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Nortriptyline hydrochloride in urology
NORTRIPTYLINE HYDROCHLORIDE IN UROLOGY
C. SERVADIO, M.D. 1. NISSENKORN, M. ZEIGLER,
M.D.
M.D.
From Department of Urology, Central Emek Hospital, Afula, Israel, and Surgical Research Laboratories of Hebrew University, Hadassah Medical School, Jerusalem
ABSTRACT - Forty female patients suffting fn- long periodsfromfiequency, urgency, and dysuria without any definite organic cause received nortriptyline chloride fm three weeks. In 75 per cent there was either considerable improvement or total disappearance of urinay complaints.At the same time the in vitro effects of the drug were tested using the isometrie muscle contraction technique. Nortriptyline was found to have anticholinergic properties. The importante of this effect in the clinical studu and the possible mode of action of the drug are discussed.
Many female patients diagnosed by the urologist as suffering trom cystitis display a pattern of urinary disturbances involving frequency, urgency, dysuria, and lower abdominal pain. Despite the complaints and severe disturbances in micturition, a thorough urologie and gynecologic examination of these patients often reveals very little. Treatment in such cases tends to be primarily symptomatic with overall results frequently disappointing, and relief obtained is little if any. Since it was observed that complete urinary retention without any organic explanation developed in 2 women treated with large doses of nortriptyline, and since retention disappeared completely on cessation of drug treatment, we decided to subject a number of these patients showing no clear-cut organic disease and not responding significantly to various local or systemic treatment to a brief low-dosage nortriptyline therapy. Concurrently we also examined the pharmacologic effects of nortriptyline in vitro using the isometrie muscle contraction technique. Nortriptyline (Nortylin or Aventyl) is an antidepressant drug with anticholinergic activity which reveals certain side effects, such as dryness of the mouth, constipation, and dimcult micturition.
UROLOGY
/ JUNE1975 / VOLUMEV,
NUMBERG
Material and Methods Clinical study
A group of 40 women under treatment in our clinic for prolonged disturbances in micturition, mainly frequency, without clear evidente of organic disease or urinary infection received treatment with nortriptyline tablets in the dose of 10 mg. four times a day for three weeks. Al1 candidates had undergone a comprehensive urologie checkup which included repeated urine cultures, intravenous pyelogram, cystoureteroscopy, cystometry, and on suspicion of reflux also cystography. Al1 had received various treatments with no or only temporary effect. They were asked to refrain fi-om any other type of treatment for the duration of the test period. During the test period and in subsequent follow-ups in our clinic, the patients were asked to answer a special questionnaire which included the following points: (1) the number of times voided per day and night; (2) any difficulty in continency; (3) burning sensation during micturition; (4) dficulty in voiding; (5) pain in the suprapubic region; (6) the genera1 feeling of the patient; and (7) side effects noted.
747
The first 20 patients underwent repeated cystometry in the course of treatment with nortriptyline. From the standpoint of efficacy of treatment, the condition of the patients was defined as: (1) excellent, when al1 the disturbances in micturition had totally disappeared; (2) good, when the frequency and urgency of, the necessity for, and various complaints during micturition were diminished considerably or were almost nonexistent, while nocturia stopped altogether or at the most required only one voiding; and (3) unchanged, when there was no significant response to treatment. The validity of our interpretation as to the degree of efficacy of treatment is also supported by the fact that we were able to compare the condition of the same patients before, during, and after treatment. Experimental
in vitro study
Mature white rats weighing 250 to 300 Gm. were anesthetized with ether. Through a midline incision the bladder dome was removed, cut into two strips, and immediately placed in Locke’s solution no. 2 at 5°C. Each muscle strip was then examined by the isometrie method in a l5-cc. muscle chamber containing Locke’s solution no. 2 at 37°C. with 95 per cent oxygen and 5 per cent carbon dioxide bubbling through the solution. One end of the muscle strip was tied with a fine silk thread to the bottom of the muscle chamber and the other end connected via a fine silk thread to a Grass FT-03c force displacement transducer, a Sanborn carrier preamplifier, and recorder. A sensitivity of 20 mm. pen deflection per gram tension was used, and the paper recording speed was 10 mm. per minute. The strips were submitted to a tension of 1 Gm. and spontaneous activity was allowed to recover. The strips were tested with acetylcholine and nortriptyline. Twenty experiments in al1 were performed using this technique. Results According to our criteria the condition of 8 patients was excellent with al1 disturbances in micturition gradually disappearing after six to eight days of treatment. The condition of 22 others was good, while that of the remaining 10 was unchanged. The response to treatment in the middle category is shown graphically in Figure 1. Patients that had undergone cystometry in the course of treatment showed no clear-cut changes in the cystometric curve nor in the volume capacity of the bladder at the prescribed
748
f
DUIIYC WEIIYIYr
14
D,Un*AL*
*WV’**”4
HO.or P11IEYr8 2
4
6
8
10
12
14
FIGURE 1. Effect of nortriptyline nocturnal jì-equency of micturition.
