Rationale and Evidence for the Use of Oxcarbazepine in Neuropathic Pain

Vol. 25 No. 5S May 2003 Journal of Pain and Symptom Management S31 Neuropathic Pain: From Mechanisms to Treatment Strategies Rationale and Evidence for the Use of Oxcarbazepine in Neuropathic Pain Enrique Carrazana, MD and Imao Mikoshiba, PhD Neuroscience, Clinical Development and Medical Affairs (E.C.), Novartis Pharmaceuticals, East Hanover, New Jersey, USA, and Kissei Pharmaceutical Company Ltd. (I.M.), Tokyo, Japan Abstract Oxcarbazepine is a second-generation antiepileptic drug (AED) with proven efficacy in managing partial epileptic seizures, with or without secondary generalization, in adults and children. The overlap between the underlying pathophysiologic mechanisms of some epilepsy models and neuropathic pain models supports the rationale for using certain AEDs in the treatment of neuropathic pain. Several AEDs have reportedly produced analgesia in a range of neuropathic pains, including painful diabetic neuropathy (PDN) and post-herpetic neuralgia. Increasing evidence suggests that oxcarbazepine can provide significant analgesia in several neuropathic pain conditions, including trigeminal neuralgia and PDN, and is also may be effective in treating neuropathic pain refractory to other AEDs, such as carbamazepine and gabapentin. The analgesic effects of oxcarbazepine, and its generally improved safety and tolerability profile compared with other standard AEDs, suggests that oxcarbazepine will be an important addition to the neuropathic pain armamentarium. The rationale and evidence to support the efficacy of oxcarbazepine are presented here. J Pain Symptom Manage 2003; 25:S31 S35. 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Neuropathic pain, antiepileptic drug, oxcarbazepine, trigeminal neuralgia, refractory pain, painful diabetic neuropathy Introduction Analgesic action was first reported for an antiepileptic drug (AED) in 1942, when phenytoin was found to be effective in some patients with trigeminal neuralgia (TGN). 1 Twenty years later, Blom reported that carbamazepine was also effective in treating TGN. 2 This was subsequently confirmed in three placebo-controlled Address reprint requests to: Enrique Carrazana, MD, Neuroscience, Clinical Development and Medical Affairs, Novartis Pharmaceuticals, Building 403, Room 362, 59 Route 10, East Hanover, NJ, 07936-1080, USA. trials, which clearly demonstrated the efficacy of carbamazepine treatment in patients with TGN. 3 5 Carbamazepine (100 2400 mg/day) was associated with improved pain relief in 70 75% of patients, compared with up to 25% of patients receiving placebo. 4,5 In another study, involving 70 patients with TGN, carbamazepine significantly reduced the severity of pain by 58%, compared with a 26% reduction with placebo (P 0.05). 3 Carbamazepine was subsequently approved by the US Food and Drug Administration (FDA) as a treatment for TGN, and is currently considered to be the drug of choice for TGN. Since then, several AEDs have been shown to produce analgesia in 2003 U.S. Cancer Pain Relief Committee 0885-3924/03/$ see front matter Published by Elsevier. All rights reserved. doi:10.1016/s0885-3924(03)00067-8

S32 Carrazana and Mikoshiba Vol. 25 No. 5S May 2003 neuropathic pain, and have also proved effective in treating several types of neuropathic pain, including painful diabetic neuropathy and post-herpetic neuralgia. 6 The overlap between the underlying pathophysiologic mechanisms of some epilepsy models and neuropathic pain models supports the rationale for using certain AEDs in the treatment of neuropathic pain. 6,7 Peripheral and central neuroplasticity, such as peripheral overexpression and accumulation of sodium channels at sites of nerve damage, altered activity at central glutamate receptor sites, and increased calcium flux into cells, have been implicated in the pathophysiology of neuropathic pain. Based on their mode of actions, certain AEDs may target peripheral and/or central sensitization mechanisms involved in neuropathic pain. 8 For example, oxcarbazepine (Trileptal, Novartis International AG, Basel, Switzerland), carbamazepine, and phenytoin block sodium channels, thereby reducing the hyperexcitability of damaged peripheral nerves. 