British Journal of Oral Surgery (1976), 13, 289-293
ADVERSE
REACTIONS
TO CARBAMAZEPINE
(TEGRETOL)
SHAKIR S. AL-UBAIDY, Ph.D., M.Sc., B.D.S. and FERGAL F. NALLY, F.D.S.R.C.S.(Eng.), F.F.D.R.C.S.I., L.R.C.P.(Irel.),
L.R.C.S.(Irel.)
Department of Oral Medicine, Institute of Dental Surgery, University of London, Eastman Dental Hospital, London WCrX 8LD A review of the literature on adverse reactions to carbamazepine Summary. used in treatment of paroxysmal trigeminal neuralgia is presented and a survey of 120' cases is reported. The case reports were selected to emphasise some of the adverse reactions to carbamazepine. The blood picture was monitored every month while patients were on carbamazepine therapy. As with any medication, side-effects and complications may occur. When a patient shows a minor intolerance to the drug, the dose should be reduced to the one that controls the symptoms incompletely but pr&ces no adverse effects. As the patient acquires greater tolerance the dosage may be gradually increased. Periodic monitoring of the blood picture and of liver and kidney function is important.
INTRODUCTION CARBAMAZEPINE is an anticonvulsant drug which is also effective in the management of paroxysmal trigeminal neuralgia. It is an iminostilbene derivative, is chemically unlike epanutin, but it is closely related to imipramine hydrochloride (Tofranil), with the chemical formula 5-Carbamyl-gH-dibenzo-b-f-azepine. Blom (1962) reported that it also affects bulbar and spinal reflexes, including the polysynaptic linguo-mandibular reflex, which is probably relevant to its mode of action in trigeminal neuralgia. Spillane (1964) reported that one patient died of aplastic anaemia, one developed jaundice, and one diabetes mellitus. Other sideeffects included giddiness, unsteadiness and drowsiness. The purpose of this paper is to describe some of the adverse reactions to carbamazepine therapy in a group of 120 patients under our care over a IO-year period. It was apparent from the review of 120 cases with trigeminal neuralgia that carbamazepine was found to be effective in 84 per cent. Pain relief was noted within 24 hours in 75 per cent. The blood picture was monitored every month while patients were on therapy. Figure I shows the persistent drop in the white blood cell count over an 84-month period in this group. It was decided to stop the drug if the cell count fell below 3000 per cm and this adds to the significance of the findings in Figure I. A more detailed study of the effect of increasing dose of carbamazepine (up to IOOO mg) in 3 months was undertaken (Fig. 2). It will be seen that a significant drop occurred in the early stages of treatment and this was followed by a gradual decline as the dose was increased. Two case reports are presented to illustrate some points in the discussion.
Case I. A 47-year-old man was referred with severe pain in the upper jaw on the left side of 3 months’ duration. There was a history of a fractured skull when he was 12 years old. He had been investigated for epilepsy at the age of 17 years and phenobarbitone
30 mg twice a day was prescribed. Received 19.8.75.
289
He was involved Accepted 4.9.75
in a road traffic accident
BRITISH
290
JOURNAL OF ORAL SURGERY
9000
a
t;
u % ” ; z
8000 7000 6000 5000 4000 3000 2000
loo0 tl 0
2
4
6
8
IO
12
Duration
24
36
of Therapy
48
60
72
84
(Mths)
FIG. I Graph showing the persistent drop in white blood cell count over an Q-month
11000
period.
b-
IO 000 9000
-
8000 7000
-
6000
-
5000
-
4000
-
3000
-
2000
-
1000
o-
I
I
I
I
I
I
100
200
400
600
800
Dose of Carbamazepine
I 1000
(mg)
FIG. 2 Showing the effect of increasing dose of carbamazepine in 3 months on the white blood cell count in 120 cases.