16
18
20
22
on diurnal and
low dosage of 40 mg. per day. None of the patients suffered any adverse side effects as a result of treatment. However, in al1 patients in whom nortriptyline had a beneficial effect there was a recurrence of the disturbances shortly after cessation of treatment. In the in vitro study, spontaneous activity reappeared in ten to twenty minutes after immersion in the muscle bath. In al1 strips tested 1 microgram per milliliter of acetylcholine produced a marked stimulatory contraction (Fig. 2A). In 3 of 5 cases 50 micrograms per milliliter of nortriptyline had no effect on the basic tone of the bladder dome. In 2 cases there was an insignificant decrease in basic tone (Fig. 2B). Fifty micrograms per milliliter of nortriptyline added to the muscle bath after treatment with 1 microgram per milliliter of acetylcholine produced a fa11 in muscle tension inhibiting the stimulatory effect of acetylcholine (Fig. 3A). After treatment with 25 micrograms per milliliter of nortriptyline the bladder dome did not respond to the further addition of 1 microgram per milliliter of acetylcholine. Nortriptyline blocked the bladder dome’s response to acetylcholine (Fig. 3B). Comment In the present clinical study nortriptyline had a positive therapeutic effect on 75 per cent of the patients suffering from disturbances in micturition with no clear-cut pathology of the urinary tract. The beneficial effects of the drug may be attributed to its three known pharmacologic properties. The anticholinergic effect of nortriptyline finds its clinical expression in side effects when
UROLOGY
/ JUNE1975 / VOLUMEV,
NUMBERG
ACETYLCHOLINE
FIGURE 2. (A) Marked contraction of bladder muscle (in vitro) produced by acetylcholine. (B) Znsignijìcant effect of nortriptyline on bladder tone (in vitro).
NORTRIPTYLINE
s” wml
ACETYLCHOLINE
FIGURE 3. (A) Nortriptyline clearly inhibits stimulatory effect of acetylcholine. (B) Nortriptyline given prior to acetylcholine, clearly prevents bladder contraction because of its anticholinergic effect.
UROLOGY
/ JUNE1975 / VOLUMEV,
NORTRIPTYLINE 25 Ir+1
NUMBERG
NORTRIPTYLINE
ACETYLCHOLINE 1 Ccpl
749
given as an antidepressant in high doses. The in vitro study clearly demonstrates its anticholinergit effect. The bladder dome is rich in cholinergit receptors as seen by the stimulatory effect of 1 microgram per milliliter of acetylcholine. Twenty-five micrograms per milliliter of nortriptyline black this stimulatory effect when the bladder is pretreated with nortriptyline. Nortriptyline also inhibits the stimulatory effect of 1 microgram per milliliter of acetylcholine when added to the bath after acetylcholine. Other laboratory studies revealed similar findings. ’ In vivo the cholinergic activity of the bladder is via the parasympathetic innervation whose stimulation results in enhanced contraction of the detrusor urinae muscle, whereas its depression leads to relaxation of this muscle. Anticholinergic drug therapy is customary in cases of frequency. It is interesting to note that the use of nortriptyline in high doses may result in complete >retention, as we have seen in 2 patients, and the medical literature cites cases of paralytic ileus after nortriptyline treatment2 The analgesic effect of nortriptyline is more pronounced than imipramine.3 This effect may alleviate urinary complaints such as dysuria and suprapubic pain. Nortriptyline has been found to have a palliative effect in the treatment of psychosomatic diseases as wel1 as a tranquilizing effect on restive, anxious patients facing diagnostic tests or undergoing various treatments.4s5 It is probably the combined effect of these three properties which renders nortriptyline effective in the treatment of urinary complaints. It is clearly obvious that al1 patients displaying disturbances in micturition should undergo thorough urologie examination before any decision on therapy is reached; and if there is a distinct organic cause, appropriate treatment should be given. At the same time, however, one should not overlook the mental factor which could play a supportive or contributory role in the cause of the disturb6 When the mental state of the patient ante . comes into play, a tranquilizing drug, such as nortriptyline, could be effective in alleviating symptoms both through its direct effect on the urinary tract as wel1 as through its antidepressant properties. Although we have not applied double-blind procedures on our patients, we believe that we
750
