Tegretol* in the treatment of trigeminal neuralgia in thirty patients
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CLEVELAND CLINIC QUARTERLY Volume 36, January 1969
Copyright © 1969 by T h e Cleveland Clinic Foundation Printed in U.S.A.
Tegretol* in the treatment of trigeminal
neuralgia in thirty patients
DOMINICK C. ADORNATO, JR., M.D.t
DONALD F. DOHN, M.D.
D e p a r t m e n t of Neurologic Surgery
T H E earliest k n o w n description of a p a i n f u l affliction of the face which
might be considered as trigeminal neuralgia, according to Stookey and
Ransohoff, 1 is f o u n d in the writings of Aretaeus in the first century A.D.,
and the first full description by a physician of tic d o u l o u r e u x together with
an account of his treatment is that by Locke. I n 1776, Fothergill 2 reported
14 cases of facial p a i n that was typical trigeminal neuralgia.
T h e medical treatment of this disease has been disappointing since the
entity was first described. I n recent years, anticonvulsants have been
advocated as therapy for trigeminal neuralgia. 3 - 7 Blom 5 contended that
diphenylhydantoin, in addition to its anticonvulsant properties, affects
synaptic transmission at levels caudal to the mesencephalon, and on this
basis he has used the d r u g in the treatment of tic douloureux. T h e
beneficial effects have generally been confirmed, 8 " 13 however results with
this d r u g are variable. Administered in low doses, diphenylhydantoin often
is ineffective, while the high dosages sometimes necessary to control
symptoms are poorly tolerated.
Blom 3 and others 6 - 8 ' 1 4 - 2 3 have reported their experience with Tegretol
in the treatment of trigeminal neuralgia. T h e results have been most
promising in that the d r u g produced a consistent decrease in p a i n f u l
paroxysms and was tolerated well by most patients. O u r report is an evalua-
tion of our experience using Tegretol in the treatment of trigeminal
neuralgia in 30 patients.
Materials and methods
Tegretol was administered to a total of 36 patients, of whom 30 h a d
trigeminal neuralgia. T h e other six patients h a d atypical facial p a i n and
are excluded f r o m this study. T h e diagnosis of trigeminal neuralgia was
made on the basis of the following four criteria: (1) paroxysmal p a i n with
intervals of relief, (2) pain confined to the area of the trigeminal nerve,
(3) n o objective evidence of motor or sensory deficit along the distribution
of the trigeminal nerve, a n d (4) the presence of trigger areas. T h e presence
* Carbamazepine, G-32883, supplied for this study through the courtesy of T. P. S. Watts,
M.D., Geigy Pharmaceuticals, Ardsley, New York 10502.
f Fellow, Department of Neurologic Surgery.
17
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of trigger areas is n o t absolutely necessary, b u t it is a v a l u a b l e a d j u n c t
in confirming the diagnosis. 1
All SO p a t i e n t s w i t h trigeminal n e u r a l g i a were seen a n d e x a m i n e d by one
or by b o t h of us. T h e i r progress was followed by m e a n s of p e r s o n a l inter-
view or by q u e s t i o n n a i r e at m o n t h l y intervals. O u r e v a l u a t i o n of T e g r e t o l ,
in the m a n n e r of an u n c o n t r o l l e d study, b e g a n in J a n u a r y 1965. It was
concluded i n J a n u a r y 1968, in order to have a six-month follow-up p e r i o d
for those p a t i e n t s w h o h a d been treated w i t h i n the last year.
