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Doxepin in the Treatment of Female Detrusor Overactivity: A Randomized Double-Blind Crossover Study
0022-5347/89/1424-1024$02.00/0 Vol. 142, October
THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
Urological Neurology and Urodynamics DOXEPIN IN THE TREATMENT OF FEMALE DETRUSOR OVERACTIVITY: A RANDOMIZED DOUBLE-BLIND CROSSOVER STUDY GUNNAR LOSE, LISBETH J0RGENSEN
AND
PER THUNEDBORG
From the Department of Uro/,ogy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
ABSTRACT
A total of 19 women with detrusor overactivity and associated symptoms completed a doubleblind placebo-controlled crossover study of doxepin. All patients had previously failed to respond to conventional pharmacotherapy. Doxepin was given at bedtime in a single 50 mg. dose for the first 2 weeks and, if needed, the dose was increased with 25 mg. in the morning for the last week of the 3-week treatment period, which was followed by 2 weeks of washout before crossover. The preference for doxepin to placebo was statistically significant (p less than 0.01). Doxepin caused a significant decrease in the nighttime micturition frequency and the nighttime incontinence episodes (p less than 0.05). Urine loss at the standardized 1-hour pad weighing test decreased significantly during treatment with doxepin although statistical significance (p equals 0.07) was not obtained. Cystometric parameters (first sensation and maximum cystometric capacity) improved significantly during treatment with doxepin (p less than 0.06 and less than 0.04, respectively). Side effects were frequent but mild. Suggestions for use of this tricyclic antidepressant in women with detrusor overactivity and possible mechanisms of action are discussed. (J. Urol., 142: 1024-1026, 1989}
The management of detrusor overactivity remains a challenge to the physician. Oral durg therapy still is the most common form of treatment and many compounds have been used in an attempt to treat storage failure by decreasing bladder contractility. 1• 2 However, the need for effective drugs with few side effects is recognized widely. The tricyclic antidepressant imipramine has been demonstrated to be useful clinically in the treatment of overactive detrusor function. 3- 6 However, scant data exist concerning the effect of other tricyclic antidepressants on the lower urinary tract. Recently, doxepin* was found in an in vitro study using bladder strips from the rabbit to be more potent than other tricyclic compounds, including imipramine with respect to antimuscarinic and musculotropic relaxant activity.7 From a clinical viewpoint doxepin may seem to have a more ideal profile of effects and side effects than imipramine for treatment of patients with detrusor overactivity. We assessed the effect of doxepin on cystometrically demonstrated detrusor overactivity in women and the associated symptoms compared to placebo in a randomized, double-blind, crossover study. PATIENTS AND METHODS
A total of 20 female outpatients (median age 53 years, range 29 to 78) with detrusor overactivity during sitting medium-fill (50 ml. per minute) water cystometry accompanied by either frequency, urgency or urge incontinence entered the trial after providing informed consent. Detrusor overactivity was defined as involuntary detrusor contractions exceeding 15 cm. water during cystometry. All patients had previously failed to respond to conventional drug therapy (table 1). Sixteen patients had previously undergone a urogenital operation, including a suprapubic anti-incontinence procedure in 12, vaginal repair in 9 and hysterectomy in 7. One patient had neurogenic bladder dysfunction secondary to myelitis of the spinal cord. Accepted for publication May 3, 1989. * Ercopharm A/8, Copenhagen, Denmark.