7,8 Oxcarbazepine has been shown to inhibit highfrequency firing of nerves without impairing normal impulse conduction. 9 The dual mode of action of oxcarbazepine, modulating both voltage-sensitive sodium channels 10 and highvoltage activated N-type calcium channels, 11 raises the possibility that oxcarbazepine can target certain underlying mechanisms known to be important in the genesis of both peripheral and central sensitization, as discussed in more detail elsewhere in this supplement. Oxcarbazepine Oxcarbazepine is a second-generation AED with proven efficacy as monotherapy and combination therapy in managing partial epileptic seizures, with or without secondary generalization, in adults and children. Head-to-head trials with other first-line AEDs have shown oxcarbazepine to be of comparable efficacy in controlling seizures, while exhibiting a significantly better tolerability profile. 12 14 Fewer patients developed rash or hypersensitivity to oxcarbazepine compared with patients receiving carbamazepine or phenytoin. 12 14 In addition, oxcarbazepine is not associated with serious idiosyncratic hematologic or hepatic effects. For this reason, there is no need for routine monitoring of hematologic and hepatic profiles during treatment with oxcarbazepine. 15,16 Oxcarbazepine also has predictable, linear pharmacokinetics and minimal drug-drug interactions, which facilitate its use as combination therapy, if necessary (Table 1). 15,16 Furthermore, oxcarbazepine does not autoinduce its metabolism; therefore, dose titration and dosage adjustment are relatively simple, and steady-state levels of the drug can be achieved. 15,16 Oxcarbazepine also has a convenient twicedaily dosing regimen and can be taken with or without food, thus facilitating patient compliance. Oxcarbazepine as a Treatment for Neuropathic Pain Clinical Evidence in Trigeminal Neuralgia A series of open-label studies suggest that oxcarbazepine has substantial efficacy in alleviating the pain associated with TGN, with relatively few clinically significant adverse events. 17,18 In most cases, pain relief was noted within 24 48 hours of receiving oxcarbazepine treatment. In addition, some patients obtained pain relief with oxcarbazepine despite having previously responded poorly (in terms of efficacy or tolerability) to carbamazepine. The first double-blind, crossover trial to evaluate the efficacy of oxcarbazepine (900 2100 mg/ day) versus carbamazepine (400 1200 mg/ day) reported a comparable analgesic effect between the two treatments, leading to the conclusion that oxcarbazepine offers an alternative to carbamazepine in the treatment of TGN. 19 This finding was confirmed by the results of three subsequent multicenter, doubleblind, randomized trials comparing the efficacy and tolerability of oxcarbazepine versus carbamazepine in patients with newly diagnosed or refractory TGN. 20 Meta-analysis of Table 1 Advantages of Oxcarbazepine Over Carbamazepine in Neuropathic Pain No monitoring of hematologic parameters required Fewer drug-drug interactions No autoinduction of metabolism Comparable efficacy Improved tolerability 27% cross sensitivity with carbamazepine Twice-daily dosing schedule

Vol. 25 No. 5S May 2003 Use of Oxcarbazepine in Neuropathic Pain S33 data from these trials showed that oxcarbazepine was as efficacious as carbamazepine in reducing the number of weekly pain attacks (in 88% versus 88% of patients, respectively) and evoked pain (in 58% versus 62% of patients, respectively) (Fig. 1). However, similar to the findings in the epilepsy trials, oxcarbazepine was associated with substantially fewer adverse events than carbamazepine; in particular, there were fewer incidences of vertigo, dizziness, ataxia, and fatigue with oxcarbazepine. Tolerability was reported as good to excellent by 62% of patients receiving oxcarbazepine, compared with 48% of patients receiving carbamazepine. The recommended starting dose for oxcarbazepine treatment in TGN is approximately 600 mg/day (300 mg twice daily), with increases of 150-300 mg every few days according to the clinical response. In the majority of patients, the effective dose ranges from 600 mg/ day to 1200 mg/day; however, patients with refractory TGN may require doses as high as 2400 mg/day. Fig. 1. Efficacy of oxcarbazepine versus carbamazepine in patients with trigeminal neuralgia (meta-analysis of 3 trials). Reproduced with kind permission. 