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Priscoline for pain in poliomyelitis
PRISCOLINE FOR PAIN IN P O L I O M Y E L I T I S WILLIAM
A. REILLY, M.D., AND AaDWIN
H. BARSANTI, M.D.
LITTLE ]~OCK,A R K . N ANY disease process where the etiology is unknown, and the treatment therefore nonspecific, efforts toward symptomatic therapy are made. According to Shaw and Thelander, 1 in poliomyelitis, "The early treatment of the paralytic stage is entirely symptomatic . . . . Early measures are suited only to maximum comfort of the patient and are accomplished by careful nursing, gentle handling, enforced recumbency, and protection." Various drugs have been employed to control the pain, muscle spasm, tenderness, and hyperesthesias occurring in the acute stage of the disease. Such drugs have included the use of neostigmine 2 and curare2 The results, for the most part, have been equivocal. More recently, intravenous procaine, 4, s diethylaminoethanol hydrochloride,5 and Priscoline hydrochloride have been used with promising success. This paper is concerned with the use of 2benzyliminazoline hydrochloride (Priscoline "~) in the treatment of thirty-seven patients with acute poliomyelitis during the smnmer and fall of 1949, at the University of Arkansas Hospital of the School of Medicine.
I
COMMENT
Prisco]ine is an antagonist to epinephrine-like substances formed at the vascular myoneural junction. As has been shown by Smith and associates, ~ and by other workers in poliomyelitis, there is definite involvement of the sympathetic nervous system in acute poliomyelitis. Pathologic studies demonstrate varying degrees of involvement, not only in the anterior horn cells, but also in the sympathetic cells in the lateral horn of the spinal cord and in tile sympathetic ganglia. 0seillometric studies have demonstrated angiospasm in the peripheral circulation in all forms of poliomyelitis. Indirect evidence for involvement of the sympathetic nervous system, such as urinary retention, pylorospasm, Hornet's syndrome, constriction and/ or dilatation of blood vessels in the skin, is observed in many patients. These vasomotor and sweat secretory disturbances have also been described by Kuntz. s Smithwick and others 9 have shown that lumbar sympathectomies in cases of residual paralysis were accompanied by accelerated rate of growth i n the involved extremity. On the basis of this evidence, it has been presumed that the well-known findings of pain and spasm seen in acute poliomyelitis might be ascribed to the action of the virus on the cells of the sympathetic nervous system, either centrally or more peripherally. If this reflex spasm and pain could be controlled, patients not only would be made more comfortable, but it would allow the physiotherapist greater freedom. In this series of cases we have attempted to assay the effectiveness of F r o m t h e D e p a r t m e n t of P e d i a t r i c s , U n i v e r s i t y of A r k a n s a s S c h o o l of M e d i c i n e , L i t t l e J o u r n a l S e r i e s N o . 899 U n i v e r s i t y O f : A r k a n s a s . *Priscoline was generously supplied by Ciba Pharmaceutical P r o d u c t s , Inc., S u m m i t , N. J., t h r o u g h J o c k L. G r a e m e , M.D.
l~ock.