Exclusion criteria were acute cystitis, pregnancy, genital prolapse or cystocele indicating an operation, diseases contraindicating tricyclic antidepressant medication and the use of drugs that affected the lower urinary tract. Before entry into the study all patients underwent a routine clinical examination, urine culture, pelvic examination and cystoscopy. Design of trial (see figure). After an initial run-in period of 1 week the patients were randomized to receive either doxepin or placebo in 3-week periods followed by 2 weeks of wash-out before crossover. During the first 2 weeks of treatment 2 tablets (50 mg. doxepin or placebo) were given 1 hour before bedtime. If the effect was unsatisfactory and the patient was free of side effects the dose was increased in the last week of treatment to 1 tablet in the morning and 2 in the evening. Study measurements. The patients were evaluated initially and at the end of each period with an interview, 3-day micturition/incontinence chart, urine culture, cystometry, 1-hour pad weighing test using a standardized bladder volume8 and electrocardiography. Blood pressure and heart rate were measured with the patient in the supine and standing positions. Statistics. For comparison of subjective preferences the sign test was used. For comparison of the quantitative data Wilcoxon's test for paired differences was used. A p value of less than 0.05 was considered statistically significant. RESULTS
One patient withdrew from the study for personal reasons. Thus, the series comprised 19 women. The dose of doxepin was increased from 50 to 75 mg. in 17 women after 2 weeks of treatment. Two patients did not increase the dose although the effect of 50 mg. was unsatisfactory. The placebo dose was increased in 14 patients. Three women forgot to increase the dose despite unsatisfactory effect and 2 did not increase it due to side effects. Treatment with doxepin was preferred by 14 patients, while 2 preferred placebo. This difference was statistically significant (p <0.01). Three patients had no preference. Of the 14 patients
1024
1025
DOXEPIN IN TREATMENT OF FEMALE DETRUSOR OVERACTIVITY TABLE 1.
Previous drug therapy in 19 women who completed the trial Drug Emepronium bromide lmipramine Estrogen Terodiline Ephedrine Phenoxybenzamine
14 6 4 2 2
somg
Wash out
Period 2
1smg
somg
3 weeks
t
2 weeks
t
1smg
3 weeks
EVALUATION
t
t
Design of trial
who preferred doxepin 12 claimed to have become continent during treatment, while 2 were improved. The 2 patients who preferred placebo were improved. The number of nighttime voidings and incontinence episodes decreased significantly during treatment with doxepin compared to the run-in period and placebo treatment (table 2). When one considers the daytime frequency there was no significant decrease during doxepin treatment. The number of daytime incontinence episodes decreased significantly during treatment with doxepin as judged from the micturition chart and the 1-hour pad weighing test. The difference between the doxepin and placebo treatments was not statistically significant. The cystometric data are given in table 3. Uninhibited detrusor contractions disappeared in 5 women during treatment with doxepin versus 3 with placebo. The median volume at first TABLE 2.
Day: Voidings Incontinence episodes Urine loss (gm.) Night: Voidings Incontinence episodes
Doxepin
Placebo
14
3 2 2
8 8 4 1
1 0 0
1
1
active drug/placebo
Period 1
Side effects in 19 women who completed the trial
Total No. women Fatigue Dryness of mouth Dizziness Weakness Blurred vision
RANDOMIZED
Run in
TABLE 4.
No. Women Treated
sensation increased by 117% (p <0.02) and the median maximum cystometric capacity increased by 58% (p = 0.08) during doxepin treatment compared to the run-in period, while the corresponding values were 33 and 21 %, respectively, during placebo treatment, which was not statistically significant (p = 0.79 and 0.84). The difference between the median volume at first sensation and maximum cystometric capacity during doxepin versus placebo was significant (p = 0.06 and 0.04, respectively). During doxepin treatment residual urine was unchanged compared to the run-in period but it was significantly greater compared to the placebo group (p <0.05). Side effects occurred in 14 women during treatment with doxepin versus 3 during placebo treatment (table 4). These side effects were well tolerated and did not deter 17 patients from requesting continued treatment with doxepin after the randomization code was broken. No patient ceased treatment because of side effects. Five women stated spontaneously that their sleep was significantly improved during treatment with doxepin. No significant changes occurred in the blood pressure, heart rate and electrocardiogram in any of the treatment groups. No case of orthostatic hypotension was seen during treatment with doxepin. DISCUSSION
Our study demonstrates that the well known tricyclic antidepressive drug doxepin is significantly better than placebo in improving the symptoms and urodynamic parameters of female detrusor overactivity. Statistical significance in favor of doxepin was not obtained for all test parameters. However, it should be considered that our series was small and comprised patients who had been treated unsuccessfully in the past with other drugs. Furthermore, in most of the patients detrusor overactivity developed or persisted after an anti-incontinence operation, which implies a poor response to drug treatment. 9 We chose the crossover design to save patients well aware of the methodological problems in the form of period effect and carry-over effect, which have led to some skepticism concerning this
Frequency of voiding and leaking episodes per 3 days, and urine loss at the I -hour pad weighing test Run-In*
P Value (run-in versus doxepin)
Doxepin*
P Value (doxepin versus placebo)
Placebo*
P Value (placebo versus run-in)
26 (4-99) 4 (0-26) 39 (0-101)
0.15 Not significant 0.07
22 (9-78) 1 (0-28) 6 (0-95)
Not significant Not significant 0.17
22 (10-63) 3.5 (0-19) 40 (0-114)
Not significant Not significant Not significant
4 (0-16) 1 (0-5)
0.01 <0.01
1 (0-6) 0 (0-6)
<0.001 <0.05
4 (0-13) 1 (0-5)
Not significant <0.01
* Median (range). TABLE 3.
