Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment

Journal of Pain Research, Jul 2017

Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment Jan M Keppel Hesselink,1 Michael E Schatman2,3 1Institute for Neuropathic Pain, Bosch en Duin, the Netherlands; 2Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA; 3Boston Pain Care, Waltham, MA, USAIntroductionMost review articles support carbamazepine as a first-line pharmacotherapy for idiopathic trigeminal neuralgia.1–3 However, the empirical support for this recommendation is somewhat suspect. Phenytoin, as the prototype for all anticonvulsants, was already positioned as an analgesic compound 70 years ago. Since these initial findings, the data that have been gathered have supported the use of anticonvulsants as painkillers – from phenytoin up to and including more recent anticonvulsants such as gabapentin and pregabalin. Since 1942, a number of papers supported phenytoin’s therapeutic effects in trigeminal neuralgia (Table 1). The introduction of carbamazepine in 1962 by Geigy shifted the interest of neurologists from phenytoin as a treatment for trigeminal neuralgia to carbamazepine, without sound scientific evidence. To date, no convincing randomized controlled trials (RCTs) have been published supporting the role of carbamazepine in trigeminal neuralgia, and we could not identify a single study comparing the effects of phenytoin with those of carbamazepine. Accordingly, phenytoin should probably be considered more often as a viable therapy for (treatmentresistant) trigeminal neuralgia.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.dovepress.com/getfile.php?fileID=37479

Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment

Journal of Pain Research Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment Jan M Keppel Hesselink 2 Michael E Schatman 0 1 0 Boston Pain Care , Waltham, Ma, USa 1 department of Public Health and Community Medicine, t ufts University School of Medicine , Boston, Ma, USa 2 institute for Neuropathic Pain , Bosch en duin , the Netherlands PowerdbyTCPDF(ww.tcpdf.org) - Trigeminal neuralgia: one of the first repositioning indications of phenytoin The exploration of phenytoin as an analgesic in neuralgic pain started 5 years after Putnam and Merritt identified the compound in 1937 as a treatment for convulsions.4 In 1942, a French otolaryngologist reported that 200–300 mg phenytoin daily was effective in reducing pain in three patients suffering from trigeminal neuralgia.5 In 1944, a case study of a patient suffering from paroxysmal abdominal pain but responding well to phenytoin was presented; the pain attacks in his case were (perhaps erroneously) interpreted as a form of focal symptomatic epilepsy.6 The first indication in the field of pain that was explored intensively as a new indication (repositioning) for phenytoin was trigeminal neuralgia, most likely due to its paroxysmal character – reminiscent of epileptic discharges. Based on some of these anecdotal reports of a possible analgesic role of phenytoin in the treatment of trigeminal neuralgia or “tic douloureux,” phenytoin was identified as a putative anti-trigeminal pain therapy in a number of sources published as early as the 1950s.7–10 8 1 0 2 l u J 2 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s rvepe l.yno Bergouignan and d’Aulnay continued his work in this .doww lsuea field and, in 1951, reported on the successful treatment with //w no phenytoin in 17 patients suffering from trigeminal neuralgia tt:sp rspe (300–600 mg/day). There was only one non-responder in his ohm roF study, and the clinical effect was reported to emerge quickly fr (within 24 hours).11 dade This indication was supported by electrophysiological lno studies of the inhibition of potentials in the trigeminal nerve dow by phenytoin.12 Evoked delayed potentials in the trigeminal rcha nerve could be abolished by the intravenous administration see of 50 mg phenytoin.13 inaR In 1954, a case series of 45 patients suffering from trigemfoP inal neuralgia who were treated with 300–600 mg phenytoin/ lran day was published. Sixteen patients were full responders, Juo 23 patients responded partially, and there were five nonresponders.14 In a follow-up study by the same author, 59 patients diagnosed with trigeminal neuralgia were treated with 300–600 mg phenytoin/day, and 57 became completely free of pain whereas only two were non-responders.15,16 A further series of 20 patients were reported in 1960, with symptomatic relief reported by 14 of the subjects.17 At the National Workshop of Clinical Use of Phenytoin in Chengdu, People’s Republic of China, in 1995, the authors presented the results of 36 patients with trigeminal neuralgia, who had been randomly assigned to three treatment groups: phenytoin (17 patients); carbamazepine (11 patients); and combined phenytoin and carbamazepine (8 patients). After 4 weeks of treatment, the effects of phenytoin and carbamazepine were comparable (82.35% and 81.81% responders, respectively), whereas combination treatment was superior.18 submit your manuscript | www.dovepress.com Dovepress All studies were published between 1942 and 1995; after 1995, we could not identify any outcome study evaluating phenytoin in trigeminal neuralgia. In 2012, the Cochrane collaboration could not identify any RCTs of phenytoin in neuropathic pain.27 the entrance of Geigy 32883: carbamazepine In 1958, the chemist Walter Schindler first described a number of N-heterocyclic compounds in a patent, one being carbamazepine; a year later, a second patent related to this matter was filed by Geigy. The inventors were Schindler and Charles Gansser. Initially, the compound was known as Geigy 32883 and, in 1962, G32883 was registered for the treatment of trigeminal neuralgia. In 1962, the first clinical article was published in The Lancet by Blom from the University of Uppsala, Sweden.28 He directly linked the general clinical experiences known up to that point for phenytoin to the effects of the new Geigy drug in his own hands. Blom stated: “It soon became evident that the effect was very good – probably better than that of diphenylhydantoin.” (p.839) This conclusion was based only on his experience with 11 patients in an open study, yet it seemingly legitimized the new Geigy drug (which was patent protected) as a superior treatment for trigeminal neuralgia. Seven of these 11 patients were previously treated with phenytoin: there were two non-responders on phenytoin, both responding to carbamazepine; two responders on phenytoin became non-responders after 2 years and subsequently responded to carbamazepine; two patients could (...truncated)


This is a preview of a remote PDF: https://www.dovepress.com/getfile.php?fileID=37479

Jan M Keppel Hesselink, Michael E Schatman. Phenytoin and carbamazepine in trigeminal neuralgia: marketing-based versus evidence-based treatment, Journal of Pain Research, 2017, pp. 1663-1666, DOI: 10.2147/JPR.S141896