0022-5347/78/1201-0060$02.00/0 Vol. 120, July Printed in U.S.A.
THE JOURNAL OF UROWGY
Copyright © 1978 by The Williams & Wilkins Co.
PHENOXYBENZAMINE AND SWEATING IN THE SPINAL CORD INJURY PATIENT FRED S. SHESSEL, HERNAN M. CARRION*
AND
VICTOR A. POLITANO
From the Department of Urology, University of Miami School of Medicine and Spinal Cord Injury Service, Jackson Memorial Hospital, Miami, Florida
ABSTRACT
There were 10 patients with cervical spinal cord lesions and hyperhidrosis treated with the alpha-adrenergic blocking agent, phenoxybenzamine. Five of the 7 patients completing the study experienced marked diminution or elimination of the profuse sweating pattern. Phenoxybenzamine is an a-adrenergic blocking agent that has been used in the treatment of patients with neurogenic bladders. The establishment of a voiding pattern, a reduction in residual urine volume, the disappearance of reflux and an improvement in ureterocalicectasis have been attributed to its use in selected patients. 1- 2 Its sympatholytic activity has been used prophylactically and therapeutically to treat autonomic dysreflexia in spinal cord injury patients. 3 The sweating mechanism in man is under dual control. Apocrine glands, located in the axillae and groins, respond to circulating catecholamines with modulation by sympathetic fibers. Eccrine glands, primarily responsible for the thermoregulatory system, are innervated by postganglionic cholinergic neurons of the sympathetic system. 4 The neurotransmitter for sympathetic ganglia and postganglionic sudomotor fibers is acetylcholine. However, within the ganglia adrenergic synapses contribute to the summation of inhibitory and excitatory responses affei::ting the postganglionic dendrites. 5 In addition to a receptor blockade phenoxybenzamine inhibits postsynaptic neuronal uptake of norepinephrine, thus inhibiting transmission across these modifying adrenergic fibers. 6 Our current study represents an attempt to combine the potential ganglionic blocking and bladder function enhancing properties of this drug.
RESULTS
Of the 10 patients 3 requested termination of the study before the first week for personal reasons. Five of the remaining 7 patients recognized substantial reductions in or elimination of their previous patterns of hyperhidrosis (see table). The 2 patients without Foley catheters demonstrated residual urine volumes consistent with their response to the drug. One of these 2 patients experienced a diminution in sweating and a decrease in residual urine (150 to 75 cc), while in the other patient sweating was unrelieved and the residual urine volume remained at 200 cc. None of the patients suffered elevations in core body temperature during the study. CASE REPORTS
Case 1. H. M. Phenoxybenzamine was begun on July 28, 1976 with complete cessation of abnormal sweating by July 30. The drug was discontinued on August 4, by patient request, with resumption of hyperhidrosis by August 8. Therapy was reinstituted, again by patient request, on August 11, with relief of sweating by August 13. Throughout this period and for the next 30 days of treatment the patient experienced no episodes of autonomic dysreflexia. Case 2. S. C., a 20-year-old white man, had a 3-year history of C6 quadriplegia secondary to a wrestling accident. He suffered nocturnal sweating episodes despite 25 mg. methantheline bromide every 6 hours and had residual urine volumes of 100 to 200 cc. The patient was given phenoxybenzamine and during the next 2 weeks the sweating was reduced substantially. Moreover, the residual urine volume decreased to 75 cc. However, after 6 weeks of therapy the residual urine volume and the sweating increased and phenoxybenzamine was stopped.
METHODS AND MATERIALS
We chose for study 10 patients from the rehabilitation unit of our hospital because of their patterns of excessive sweating. Profuse sweating was recognized by the patient and documented by the nursing staff. Each patient was advised of the nature of the study and asked to evaluate the degree of sweating at weekly intervals. Observation comparisons were made by the primary care nurse. The l'O men ranged from 18 to 35 years old. All patients had sustained cervical lesions resulting in quadriplegia, with durations of 5 months to 7 years. Each was given 10 mg. oral phenoxybenzamine twice daily. Vital signs were monitored before each dose and the medication was withheld if the blood pressure was less than 100 systolic or 60 diastolic. Other indications to discontinue the drug included orthostatic changes or patient desire to terminate the study. Dosage was increased in 10 mg. increments on a weekly basis until satisfactory results had been obtained or until a total dose of 40 mg. daily was reached. Throughout this period the patients without Foley catheters were monitored in regard to residual urine volumes.