Detrusor instability (No. women) First sensation (ml.)* Maximum cystometric capacity (ml.)* Residural urine (ml.)* * Median (range).
Results of cystometric measurements after each treatment period Run-In
Doxepin
Placebo
P Value (doxepin versus placebo)
19 60 (25-212) 144 (55-300) 5 (0-75)
14 112 (20-24 7) 227 (29-365) 5 (0-25)
16 80 (18-264) 175 (34-316) 0 (0-75)
Not significant 0.06 0.04 0.014
1026
LOSE, J0RGENSEN AND THUNEDBORG
design. 10' 11 We have included a washout period to counteract the carry-over effect. Our results are in agreement with previous studies on imipramine. 3 - 6 Doxepin has been shown in vitro to possess a more pronounced detrusor inhibiting effect than imipramine. 7 However, it is not possible to extrapolate from such data to the in vitro potencies. This problem must be elucidated in a clinical trial. Tricyclic antidepressants possess a wide spectrum of effects and these drugs also are used to treat certain nonpsychiatric disorders, such as chronic pain syndromes, the irritable colon syndrome and peptic ulcer disease. 12- 14 The precise mode of action oftricyclic antidepressants on the bladder still is unclear. Many mechanisms may be proposed, including a central possible antidepressant effect,1 5 a peripheral anticholinergic effect,7' 15 ' 16 a direct musculotropic relaxant effect, 16 an a-adrenergic potentiating or a-adrenolytic effect,1 6 a local anesthetic effect, 17 a histamine antagonistic effect (Hl and H2),1 4 a calcium antagonistic effect18 or an enkephalin-like activity. 13 Since the etiologies of detrusor overactivity remain unclear it is impossible to know which mechanisms are the most relevant. Doxepin may improve storage failure by decresing bladder contractility and/or decreasing sensory input. A central, possibly antidepressive effect, via an increase in the level of biogenic amines in the central nervous system, also may be relevant. In this context it is interesting to note that women with detrusor overactivity seem to be more depressed than the normal population. 19 However, it may be difficult to assess what comes first, detrusor overactivity or the psychological symptoms. Our patients were not examined by a psychiatrist but none had overt signs of a psychiatric disorder. However, the proved anxiolytic and antidepressive actions of doxepin certainly should be considered in the selection of treatment for patients with detrusor overactivity who are depressed or anxious. It is important to inform the patient that doxepin is used to treat psychiatric disorders when prescribing the drug. Tricyclic antidepressants differ in the profile of their effects and side effects. Doxepin is well tolerated also in the elderly and in patients with cardiovascular disease. 20 Generally, it has caused fewer or less troublesome side effects than imipramine. 20 Side effects tend to be dose-related in female patients. 20 In this context it should be considered that the dose used in psychiatric conditions usually is about 150 to 300 mg. per day which is more than double the dose used in this study. Dry mouth, drowsiness or sedation and constipation are the most commonly reported side effects but they often are mild. 20 This finding is in accordance with our results. The sedative effect, however, may be helpful to treat sleep disturbances that often accompany severe detrusor overactivity with nocturia. This particular impact of doxepin on the nighttime problems seems to be unique compared to conventional anticholinergic and calcium blocking agents. Daytime drowsiness can be counteracted by giving the major portion or the total daily dose at bedtime, as done in our study. Postural hypotension and cardiotoxicity seem to be minor problems with doxepin compared to imipramine. 20 The median volume of residual urine was 5 ml. during doxepin treatment versus O ml. during placebo treatment. Although this difference was statistically significant it seems of no clinical importance, since in no patient was a marked increase noted. Doxepin is well absorbed from the gut. 20 The bioavailability is variable owing to extensive first-pass metabolism in the liver. 15 The plasma half-time is 8 to 24 hours, which allows for once daily administration. Therapeutic response appears to correlate with plasma level of the active metabolite desmethyldoxepin or of doxepin plus desmethyldoxepin. Monitoring of plasma concentration is easy to perform. Finally, the cost of
