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The side effects of carbamazepine therapy
The side effects of carbamazepinetherapy T. H. Redpath, F.D.S., M.R.C.S., L.R.C.P., and J. J. Gayford, M.B.B.S., B.D.S., F.D.S.R.C.S., London, England DEPARTMENT
OF ORAL
MEDICINE,
EASTMAN
DENTAL
HOSPITAL
I
n the 6 years since 1962, when Bloml originally reported the beneficial effects of carbamazepine (Tegretol) in six of eleven patients suffering from paroxysmal trigeminal neuralgia, the clinical effectiveness of this agent in approximately 70 per cent of the cases in which it has been used has been well documented.2-5 It has become the treatment of choice for this condition, replacing in most cases alcoholic injection or surgical section of the trigeminal nerve. Side effects from the drug are common, and the purpose of this article is to assess their occurrence and the precautions which should be taken for their prevention. Chemically, carbamazepine is an iminodibenzyl derivative related to imipramine, and in animal experiments Hernandez-Peon6 showed that the drug has a certain selectivity of action upon the neurons involved in the central transmission of trigeminal pain impulses. SIDE EFFECTS A review of the literature shows that up to 70 per cent of the patients who take carbamazepine experience minor side effects, such as vertigo, ataxia, drowsiness, or gastrointestinal upsets, which generally subside in 2 to 7 days. Areas of paresthesia in the distribution of the trigeminal nerve are not uncommon.*, ‘3 8 Three fatal cases of aplastic anemia have been reported,3* 8 and in a fourth case the patient recovered spontaneously.1° It is interesting to note that three of the four patients had similar total doses of 140 to 180 grams. About 70 per cent of the patients treated by Taylor2 complained of dryness of the mouth. Gamstorpll found that side effects usually disappeared with a temporary reduction in dose, and Walsh and Smiths concluded that the occurrence of adverse reactions was definitely related to dose. In the series reported by Burke and colleagues4 the incidence of side effects was reduced when patients were given a small initial dose (100 mg. twice daily for 2 days), which was then increased unt.il relief was obtained. 299
300
Redpath
O.R., ox. & O.P. September, 1968
and Gayford
Table I. Reported side effects o 1’ carbamazepinc therap! I
No. of (‘uses
Author Blom
(1963) 16
40
(1963) 2
52
Taylor Spillane
(1964) 3
Vanderfield Burke
and associates
Campbell Donner
(1964) 7
and associates and Frisk
Walsh and Smith Dalessio Rockliffe Present
(1965)4
Gadrointestincrl complaints
12 (35 cases wit,h complaints
in these groups)
13
29
9
1
1
70
10
7
1
70
10
21
75
(1966)s
20
and Davies
Vertigo
52
(1965)17
and Abbott
series
(1966) 5
9 t,axiu
(1966) 1s
23
(1966) 1s
20 25
13
5
1
4
7
8
5
4
In addition to the series summarized in Table I, other possible side effects of the drug have been reported. Spillane’s3 series included one case of diabetes and one of obstructive jaundice; in both casesthere was good reason to suppose that these developments were coincidental. The mixed cholestatic hepatitic type of jaundice reported by RamseyI was clearly induced by carbamazepine as it recurred with a drug challenge. CoombeP reported the case of a 41-year-old woman who had previously shown sensitivity to many other drugs and who developed Stevens-Johnson syndrome which was clearly related to the administration of carbamazepine. A 63-year-old woman with a history of lichenified eczema reacted to the drug on two occasions with a dermatologic lesion closely resembling lupus erythematosus.14 RESULTS
The present series of twenty-five patients, comprising sixteen females and nine males with a mean age of 54 years, were treated with doses of carbamazepine ranging from 200 to 1,200 mg. daily for periods of up to 34 weeks. Twelve patients experienced side effects, most commonly a transient ataxia or vertigo, which occurred in seven cases, usually at the beginning of treatment but sometimes apparently related to a high dosage. Nausea and vomiting in four caseswere also of short duration. One patient developed an itchy maculopapular rash over the lower abdomen and thighs, which resolved after therapy had been discontinued. On 1 gram of ca.rbamazepine daily, another patient,
