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
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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
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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
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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)