ADVERSEREACTIONSTOCARBAMAZEPINE(TEGRETOL)
291
in 1956 and sustained a fractured skull, and at operation the left carotid artery was ligated. This resulted in a left retro-orbital arterio-venous fistula and unilateral proptosis. A fascia lata graft had to be used for a C.S.F. leak and since the accident he has had bilateral carotid angiograms. On examination he had extreme difficulty in talking due to the pain. He had an obvious scar over the left frontal area and left proptosis (Fig. 3). Fairly severe conjunctivitis was also noted. A diagnosis of paroxysmal trigeminal neuralgia was made and accordingly 400 mg carbamazepine daily increasing to 600 mg daily was prescribed. The initial white cell count was 5200 per cmm and it dropped to 2500 per c.mm. Eight weeks after starting carbamazepine therapy the dose was reduced immediately to prevent further drop. Case 2. A To-year-old man was referred with severe pain in the left side of the lower jaw. A diagnosis of paroxysmal trigeminal neuralgia was made and carbamazepine The initial response was favourable, but the pain was not completely therapy started. controlled on 200 mg daily. As the dose was increased to 800 mg daily he experienced giddiness, drowsiness, anorexia, gastrointestinal disturbances and an extensive urticarial rash developed over the chest, shoulders, arms, legs and back (Fig. 4). His eosinophils count increased from 180 per c.mm to 830 per c.mm (3 per cent to 9 per cent) and a skin biopsy was reported as follows: Macro: A strip of skin measuring 25 x 5 x 2.5 cm. Micro: The covering epidermis appears slightly atrophic and focal aggregations of chronic inj?ammatory cells are seen in the dermis. The appearances are, however, histologically non-diagnostic.
Carbamazepine was immediately terminated and piriton 12 mg daily was administered for about IO days. The rash gradually disappeared. A skin patch test with carbamazepine was positive. In the meantime, the pain returned and he was started on phenytoin sodium (epanutin) therapy, zoo mg taken orally daily. The response was favourable, and 2 days later he was free of pain and reported that he had only a single, momentary attack in the previous 24 hours. The pain did not recur and he was kept on minimum maintenance dose. Other toxic effects in this group, included vertigo, 33 per cent, drowsiness 52 per cent, postural hypotension in IO cases. One patient of 55 years of age, on carbamazepine therapy for 5 years developed diabetes which has rendered his trigeminal neuralgia out Five patients developed urticarial rashes and therapy was discontinued (two of control. cases) or changed to another anticonvulsant agents (three cases).
DISCUSSION The widespread interest being taken in this compound is reflected by the number of studies reporting adverse reactions. The toxic effects vary, tending to be worse initially and then subside. They include vertigo, drowsiness, erythematous morbilliform and urticarial rashes, anorexia, vomiting and diarrhoea. Carnaille et al. (1966) have surveyed the therapeutic effects of carbamazepine on facial pain in 664 cases; 108 of these were personally observed and 556 were treated by other physicians. Adverse reactions affected only 30 per cent of the 108 cases; they were generally mild and consisted of giddiness, gastrointestinal disturbances, somnolence and, most serious, allergic skin reactions which led to a discontinuation of the drug in three cases. Bonduelle (rg64), in his study of 60 patients with facial pain of various types which were treated with carbamazepine showed the drug to be most effective in cases of
292
BRITISH
JOURNAL OF ORAL SURGERY
FIG. 3 Showing left eye proptosis in a 47-year-old man (Case I).
FIG. 4 Shows extensive urticarial rash over the volar aspect of the forearm.