Side effects of carbamazepke therapy
Volume 26 Number 3
Drowsiness 3
Rash
None
1
24
Others
Xerostomia (35 eases) j occasional paresthesias
4 3
Mental confusion ( 3 elderly patients) j 1 fatal aplastic anemia Paresthesia
3 27
10
10
1
301
(2)
28
Diplopia (l), stabilizing or psychotrophic effect in 50 per cent
5
Paresthesia
(2 per cent)
Headache (4), dysuria tinitus (1) 13
Depression
(1)
( 1)) paresthesia
(1)
despite being free from facial pain, developed severe depression: this was attributed to the drug, as it ceased when the patient was able to stop treatment. The same patient also experienced paresthesia in the distribution of the affected branch of the trigeminal nerve. No significant depression of the leukocyte counts carried out at monthly intervals throughout the duration of treatment was demonstrated in any of the cases. DISCUSSION The minor initial side effects of carbamazepine, such as ataxia, vertigo, and drowsiness, will usually subside within one week a.fter the beginning of treatment. However, they can be avoided in the majority of cases if therapy is commenced with small doses (100 mg. twice daily for 2 days) and then increased to the minimal effective therapeutic level in increments bf 200 mg. Vertigo is a serious problem only in the elderly, persons undergoing hypotensive therapy, or those with special occupational hazards. Ataxia is a contraindication to the use of the drug in persons with disseminated sclerosis. In some cases these minor side effects will remit with a temporary reduction in dosage. The drug should be discontinued if a sensitivity rash develops, especially in view of the fact that one of the two fatal cases of aplastic anemia reported by Donaldson and Graham9 was preceded by a rash. In all cases white cell counts and hemoglobin determinations should be carried out at monthly intervals and patients should be instructed to seek medical advice immediately if they experience such symptoms as excessive breathlessness, tiredness, or sore throat.
The maximum rc~rommm~clt~l tlosc of w rbamazepinc~ is 1,600 trig. p(‘r tlay, and this should be gradually reduced and, if possible, discontinued when thcl pat.ient has been fret of symptoms for 2 months. In this way’, the drug can bc used to tide the patient over through acute exacerbat.ions of the disease. Although Burke and Selby’s’” serials included patients who had been taking the drug for up to 2 years with no untoward effects, administration should cease whenever a natural remission permits. It is recommended that carbamazepine should not, be given within 3 weeks of the administration of monoamine oxidasc inhibitors or during pregnancy. CONCLUSIONS Carbamazepine is an effective medical breatment, in up to 70 per cent of persons with paroxysmal trigeminal neuralgia. Side effects are common and limit its use in the elderly and in persons with disseminated sclerosis, with the concomitant administration of monoamine oxidase inhibitors, and in other special cases. The drug should be used only when facilities for regular blood investigations are araila.blr. SUMMARY The side effects of carbamazepine used in the treatment of paroxysmal trigeminal neuralgia have been reviewed. A dosage schedule and a scheme of management have been suggested. We would like to thank Professor Sir Robert Bradlaw for his help and encoqragement and for permission to use his cases in the preparation of this paper. REFERENCES