T h e p a t i e n t s ' ages r a n g e d f r o m 27 to 86 years, w i t h most of t h e p a t i e n t s
b e y o n d the fifth decade of life. T h e r e were 20 w o m e n a n d 10 m e n , a sex
r a t i o of 2 : 1 . T h e incidence of right-sided involvement was slightly m o r e
t h a n the left-sided, a n d in one p a t i e n t there was bilateral third-division
involvement. T h e second a n d t h i r d divisions of the trigeminal n e r v e were
most o f t e n affected, in a b o u t e q u a l frequencies. Sixteen p a t i e n t s r e p o r t e d
u n i l a t e r a l p a i n i n more t h a n one division. T h e d u r a t i o n of illness r a n g e d
f r o m two m o n t h s to 30 years, the average time being a b o u t eight years. Of
the 30 patients, 21 h a d b e e n treated previously w i t h d i p h e n y l h y d a n t o i n in
dosages r a n g i n g between 100 m g a n d 200 m g t.i.d. F o u r patients h a d good
relief of p a i n , a l t h o u g h temporary; two patients o b t a i n e d some relief;
a n d 15 p a t i e n t s h a d n o relief of p a i n .
T e n p a t i e n t s h a d previously u n d e r g o n e surgical neurolysis of the sensory
root of the trigeminal nerve, w i t h poor results. T w o p a t i e n t s h a d u n d e r -
gone neurolysis twice w i t h i n one year, a n d in one p a t i e n t neurolysis was
done twice w i t h i n six m o n t h s .
N o n e of the p a t i e n t s included in o u r study h a d associated illness, such
as m u l t i p l e sclerosis or a cerebellar-pontine angle t u m o r either initially or
later.
T e g r e t o l was administered to all 30 p a t i e n t s in dosages r a n g i n g f r o m
200 m g t.i.d. to 200 m g q.i.d. Eight patients were totally asymptomatic o n
200 m g b.i.d., a n d in one patient, 100 m g t.i.d. would completely control
the p a i n . T h e d u r a t i o n of t r e a t m e n t r a n g e d f r o m six m o n t h s to three
years. T h e f o l l o w i n g six initial laboratory d e t e r m i n a t i o n s were m a d e for
each p a t i e n t before a d m i n i s t r a t i o n of T e g r e t o l : complete b l o o d c o u n t a n d
differential count, platelet count, urinalysis, serum g l u t a m i c oxaloacetic
transaminase content, s e r u m alkaline p h o s p h a t a s e content, sulfobromo-
p h t h a l e i n r e t e n t i o n . D e t e r m i n a t i o n s of the values were repeated at m o n t h l y
intervals a f t e r a d m i n i s t r a t i o n of the drug.
Results
All 30 p a t i e n t s were pain-free w i t h i n 24 h r a f t e r receiving T e g r e t o l . T w o
patients h a d recurrence of pain, one w i t h i n the first week a n d the other
a f t e r 48 days of t r e a t m e n t . Twenty-eight p a t i e n t s h a d complete remis-
sion of p a i n w i t h n o recurrences. All of the patients were once again
able to eat solid food, d r i n k hot a n d cold liquids, a n d brush their teeth.
Twenty-eight patients received the d r u g for times r a n g i n g f r o m six
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m o n t h s to three years w i t h n o m a j o r adverse effects. T h e two p a t i e n t s
receiving the d r u g for less t h a n six m o n t h s were those w h o h a d re-
currence of p a i n . A d m i n i s t r a t i o n of the d r u g to the first p a t i e n t was
s t o p p e d after one week, a n d to the other a f t e r 48 days. B o t h of those pa-
tients h a d complete relief of p a i n after u n d e r g o i n g neurolysis. T h e course
of T e g r e t o l h a d to be stopped after one week i n a t h i r d p a t i e n t because of
the d e v e l o p m e n t of a n e r y t h e m a t o u s rash. T h e d r u g was w i t h h e l d for 10
days a n d t h e n administered, w i t h n o recurrence of the rash. O t h e r
adverse effects included lethargy, headache, nausea, a n d light-headedness.
Of the 28 p a t i e n t s w h o o b t a i n e d complete relief of p a i n , f r o m the d r u g ,
n i n e d i s c o n t i n u e d t r e a t m e n t i n the belief that they h a d b e e n cured. All
n i n e experienced p a i n again w i t h i n 24 hr, b u t the p a i n d i s a p p e a r e d w h e n
they again took T e g r e t o l .