have obtained sufficient data on the state of each patient, before, during, and after treatment to justify our conclusions. In those cases in which nortriptyline had a beneficial effect, our patients requested the continuation of the treatment beyond the experimental trial period, because they reported recurrence of their complaints and claim that only this drug produced a calming and palliative effect. Indeed our impression and experience tends to confirm this claim. The 2 patients who had come for treatment because of absolute retention received nortriptyline in high dosages (125 mg. per day), whereas the dosage used by US on the experimental group was considerably lower (40 mg. per day). The use of a lower dose probably accounts for the absente of any adverse side effects. On the other hand, it probably explains the absente of any marked effects on the cystometric plot and could explain why the drug did not produce a higher success rate in our patients. It may be reasonable to suppose that in patients not responding satisfactorily to the lower dose level, the dose could be gradually increased without endangering the patient. Centra1 Emek Hospita1 Afiula, Israel (DR. SERVADIO) ACKNOWLEDGMENT. We wish to thank the Department of Experimental Surgery, Hadassah University Hospital, Jerusalem, and Prof. M. Caine and Prof. N. Babinowitz in particular for their support. References 1. BATHBUN, It. C., and SLATER, J. H.: Amitryptyline and nortriptyline as antagonists of central and peripheral cholinergic activation. Psychopharmacologia 4: 114 (1963). 2. MILNER, G., and HILLS, N. F.: Adynamic ileus and nortriptyline, Br. Med. J. 1: 841 (1966). 3. OPITZ, K., and BORCHERT,U. : über die analgetische Wirkung von Thymoleptica, Arzneim. Forsch. 18: 316 (1968). 4. BENNET, J. F.: The constellation of depression. Its treatment with nortriptyline: clinical evaluation of nortriptyline, J. Nerv. Ment. Dis. 135: 59 (1962). Nortriptyline, an antidepressant, Dis. PEJZMAN, 0.: Nerv. Syst. 25: 569 (1964). SEID, B.: A study of antianxiety effects in urological patients, Curr. Ther. Res. 6: 156 (1964). CAMPBELL,M. F., and HARRISON,J. H.: Urology, 3rd ed., Philadelphia, W. B. Saunders, 1970, p. 2048.
UROLOGY / JUNE 1975 / VOLUME V, NUMBER 6
C. SERVADIO, M.D. 1. NISSENKORN, M. ZEIGLER,
M.D.
M.D.
From Department of Urology, Central Emek Hospital, Afula, Israel, and Surgical Research Laboratories of Hebrew University, Hadassah Medical School, Jerusalem
ABSTRACT - Forty female patients suffting fn- long periodsfromfiequency, urgency, and dysuria without any definite organic cause received nortriptyline chloride fm three weeks. In 75 per cent there was either considerable improvement or total disappearance of urinay complaints.At the same time the in vitro effects of the drug were tested using the isometrie muscle contraction technique. Nortriptyline was found to have anticholinergic properties. The importante of this effect in the clinical studu and the possible mode of action of the drug are discussed.
Many female patients diagnosed by the urologist as suffering trom cystitis display a pattern of urinary disturbances involving frequency, urgency, dysuria, and lower abdominal pain. Despite the complaints and severe disturbances in micturition, a thorough urologie and gynecologic examination of these patients often reveals very little. Treatment in such cases tends to be primarily symptomatic with overall results frequently disappointing, and relief obtained is little if any. Since it was observed that complete urinary retention without any organic explanation developed in 2 women treated with large doses of nortriptyline, and since retention disappeared completely on cessation of drug treatment, we decided to subject a number of these patients showing no clear-cut organic disease and not responding significantly to various local or systemic treatment to a brief low-dosage nortriptyline therapy. Concurrently we also examined the pharmacologic effects of nortriptyline in vitro using the isometrie muscle contraction technique. Nortriptyline (Nortylin or Aventyl) is an antidepressant drug with anticholinergic activity which reveals certain side effects, such as dryness of the mouth, constipation, and dimcult micturition.
UROLOGY
/ JUNE1975 / VOLUMEV,
NUMBERG
Material and Methods Clinical study
A group of 40 women under treatment in our clinic for prolonged disturbances in micturition, mainly frequency, without clear evidente of organic disease or urinary infection received treatment with nortriptyline tablets in the dose of 10 mg. four times a day for three weeks. Al1 candidates had undergone a comprehensive urologie checkup which included repeated urine cultures, intravenous pyelogram, cystoureteroscopy, cystometry, and on suspicion of reflux also cystography. Al1 had received various treatments with no or only temporary effect. They were asked to refrain fi-om any other type of treatment for the duration of the test period. During the test period and in subsequent follow-ups in our clinic, the patients were asked to answer a special questionnaire which included the following points: (1) the number of times voided per day and night; (2) any difficulty in continency; (3) burning sensation during micturition; (4) dficulty in voiding; (5) pain in the suprapubic region; (6) the genera1 feeling of the patient; and (7) side effects noted.