711
712
TI-IE JOURNAL
OF
PEDIATRICS
Priscoline as compared with hot packs and the usual forms of analgesia. The opinions of the house staff, nurses, p h y s i o t h e r a p y department, and attending orthopedists were carefully considered before final appraisal was made. DOSAGE
AND
AD~CIII~ISTRATION
Except in the early cases, all patients received increasing parenteral doses every three or four hours till flushing occurred; they were then maintained on the preflushing dose, either parenterally or orally. The initial dose varied with the size and age of the patient. ~n general, children u n d e r 5 years began with 10 rag. i n t r a m u s c u l a r l y and this dose was increased b y 5 rag. every four hours. Older children received 25 to 50 rag. as an initial dose and this was increased by 10 to 15 rag. every four hours. W h e r e v e r possible, it was a t t e m p t e d to maintain patients on an oral dose. The d r u g was stopped a f t e r another seven to ten days. I n those where no appreciable effects were observed, hot packs were employed. I n most cases, blood pressure readings were recorded before and a f t e r administration of the drug. All side reactions were noted. I n general, bulbar patients were not given Friscoline because of the danger of adversely affecting blood pressures, which were already undergoing marked fluctuations as a result of the disease itself. I n a few cases where there was spinal as well as bulbar disease, Priscoline was tried if the blood pressure was normal f r o m the onset. Table I summarizes the distribution of cases. TABLE I TYPE OF INVOLVEIVIENT Spinal Spinal + encephalitic Spinal + bulbar Tetanus Total
I
NUMRER 30 2 3 1 36
t
PER CENT OF TOTAL 83.3 5.5 8.4 2.8 100.0
RESULTS
I n any s t u d y where the results are ahnost entirely evaluated on the basis of symptoms such as Fain, variable factors which cannot be controlled are automatically introduced. The following clinical impressions are tabulated according to whether patients were or were not benefited with r e g a r d to relief of pain and spasm, increased warmth in extremities, and greater ease of manipulation by the physiotherapist. ]n a certain number, the results could not be completely evaluated for a variety of reasons: patient left the hospital, unsuitable ease, delirium, fluctuation blood pressure, etc. In a few, the results were equivocal, so they were classified as "doubtful benefit." It will be seen by the figures in Table II that less than 25 per cent of the patients treated were definitely benefited by the drug, whereas almost 45 per cent of them were definitely not benefited. In three of the nine patients benefited, this occurred only following parenteral doses of the drug. Oral doses had apparently no effect. As a matter of interest, a patient with tetanus was given Priseoline to see if there would be any effect on the muscular rigidity. None was noted.
REILLY AND BARSANTI:
PRISCOLINE FOR PAIN I N POLIOMYELITIS
713
TABLE II RESULTS Benefited D o u b t f u l benefit N o t benefited N o t completely evaluable Total
I
NUMBER, 8 4 16 8 36
I
PEF~ CENT
OF 22.2 11.2 44.4 22.2 I00.0
TOTAL
TOXICITY
Table I l I summarizes the undesirable side effect of the drug. It will be noted that the most important was the production of hypertension. It was the only side effect responsible for discontinuing the drug permanently in a given patient. One 18-year-old boy with spinal disease affecting all extremities and intercostals, showed disappearance of pain and tenderness on the fifth day of t h e r a p y ; on the seventeenth day of therapy, he developed gastrointestinal bleeding and a gastric ulcer was demonstrated by x-ray. Some rise in blood pressure had also been noted. W h e t h e r the bleeding was the effect of the hypertension per se, or due to a disturbance of the autonomic nervous system by the disease process a n d / o r the drug, is questionable. TABLE I SIDE EFIOECTS Hypertension Nausea--vomiting Pruritis H y p o t e n s i o n and Paresthesias
NUMBER BULBAR 3
III OF I
PATIENTS SPIIgAL 4
3 1 1
PER CENT OF TOTAL PATIENTS 19.4 8.3 2.8 2.8
As is seen in Table III, seven patients showed a rising blood pressure while only one developed hypotension, even though, theoretically, this drug would be expected to produce a lowering of the blood pressure by virtue of its sympathicolytic action. F o u r of the patients had only spinal involvement and three had spinal plus bu]bar disease. The drug was not given to bu]bar patients who showed aberrations in blood pressure. The blood pressure in the spinal patients returned to normal soon after the drug was discontinued, but in one ease it remained elevated for one month. The blood pressure continued to fluctuate in tile bulbar ease. Nausea and vomiting was seen in three eases, but in all three, the drug was resumed after a short period of rest with no f u r t h e r symptoms noted. One patient developed severe pruritis, and one hypotension with paresthesias over the entire body. SUMMARY AND CONCLUSIONS 1. Thirty-five cases of poliomyelitis and one case of tetanus were treated with Priscoline in an effort to reduce pain and spasm. 2. Less than one-fourth were definitely benefited; almost one-half were not benefited at all. The remainder were either doubtful or could not be completely evaluated.