DISCUSSION
The presence of 2 types of sweat glands in humans is of more phylogenetic than physiologic interest. The odoriferous secretions of the apocrine glands serve the function of individual recognition and sexual attraction in other species. By contrast, the more numerous eccrine glands assist tactile sensibility and improve surface adhesion, and constitute the primary thermoregulatory mechanism in man. 7 However, both types of sweat glands are controlled by the sympathetic system. Eccrine glands are innervated directly by postganglionic sympathetic fibers and, in man, do not function in the presence of denervation (for example sympathectomy). The fact that the neurotransmitter substance for these fibers is acetylcholine4 provides the rationale for inhibition of sweating by parasympatholytic agents, such as methanthelene bromide and propantheline bromide. The type of sympathetic innervation in humans is yet undetermined but a-adrenergic activity
Accepted for publication September 23, 1977. Read at annual meeting of Southeastern Section, American Urological Association, New Orleans, Louisiana, March 27-31, 1977. * Requests for reprints: Department of Urology, 1700 N. W. 10th Ave., Miami, Florida 33136. 60
Sweating Decrease Residual urine: Decrease No Change
No Change
resumed. Non-responders had no ual urine volumes.
H1
or residVi
CONCLUSION
1 4
Phenoxybenzamine produced a decrease in sweating in 5 of 7 patients, 4 of whom had Foley catheters and, therefore, no change was noted in residual urine volumes. The other 2 patients had residual urine volumes consistent with response to ex blockade.
is stimulatory in sheep, goats, dogs and oxen. 7 Except in the case of thyrotoxicosis /3 blockade does not affect human sweating, 8 while a blockade nullifies epinephrine induced sweating.fl The primary neurotransmitter in sympathetic ganglia is acetylcholine. Its action is nicotinic and not inhibited by atropine. However, the ultimate response of the postganglionic fiber depends upon the summation of inhibitory and excitatory stimuli, some of which are mediated by norepinephrine neurotransmission. 3 Phenoxybenzamine blocks post-synaptic neuronal uptake of norepinephrine, thereby indirectly influencing ganglionic transmission. 6 Spinal cord injury patients have profuse sweating that may be normal or abnormal. Since sympathetic denervation produces anhidrosis these patients respond to elevations in core body temperature with excessive sweating in areas above the level of the lesion. However, such hyperhidrosis also may occur with sympathetic overactivity after irritative stimuli, 10 resulting in dehydration and metabolic abnormalities. The attempt to block this last pathologic type of sweating with phenoxybenzamine originated with its use in neurogenic bladders. Anatomic and experimental evidence has documented the concentration of sympathetic fibers around the vesical neck 11 and the influence on the internal urethral mechanism. 12 In clinical application phenoxybenzamine has lowered urethral resistance and intravesical voiding pressure. 12 In addition, it has been found to lower residual urine, 1 relieve upper tract dilatation and eliminate reflux. 2 While, traditionally, parasympatholytic agents have been the therapeutic modality chosen for sweating they diminish detrusor function and impair voiding. Therefore, the use of phenoxybenzamine is an effort to diminish the sweating of sympathetic hyperactivity while preserving and, perhaps, enhancing voiding capabilities. The extreme of sympathetic discharge in spinal cord injury patients is autonomic dysreflexia, characterized by headache, hypertension, bradycardia and sweating. McGuire and associates have treated successfully this syndrome with phenoxybenzamine.'1 However, they note that sweating persisted in their patients despite relief from the other symptoms in the complex. Our study is at variance with this finding. In 5 of 7 patients hyperhidrosis was diminished markedly or eliminated by the administration of phenoxybenzamine. The status of bladder function, as measured by residual urine volume, reflected the response to a blockade. Residual urine volume decreased when sweating was relieved and increased when sweating
Although phenoxybenzamine has demonstrated some acetylcholine blocking properties'" its primary function is a adrenergic blockade. It also can inhibit post-synaptic uptake ofnorepinephrine and thereby, theoretically, influence ganglionic transmission. In the spinal cord injury patient sympatholysis can aid voiding. Our study indicates that relief from hyperhidrosis also may result from treatment with phenoxybenzamine and this therapy avoids the use of parasympatholytic agents that decrease detrusor function. It also provides prophylaxis against autonomic dysreflexia. While patients must be monitored for orthostatic hypotension the potential benefits, perhaps, justify a trial of phenoxybenzamine in the profusely sweating spinal cord injury patient. REFERENCES
1. Krane, R. J. and Olsson, C. A.: Phenoxybenzamine in neuro-
2.
3. 4. 5. 6. 7. 8. 9.
10. 11.
12.