Neuralgia; Its Treatment With a New Anticonvulsant Drug (G. 1. Blom, S.: Trigeminal 32883). Lancet 1: 839, 1962. 2. Taylo;; J. C.: Trigehinal Neuralgia Treated With G.32883, 5. Neurol., Neurosurg. & Psychiat, 26: 553, 1963. of Trigeminal Neuralgia With Tegretol, Practitioner 3. Spillane, J. D. : The Treatment 192: 71, 1964. M. 4. Burke, W. J. G., Grant, J. M. F., and Selby, G.: A Clinical Trial of Carbamazepine, J. Australia 1: 494, 1965. 5. CamDbell. F. G.. Graham. J. G.. and Zilkha. K. J.: A Clinical Trial of Carbamazeaine. I , J. Neuroi, Neurosurg. & Psychiat. 29: 265, li66. Upon the Transmission of 6. Hernandez-Peon, R. : The Central Action of Carbamazepine Triaeminal Pain Impulses. Med. Pharmacol. Exper. (Base11 12: 73. 1965. 7. Var?derfield, G.: T&e Midical Control of Trcgemihal Neuralgia: A Preliminary Report of G.32883, M. J. Australia 2: 82, 1964. 8. Walsh, T. J., and Smith, J. L.: The Treatment of Tic Doulourcux With Tegretol, Am. J. ODhth. 61: 550. 1966. 9. Donaldson, G. W.‘K., and Graham, J. G.: Aplastic Anaemia Following the Administration of Tegretol, Brit. J. Clin. Pratt. 19: 699, 1965. Anaemia After Carb10. Dyer, N. H., Hughes, D. T. D., and Jenkins, G. C.: Aplastic amazepine. Brit. M. J. 5479: 108. 1966. 11. Gamsiorp,’ I.: A Clinical Triai of Tegretol in Children With Epilepsy, Develop. Mrd. Child. Neurol. 8: 296, 1966. Jaundice, Brit. M. J. 4: 155, 1967. 12. Ramsey, I. D.: Carbamazepine-Induced 13. Coombes. Stevens-Johnson Svndrome Associated With CarbamazeDine. I , M. J. Australia 1:B. W.: 1965. 895, Brit. M. J. 2: 1434, 1966. 14. Simpson, J. R.: Collagen Disease Due to Carbamazepine, 15. Burke, W. J. G., and Selby, cf.: Trigeminal Neuralgia; Therapeutic Trial of Tegretol, Proc. Aust. Assn. Neurol. 3: 89, 1965. Treated With a New Anticonvulsant, Arch. Neurol. 9: 285, 16. Blom, S.: Tic Douloureux 1963.
Volume 26 Number 3
Side effects of carbamazepine therapy
303
17. Donner, M., and Frisk, M.: Carbamazepine Treatment of Epileptic and Psychic Symptoms in Children and Adolescents, Ann. paediat. Fenniae 11: 91,1965. 18. Dalessio, D. J., and Abbott, K. H.: A New Agent in the Treatment of Tic Doulourew, Headache 6: 103, 1966. 19. Rockliffe, B. W., and Davies, E. H.: Controlled Sequential Trials of Carbamazepine in Trigeminal Neuralgia, Arch. Neurol. 15: 129, 196G.
OF ORAL
MEDICINE,
EASTMAN
DENTAL
HOSPITAL
I
n the 6 years since 1962, when Bloml originally reported the beneficial effects of carbamazepine (Tegretol) in six of eleven patients suffering from paroxysmal trigeminal neuralgia, the clinical effectiveness of this agent in approximately 70 per cent of the cases in which it has been used has been well documented.2-5 It has become the treatment of choice for this condition, replacing in most cases alcoholic injection or surgical section of the trigeminal nerve. Side effects from the drug are common, and the purpose of this article is to assess their occurrence and the precautions which should be taken for their prevention. Chemically, carbamazepine is an iminodibenzyl derivative related to imipramine, and in animal experiments Hernandez-Peon6 showed that the drug has a certain selectivity of action upon the neurons involved in the central transmission of trigeminal pain impulses. SIDE EFFECTS A review of the literature shows that up to 70 per cent of the patients who take carbamazepine experience minor side effects, such as vertigo, ataxia, drowsiness, or gastrointestinal upsets, which generally subside in 2 to 7 days. Areas of paresthesia in the distribution of the trigeminal nerve are not uncommon.*, ‘3 8 Three fatal cases of aplastic anemia have been reported,3* 8 and in a fourth case the patient recovered spontaneously.1° It is interesting to note that three of the four patients had similar total doses of 140 to 180 grams. About 70 per cent of the patients treated by Taylor2 complained of dryness of the mouth. Gamstorpll found that side effects usually disappeared with a temporary reduction in dose, and Walsh and Smiths concluded that the occurrence of adverse reactions was definitely related to dose. In the series reported by Burke and colleagues4 the incidence of side effects was reduced when patients were given a small initial dose (100 mg. twice daily for 2 days), which was then increased unt.il relief was obtained. 299
300
Redpath