714
THE JOURNAL OF PEDIATRICS
3. This is a worth-while drug when it acts favorably; in our hands it is about as effective as other drug's and safer than some, especially curare. 4. Fluctuating blood pressure was observed in all eases where there was bulbar involvement. This was probably due to the disease itself, although hypertension was noted in four cases where there was apparently only spinal disease. 5. It was felt by all observers that hot packs proved superior in the relief of pain and spasm, in the majority of patients. 6. From the experimental and clinical evidence, it would appear that a sympathetic antagonist would be the drug of choice in the control of pain and Spasm, especially if it could be given orally. Therefore, further study of such drugs is indicated. T h e authors acknowledge the appraisals of this drug by the following house-officers who also observed these p a t i e n t s : John A. IKarrel, Jr., MI.D, Luther R. White, M.D., and MMarion K. Ledbetter, MI.D. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
Shaw, E. ]3., and Thelander, If. E.: Pediatrics 4: 277, 1949. Fox, MI. J., and Spankus, W. It.: J. A. MI. A. 128: 720, 1945. Ransohoff, N. S.: New York State J. Med. 47: 151, 1947. Graabard~ D. J., Robertazzi, R. W , and Peterson, Xg. C.: New York State J. ivied. 47: 2187, 1947. Smith, E., Graubard~ D. J., Goldstein, N., and ]~ikoff, W. : New York State J. Med. 48: 2608, 1948. Smith~ E , Rosenblatt, P., and Limauro, A . B . : J. PEDIAT. 34: 1, 1949. Bodian, D.: J. A. M. A. 134: 1148, ]947. Kuntz, A.: The Autonomic Nervous System, ed. 3~ Philadelphia, 1945~ Lea & Febiger. White, J. C., and Smithwick, R. It.: The Autonomic Nervous System, New York, 194], The MMacmillan Company.
A. REILLY, M.D., AND AaDWIN
H. BARSANTI, M.D.
LITTLE ]~OCK,A R K . N ANY disease process where the etiology is unknown, and the treatment therefore nonspecific, efforts toward symptomatic therapy are made. According to Shaw and Thelander, 1 in poliomyelitis, "The early treatment of the paralytic stage is entirely symptomatic . . . . Early measures are suited only to maximum comfort of the patient and are accomplished by careful nursing, gentle handling, enforced recumbency, and protection." Various drugs have been employed to control the pain, muscle spasm, tenderness, and hyperesthesias occurring in the acute stage of the disease. Such drugs have included the use of neostigmine 2 and curare2 The results, for the most part, have been equivocal. More recently, intravenous procaine, 4, s diethylaminoethanol hydrochloride,5 and Priscoline hydrochloride have been used with promising success. This paper is concerned with the use of 2benzyliminazoline hydrochloride (Priscoline "~) in the treatment of thirty-seven patients with acute poliomyelitis during the smnmer and fall of 1949, at the University of Arkansas Hospital of the School of Medicine.