13.
genic bladder dysfunction. II. Clinical considerations. J. Urol., HO: 653, 1973. Stockamp, K. and Schreiter, F.: Alpha-adrenolytic treatment of the congenital neuropathic bladder. Urol. Int., 30: 33, 1975. McGuire, E. J., Wagner, F. M. and Weiss, R. M.: Treatment of autonomic dysreflexia with phenoxybenzamine. J. Urol., 115: 53, 1976. Mountcastle, V. B.: Medical Physiology. St. Louis: C. V. Mosby Co., 1968. Appenzeller, 0.: Autonomic Nervous System. New York: American Elsevier Publishing Co., Inc., pp. 56-74, 1976. Steiner, G. and Schiinbaurn, E.: Immunosympathectomy. New York: American Elsevier Publishing Co., p. 19, 1972. Robertshaw, D.: Proceedings: neural and humoral control of apocrine glands. J. Invest. Derm., 63: 160, 1974. Allen, J. A., Jenkinson, D. J. and Roddie, I. C.: The effect of /3adrenoceptor blockade in human sweating. Brit. J. Pharmacol., 47: 487, 1973. Montagne, W., Ellis, R. A. and Silver, A. F.: Advances in Biology of Skin. Volume 3, Eccrine Sweat Glands and Eccrine Sweating. New York: Pergamon Press, p. 23, 1962. Johnson, R. H. and Spalding, J. M. K.: Disorders of the autonomic nervous system. In: Contemporary Neurology. Philadelphia: F. A. Davis Co., series II, vol. 11, 1974. Krane, R. J. and Olsson, C. A.: Phenoxybenzamine in neurogenic bladder dysfunction. I. A theory ofmicturition. J. Urol., 110: 650, 1973. Tanagho, E. A., Meyers, F. H. and Smith, D. L.: Urethral resistance: its components and implications. I. Smooth muscle component. Invest. Urol., 7: 136, 1969. Refsum, H. and Landmark, K.: Competitive antagonism between phenoxybenzamine and acetylcholine in isolated rat atria. Acta Pharmacol. Toxicol., 33: 17, 1973. EDITORIAL COMMENT
These authors have described a further benefit of phenoxybenzamine- relief of hyperhydrosis in cervical cord injury patients. My experience has been that the problems of postural hypotension, persistent tachycardia and impairment of sexual function have limited the application of this drug in the treatment of neuromuscular dysfunction of the lower urinary tract. W .E .B.
THE JOURNAL OF UROWGY
Copyright © 1978 by The Williams & Wilkins Co.
PHENOXYBENZAMINE AND SWEATING IN THE SPINAL CORD INJURY PATIENT FRED S. SHESSEL, HERNAN M. CARRION*
AND
VICTOR A. POLITANO
From the Department of Urology, University of Miami School of Medicine and Spinal Cord Injury Service, Jackson Memorial Hospital, Miami, Florida
ABSTRACT
There were 10 patients with cervical spinal cord lesions and hyperhidrosis treated with the alpha-adrenergic blocking agent, phenoxybenzamine. Five of the 7 patients completing the study experienced marked diminution or elimination of the profuse sweating pattern. Phenoxybenzamine is an a-adrenergic blocking agent that has been used in the treatment of patients with neurogenic bladders. The establishment of a voiding pattern, a reduction in residual urine volume, the disappearance of reflux and an improvement in ureterocalicectasis have been attributed to its use in selected patients. 1- 2 Its sympatholytic activity has been used prophylactically and therapeutically to treat autonomic dysreflexia in spinal cord injury patients. 3 The sweating mechanism in man is under dual control. Apocrine glands, located in the axillae and groins, respond to circulating catecholamines with modulation by sympathetic fibers. Eccrine glands, primarily responsible for the thermoregulatory system, are innervated by postganglionic cholinergic neurons of the sympathetic system. 4 The neurotransmitter for sympathetic ganglia and postganglionic sudomotor fibers is acetylcholine. However, within the ganglia adrenergic synapses contribute to the summation of inhibitory and excitatory responses affei::ting the postganglionic dendrites. 5 In addition to a receptor blockade phenoxybenzamine inhibits postsynaptic neuronal uptake of norepinephrine, thus inhibiting transmission across these modifying adrenergic fibers. 6 Our current study represents an attempt to combine the potential ganglionic blocking and bladder function enhancing properties of this drug.