O.R., ox. & O.P. September, 1968
and Gayford
Table I. Reported side effects o 1’ carbamazepinc therap! I
No. of (‘uses
Author Blom
(1963) 16
40
(1963) 2
52
Taylor Spillane
(1964) 3
Vanderfield Burke
and associates
Campbell Donner
(1964) 7
and associates and Frisk
Walsh and Smith Dalessio Rockliffe Present
(1965)4
Gadrointestincrl complaints
12 (35 cases wit,h complaints
in these groups)
13
29
9
1
1
70
10
7
1
70
10
21
75
(1966)s
20
and Davies
Vertigo
52
(1965)17
and Abbott
series
(1966) 5
9 t,axiu
(1966) 1s
23
(1966) 1s
20 25
13
5
1
4
7
8
5
4
In addition to the series summarized in Table I, other possible side effects of the drug have been reported. Spillane’s3 series included one case of diabetes and one of obstructive jaundice; in both casesthere was good reason to suppose that these developments were coincidental. The mixed cholestatic hepatitic type of jaundice reported by RamseyI was clearly induced by carbamazepine as it recurred with a drug challenge. CoombeP reported the case of a 41-year-old woman who had previously shown sensitivity to many other drugs and who developed Stevens-Johnson syndrome which was clearly related to the administration of carbamazepine. A 63-year-old woman with a history of lichenified eczema reacted to the drug on two occasions with a dermatologic lesion closely resembling lupus erythematosus.14 RESULTS
The present series of twenty-five patients, comprising sixteen females and nine males with a mean age of 54 years, were treated with doses of carbamazepine ranging from 200 to 1,200 mg. daily for periods of up to 34 weeks. Twelve patients experienced side effects, most commonly a transient ataxia or vertigo, which occurred in seven cases, usually at the beginning of treatment but sometimes apparently related to a high dosage. Nausea and vomiting in four caseswere also of short duration. One patient developed an itchy maculopapular rash over the lower abdomen and thighs, which resolved after therapy had been discontinued. On 1 gram of ca.rbamazepine daily, another patient,
Side effects of carbamazepke therapy
Volume 26 Number 3
Drowsiness 3
Rash
None
1
24
Others
Xerostomia (35 eases) j occasional paresthesias
4 3
Mental confusion ( 3 elderly patients) j 1 fatal aplastic anemia Paresthesia
3 27
10
10
1
301
(2)
28
Diplopia (l), stabilizing or psychotrophic effect in 50 per cent
5
Paresthesia
(2 per cent)
Headache (4), dysuria tinitus (1) 13
Depression
(1)
( 1)) paresthesia
(1)
despite being free from facial pain, developed severe depression: this was attributed to the drug, as it ceased when the patient was able to stop treatment. The same patient also experienced paresthesia in the distribution of the affected branch of the trigeminal nerve. No significant depression of the leukocyte counts carried out at monthly intervals throughout the duration of treatment was demonstrated in any of the cases. DISCUSSION The minor initial side effects of carbamazepine, such as ataxia, vertigo, and drowsiness, will usually subside within one week a.fter the beginning of treatment. However, they can be avoided in the majority of cases if therapy is commenced with small doses (100 mg. twice daily for 2 days) and then increased to the minimal effective therapeutic level in increments bf 200 mg. Vertigo is a serious problem only in the elderly, persons undergoing hypotensive therapy, or those with special occupational hazards. Ataxia is a contraindication to the use of the drug in persons with disseminated sclerosis. In some cases these minor side effects will remit with a temporary reduction in dosage. The drug should be discontinued if a sensitivity rash develops, especially in view of the fact that one of the two fatal cases of aplastic anemia reported by Donaldson and Graham9 was preceded by a rash. In all cases white cell counts and hemoglobin determinations should be carried out at monthly intervals and patients should be instructed to seek medical advice immediately if they experience such symptoms as excessive breathlessness, tiredness, or sore throat.