747
The first 20 patients underwent repeated cystometry in the course of treatment with nortriptyline. From the standpoint of efficacy of treatment, the condition of the patients was defined as: (1) excellent, when al1 the disturbances in micturition had totally disappeared; (2) good, when the frequency and urgency of, the necessity for, and various complaints during micturition were diminished considerably or were almost nonexistent, while nocturia stopped altogether or at the most required only one voiding; and (3) unchanged, when there was no significant response to treatment. The validity of our interpretation as to the degree of efficacy of treatment is also supported by the fact that we were able to compare the condition of the same patients before, during, and after treatment. Experimental
in vitro study
Mature white rats weighing 250 to 300 Gm. were anesthetized with ether. Through a midline incision the bladder dome was removed, cut into two strips, and immediately placed in Locke’s solution no. 2 at 5°C. Each muscle strip was then examined by the isometrie method in a l5-cc. muscle chamber containing Locke’s solution no. 2 at 37°C. with 95 per cent oxygen and 5 per cent carbon dioxide bubbling through the solution. One end of the muscle strip was tied with a fine silk thread to the bottom of the muscle chamber and the other end connected via a fine silk thread to a Grass FT-03c force displacement transducer, a Sanborn carrier preamplifier, and recorder. A sensitivity of 20 mm. pen deflection per gram tension was used, and the paper recording speed was 10 mm. per minute. The strips were submitted to a tension of 1 Gm. and spontaneous activity was allowed to recover. The strips were tested with acetylcholine and nortriptyline. Twenty experiments in al1 were performed using this technique. Results According to our criteria the condition of 8 patients was excellent with al1 disturbances in micturition gradually disappearing after six to eight days of treatment. The condition of 22 others was good, while that of the remaining 10 was unchanged. The response to treatment in the middle category is shown graphically in Figure 1. Patients that had undergone cystometry in the course of treatment showed no clear-cut changes in the cystometric curve nor in the volume capacity of the bladder at the prescribed
748
f
DUIIYC WEIIYIYr
14
D,Un*AL*
*WV’**”4
HO.or P11IEYr8 2
4
6
8
10
12
14
FIGURE 1. Effect of nortriptyline nocturnal jì-equency of micturition.
16
18
20
22
on diurnal and
low dosage of 40 mg. per day. None of the patients suffered any adverse side effects as a result of treatment. However, in al1 patients in whom nortriptyline had a beneficial effect there was a recurrence of the disturbances shortly after cessation of treatment. In the in vitro study, spontaneous activity reappeared in ten to twenty minutes after immersion in the muscle bath. In al1 strips tested 1 microgram per milliliter of acetylcholine produced a marked stimulatory contraction (Fig. 2A). In 3 of 5 cases 50 micrograms per milliliter of nortriptyline had no effect on the basic tone of the bladder dome. In 2 cases there was an insignificant decrease in basic tone (Fig. 2B). Fifty micrograms per milliliter of nortriptyline added to the muscle bath after treatment with 1 microgram per milliliter of acetylcholine produced a fa11 in muscle tension inhibiting the stimulatory effect of acetylcholine (Fig. 3A). After treatment with 25 micrograms per milliliter of nortriptyline the bladder dome did not respond to the further addition of 1 microgram per milliliter of acetylcholine. Nortriptyline blocked the bladder dome’s response to acetylcholine (Fig. 3B). Comment In the present clinical study nortriptyline had a positive therapeutic effect on 75 per cent of the patients suffering from disturbances in micturition with no clear-cut pathology of the urinary tract. The beneficial effects of the drug may be attributed to its three known pharmacologic properties. The anticholinergic effect of nortriptyline finds its clinical expression in side effects when
UROLOGY
/ JUNE1975 / VOLUMEV,
NUMBERG
ACETYLCHOLINE
FIGURE 2. (A) Marked contraction of bladder muscle (in vitro) produced by acetylcholine. (B) Znsignijìcant effect of nortriptyline on bladder tone (in vitro).
NORTRIPTYLINE
s” wml
ACETYLCHOLINE
FIGURE 3. (A) Nortriptyline clearly inhibits stimulatory effect of acetylcholine. (B) Nortriptyline given prior to acetylcholine, clearly prevents bladder contraction because of its anticholinergic effect.
