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Phenothiazine-induced Stress Incontinence
or Copyright © 19'7]
;JoL l•:)9, 8 p:'il Printed
ilkins
PHENOTHIAZINE-INDUCED STRESS THEODORE VAN PUTTEN, 11/!ICHAEL D. MALKIN
AND
IvlICHAEL S. WEISS
From the Brentwood Veterans Administration Hospital and Uniuersity of California School of Medicine, Los Angeles, California
Recently, stress incontinence caused phenothiazines was noted in 3 female psychiatric patients. The incontinence was not of the overflow Phenothiazine-induced stress incontinence has not been reported previously. CASE REPORTS
Case I. A 40-year-old nulliparous, white woman complained of severe stress incontinence 2 years in duration. She was receiving 200 mg. mellaril 3 times a The diagnosis is chronic paranoid schizophrenia but the patient has been well compensated as an outpatient on mellaril for the past 2 years. There is no evidence of conflicts centering around urination nor a history of enuresis. With coughing or sneezing she spilled rather larger quantities of urine to the that she would sit on a sheet lest she stain the furniture. She considered the incontinence uc,rn,w~c,Er, and embarrassing. She denied other urinary symptoms such as or any diffimicturition. and culture were negative. An A-B-A-B design was used. The kept accurate written records. Termination of mellaril relieved the stress incontinence completely. of 600 mg. mellaril daily was accompanied stress incontinence. Termination of mellaril again abolished the stress incontinence. The on-off effect was striking. Case 2. A
incontinence to the of urge and dies on the floor. She denied had no disturbances of norrDal rnictur1tion. She to void every hour i~t the cf b:1t contin"Jed, consultation revealed no ar,_d the no stress incontinence of unknown She was switched to 25 mg. enanthate, intramuscularly, every 2 weeks. On this low of a phenothiazine with less autonomic effect the dribbling-type incontinence ceased and stress incontinence was reduced to former inconsequential levels. Urinalysis and urine cultures were Accepted for publication August 4, 1972. 625
negative. She had delivered 1 child per vaginam and had had extremely slight stress incontinence during the past several years. Case 3. A 48-year-old mother of 3 children was hospitalized because of a depressive reaction. For the past 8 years she had experienced very mild stress incontinence. When placed on 150 mg. mellaril 4 times a day, she was embarrassed by a severe dribbling incontinence, markedly exacerbated by coughing, sneezing, laughing or even mild effort (such as climbing stairs). She required continuous use of sanitary napkins. Mellaril was stopped and replaced by 150 mg. thorazine 4 times a day. The incontinence continued. When phenothiazines were stopped, the incontinence reverted to its original minimal level. The on-off effect was striking. She denied dysuria, urgency or other urinary symptoms. and culture were normal. urograms and voiding cystograms performed as part of a hypertension were normal. Pelvic exarnination was unremarkable. D!SClTSSIOJ\;
Fairly convincing psychological reasons have been advanced to explain frequency and urgency (what would be called urgency incontinence or unstable bladder the but in these 3 no emotional determinants to explain stress incontinence could be discovered. i-, The incontinence was not related to the affective state and none of these patients had a of conflict around the system. They embarrassed the incontinence to from it. No patient exof urinary urge but urge incontinence can be clinically indistinguishable from st:ress incontinence. ·5 urge incontinence is a chronic disorder with strong aspects and in our patients the incontinence was short-li\/ed. Tl1e stress incontinence cannot be attributed to
inconti604,
'Bates, C. P .. Continence and incontinence. A clinical study of the dynamics of voiding and of the sphincter mechanism. Ann. Coll. Surg. Engl., 49: 18, 1971. 5 Frewen, W. K.: and stress incontinence; fact and fiction. J. Obst. Gynaec. Brit. Comm., 77:932, 1970.