RESULTS
Of the 10 patients 3 requested termination of the study before the first week for personal reasons. Five of the remaining 7 patients recognized substantial reductions in or elimination of their previous patterns of hyperhidrosis (see table). The 2 patients without Foley catheters demonstrated residual urine volumes consistent with their response to the drug. One of these 2 patients experienced a diminution in sweating and a decrease in residual urine (150 to 75 cc), while in the other patient sweating was unrelieved and the residual urine volume remained at 200 cc. None of the patients suffered elevations in core body temperature during the study. CASE REPORTS
Case 1. H. M. Phenoxybenzamine was begun on July 28, 1976 with complete cessation of abnormal sweating by July 30. The drug was discontinued on August 4, by patient request, with resumption of hyperhidrosis by August 8. Therapy was reinstituted, again by patient request, on August 11, with relief of sweating by August 13. Throughout this period and for the next 30 days of treatment the patient experienced no episodes of autonomic dysreflexia. Case 2. S. C., a 20-year-old white man, had a 3-year history of C6 quadriplegia secondary to a wrestling accident. He suffered nocturnal sweating episodes despite 25 mg. methantheline bromide every 6 hours and had residual urine volumes of 100 to 200 cc. The patient was given phenoxybenzamine and during the next 2 weeks the sweating was reduced substantially. Moreover, the residual urine volume decreased to 75 cc. However, after 6 weeks of therapy the residual urine volume and the sweating increased and phenoxybenzamine was stopped.
METHODS AND MATERIALS
We chose for study 10 patients from the rehabilitation unit of our hospital because of their patterns of excessive sweating. Profuse sweating was recognized by the patient and documented by the nursing staff. Each patient was advised of the nature of the study and asked to evaluate the degree of sweating at weekly intervals. Observation comparisons were made by the primary care nurse. The l'O men ranged from 18 to 35 years old. All patients had sustained cervical lesions resulting in quadriplegia, with durations of 5 months to 7 years. Each was given 10 mg. oral phenoxybenzamine twice daily. Vital signs were monitored before each dose and the medication was withheld if the blood pressure was less than 100 systolic or 60 diastolic. Other indications to discontinue the drug included orthostatic changes or patient desire to terminate the study. Dosage was increased in 10 mg. increments on a weekly basis until satisfactory results had been obtained or until a total dose of 40 mg. daily was reached. Throughout this period the patients without Foley catheters were monitored in regard to residual urine volumes.
DISCUSSION
The presence of 2 types of sweat glands in humans is of more phylogenetic than physiologic interest. The odoriferous secretions of the apocrine glands serve the function of individual recognition and sexual attraction in other species. By contrast, the more numerous eccrine glands assist tactile sensibility and improve surface adhesion, and constitute the primary thermoregulatory mechanism in man. 7 However, both types of sweat glands are controlled by the sympathetic system. Eccrine glands are innervated directly by postganglionic sympathetic fibers and, in man, do not function in the presence of denervation (for example sympathectomy). The fact that the neurotransmitter substance for these fibers is acetylcholine4 provides the rationale for inhibition of sweating by parasympatholytic agents, such as methanthelene bromide and propantheline bromide. The type of sympathetic innervation in humans is yet undetermined but a-adrenergic activity
Accepted for publication September 23, 1977. Read at annual meeting of Southeastern Section, American Urological Association, New Orleans, Louisiana, March 27-31, 1977. * Requests for reprints: Department of Urology, 1700 N. W. 10th Ave., Miami, Florida 33136. 60
Sweating Decrease Residual urine: Decrease No Change
No Change
resumed. Non-responders had no ual urine volumes.
H1
or residVi
CONCLUSION
1 4
Phenoxybenzamine produced a decrease in sweating in 5 of 7 patients, 4 of whom had Foley catheters and, therefore, no change was noted in residual urine volumes. The other 2 patients had residual urine volumes consistent with response to ex blockade.