I
COMMENT
Prisco]ine is an antagonist to epinephrine-like substances formed at the vascular myoneural junction. As has been shown by Smith and associates, ~ and by other workers in poliomyelitis, there is definite involvement of the sympathetic nervous system in acute poliomyelitis. Pathologic studies demonstrate varying degrees of involvement, not only in the anterior horn cells, but also in the sympathetic cells in the lateral horn of the spinal cord and in tile sympathetic ganglia. 0seillometric studies have demonstrated angiospasm in the peripheral circulation in all forms of poliomyelitis. Indirect evidence for involvement of the sympathetic nervous system, such as urinary retention, pylorospasm, Hornet's syndrome, constriction and/ or dilatation of blood vessels in the skin, is observed in many patients. These vasomotor and sweat secretory disturbances have also been described by Kuntz. s Smithwick and others 9 have shown that lumbar sympathectomies in cases of residual paralysis were accompanied by accelerated rate of growth i n the involved extremity. On the basis of this evidence, it has been presumed that the well-known findings of pain and spasm seen in acute poliomyelitis might be ascribed to the action of the virus on the cells of the sympathetic nervous system, either centrally or more peripherally. If this reflex spasm and pain could be controlled, patients not only would be made more comfortable, but it would allow the physiotherapist greater freedom. In this series of cases we have attempted to assay the effectiveness of F r o m t h e D e p a r t m e n t of P e d i a t r i c s , U n i v e r s i t y of A r k a n s a s S c h o o l of M e d i c i n e , L i t t l e J o u r n a l S e r i e s N o . 899 U n i v e r s i t y O f : A r k a n s a s . *Priscoline was generously supplied by Ciba Pharmaceutical P r o d u c t s , Inc., S u m m i t , N. J., t h r o u g h J o c k L. G r a e m e , M.D.
l~ock.
711
712
TI-IE JOURNAL
OF
PEDIATRICS
Priscoline as compared with hot packs and the usual forms of analgesia. The opinions of the house staff, nurses, p h y s i o t h e r a p y department, and attending orthopedists were carefully considered before final appraisal was made. DOSAGE
AND
AD~CIII~ISTRATION
Except in the early cases, all patients received increasing parenteral doses every three or four hours till flushing occurred; they were then maintained on the preflushing dose, either parenterally or orally. The initial dose varied with the size and age of the patient. ~n general, children u n d e r 5 years began with 10 rag. i n t r a m u s c u l a r l y and this dose was increased b y 5 rag. every four hours. Older children received 25 to 50 rag. as an initial dose and this was increased by 10 to 15 rag. every four hours. W h e r e v e r possible, it was a t t e m p t e d to maintain patients on an oral dose. The d r u g was stopped a f t e r another seven to ten days. I n those where no appreciable effects were observed, hot packs were employed. I n most cases, blood pressure readings were recorded before and a f t e r administration of the drug. All side reactions were noted. I n general, bulbar patients were not given Friscoline because of the danger of adversely affecting blood pressures, which were already undergoing marked fluctuations as a result of the disease itself. I n a few cases where there was spinal as well as bulbar disease, Priscoline was tried if the blood pressure was normal f r o m the onset. Table I summarizes the distribution of cases. TABLE I TYPE OF INVOLVEIVIENT Spinal Spinal + encephalitic Spinal + bulbar Tetanus Total
I
NUMRER 30 2 3 1 36
t
PER CENT OF TOTAL 83.3 5.5 8.4 2.8 100.0
RESULTS
I n any s t u d y where the results are ahnost entirely evaluated on the basis of symptoms such as Fain, variable factors which cannot be controlled are automatically introduced. The following clinical impressions are tabulated according to whether patients were or were not benefited with r e g a r d to relief of pain and spasm, increased warmth in extremities, and greater ease of manipulation by the physiotherapist. ]n a certain number, the results could not be completely evaluated for a variety of reasons: patient left the hospital, unsuitable ease, delirium, fluctuation blood pressure, etc. In a few, the results were equivocal, so they were classified as "doubtful benefit." It will be seen by the figures in Table II that less than 25 per cent of the patients treated were definitely benefited by the drug, whereas almost 45 per cent of them were definitely not benefited. In three of the nine patients benefited, this occurred only following parenteral doses of the drug. Oral doses had apparently no effect. As a matter of interest, a patient with tetanus was given Priseoline to see if there would be any effect on the muscular rigidity. None was noted.