As stated previously, the progress of each p a t i e n t was followed at m o n t h l y
intervals. O n l y one p a t i e n t h a d a b n o r m a l results of l a b o r a t o r y tests. T h i s
p a t i e n t showed an increase in the s u l f o b r o m o p h t h a l e i n r e t e n t i o n f r o m 1
p e r c e n t to 10 percent in o n e m o n t h . T h e course of T e g r e t o l was dis-
c o n t i n u e d for two weeks, a f t e r which time the s u l f o b r o m o p h t h a l e i n reten-
t i o n was 2.1 percent. T h e course of T e g r e t o l was restarted a n d all succeed-
i n g s u l f o b r o m o p h t h a l e i n r e t e n t i o n values have been n o r m a l ; a l a b o r a t o r y
e r r o r possibly could account for the discrepancy.
Comment
T e g r e t o l is a n iminostilbene. I t is related to the i m i p r a m i n e g r o u p of
drugs b u t n o t to the h y d a n t o i n s . Its m a i n p h a r m a c o l o g i c p r o p e r t y is a p o t e n t
a n t i c o n v u l s a n t action, especially w i t h respect to strychnine-produced
seizure activity, suggesting t h a t the site of action is at the spinal cord
level. 2 3 T h e d r u g has b e e n f o u n d to i n h i b i t polysynaptic reflexes such as
the l i n g u o - m a n d i b u l a r reflex of cats; the m o n o s y n a p t i c reflexes such as
the patellar reflex are only slightly affected. 2 4 T h e m a n u f a c t u r e r of
T e g r e t o l states that the m e d i c a t i o n i n h i b i t s n e u r o m u s c u l a r transmission
a n d t h a t it has a significant b u t n o t p r o n o u n c e d sedative effect a n d only a
slight analgesic effect.
A l t h o u g h serious b l o o d dyscrasias such as aplastic a n e m i a 2 5 ' 2 6 have
b e e n r e p o r t e d after its use, we have not seen any serious adverse effects.
M i n o r effects such as m i l d headache, nausea, light-headedness, lethargy, a n d
a skin rash occurred in seven patients. T h e s e u n t o w a r d effects were transi-
tory a n d the p a t i e n t s d i d n o t have to discontinue use of the d r u g , except
for o n e p a t i e n t in w h o m it p r o d u c e d a skin rash. T h e m e d i c a t i o n was
w i t h h e l d f r o m t h a t p a t i e n t for 10 days, d u r i n g which time the rash re-
gressed a n d the course of t h e r a p y was restarted w i t h n o f u r t h e r difficulty.
Mechanism of action of Tegretol
T h e pathogenesis of t r i g e m i n a l n e u r a l g i a is n o t k n o w n . M a n y theories
of etiology have b e e n proposed, b u t there has b e e n little or n o agreement.
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T h e r e seems to be a m a j o r division a m o n g the various a u t h o r s i n t o
those w h o propose a p e r i p h e r a l cause 2 7 ' 2 9 as opposed to those suggesting
d i s t u r b a n c e in the b r a i n stem. 7 ' 12 ' 30
Similarly, the m e c h a n i s m of action of T e g r e t o l a n d of d i p h e n y l l i y d a n t o i n
in the control of tic d o u l o u r e u x is n o t k n o w n . T h e r e has b e e n significant
evidence, though, to suggest t h a t the effect of b o t h drugs is central,
seeming to s u p p o r t the concept of a central pathogenesis of the disorder.