ADVERSE REACTIONS TO CARBAMAZEPINE (TEGRETOL)
293
trigeminal neuralgia, though some improvement was also obtained in symptomatic facial neuralgia probably because of its chemical similarity to the tricyclic antidepressants. Two-thirds of the patients developed adverse effects; these included nausea, asthenia, vertigo and an eczematous rash, but it was necessary to interrupt treatment in only I0 per cent of cases. A leucopenia was noted in 15 per cent of cases. Burke (1965) reported that of 68 patients with trigeminal neuralgia who were treated by tegretol, 2 patients developed recurrent skin rashes and withdrawal Kruger (1966) reported that a severe general of the treatment was inevitable. reaction to carbamazepine in a 59-year-old woman with liver disease: the clinical picture included somnolence, an exanthematous rash, facial oedema, fever and haematological abnormalities. The author suggested that this reaction was probably allergic in nature. Two patients, aged 60 and 52, developed a fatal pancytopenia after receiving carbamazepine for 8 to 12 months respectively. The authors consider that the haematological reaction may have been attributable to the drug in the first case but the second patient suffered from malignant disease with which the pancytopenia might have been associated (Donaldson and Graham, 1965). Dyer et al. (1966) reported a 58-year-old woman with trigeminal neuralgia developed pancytopenia after receiving 180 mg of carbamazepine over a 9-month period. She recovered after treatment with blood transfusions. The Stevens-Johnson syndrome has been reported in association with treatment of carbamazepine (Inglis, 1965). ACKNOWLEDGEMENTS We wish to thank Mr Khee Wee Lee for the histopathology report. We are also grateful to Dr G. Blake for the haematology investigations and Dr J. J. Prior for the radiographs. Our thanks are also due to Mr J. Morgan for the illustrations and to Miss Helen Savva for preparing the manuscript. REFERENCES BLOM, S. (1962). Lancet, I, 839. SPILLANE, J. D. (1964). Practitioner, 192, 71. CARNAILLE,H., DE COSTER,J., TYBERGHEIN,J. & DEREYMAEKER, A. (1966). Acta Neurologica et Psychiatrica Belgique, 6613, 175. BONDUELLE,M. (1964). Presse medicale, 72, 1905. BURKE, W. J. G. (1965). Medical Journal of Australia, 3, 494. KRUGER,W. (1966). Medizinische Klinik, 61117. 674. DONALDSON, G. W. K. & GRAHAM,J. F. (1965). British Journal of Clinical Practice, 19172, 699. DYER, N. H., HUGHES,D. T. & JENKINS,G. C. (1966). British Medical Journal, 5479, 108. INGLIS, W. (1965). Medical Journal of Australia, 2, 94.
ADVERSE
REACTIONS
TO CARBAMAZEPINE
(TEGRETOL)
SHAKIR S. AL-UBAIDY, Ph.D., M.Sc., B.D.S. and FERGAL F. NALLY, F.D.S.R.C.S.(Eng.), F.F.D.R.C.S.I., L.R.C.P.(Irel.),
L.R.C.S.(Irel.)
Department of Oral Medicine, Institute of Dental Surgery, University of London, Eastman Dental Hospital, London WCrX 8LD A review of the literature on adverse reactions to carbamazepine Summary. used in treatment of paroxysmal trigeminal neuralgia is presented and a survey of 120' cases is reported. The case reports were selected to emphasise some of the adverse reactions to carbamazepine. The blood picture was monitored every month while patients were on carbamazepine therapy. As with any medication, side-effects and complications may occur. When a patient shows a minor intolerance to the drug, the dose should be reduced to the one that controls the symptoms incompletely but pr&ces no adverse effects. As the patient acquires greater tolerance the dosage may be gradually increased. Periodic monitoring of the blood picture and of liver and kidney function is important.
INTRODUCTION CARBAMAZEPINE is an anticonvulsant drug which is also effective in the management of paroxysmal trigeminal neuralgia. It is an iminostilbene derivative, is chemically unlike epanutin, but it is closely related to imipramine hydrochloride (Tofranil), with the chemical formula 5-Carbamyl-gH-dibenzo-b-f-azepine. Blom (1962) reported that it also affects bulbar and spinal reflexes, including the polysynaptic linguo-mandibular reflex, which is probably relevant to its mode of action in trigeminal neuralgia. Spillane (1964) reported that one patient died of aplastic anaemia, one developed jaundice, and one diabetes mellitus. Other sideeffects included giddiness, unsteadiness and drowsiness. The purpose of this paper is to describe some of the adverse reactions to carbamazepine therapy in a group of 120 patients under our care over a IO-year period. It was apparent from the review of 120 cases with trigeminal neuralgia that carbamazepine was found to be effective in 84 per cent. Pain relief was noted within 24 hours in 75 per cent. The blood picture was monitored every month while patients were on therapy. Figure I shows the persistent drop in the white blood cell count over an 84-month period in this group. It was decided to stop the drug if the cell count fell below 3000 per cm and this adds to the significance of the findings in Figure I. A more detailed study of the effect of increasing dose of carbamazepine (up to IOOO mg) in 3 months was undertaken (Fig. 2). It will be seen that a significant drop occurred in the early stages of treatment and this was followed by a gradual decline as the dose was increased. Two case reports are presented to illustrate some points in the discussion.