REILLY AND BARSANTI:
PRISCOLINE FOR PAIN I N POLIOMYELITIS
713
TABLE II RESULTS Benefited D o u b t f u l benefit N o t benefited N o t completely evaluable Total
I
NUMBER, 8 4 16 8 36
I
PEF~ CENT
OF 22.2 11.2 44.4 22.2 I00.0
TOTAL
TOXICITY
Table I l I summarizes the undesirable side effect of the drug. It will be noted that the most important was the production of hypertension. It was the only side effect responsible for discontinuing the drug permanently in a given patient. One 18-year-old boy with spinal disease affecting all extremities and intercostals, showed disappearance of pain and tenderness on the fifth day of t h e r a p y ; on the seventeenth day of therapy, he developed gastrointestinal bleeding and a gastric ulcer was demonstrated by x-ray. Some rise in blood pressure had also been noted. W h e t h e r the bleeding was the effect of the hypertension per se, or due to a disturbance of the autonomic nervous system by the disease process a n d / o r the drug, is questionable. TABLE I SIDE EFIOECTS Hypertension Nausea--vomiting Pruritis H y p o t e n s i o n and Paresthesias
NUMBER BULBAR 3
III OF I
PATIENTS SPIIgAL 4
3 1 1
PER CENT OF TOTAL PATIENTS 19.4 8.3 2.8 2.8
As is seen in Table III, seven patients showed a rising blood pressure while only one developed hypotension, even though, theoretically, this drug would be expected to produce a lowering of the blood pressure by virtue of its sympathicolytic action. F o u r of the patients had only spinal involvement and three had spinal plus bu]bar disease. The drug was not given to bu]bar patients who showed aberrations in blood pressure. The blood pressure in the spinal patients returned to normal soon after the drug was discontinued, but in one ease it remained elevated for one month. The blood pressure continued to fluctuate in tile bulbar ease. Nausea and vomiting was seen in three eases, but in all three, the drug was resumed after a short period of rest with no f u r t h e r symptoms noted. One patient developed severe pruritis, and one hypotension with paresthesias over the entire body. SUMMARY AND CONCLUSIONS 1. Thirty-five cases of poliomyelitis and one case of tetanus were treated with Priscoline in an effort to reduce pain and spasm. 2. Less than one-fourth were definitely benefited; almost one-half were not benefited at all. The remainder were either doubtful or could not be completely evaluated.
714
THE JOURNAL OF PEDIATRICS
3. This is a worth-while drug when it acts favorably; in our hands it is about as effective as other drug's and safer than some, especially curare. 4. Fluctuating blood pressure was observed in all eases where there was bulbar involvement. This was probably due to the disease itself, although hypertension was noted in four cases where there was apparently only spinal disease. 5. It was felt by all observers that hot packs proved superior in the relief of pain and spasm, in the majority of patients. 6. From the experimental and clinical evidence, it would appear that a sympathetic antagonist would be the drug of choice in the control of pain and Spasm, especially if it could be given orally. Therefore, further study of such drugs is indicated. T h e authors acknowledge the appraisals of this drug by the following house-officers who also observed these p a t i e n t s : John A. IKarrel, Jr., MI.D, Luther R. White, M.D., and MMarion K. Ledbetter, MI.D. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
Shaw, E. ]3., and Thelander, If. E.: Pediatrics 4: 277, 1949. Fox, MI. J., and Spankus, W. It.: J. A. MI. A. 128: 720, 1945. Ransohoff, N. S.: New York State J. Med. 47: 151, 1947. Graabard~ D. J., Robertazzi, R. W , and Peterson, Xg. C.: New York State J. ivied. 47: 2187, 1947. Smith, E., Graubard~ D. J., Goldstein, N., and ]~ikoff, W. : New York State J. Med. 48: 2608, 1948. Smith~ E , Rosenblatt, P., and Limauro, A . B . : J. PEDIAT. 34: 1, 1949. Bodian, D.: J. A. M. A. 134: 1148, ]947. Kuntz, A.: The Autonomic Nervous System, ed. 3~ Philadelphia, 1945~ Lea & Febiger. White, J. C., and Smithwick, R. It.: The Autonomic Nervous System, New York, 194], The MMacmillan Company.