effective relief of pain chronic neuropathic pain. At present, voltage-gated Naϩ only in a minority of the patients treated. Hopefully, (VGSCs) and Ca2ϩ channels (VGCCs) are the primary tar- future advances in our ability to diagnose the under- gets of these medications. lying pathophysiologic abnormality that leads to Most of the ion channel modulators in clinical use for chronic pain will allow treatments designed to target the specific molecular changes in an ion channel sub- type that is responsible for the symptoms and signs in Supported in part by an unrestricted educational grant from Novartis Pharmaceuticals. RHD has received research support, consulting fees, or that individual patient. lecture honoraria in the past year from Abbott Laboratories, Eli Lilly & Anticonvulsants (carbamazepine and phenytoin) and Co., Endo Pharmaceuticals, EpiCept Corporation, NeurogesX, Novartis Pharmaceuticals, Organon, Ortho-McNeil Pharmaceutical, Pfizer, Purdue systemic local anesthetics (lidocaine and mexiletine) Pharma, Ranbaxy Corporation, Reliant Pharmaceuticals, Renovis, and comprise the first generation of agents. They share a UCB Pharma. ϩ Address reprint requests to John D. Markman, MD, University of Roches- primary site of therapeutic action at the Na channels ter School of Medicine and Dentistry, 601 Elmwood Avenue, Box 604, found in neural tissue. A newer generation of drugs, Rochester, NY 14642. E-mail: [email protected] including topiramate, lamotrigine, and oxcarbazepine, 1526-5900/$32.00 ϩ 2ϩ © 2006 by the American Pain Society have also demonstrated activity at both Na and Ca doi:10.1016/j.jpain.2005.09.008 channel subtypes, with fewer side-effects. Initially ap- S38 REPORT/Markman and Dworkin S39 proved on evidence of this latter generation’s benefit as nor in any specific location in the sensory pathways antiepileptic agents, their role in the treatment of neu- where the pain can be localized.50 In some instances, ropathic pain has not been uniformly demonstrated. The variability in the type of channel expressed as a conse- analgesic properties of gabapentin and the related pre- quence of nerve injury would appear to account for not gabalin appear to be related to a strong affinity for a only the degree and type of hyperexcitability but also ␣ ␦ 24,75 specific 2 channel subunit. Another anticonvulsant differences in ion channel medication efficacy. For with some evidence for analgesic effects, levetiracetam, example, some clinical investigators have found that is clearly not active at Naϩ channels and may be active at pain from peripheral sites of nerve injury may be more ϩ Ca2 channels. sensitive to Naϩ channel modulators than pain arising Other classes of agents include ziconotide, which was from lesions of the central nervous system.40 Although it developed as an analgesic because it was found to an- is certain that ion channels play a central role in cellular ϩ tagonize the N-type Ca2 channel. It represents one of excitability, multiple processes at all levels of the the few successful attempts to develop an analgesic neuraxis are crucial to the cellular underpinnings of neu- through highly mechanism-selective drug development ropathic pain. efforts. Despite decades of widespread clinical use of The afferent barrage from peripheral nociceptors tricyclic antidepressants for neuropathic pain and mul- leads, in turn, to central sensitization. This phenomenon tiple controlled clinical trials, the recognition that the encompasses the structural changes in connectivity of analgesic activity of these drugs may depend in part on second- and third-order neurons in the central nervous ϩ actions at ion channel targets—especially Na chan- system induced by tachykinins such as substance P and nels—is a recent phenomenon. neurokinin A. In the spinal cord and at supraspinal sites, glutamate, acting at excitatory amino acid receptors (eg, Neurobiology of Neuropathic Pain: The NMDA), can amplify sensory input from the periphery. Role of Ion Channels Expansion of neuronal receptive fields and neuronal re- organization in the dorsal horn all have been found to Neuropathic pain can be defined as pain caused by account for some degree of altered sensory process- lesions of the peripheral or central nervous system ing.105 Regulation of other receptor types and modula- manifesting with positive (eg, pain) and negative (eg, tion of local or descending inhibitory pathways can af- 4 sensory loss) phenomena. Common causes include fect the dynamic clinical presentations of neuropathic trauma leading to nerve injury and deafferentation, syndromes. Among the large number of neuroplastic toxins (eg, chemotherapy), metabolic injury (eg, dia- changes now associated with neuropathic pain, the most betic neuropathy), and infections (eg, PHN). The exact amenable therapeutic target has been the peripheral ion mechanism by which each process results in a neuro- channels implicated in ectopic discharge. However, even pathic pain syndrome remains unclear. However, as an this relatively well studied phenomenon has not led to example, consider axonal and demyelinating injuries, substantial mechanism-based breakthroughs in our ther- which can produce structural changes in the neuronal apeutic options. membrane. Changes in the membrane-bound proteins that form ion channels may alter the electrical proper- ties of the injured neuron, called remodeling.94 Pre- Diagnostic Challenges and the Limits of clinical studies of neuropathic pain suggest that the Mechanism-Based Approaches net effect of membrane remodeling is to make neu- rons more excitable. The tendency to action potential The challenge of a mechanism-based approach to generation and propagation in injured primary sen- treating neuropathic pain lies in the fact that the history sory neurons can occur in the context of nerve injury.23 and clinical examination do not disclose a precise neuro- Increased activity is seen both at the local site of nerve physiologic pain mechanism. The diagnosis of neuro- injury and more remotely in the associated dorsal root pathic pain rests on the demonstration of a lesion in the ganglia and dorsal horn of the spinal cord. These pat- nervous system and the recognition of a related constel- terns of abnormal and excessive discharge are thought lation of sensory signs and symptoms. A varied array of to account for the positive symptoms reported by pa- metabolic, ischemic, immune-mediated, and toxic insults tients with neuropathic pain. Positive sensory phe- can result in neuropathic pain. Importantly, the
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