Case I. A 47-year-old man was referred with severe pain in the upper jaw on the left side of 3 months’ duration. There was a history of a fractured skull when he was 12 years old. He had been investigated for epilepsy at the age of 17 years and phenobarbitone
30 mg twice a day was prescribed. Received 19.8.75.
289
He was involved Accepted 4.9.75
in a road traffic accident
BRITISH
290
JOURNAL OF ORAL SURGERY
9000
a
t;
u % ” ; z
8000 7000 6000 5000 4000 3000 2000
loo0 tl 0
2
4
6
8
IO
12
Duration
24
36
of Therapy
48
60
72
84
(Mths)
FIG. I Graph showing the persistent drop in white blood cell count over an Q-month
11000
period.
b-
IO 000 9000
-
8000 7000
-
6000
-
5000
-
4000
-
3000
-
2000
-
1000
o-
I
I
I
I
I
I
100
200
400
600
800
Dose of Carbamazepine
I 1000
(mg)
FIG. 2 Showing the effect of increasing dose of carbamazepine in 3 months on the white blood cell count in 120 cases.
ADVERSEREACTIONSTOCARBAMAZEPINE(TEGRETOL)
291
in 1956 and sustained a fractured skull, and at operation the left carotid artery was ligated. This resulted in a left retro-orbital arterio-venous fistula and unilateral proptosis. A fascia lata graft had to be used for a C.S.F. leak and since the accident he has had bilateral carotid angiograms. On examination he had extreme difficulty in talking due to the pain. He had an obvious scar over the left frontal area and left proptosis (Fig. 3). Fairly severe conjunctivitis was also noted. A diagnosis of paroxysmal trigeminal neuralgia was made and accordingly 400 mg carbamazepine daily increasing to 600 mg daily was prescribed. The initial white cell count was 5200 per cmm and it dropped to 2500 per c.mm. Eight weeks after starting carbamazepine therapy the dose was reduced immediately to prevent further drop. Case 2. A To-year-old man was referred with severe pain in the left side of the lower jaw. A diagnosis of paroxysmal trigeminal neuralgia was made and carbamazepine The initial response was favourable, but the pain was not completely therapy started. controlled on 200 mg daily. As the dose was increased to 800 mg daily he experienced giddiness, drowsiness, anorexia, gastrointestinal disturbances and an extensive urticarial rash developed over the chest, shoulders, arms, legs and back (Fig. 4). His eosinophils count increased from 180 per c.mm to 830 per c.mm (3 per cent to 9 per cent) and a skin biopsy was reported as follows: Macro: A strip of skin measuring 25 x 5 x 2.5 cm. Micro: The covering epidermis appears slightly atrophic and focal aggregations of chronic inj?ammatory cells are seen in the dermis. The appearances are, however, histologically non-diagnostic.
Carbamazepine was immediately terminated and piriton 12 mg daily was administered for about IO days. The rash gradually disappeared. A skin patch test with carbamazepine was positive. In the meantime, the pain returned and he was started on phenytoin sodium (epanutin) therapy, zoo mg taken orally daily. The response was favourable, and 2 days later he was free of pain and reported that he had only a single, momentary attack in the previous 24 hours. The pain did not recur and he was kept on minimum maintenance dose. Other toxic effects in this group, included vertigo, 33 per cent, drowsiness 52 per cent, postural hypotension in IO cases. One patient of 55 years of age, on carbamazepine therapy for 5 years developed diabetes which has rendered his trigeminal neuralgia out Five patients developed urticarial rashes and therapy was discontinued (two of control. cases) or changed to another anticonvulsant agents (three cases).
