Sodium channel-blocking agents

Focus

Sodium Channel-blocking Agents Their Use in Neuropathic Pain Conditions Darrell L. Tanelian and Raymond A. Victory

Neuropathic pain conditions are due to damage or permanent alteration of the peripheral or central nervous system. These conditions are generally chronic and less responsive to opiates than nociceptive (acute) pain conditions; as such, they are very difficult to treat clinically. Numerous classes of drugs, including opiates, antidepressants, anticonvulsants, local anesthetics, antiarrhythmics, steroids, antipsychotic agents, and topical capsaicin have been used to treat neuropathic pain. One mechanism common to several of these pharmacological agents is their ability to block sodium channels in a use-dependent fashion. In this focus article clinical evidence of the effectiveness of sodium channel-blocking drugs for relieving neuropathic pain will be presented. Experimental evidence for the site of action of these drugs will be discussed, along with future studies that are needed to develop new, more effective, agents. Key words: neuropathic pain, chronic pain, mexiletine, carbamazepine, phenytoin, local anesthetics, lidocaine, procaine

odium channel-blocking agents (systemic local anesthetics, carbamazepine, phenytoin, and mexiletine) have been reported to relieve pain resulting from numerous pain conditions, especially neuropathies, for over 50 years. 6 ,29 These agents are effective in many neuropathic pain states, whether the origin of the pain is in the central or peripheral nervous system. Conditions that have responded to these agents include peripheral neuropathies, such as trigeminal neuralgia, postherpetic neuralgia, diabetic

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From the Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center, Dallas, TX. Reprint requests: Darrell Tanelian, PhD, MD, Department of Anesthesiology and Pain Management, Pain Research Program, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9068.

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neuropathy, glossopharyngeal neuralgia, and neuropathy secondary to metastatic infiltration;33,48 as well as central pain conditions following stroke, thalamic lesions, and multiple sclerosis. 3,24,34,39 Other peripheral pain conditions responsive to sodium channel blockers include adiposis dolcrosa--" and burn pain." Despite hundreds of clinical studies, the pain conditions most responsive to these agents and the agent of choice for a particular chronic pain syndrome have not been fully agreed on. The use of sodium channel-blocking agents to relieve pain has been restricted primarily to chronic pain syndromes, rather than the treatment of acute pain. Chronic pain syndromes encompass many neuropathic pain states that are less responsive to opiates than nociceptive (acute) pain,'? thus necessitating the use of nonopioid pharmacology. One practical consideration for the management of acute pain with sodium channel blockers is the need for rapid titration of drug, which is only possible via the intravenous route, raising concerns of cardiac and central nervous system toxicity if plasma levels are not regularly measured. Nevertheless, several studies have been conducted on postoperative or experimental pain, with conflicting results suggesting good analqesia''-" or no pain relief at aI1. 7,9,45 The exact mechanism and site of action of these drugs for pain relief are not known, but scientific evidence suggests that they work by blocking or modulating sodium channels. A common molecular basis for the action of local anesthetics, class 1 antiarrhythmics (mexiletine) and some anticonvulsants (carbamazepine and phenytoin), is their voltage and frequency-dependent inhibition of sodium channels. The ability of these agents to selectively block more active or depolarized nerves makes them useful for blocking pain pathways in which neuronal activity is increased while not interfering with normal sensory or motor function. For example, lidocaine can reduce the excitability of rapidly firing axons at concentrations 40 times lower than clinically necessary to produce nerve block."