626
VAN PUTTEN, MALKIN AND WEISS
the anticholinergic action of the phenothiazines because stress incontinence does not occur with pure anticholinergic drugs. Overflow incontinence caused by the anticholinergic action of the phenothiazines is, of course, well known. There is evidence that the resting intraurethral pressure is decreased in female subjects with stress incontinence. •-s The sphincteric mechanism responsible for the maintenance of urethral pressure is unclear but it seems certain that the internal sphincter plays a part. 9 It has long been known that the internal sphincter and bladder neck constrict independently of detrusor activity in response to sympathetic stimulation. 10 · 11 This was thought to be of little functional significance since section of the sympathetic nerve supply leads to no significant alteration of normal micturition. 10 • 11 Kleeman recently demonstrated that, in dogs, sympathomimetic drugs with an alpha effect (epinephrine, norepinephrine, phenylephrine) cause bladder neck constriction with a sharp concomitant rise in urethral resistance. 12 Ephedrine-a sympathomimetic drug-has actually been used in the treatment of stress incontinence with at least a measure of success. 13 Kleeman reported on a 69-year-old woman with stress incontinence induced by reserpine-a sympatholytic drug. 12 To our knowledge this was the first reported case of drug-induced stress incontinence. The incontinence was attributed to decreased internal sphincter tone in a female subject already predisposed to stress incontinence by a small cystourethrocele. Since phenothiazines (particularly mellaril and thorazine) exhibit strong alpha adrenergic blocking activity, it is likely that they could decrease 6 Toews, H. A.: lntraurethral and intravesical pressures in normal and stress-incontinent women. Obst. Gynec., 29: 613, 1967. 7 Enhorning, G.: Simultaneous recording of intravesical and intra-urethral pressure. A study on urethral closure in normal and stress incontinent women. Acta Chir. Scand., suppl. 276, p. 1, 1961. 'Enhorning, G., Miller, E. R. and Hinman, F., Jr.: Urethral closure studied with cineroentgenography and simultaneous bladder-urethra pressure recording. Surg., Gynec. & Obst., 118: 507, 1964. 9 Boyarsky, S. and Ruskin, H.: Physiology of the bladder. In: Urology, 3rd ed. Edited by M. F. Campbell and J. H. Harrison. Philadelphia: W. B. Saunders Co., vol. I, pp. 105-135, 1970. 1 ° Kuru, M.: Nervous control of micturition. Physiol. Rev., 45: 425, 1965. 11 Denny-Brown, D.: The state of the bladder and its sphincters in complete transverse lesions of the spinal cord and cauda equina. Brain, 56: 397, 1933. 12 Kleeman, F. J.: The physiology of the internal urinary sphincter. J. Urol., 104: 549, 1970. "Rashbaum, M. and Mandelbaum, C. C.: Nonoperative treatment of urinary incontinence in women. Amer. J. Obst. Gynec., 36: 777, 1948.
internal sphincter tone. 14 In women with mild pre-existing stress incontinence this additional reduction in internal sphincter tone could produce disabling incontinence. Further evidence for phenothiazine-induced internal sphincter relaxation comes from the observation of aspermia in men. 15 Aspermia is the absence of ejaculation during coitus or masturbation. Normally, the internal sphincter closes forcefully during orgasm to prevent regurgitation of seminal fluid into the bladder. 16 In phenothiazine-induced aspermia, male subjects pass white, sperm-containing urine. Aspermia has also been reported with phenoxybenzamine, a potent alpha adrenergic blocking agent. 15 Phenoxybenzamine blocks the constricting effect of epinephrine on the internal sphincter in dogs. 12 While this explanation of internal sphincter relaxation caused by the sympatholytic action of phenothiazines fits nicely into the existing data, it does not explain why these patients demonstrated only minimal evidence of other adrenergic blocking effects such as postural hypotension. Since bladder control has extensive central nervous system representation, phenothiazines may induce incontinence by means of a central effect. 10 It is not known if tolerance to phenothiazineinduced internal sphincter relaxation will develop. The 2-year period of stress incontinence in case 1 suggests that at least in some individuals it will not. The development of tolerance to such side effects as hypotension and drowsiness is rather well documented. 14 Th& incidence of phenothiazine-induced stress incontinence in anatomically predisposed women is probably quite low, since phenothiazineinduced aspermia in men occurs in less than 5 to 30 per cent of cases. 15 • 17 SUMMARY
Three cases are presented of severe stress incontinence apparently caused by phenothiazines. It is postulated that the alpha adrenergic blocking properties of the phenothiazines induce internal urinary sphincter relaxation in anatomically predisposed female subjects. 14 Jarvik, M. E.: Drugs used in the treatment of psychiatric disorders. In: The Pharmacological Basis of Therapeutics. Edited L. S. Goodman and A. Gilman. London: The Macmillan Co., pp. 151-169, 1970. 15 Shader, R. I.: Ejaculation disorders. In: Psychotrophic Drug Side Effects. Edited by R. I. Shader and A. DiMascio. Baltimore: The Williams & Wilkins Co., pp. 72-76, 1970. 16 Denny-Brown, D. E.: Nervous disturbances of vesical sphincter. New Engl. J. Med., 215: 647, 1936. "Blair, J. H. and Simpson, G. M.: Effect of antipsychotic drugs on reproductive functions. Dis. Nerv. Syst., 27: 645, 1966.