UROLOGY
/ JUNE1975 / VOLUMEV,
NORTRIPTYLINE 25 Ir+1
NUMBERG
NORTRIPTYLINE
ACETYLCHOLINE 1 Ccpl
749
given as an antidepressant in high doses. The in vitro study clearly demonstrates its anticholinergit effect. The bladder dome is rich in cholinergit receptors as seen by the stimulatory effect of 1 microgram per milliliter of acetylcholine. Twenty-five micrograms per milliliter of nortriptyline black this stimulatory effect when the bladder is pretreated with nortriptyline. Nortriptyline also inhibits the stimulatory effect of 1 microgram per milliliter of acetylcholine when added to the bath after acetylcholine. Other laboratory studies revealed similar findings. ’ In vivo the cholinergic activity of the bladder is via the parasympathetic innervation whose stimulation results in enhanced contraction of the detrusor urinae muscle, whereas its depression leads to relaxation of this muscle. Anticholinergic drug therapy is customary in cases of frequency. It is interesting to note that the use of nortriptyline in high doses may result in complete >retention, as we have seen in 2 patients, and the medical literature cites cases of paralytic ileus after nortriptyline treatment2 The analgesic effect of nortriptyline is more pronounced than imipramine.3 This effect may alleviate urinary complaints such as dysuria and suprapubic pain. Nortriptyline has been found to have a palliative effect in the treatment of psychosomatic diseases as wel1 as a tranquilizing effect on restive, anxious patients facing diagnostic tests or undergoing various treatments.4s5 It is probably the combined effect of these three properties which renders nortriptyline effective in the treatment of urinary complaints. It is clearly obvious that al1 patients displaying disturbances in micturition should undergo thorough urologie examination before any decision on therapy is reached; and if there is a distinct organic cause, appropriate treatment should be given. At the same time, however, one should not overlook the mental factor which could play a supportive or contributory role in the cause of the disturb6 When the mental state of the patient ante . comes into play, a tranquilizing drug, such as nortriptyline, could be effective in alleviating symptoms both through its direct effect on the urinary tract as wel1 as through its antidepressant properties. Although we have not applied double-blind procedures on our patients, we believe that we
750
have obtained sufficient data on the state of each patient, before, during, and after treatment to justify our conclusions. In those cases in which nortriptyline had a beneficial effect, our patients requested the continuation of the treatment beyond the experimental trial period, because they reported recurrence of their complaints and claim that only this drug produced a calming and palliative effect. Indeed our impression and experience tends to confirm this claim. The 2 patients who had come for treatment because of absolute retention received nortriptyline in high dosages (125 mg. per day), whereas the dosage used by US on the experimental group was considerably lower (40 mg. per day). The use of a lower dose probably accounts for the absente of any adverse side effects. On the other hand, it probably explains the absente of any marked effects on the cystometric plot and could explain why the drug did not produce a higher success rate in our patients. It may be reasonable to suppose that in patients not responding satisfactorily to the lower dose level, the dose could be gradually increased without endangering the patient. Centra1 Emek Hospita1 Afiula, Israel (DR. SERVADIO) ACKNOWLEDGMENT. We wish to thank the Department of Experimental Surgery, Hadassah University Hospital, Jerusalem, and Prof. M. Caine and Prof. N. Babinowitz in particular for their support. References 1. BATHBUN, It. C., and SLATER, J. H.: Amitryptyline and nortriptyline as antagonists of central and peripheral cholinergic activation. Psychopharmacologia 4: 114 (1963). 2. MILNER, G., and HILLS, N. F.: Adynamic ileus and nortriptyline, Br. Med. J. 1: 841 (1966). 3. OPITZ, K., and BORCHERT,U. : über die analgetische Wirkung von Thymoleptica, Arzneim. Forsch. 18: 316 (1968). 4. BENNET, J. F.: The constellation of depression. Its treatment with nortriptyline: clinical evaluation of nortriptyline, J. Nerv. Ment. Dis. 135: 59 (1962). Nortriptyline, an antidepressant, Dis. PEJZMAN, 0.: Nerv. Syst. 25: 569 (1964). SEID, B.: A study of antianxiety effects in urological patients, Curr. Ther. Res. 6: 156 (1964). CAMPBELL,M. F., and HARRISON,J. H.: Urology, 3rd ed., Philadelphia, W. B. Saunders, 1970, p. 2048.
UROLOGY / JUNE 1975 / VOLUME V, NUMBER 6