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The site of action of sodium channel blockers continues to be debated, with evidence suggesting both peripheral and central nervous system actions. A peripheral nerve site of action for all of these agents is supported by several studies. 113,17,22,56 Burchiel demonstrated that rat saphenous neuroma discharge could be inhibited by carbamazepine at clinically relevant serum levels of 10-18.5 jJg/mL.13 A subsequent study of rat sciatic neuromas demonstrated the ability of subanesthetic concentrations of intravenous lidocaine, tocainide, and mexiletine to suppress neuroma discharge without producing conduction block." Tanelian and Maciver, using an acute corneal nerve injury model, demonstrated that injury discharge in A-delta and C-fiber nociceptors could be suppressed by lidocaine at an EDso of 5.7 j.Jg/mL, which corresponds to clinically analgesic concentrations." Systemic subanesthetic lidocaine delivery has been shown to suppress ectopic impulse generation, not only at the site of peripheral nerve injury, but also in the axotomized dorsal root ganglion cells." Most recently, Abram and Yaksh, using models of both thermal hyperalgesia due to nerve compression and the formalin test, concluded that the predominant analgesic effect of systemic lidocaine is through suppression of spontaneous impulse generation arising from injured nerve segments or associated dorsal root ganglion. 1 A peripheral site of action for sodium channel-blocking agents is also supported by pathophysiological evidence that in many neuropathic pain states demyelination and spontaneous ectopic generation of nerve impulses occurs. 4,12,37,38,57 These demyelinated internodal axolemma regions and neuroma "end bulbs" have been immunohistochemically shown to acquire sodium channels." Several studies propose that sodium channel blockers produce analgesia at a central nervous system site of action. In a rat model, systemic lidocaine and tocainide were shown to suppress the C-fiber-evoked polysynaptic reflex generated by stimulating the sural nerve." Using chronic peripheral nerve pain models (section or compression by ligatures), Sotgiu et al. concluded that systemic lidocaine in subanesthetic doses preferentially acts on hyperactive dorsal horn widedynamic-range neurons to produce analqesia." It is possible that both these hypotheses are true and that sodium channel-blocking agents act both centrally and peripherally within the nervous system.

EFFICACY OF SODIUM CHANNEL BLOCKERS FOR CLINICAL CONDITIONS Local Anesthetics Intravenous infusion of local anesthetic agents has been advocated for treatment of both acute and chronic

pain for many years. There have been reports of the successful use of intravenous local anesthetic agents for many pain conditions, including neuralgia pain, burn pain, thalamic syndrome, cancer pain, and pain due to adiposis dolorosa. 2,24,3o,32 Graubard (1949) was one of the first to report the successful use of intravenous procaine for the treatment of pain in 448 patients." This was an uncontrolled study on patients with numerous different neuropathic and nociceptive pain conditions. Since then, many studies have demonstrated the efficacy of intravenous lidocaine in treating pain caused by diabetic neuropathy.v"" Kastrup et aI., in a randomized, double-blind study of 15 patients with diabetic neuropathy, infused either saline or 5 mg/kg of lidocaine intravenously (mean plasma concentration of 3.6 j.Jg/mL).32 Pain scores were reduced in 11 patients for a period of 3 to 21 days." In another study, Bach et al. demonstrated that intravenous lidocaine increases the nociceptive flexion reflex threshold but did not change the thermal sensibility in patients with diabetic neuropathy.' In another study on patients with neuropathic pain, systemic lidocaine at plasma concentrations between 1.5 and 2 j.Jg/mL markedly reduced neuralgic pain." However, in the same study, higher concentrations of lidocaine (>3 jJg/mL) were required to relieve experimentally induced ischemic pain in the same patients. Other peripheral neuropathic pain conditions have responded to intravenous lidocaine. 2,28,31,41,44 Rowbotham et al. demonstrated the analgesic efficacy of intravenous lidocaine in patients with postherpetic neuralqia." In this study, plasma lidocaine levels ranged from 1 to 4.8 IJg/mL. Marchettini et al.35 reported pain relief in 10 patients with chronic neuropathic pain of diverse etiologies and a coincident decrease in the area of mechanical hyperalgesia that had been associated with their pain. 2,31,35,41 The burning pain and allodynia caused by the idiopathic condition adiposis dolorosa (Dercum's disease) has responded well to intravenous lidocaine in several studies. 2,31,41 Interestingly, infusions of 3 mg/kg, given over a 30-minute period, produced long-term pain relief, from 2 to 12 months, in the study conducted by Atkinson." There is also evidence that intravenous lidocaine is effective for central neuropathic pain syndromes; such as the deep burning pain that can arise following a cerebrovascular accident." In one series of 4 patients with poststroke pain, intravenous lidocaine produced total pain relief with a duration of hours to days. The analgesic effect was dose related and the plasma lidocaine concentration required for total pain relief was 5 to 6 jJg/mL.24 In contrast, Galer et al. demonstrated that intravenous lidocaine was more effective for pain originating in the peripheral nervous system than for central pain." In this study, peripheral nerve pain was relieved by intravenous lidocaine in 87% of patients, compared