The maximum rc~rommm~clt~l tlosc of w rbamazepinc~ is 1,600 trig. p(‘r tlay, and this should be gradually reduced and, if possible, discontinued when thcl pat.ient has been fret of symptoms for 2 months. In this way’, the drug can bc used to tide the patient over through acute exacerbat.ions of the disease. Although Burke and Selby’s’” serials included patients who had been taking the drug for up to 2 years with no untoward effects, administration should cease whenever a natural remission permits. It is recommended that carbamazepine should not, be given within 3 weeks of the administration of monoamine oxidasc inhibitors or during pregnancy. CONCLUSIONS Carbamazepine is an effective medical breatment, in up to 70 per cent of persons with paroxysmal trigeminal neuralgia. Side effects are common and limit its use in the elderly and in persons with disseminated sclerosis, with the concomitant administration of monoamine oxidase inhibitors, and in other special cases. The drug should be used only when facilities for regular blood investigations are araila.blr. SUMMARY The side effects of carbamazepine used in the treatment of paroxysmal trigeminal neuralgia have been reviewed. A dosage schedule and a scheme of management have been suggested. We would like to thank Professor Sir Robert Bradlaw for his help and encoqragement and for permission to use his cases in the preparation of this paper. REFERENCES
Neuralgia; Its Treatment With a New Anticonvulsant Drug (G. 1. Blom, S.: Trigeminal 32883). Lancet 1: 839, 1962. 2. Taylo;; J. C.: Trigehinal Neuralgia Treated With G.32883, 5. Neurol., Neurosurg. & Psychiat, 26: 553, 1963. of Trigeminal Neuralgia With Tegretol, Practitioner 3. Spillane, J. D. : The Treatment 192: 71, 1964. M. 4. Burke, W. J. G., Grant, J. M. F., and Selby, G.: A Clinical Trial of Carbamazepine, J. Australia 1: 494, 1965. 5. CamDbell. F. G.. Graham. J. G.. and Zilkha. K. J.: A Clinical Trial of Carbamazeaine. I , J. Neuroi, Neurosurg. & Psychiat. 29: 265, li66. Upon the Transmission of 6. Hernandez-Peon, R. : The Central Action of Carbamazepine Triaeminal Pain Impulses. Med. Pharmacol. Exper. (Base11 12: 73. 1965. 7. Var?derfield, G.: T&e Midical Control of Trcgemihal Neuralgia: A Preliminary Report of G.32883, M. J. Australia 2: 82, 1964. 8. Walsh, T. J., and Smith, J. L.: The Treatment of Tic Doulourcux With Tegretol, Am. J. ODhth. 61: 550. 1966. 9. Donaldson, G. W.‘K., and Graham, J. G.: Aplastic Anaemia Following the Administration of Tegretol, Brit. J. Clin. Pratt. 19: 699, 1965. Anaemia After Carb10. Dyer, N. H., Hughes, D. T. D., and Jenkins, G. C.: Aplastic amazepine. Brit. M. J. 5479: 108. 1966. 11. Gamsiorp,’ I.: A Clinical Triai of Tegretol in Children With Epilepsy, Develop. Mrd. Child. Neurol. 8: 296, 1966. Jaundice, Brit. M. J. 4: 155, 1967. 12. Ramsey, I. D.: Carbamazepine-Induced 13. Coombes. Stevens-Johnson Svndrome Associated With CarbamazeDine. I , M. J. Australia 1:B. W.: 1965. 895, Brit. M. J. 2: 1434, 1966. 14. Simpson, J. R.: Collagen Disease Due to Carbamazepine, 15. Burke, W. J. G., and Selby, cf.: Trigeminal Neuralgia; Therapeutic Trial of Tegretol, Proc. Aust. Assn. Neurol. 3: 89, 1965. Treated With a New Anticonvulsant, Arch. Neurol. 9: 285, 16. Blom, S.: Tic Douloureux 1963.
Volume 26 Number 3
Side effects of carbamazepine therapy
303
17. Donner, M., and Frisk, M.: Carbamazepine Treatment of Epileptic and Psychic Symptoms in Children and Adolescents, Ann. paediat. Fenniae 11: 91,1965. 18. Dalessio, D. J., and Abbott, K. H.: A New Agent in the Treatment of Tic Doulourew, Headache 6: 103, 1966. 19. Rockliffe, B. W., and Davies, E. H.: Controlled Sequential Trials of Carbamazepine in Trigeminal Neuralgia, Arch. Neurol. 15: 129, 196G.