20 Clinical Evidence in Other Neuropathic Pain Conditions Gabapentin is often used to treat neuropathic pain; however, a substantial proportion of patients find this drug ineffective, partially effective or poorly tolerated. In an open-label study evaluating the efficacy of oxcarbazepine in 18 patients with complex regional pain syndrome refractory to gabapentin treatment, oxcarbazepine (150 2000 mg/day) markedly reduced the mean visual analog scale (VAS) score (from 7.4 to 3.3) and the mean McGill Short-Form score (from 28.1 to 9.3), with 33% and 39% of patient responses reported as good and excellent, respectively. 21 Oxcarbazepine was well tolerated, with adverse events (nausea, headache and constipation) reported in only 4 out of 18 (22%) patients. Oxcarbazepine (150 900 mg/day) has also been reported to be effective in a cohort of patients with painful radiculopathy refractory to gabapentin. 22 In total, 15 of 18 (83%) patients reported good to excellent responses following the addition of oxcarbazepine. Significant improvement was seen in patients with symptoms described as burning and allodynia. Overall, oxcarbazepine was well tolerated, with the main adverse events being dizziness, headache, and nausea. A recent open-label trial evaluated the efficacy and tolerability of oxcarbazepine (administered in two dose-escalating phases: up to 900 mg/day in Phase I and up to 1500 mg/day in Phase II), in 12 patients with central pain following spinal cord injury. Seven of the 12 patients in the trial had allodynia. Oxcarbazepine provided moderate pain relief in 58% (7/12) of patients overall, and in 100% (7/7) of the patients with allodynia. Adverse effects were mild and reversible, and included blurred vision, sedation, dizziness, and hyponatremia. The authors suggested that the mechanisms of pain may differ among spinal cord injury patients with and without allodynia. In addition, oxcarbazepine treatment was considered to be beneficial in the treatment of patients with allodynia. 23 Clinical Evidence in Painful Diabetic Neuropathy Data from a limited number of reports have led to the use of carbamazepine in the treatment of painful diabetic neuropathy. For example, carbamazepine (median dose 600 mg/ day) provided moderate-to-complete pain relief in 63% (19/30) of patients with painful diabetic neuropathy, compared with 20% (6/30) of patients receiving placebo (P 0.05). 24 Evidence that oxcarbazepine may also be effective in treating painful diabetic neuropathy is accumulating. Data from an open-label prospective study indicate that oxcarbazepine (mean

S34 Carrazana and Mikoshiba Vol. 25 No. 5S May 2003 effective dose 814 mg/day, range 150 1200 mg/ day) may significantly improve pain scores in patients with painful diabetic neuropathy: the VAS score for pain declined from 66.3 at baseline to 34.3 at the end of the trial (P 0.0001). 25 Significant improvements were also reported in the McGill total pain score and the Bodily Pain category of the SF-36 Quality of Life questionnaire. Oxcarbazepine was well tolerated, with the most frequent adverse events being similar to those reported in epilepsy studies. In Japan, five studies are currently investigating the efficacy of oxcarbazepine in treating neuropathic pain. In one, an open-label study involving 32 patients with painful diabetic neuropathy, oxcarbazepine (target dose 600 mg/day, following weekly titration from 100 mg/day, through 200 mg/day and 400 mg/day, to 600 mg/day) reduced the mean VAS score from 6.7 cm at baseline to 3.8 cm with 600 mg/day. Another study is a randomized, double-blind, placebocontrolled trial designed to determine the recommended dose of oxcarbazepine (200 mg/ day, 400 mg/day, or 600 mg/day) in Japanese patients with painful diabetic neuropathy. Two hundred and four patients were enrolled in the trial and randomized to the treatment arms. The results indicated a significant improvement in the VAS scores for patients randomized to oxcarbazepine, compared with those randomized to placebo (unpublished data). A large, international clinical development program was also initiated in 2001 to further examine the efficacy and tolerability of oxcarbazepine in