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with only 31% relief in patients with spinal cord and poststroke pain. There was some difference in methodology between these two studies that may explain the contrasting results. In the study by Edmondson et al. a bolus of lidocaine was given and adequate plasma lidocaine levels were attained. " However, in the study by Galer et aI., a continuous infusion of lidocaine was commenced without an initial bolus dose and plasma lido caine levels were not measured." There are many reports of cancer pain that could not be controlled on opioids , but did respond to sodium channel blockers. 1o,54,55 Brose and Cousins demonstrated that subcutaneous infusion of lidocaine, with plasma concentrations in the range of 2 to 5 IJg/mL, can result in pain relief for patients with metastatic invasion of neural tissue for up to 6 months. " However, a randomized controlled trial, in patients with neuropathic cancer pain, demonstrated no difference between intravenous lidocaine infusion and placebo ." It is difficult to explain the lack of response in this study; however, plasma lidocaine concentrations were not measured and the patients may have had more invasive disease than in the previously mentioned study." Intravenous lidocaine did not prove to be as effective for nociceptive pain as it has in studies of neuropathic pain . Several studies have been conducted on postoperative or experimental pain, with conflicting results suggesting good analqesia''-" or no pain relief at aI1. 7,9,45 Interestingly, lidocaine has greater analgesic efficacy in treating burn pain, which is generally considered nociceptive , than it does for postoperative pain." In a study on the use of lidocaine infusion in patients with pain following second-degree burns, Jonsson et al. demonstrated a marked analgesic effect, that obviated the need for supplementary opioid analqesia."

Antiarrhythmics (Mexiletine) Mexiletine is structurally similar to lidocaine and it also has analgesic efficacy in clinical neuropathic pain syndromes, such as peripheral neuropathies and central pain syndromes. 10 ,16,21 ,42,51 Mexiletine was first shown to be effective for the treatment of diabetic neuropathy by Dejgard et aI., using a randomized double-blind crossover trial in 16 patients ." In this study, mexiletine in doses up to 10 mg/kg/day produced significant relief of pain , dysesthesia, and paresthesia, without altering vibration thresholds or autonomic nerve function tests . In a much larger multicenter study, Stracke et al., using visual analog pain scales and McGill pain scores , demonstrated that mexiletine significantly improved stabbing or burning pain and heat sensations in patients with diabetic neuropathy at a dose of 450 mg/day.51 It is important to note that, when looking at only global assessment of visual analog pain scales among patients , there was no difference between mexiletine

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and placebo in the study by Stracke et al. Therefore , it is important to categorically investigate the specific type of pain sensations that mayor may not be improved by a given drug therapy. A variety of other chronic peripheral neuropathic pain conditions have been improved by rnexiletine. P>' Chabal et aI., using a double-blind placebo-controlled study, administered mexiletine in doses up to 750 mg/day and found mexiletine to produce a significant reduction in pain scores ." Mexiletine has been shown to improve centrally mediated pain as well. In 8 of 9 patients, thalamic pain syndrome has been improved by using mexiletine at a dose of 10 mg/kg/day.3