;JoL l•:)9, 8 p:'il Printed
ilkins
PHENOTHIAZINE-INDUCED STRESS THEODORE VAN PUTTEN, 11/!ICHAEL D. MALKIN
AND
IvlICHAEL S. WEISS
From the Brentwood Veterans Administration Hospital and Uniuersity of California School of Medicine, Los Angeles, California
Recently, stress incontinence caused phenothiazines was noted in 3 female psychiatric patients. The incontinence was not of the overflow Phenothiazine-induced stress incontinence has not been reported previously. CASE REPORTS
Case I. A 40-year-old nulliparous, white woman complained of severe stress incontinence 2 years in duration. She was receiving 200 mg. mellaril 3 times a The diagnosis is chronic paranoid schizophrenia but the patient has been well compensated as an outpatient on mellaril for the past 2 years. There is no evidence of conflicts centering around urination nor a history of enuresis. With coughing or sneezing she spilled rather larger quantities of urine to the that she would sit on a sheet lest she stain the furniture. She considered the incontinence uc,rn,w~c,Er, and embarrassing. She denied other urinary symptoms such as or any diffimicturition. and culture were negative. An A-B-A-B design was used. The kept accurate written records. Termination of mellaril relieved the stress incontinence completely. of 600 mg. mellaril daily was accompanied stress incontinence. Termination of mellaril again abolished the stress incontinence. The on-off effect was striking. Case 2. A
incontinence to the of urge and dies on the floor. She denied had no disturbances of norrDal rnictur1tion. She to void every hour i~t the cf b:1t contin"Jed, consultation revealed no ar,_d the no stress incontinence of unknown She was switched to 25 mg. enanthate, intramuscularly, every 2 weeks. On this low of a phenothiazine with less autonomic effect the dribbling-type incontinence ceased and stress incontinence was reduced to former inconsequential levels. Urinalysis and urine cultures were Accepted for publication August 4, 1972. 625
negative. She had delivered 1 child per vaginam and had had extremely slight stress incontinence during the past several years. Case 3. A 48-year-old mother of 3 children was hospitalized because of a depressive reaction. For the past 8 years she had experienced very mild stress incontinence. When placed on 150 mg. mellaril 4 times a day, she was embarrassed by a severe dribbling incontinence, markedly exacerbated by coughing, sneezing, laughing or even mild effort (such as climbing stairs). She required continuous use of sanitary napkins. Mellaril was stopped and replaced by 150 mg. thorazine 4 times a day. The incontinence continued. When phenothiazines were stopped, the incontinence reverted to its original minimal level. The on-off effect was striking. She denied dysuria, urgency or other urinary symptoms. and culture were normal. urograms and voiding cystograms performed as part of a hypertension were normal. Pelvic exarnination was unremarkable. D!SClTSSIOJ\;
Fairly convincing psychological reasons have been advanced to explain frequency and urgency (what would be called urgency incontinence or unstable bladder the but in these 3 no emotional determinants to explain stress incontinence could be discovered. i-, The incontinence was not related to the affective state and none of these patients had a of conflict around the system. They embarrassed the incontinence to from it. No patient exof urinary urge but urge incontinence can be clinically indistinguishable from st:ress incontinence. ·5 urge incontinence is a chronic disorder with strong aspects and in our patients the incontinence was short-li\/ed. Tl1e stress incontinence cannot be attributed to
inconti604,
'Bates, C. P .. Continence and incontinence. A clinical study of the dynamics of voiding and of the sphincter mechanism. Ann. Coll. Surg. Engl., 49: 18, 1971. 5 Frewen, W. K.: and stress incontinence; fact and fiction. J. Obst. Gynaec. Brit. Comm., 77:932, 1970.