DISCUSSION The widespread interest being taken in this compound is reflected by the number of studies reporting adverse reactions. The toxic effects vary, tending to be worse initially and then subside. They include vertigo, drowsiness, erythematous morbilliform and urticarial rashes, anorexia, vomiting and diarrhoea. Carnaille et al. (1966) have surveyed the therapeutic effects of carbamazepine on facial pain in 664 cases; 108 of these were personally observed and 556 were treated by other physicians. Adverse reactions affected only 30 per cent of the 108 cases; they were generally mild and consisted of giddiness, gastrointestinal disturbances, somnolence and, most serious, allergic skin reactions which led to a discontinuation of the drug in three cases. Bonduelle (rg64), in his study of 60 patients with facial pain of various types which were treated with carbamazepine showed the drug to be most effective in cases of
292
BRITISH
JOURNAL OF ORAL SURGERY
FIG. 3 Showing left eye proptosis in a 47-year-old man (Case I).
FIG. 4 Shows extensive urticarial rash over the volar aspect of the forearm.
ADVERSE REACTIONS TO CARBAMAZEPINE (TEGRETOL)
293
trigeminal neuralgia, though some improvement was also obtained in symptomatic facial neuralgia probably because of its chemical similarity to the tricyclic antidepressants. Two-thirds of the patients developed adverse effects; these included nausea, asthenia, vertigo and an eczematous rash, but it was necessary to interrupt treatment in only I0 per cent of cases. A leucopenia was noted in 15 per cent of cases. Burke (1965) reported that of 68 patients with trigeminal neuralgia who were treated by tegretol, 2 patients developed recurrent skin rashes and withdrawal Kruger (1966) reported that a severe general of the treatment was inevitable. reaction to carbamazepine in a 59-year-old woman with liver disease: the clinical picture included somnolence, an exanthematous rash, facial oedema, fever and haematological abnormalities. The author suggested that this reaction was probably allergic in nature. Two patients, aged 60 and 52, developed a fatal pancytopenia after receiving carbamazepine for 8 to 12 months respectively. The authors consider that the haematological reaction may have been attributable to the drug in the first case but the second patient suffered from malignant disease with which the pancytopenia might have been associated (Donaldson and Graham, 1965). Dyer et al. (1966) reported a 58-year-old woman with trigeminal neuralgia developed pancytopenia after receiving 180 mg of carbamazepine over a 9-month period. She recovered after treatment with blood transfusions. The Stevens-Johnson syndrome has been reported in association with treatment of carbamazepine (Inglis, 1965). ACKNOWLEDGEMENTS We wish to thank Mr Khee Wee Lee for the histopathology report. We are also grateful to Dr G. Blake for the haematology investigations and Dr J. J. Prior for the radiographs. Our thanks are also due to Mr J. Morgan for the illustrations and to Miss Helen Savva for preparing the manuscript. REFERENCES BLOM, S. (1962). Lancet, I, 839. SPILLANE, J. D. (1964). Practitioner, 192, 71. CARNAILLE,H., DE COSTER,J., TYBERGHEIN,J. & DEREYMAEKER, A. (1966). Acta Neurologica et Psychiatrica Belgique, 6613, 175. BONDUELLE,M. (1964). Presse medicale, 72, 1905. BURKE, W. J. G. (1965). Medical Journal of Australia, 3, 494. KRUGER,W. (1966). Medizinische Klinik, 61117. 674. DONALDSON, G. W. K. & GRAHAM,J. F. (1965). British Journal of Clinical Practice, 19172, 699. DYER, N. H., HUGHES,D. T. & JENKINS,G. C. (1966). British Medical Journal, 5479, 108. INGLIS, W. (1965). Medical Journal of Australia, 2, 94.