Anticonvulsants (Carbamazepine and Phenytoin) Anticonvulsant agents have been reported to relieve pain in numerous peripheral and central neuropath ic pain conditions." To review the great number of studies conducted on their efficacy for neuropathic pain is beyond the scope of this article; therefore , only a few articles will be cited. Anticonvulsant agents were first used in the treatment of trigeminal neuralgia. A successful trial of phenytoin for trigeminal neuralgia was reported in 1942. 6 In more recent years , it was demonstrated that carbamazepine is also effect ive for trigeminal neuralgia and it has been shown to be more effective than phenytoin. " In this study, Blom reported that 90% of patients with trigeminal neuralgia respond to carbamazepine and the majority of these are pain free on a 6-month follow-up vislt." Anticonvulsants have also been used for diabetic neuropathy. Ellenberg, in a study of 60 patients, demonstrated that phenytoin (300 to 400 mg/day) relieved pain in 85% of patients within 48 hours; and that their pain returned within 48 hours of its discontinuation." Similar results were obtained by Chadda and Mathur, who found phenytoin (300 mg/day) to be significantly more effective than placebo in a study of 40 patients with diabetic neuropathy." Carbamazepine is also effective for diabetic neuropathy pain . Rull et al. demonstrated 90% relief of pain and paresthesia in 30 diabetic patients at an average dose of 600 rnq/day." Eighty percent success was obtained by Chakrabarti and Samantaray in 44 of 55 patients receiving 300 to 800 mg of carbamazepine per day." In a less common neuropathic condition , glossopharyngeal neuralgia, phenytoin and carbamazepine are effective , although the success rate is not as great as that with trigeminal neuralgia Y Overall, a more encompassing study of 12 neuropathic pain conditions compared the efficacy of multiple anticonvulsant drugs in treating lancinating pain, and demonstrated pain reduction in 75% of patients given carbamazepine or phenytoin.53 There have been two studies demonstrating pain

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relief in soldiers with acute cutaneous war injuries by using topical phenytoin. 26 ,36 In central pain syndromes, such as thalamic syndrome, phenytoin has been shown to reduce pain in a dose-dependent fashion." However, there are also reports of poststroke pain that did not respond to carbamazepine but was reduced when lidocaine and mexiletine were given.24

DISCUSSION Review of the literature suggests that sodium channel blockers are effective for the treatment of numerous chronic pain conditions. Classically, these agents have been used in neuropathic pain states that are characterized by prickling, burning, or stinging pain, often associated with paroxysms of sharp, shooting, and lancinating pain. Typically, in addition to pain, these conditions are characterized by hyperalgesia, hyperpathia, and allodynia. Most studies evaluate the level of the patient's pain or degree of pain relief obtained with these drugs. There is no evidence that statistically validates that one type of pain (i.e., burning or lancinating) is better controlled by one sodium channel blocker or another. In addition to a reduction in pain rating alone, there is evidence demonstrating a reduction in the cutaneous area of mechanical hyperalgesia following intravenous lidocaine." One would expect the duration of pain relief following infusion of local anesthetics to persist for several hours. However, for unexplained reasons, the duration of analgesia following the completion of an intravenous lidocaine infusion has been reported to last for days or weeks.2 ,4.31,32 There is no experimental scientific evidence to explain this phenomenon. Based on the common mechanism of action of these drugs, it would seem logical that a positive response to an intravenous infusion of lidocaine would be predictive of the subsequent analgesic response to anticonvulsants or class 1 antiarrhythmic drugs. Intravenous lidocaine has been shown to predict the efficacy of oral mexiletine in the control of arrhythmias." The utility of an intravenous lidocaine test to predict the efficacy of oral sodium channel blockers has been alluded to in several papers24 ,52 ,54 ; however, no conclusive clinical study has statistically verified these observations. Clearly, sodium channel-blocking agents are useful for the management of chronic neuropathic pain. However, much remains to be learned regarding the appropriate selection of pain conditions that will benefit from these agents. Large-scale clinical studies are needed to determine the diagnostic utility of intravenous lidocaine infusions to differentiate neuropathic versus nociceptive pain and the predictive value of intravenous

infusions in subsequent oral therapy with sodium channel-blocking agents. Basic scientific research is required to determine the exact site of action for the analgesia produced by sodium channel drugs (i.e., peripheral versus central). Further research into possible molecular differences between peripheral versus central neuronal and cardiac sodium channels and normal versus ectopically expressed sodium channel, may lead to the discovery of new agents that can selectively relieve pain without central nervous system or cardiac toxicity.