626
VAN PUTTEN, MALKIN AND WEISS
the anticholinergic action of the phenothiazines because stress incontinence does not occur with pure anticholinergic drugs. Overflow incontinence caused by the anticholinergic action of the phenothiazines is, of course, well known. There is evidence that the resting intraurethral pressure is decreased in female subjects with stress incontinence. •-s The sphincteric mechanism responsible for the maintenance of urethral pressure is unclear but it seems certain that the internal sphincter plays a part. 9 It has long been known that the internal sphincter and bladder neck constrict independently of detrusor activity in response to sympathetic stimulation. 10 · 11 This was thought to be of little functional significance since section of the sympathetic nerve supply leads to no significant alteration of normal micturition. 10 • 11 Kleeman recently demonstrated that, in dogs, sympathomimetic drugs with an alpha effect (epinephrine, norepinephrine, phenylephrine) cause bladder neck constriction with a sharp concomitant rise in urethral resistance. 12 Ephedrine-a sympathomimetic drug-has actually been used in the treatment of stress incontinence with at least a measure of success. 13 Kleeman reported on a 69-year-old woman with stress incontinence induced by reserpine-a sympatholytic drug. 12 To our knowledge this was the first reported case of drug-induced stress incontinence. The incontinence was attributed to decreased internal sphincter tone in a female subject already predisposed to stress incontinence by a small cystourethrocele. Since phenothiazines (particularly mellaril and thorazine) exhibit strong alpha adrenergic blocking activity, it is likely that they could decrease 6 Toews, H. A.: lntraurethral and intravesical pressures in normal and stress-incontinent women. Obst. Gynec., 29: 613, 1967. 7 Enhorning, G.: Simultaneous recording of intravesical and intra-urethral pressure. A study on urethral closure in normal and stress incontinent women. Acta Chir. Scand., suppl. 276, p. 1, 1961. 'Enhorning, G., Miller, E. R. and Hinman, F., Jr.: Urethral closure studied with cineroentgenography and simultaneous bladder-urethra pressure recording. Surg., Gynec. & Obst., 118: 507, 1964. 9 Boyarsky, S. and Ruskin, H.: Physiology of the bladder. In: Urology, 3rd ed. Edited by M. F. Campbell and J. H. Harrison. Philadelphia: W. B. Saunders Co., vol. I, pp. 105-135, 1970. 1 ° Kuru, M.: Nervous control of micturition. Physiol. Rev., 45: 425, 1965. 11 Denny-Brown, D.: The state of the bladder and its sphincters in complete transverse lesions of the spinal cord and cauda equina. Brain, 56: 397, 1933. 12 Kleeman, F. J.: The physiology of the internal urinary sphincter. J. Urol., 104: 549, 1970. "Rashbaum, M. and Mandelbaum, C. C.: Nonoperative treatment of urinary incontinence in women. Amer. J. Obst. Gynec., 36: 777, 1948.
internal sphincter tone. 14 In women with mild pre-existing stress incontinence this additional reduction in internal sphincter tone could produce disabling incontinence. Further evidence for phenothiazine-induced internal sphincter relaxation comes from the observation of aspermia in men. 15 Aspermia is the absence of ejaculation during coitus or masturbation. Normally, the internal sphincter closes forcefully during orgasm to prevent regurgitation of seminal fluid into the bladder. 16 In phenothiazine-induced aspermia, male subjects pass white, sperm-containing urine. Aspermia has also been reported with phenoxybenzamine, a potent alpha adrenergic blocking agent. 15 Phenoxybenzamine blocks the constricting effect of epinephrine on the internal sphincter in dogs. 12 While this explanation of internal sphincter relaxation caused by the sympatholytic action of phenothiazines fits nicely into the existing data, it does not explain why these patients demonstrated only minimal evidence of other adrenergic blocking effects such as postural hypotension. Since bladder control has extensive central nervous system representation, phenothiazines may induce incontinence by means of a central effect. 10 It is not known if tolerance to phenothiazineinduced internal sphincter relaxation will develop. The 2-year period of stress incontinence in case 1 suggests that at least in some individuals it will not. The development of tolerance to such side effects as hypotension and drowsiness is rather well documented. 14 Th& incidence of phenothiazine-induced stress incontinence in anatomically predisposed women is probably quite low, since phenothiazineinduced aspermia in men occurs in less than 5 to 30 per cent of cases. 15 • 17 SUMMARY
Three cases are presented of severe stress incontinence apparently caused by phenothiazines. It is postulated that the alpha adrenergic blocking properties of the phenothiazines induce internal urinary sphincter relaxation in anatomically predisposed female subjects. 14 Jarvik, M. E.: Drugs used in the treatment of psychiatric disorders. In: The Pharmacological Basis of Therapeutics. Edited L. S. Goodman and A. Gilman. London: The Macmillan Co., pp. 151-169, 1970. 15 Shader, R. I.: Ejaculation disorders. In: Psychotrophic Drug Side Effects. Edited by R. I. Shader and A. DiMascio. Baltimore: The Williams & Wilkins Co., pp. 72-76, 1970. 16 Denny-Brown, D. E.: Nervous disturbances of vesical sphincter. New Engl. J. Med., 215: 647, 1936. "Blair, J. H. and Simpson, G. M.: Effect of antipsychotic drugs on reproductive functions. Dis. Nerv. Syst., 27: 645, 1966.