is stimulatory in sheep, goats, dogs and oxen. 7 Except in the case of thyrotoxicosis /3 blockade does not affect human sweating, 8 while a blockade nullifies epinephrine induced sweating.fl The primary neurotransmitter in sympathetic ganglia is acetylcholine. Its action is nicotinic and not inhibited by atropine. However, the ultimate response of the postganglionic fiber depends upon the summation of inhibitory and excitatory stimuli, some of which are mediated by norepinephrine neurotransmission. 3 Phenoxybenzamine blocks post-synaptic neuronal uptake of norepinephrine, thereby indirectly influencing ganglionic transmission. 6 Spinal cord injury patients have profuse sweating that may be normal or abnormal. Since sympathetic denervation produces anhidrosis these patients respond to elevations in core body temperature with excessive sweating in areas above the level of the lesion. However, such hyperhidrosis also may occur with sympathetic overactivity after irritative stimuli, 10 resulting in dehydration and metabolic abnormalities. The attempt to block this last pathologic type of sweating with phenoxybenzamine originated with its use in neurogenic bladders. Anatomic and experimental evidence has documented the concentration of sympathetic fibers around the vesical neck 11 and the influence on the internal urethral mechanism. 12 In clinical application phenoxybenzamine has lowered urethral resistance and intravesical voiding pressure. 12 In addition, it has been found to lower residual urine, 1 relieve upper tract dilatation and eliminate reflux. 2 While, traditionally, parasympatholytic agents have been the therapeutic modality chosen for sweating they diminish detrusor function and impair voiding. Therefore, the use of phenoxybenzamine is an effort to diminish the sweating of sympathetic hyperactivity while preserving and, perhaps, enhancing voiding capabilities. The extreme of sympathetic discharge in spinal cord injury patients is autonomic dysreflexia, characterized by headache, hypertension, bradycardia and sweating. McGuire and associates have treated successfully this syndrome with phenoxybenzamine.'1 However, they note that sweating persisted in their patients despite relief from the other symptoms in the complex. Our study is at variance with this finding. In 5 of 7 patients hyperhidrosis was diminished markedly or eliminated by the administration of phenoxybenzamine. The status of bladder function, as measured by residual urine volume, reflected the response to a blockade. Residual urine volume decreased when sweating was relieved and increased when sweating
Although phenoxybenzamine has demonstrated some acetylcholine blocking properties'" its primary function is a adrenergic blockade. It also can inhibit post-synaptic uptake ofnorepinephrine and thereby, theoretically, influence ganglionic transmission. In the spinal cord injury patient sympatholysis can aid voiding. Our study indicates that relief from hyperhidrosis also may result from treatment with phenoxybenzamine and this therapy avoids the use of parasympatholytic agents that decrease detrusor function. It also provides prophylaxis against autonomic dysreflexia. While patients must be monitored for orthostatic hypotension the potential benefits, perhaps, justify a trial of phenoxybenzamine in the profusely sweating spinal cord injury patient. REFERENCES
1. Krane, R. J. and Olsson, C. A.: Phenoxybenzamine in neuro-
2.
3. 4. 5. 6. 7. 8. 9.
10. 11.
12.
13.
genic bladder dysfunction. II. Clinical considerations. J. Urol., HO: 653, 1973. Stockamp, K. and Schreiter, F.: Alpha-adrenolytic treatment of the congenital neuropathic bladder. Urol. Int., 30: 33, 1975. McGuire, E. J., Wagner, F. M. and Weiss, R. M.: Treatment of autonomic dysreflexia with phenoxybenzamine. J. Urol., 115: 53, 1976. Mountcastle, V. B.: Medical Physiology. St. Louis: C. V. Mosby Co., 1968. Appenzeller, 0.: Autonomic Nervous System. New York: American Elsevier Publishing Co., Inc., pp. 56-74, 1976. Steiner, G. and Schiinbaurn, E.: Immunosympathectomy. New York: American Elsevier Publishing Co., p. 19, 1972. Robertshaw, D.: Proceedings: neural and humoral control of apocrine glands. J. Invest. Derm., 63: 160, 1974. Allen, J. A., Jenkinson, D. J. and Roddie, I. C.: The effect of /3adrenoceptor blockade in human sweating. Brit. J. Pharmacol., 47: 487, 1973. Montagne, W., Ellis, R. A. and Silver, A. F.: Advances in Biology of Skin. Volume 3, Eccrine Sweat Glands and Eccrine Sweating. New York: Pergamon Press, p. 23, 1962. Johnson, R. H. and Spalding, J. M. K.: Disorders of the autonomic nervous system. In: Contemporary Neurology. Philadelphia: F. A. Davis Co., series II, vol. 11, 1974. Krane, R. J. and Olsson, C. A.: Phenoxybenzamine in neurogenic bladder dysfunction. I. A theory ofmicturition. J. Urol., 110: 650, 1973. Tanagho, E. A., Meyers, F. H. and Smith, D. L.: Urethral resistance: its components and implications. I. Smooth muscle component. Invest. Urol., 7: 136, 1969. Refsum, H. and Landmark, K.: Competitive antagonism between phenoxybenzamine and acetylcholine in isolated rat atria. Acta Pharmacol. Toxicol., 33: 17, 1973. EDITORIAL COMMENT
These authors have described a further benefit of phenoxybenzamine- relief of hyperhydrosis in cervical cord injury patients. My experience has been that the problems of postural hypotension, persistent tachycardia and impairment of sexual function have limited the application of this drug in the treatment of neuromuscular dysfunction of the lower urinary tract. W .E .B.