neuropathic pain. Five trials are currently underway at study centers across the US, Europe, and Latin America. These include 4 multicenter, double-blind, randomized, placebo-controlled trials involving patients with painful diabetic neuropathy, and one trial involving patients with lumbar radiculopathy. Conclusions Current reports suggest that oxcarbazepine is an effective and well tolerated treatment for neuropathic pain. This efficacy has been noted in a broad range of neuropathic pain conditions, including TGN and painful diabetic neuropathy, and in patients refractory to other AEDs, such as carbamazepine and gabapentin. It is hoped that ongoing large, double-blind, placebo-controlled, clinical trials will confirm the efficacy and tolerability of oxcarbazepine in neuropathic pain. References 1. Bergouignan M. Cures heureuses de nevralgies faciales essentielles par le diphenylhydantoinate de soude. Rev Laryngol Otol Rhinol 1942;63:34 41. 2. Blom S. Trigeminal neuralgia: its treatment with a new anticonvulsant drug (G32883). Lancet 1962;1: 839 840. 3. Campbell FG, Graham JG, Zilkha KJ. Clinical trial of carbamazepine (Tegretol) in trigeminal neuralgia. J Neurol Neurosurg Psychiat 1966;29:265 267. 4. Killian JM, Fromm GH. Carbamazepine in the treatment of neuralgia: use and side effects. Arch Neurol 1968;19:129 136. 5. Nicol CF. A four year double-blind study of tegretol in facial pain. Headache 1969;9:54 57. 6. Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain 2002; 6(Suppl A):61 68. 7. Dickenson AH, Matthews EA, Suzuki R. Neurobiology of neuropathic pain: mode of action of anticonvulsants. Eur J Pain 2002;6(Suppl A):51 60. 8. White HS. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 1999;40(Suppl 5):S2 S10. 9. Ichikawa K, Koyama N, Kiguchi S, et al. Inhibitory effect of oxcarbazepine on high-frequency firing in peripheral nerve fibers. Eur J Pharmacol 2001;420:119 122. 10. McLean MJ, Schmutz M, Wamil AW, et al. Oxcarbazepine: mechanisms of action. Epilepsia 1994; 35(Suppl 3):S5 S9. 11. Stefani A, Pisani A, De Murtas M, et al. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. II. Modulation of highvoltage-activated calcium currents. Epilepsia 1995; 36:997 1002. 12. Dam M, Ekberg R, Loyning Y, et al. A doubleblind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;3:70 76. 13. Bill PA, Vigonius U, Pohlmann H, et al. A doubleblind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27:195 204. 14. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27:205 213. 15. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother 2002;3:59 71.

Vol. 25 No. 5S May 2003 Use of Oxcarbazepine in Neuropathic Pain S35 16. Lloyd P, Flesch G, Dieterle W. Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia 1994;35(Suppl 3):S10 S13. 17. Zakrzewska JM, Patsalos PN. Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1989; 52:472 476. 18. Farago F. Trigeminal neuralgia: its treatment with two new carbamazepine analogues. Eur Neurol 1987;26:73 83. 19. Lindstrom P. The analgesic effect of carbamazepine in trigeminal neuralgia. Pain 1987;4:S85. 20. Beydoun A, Schmidt D, D Souza J, on behalf of the Oxcarbazepine Study Group. Meta-analysis of comparative trials of oxcarbazepine versus carbamazepine in trigeminal neuralgia. Poster presented at the 21st American Pain Society Annual Meeting, Baltimore, USA, 14 17 March 2002. 21. Royal M, Bhakta B, Jensen M, et al. An openlabel trial of oxcarbazepine in patients with complex regional pain syndrome refractory to gabapentin. Poster presented at the 17th American Academy of Pain Medicine Annual Meeting, Florida, USA, 14 18 February 2001. 22. Ward S, Royal MA, Jenson M. An open-label trial of oxcarbazepine in patients with radiculopathy refractory to gabapentin. J Pain 2002;3:42. 23. Jenkins K, Kaplan SE, Leahy LF, et al. Oxcarbazepine in central neuropathic pain with allodynia following spinal cord injury. J Pain 2002;3:10. 24. Rull JA, Quibrera R, Gonzalez-Milan H, et al. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial. Diabetologia 1969;5:215 220. 25. Carrazana E, Beydoun A, Kobetz S, et al. An open-label, prospective trial of oxcarbazepine for the treatment of painful diabetic neuropathy. Poster presented at the 21st American Pain Society Annual Meeting, Baltimore, USA, 14 17 March 2002.