As stated previously, the p r o n o u n c e d a n t i c o n v u l s a n t effect of the d r u g ,
especially with regard to strychnine-produced seizure activity suggests
that its locus of action is in the spinal cord. H e r n á n d e z - P e ó n 1 0 i m p l a n t e d
m u l t i p o l a r electrodes i n t o the spinal trigeminal sensory nucleus a n d i n the
c e n t r u m m e d i a n u m of the t h a l a m i of cats t h a t were awake. Sensory
transmission of facial p a i n impulses was studied i m m e d i a t e l y before
a n d a f t e r the a d m i n i s t r a t i o n of T e g r e t o l at doses of 10 m g p e r k i l o g r a m of
b o d y weight. H e concluded t h a t the d r u g p r o d u c e d a p a r t i a l b u t signifi-
cant depression of the trigeminal-evoked potentials recorded f r o m the
b u l b a r level. T h e r e d u c t i o n observed in the spinal V sensory nucleus
never w e n t beyond 50 p e r c e n t of the initial a m p l i t u d e ; however, the
d i m i n u t i o n of the t h a l a m i c p o t e n t i a l s recorded f r o m the c e n t r u m me-
d i a n u m f r e q u e n t l y reached f r o m 80 to 90 percent of those in the p r e p h a r m a -
cologic control period. T h e r e f o r e , the partial blocking of t r i g e m i n a l p a i n im-
pulses at their e n t r a n c e to the central nervous system could be the cause
of a d i m i n u t i o n of p a i n in cases of t r i g e m i n a l neuralgia. T h e complete
disappearance of that p a i n , as observed clinically, can b e t t e r be e x p l a i n e d
by the action of the d r u g on t h a l a m i c n e u r o n s affected in sensory inte-
g r a t i o n a n d associated w i t h p a i n perception.
F r o m m a n d Killian 8 recorded extracellularly, w i t h glass microelectrodes
placed in the rostral p a r t of the spinal trigeminal nucleus of cats, the
activity of single neurons. D i p h e n y l l i y d a n t o i n , given in threshold doses of
3 m g per kilogram of b o d y weight, was f o u n d to cause a transient increase
in latency a n d a decrease in repetitive firing i n response to o r t h o d r o m i c
stimulation, while the response to a n t i d r o m i c s t i m u l a t i o n r e m a i n e d un-
changed. T h e increase i n latency was q u i t e variable. By contrast, a
t h r e s h o l d dose of T e g r e t o l (4 m g per kilogram of body weight) h a d a m u c h
m o r e prolonged a n d less variable effect w i t h response to increase in
latency a n d decrease in repetitive firing in response to o r t h o d r o m i c stimu-
lation. T e g r e t o l also h a d n o effect on response to a n t i d r o m i c stimulation.
Results b o t h of H e r n á n d e z - P e ó n 1 0 a n d of F r o m m a n d Killian 8 sub-
stantiate the view that T e g r e t o l inhibits polysynaptic transmission. Tegre-
tol has been shown to i n h i b i t polysynaptic transmission in b o t h the spinal
t r i g e m i n a l nucleus a n d in the c e n t r u m m e d i a n u m of the t h a l a m u s . Al-
t h o u g h the d r u g produces a m o r e p r o n o u n c e d i n h i b i t i o n on polysynaptic
transmission in the c e n t r u m m e d i a n u m , it c a n n o t be stated with cer-
tainty t h a t this area is its m a i n locus of action.
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Summary
T e g r e t o l was given in dosages of f r o m 100 to 800 m g to 30 p a t i e n t s w h o
h a d trigeminal neuralgia. All of the p a t i e n t s were completely free of
p a i n w i t h i n 24 hr. I n two p a t i e n t s the p a i n r e c u r r e d a n d was finally re-
lieved after neurolysis. N i n e p a t i e n t s w h o d i s c o n t i n u e d use of the drug, i n
the belief t h a t they were cured, p r o m p t l y h a d r e t u r n of p a i n w i t h i n 24
hr. T h e i r p a i n was once a g a i n completely relieved a f t e r the course of the
d r u g was restarted. N o m a j o r complications were n o t e d . G o o d results were
o b t a i n e d in 28 patients.
B o t h p e r i p h e r a l a n d central causes of t r i g e m i n a l n e u r a l g i a have b e e n
postulated by other authors. T h e p r o b a b l e m e c h a n i s m a n d locus of action
of T e g r e t o l are the i n h i b i t i o n of polysynaptic transmission in the spinal
trigeminal nucleus a n d t h a l a m u s . O n the basis of o u r experience w i t h the
d r u g we believe t h a t it has a sound a n d i m p o r t a n t place in the medical
t r e a t m e n t of trigeminal n e u r a l g i a .
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