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16. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW: The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 76:513-517, 1992 17. Chabal C, Russell L, Burchiel K: The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas. Pain 38:333-338, 1989 18. Chadda V, Mathur M: Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. J Assoc Physicians India 26:403--406, 1978 19. Chakrabarti A, Samantaray S: Diabetic peripheral neuropathy: nerve conduction studies before, during and after carbamazepine therapy.Aust N Z J Med 6:565-568, 1976 20. Cherny NI, Thaler HT, Friedlander-Klar H, Lapin J, Foley KM: Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies. Neurology 44:857-861, 1994 21. Dejgard A, Petersen P, Kastrup J: Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet 1:9-11, 1988 22. Devor M, Wall PO, Catalan N: Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 48:261-268, 1992 23. Devor M, Govrin-Lippmann R, Angelides K: Na' channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 13:1976-1992, 1993 24. Edmondson EA, Simpson RJ, Stubler OK, Beric A: Systemic lidocaine therapy for poststroke pain. South Med J 86:1093-1096, 1993 25. Ellenberg M: Treatment of diabetic neuropathy with diphenylhydantoin. NY State J Med 68:2653-2655, 1968 26. EI Zayat SG: Preliminary experience with topical phenytoin in wound healing in a war zone. Milit Med 154:178-180,1989 27. Fromm GH, Chattha AS, Terrence CF, Glass JD: Do phenytoin and carbamazepine depress excitation and/or facilitate inhibition? Eur J Pharmacol 78:403-409, 1982 28. Galer BS, Miller KV, Rowbotham MC: Response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury. Neurology 43:1233-1235,1993 29. Graubard OJ, Peterson MC: Therapeutic uses of intravenous procaine. Anesthesiology 10:175-187,1949 30. Jonsson A, Cassuto J, Hanson B: Inhibition of burn pain by intravenous lignocaine infusion. Lancet 338:151-152, 1991 31. Juhlin L: Long-standing pain relief of adiposis dolorosa (Dercum's disease) after intravenous infusion of lidocaine. J Am Acad Dermatol 15:383-385, 1986 32. Kastrup J, Petersen P, Dejgard A, Angelo HR, Hilsted J: Intravenous lidocaine infusion: a new treatment of chronic painful diabetic neuropathy? Pain 28:69-75,1987 33. Kastrup J, Bach FW, Petersen P et al: Lidocaine treatment of painful diabetic neuropathy and endogenous opioid peptides in plasma. Clin J Pain 5:239-244, 1989

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51. Stracke H, Meyer U, Schumacher H, Federlin K: Mexiletine in the treatment of diabetic neuropathy . Diabetes Care 15:1550-1555, 1992 52. Swerdlow M: Anticonvulsant drugs and chronic pain. Clin NeuropharmacoI7:51-82, 1984 53. Swerdlow M, Cundill JG: Anticonvulsant drugs used in the treatment of lancinating pain: a comparison. Anaesthesia 36:1129-1132,1981 54. Tanelian DL, Brose WG: Neuropathic pain can be relieved by drugs that are use-dependent sodium channel blockers : lidocaine, carbamazepine , and mexiletine. Anesthesiology 74:949-951 ,1991 55. Tanelian DL, Cousins MJ: Combined neurogenic and nociceptive pain in a patient with Pancoast tumor managed by epidural hydromorphone and oral carbamazepine. Pain 36:85-88, 1989

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