doxepin is low compared to widely used detrusor inhibitor drugs, such as emepronium bromide and terodiline. Based on our data and that of the literature doxepin seems to have a favorable profile of effects and side effects for treatment of female detrusor overactivity and associated symptoms. Doxepin should be considered particularly in the treatment of patients with nighttime problems and possibly in patients who are depressed or anxious. Advantages compared to conventional drugs include once-daily administration, lower cost and ease of serum monitoring. In conclusion, doxepin seems to offer a new alternative in the pharmacological treatment of detrusor overactivity and associated symptoms. REFERENCES
1. Wein, A. J.: Drug therapy for detrusor hyperactivity: where are we? Neurourol. Urodynam., 4: 337, 1985. 2. Lose, G. and Andersen, J. T.: Clinical pharmacology of the lower urinary tract. New aspects. Eur. Urol., 12: 1, 1986. 3. Cole, A. T. and Fried, F. A.: Favorable experiences with imipramine in the treatment of neurogenic bladder. J. Urol., 107: 44, 1972. 4. Raezer, D. M., Benson, G. S., Wein, A. J. and Duckett, J. W., Jr.: The functional approach to the management of the pediatric neuropathic bladder: a clinical study. J. Urol., 117: 649, 1977. 5. Castleden, C. M., George, C. F., Renwick, A. G. and Asher, M. J.: Imipramine-a possible alternative to current therapy for urinary incontinence in the elderly. J. Urol., 125: 318, 1981. 6. Castleden, C. M., Duffin, H. M. and Gulati, R. S.: Double-blind study of imipramine and placebo for incontinence due to bladder instability. Age Ageing, 15: 299, 1986. 7. Levin, R. M. and Wein, A. J.: Comparative effects of five tricyclic compounds on the rabbit urinary bladder. Neurourol. Urodynam., 3: 127, 1984. 8. Lose, G., Rosenkilde, P., Gammelgaard, J. and Schroeder, T.: Padweighing test performed with standardized bladder volume. U rology, 32: 78, 1988. 9. Steel, S. A., Cox, C. and Stanton, S. L.: Long-term followup of detrusor instability following the colposuspension operation. Brit. J. Urol., 58: 138, 1986. 10. Hills, M. and Armitage, P.: The two-period cross-over clinical trial. Brit. J. Clin. Pharm., 8: 7, 1979. 11. Brown, B. W., Jr.: The crossover experiment for clinical trials. Biometrics, 36: 69, 1980. 12. Cunha, U. V.: Antidepressants: their uses in nonpsychiatric disorders of aging. Geriatrics, 41: 63, 1986. 13. Hameroff, S. R., Cork, R. C., Scherer, K., Crago, B. R., Neuman, C., Womble, J. R. and Davis, T. P.: Doxepin effects on chronic pain, depression and plasma opioids. J. Clin. Psychiat., part 2, 43: 22, 1982. 14. Richelson, E.: The use of tricyclic antidepressants in chronic gastrointestinal pain. J. Clin. Psychiat., part 2, 43: 50, 1982. 15. Hollister, L. E.: Tricyclic antidepressants. New Engl. J. Med., 299: 1106, 1978. 16. Olubadewo, J. 0.: The effect of imipramine on rat detrusor muscle contractility. Arch. Int. Pharmacodyn. Ther., 245: 84, 1980. 17. Fredericks, C. M., Green, R. L. and Anderson, G. F.: Comparative in vitro effects of imipramine, oxybutynin and flavoxate on rabbit detrusor. Urology, 12: 487, 1978. 18. Horrobin, D. F., Manku, M. S. and Mtabaji, J. P .: A new mechanism of tricyclic antidepressant action. Blockade of prostaglandindependent calcium movements. Postgrad. Med. J., suppl. 4, 53: 19, 1977. 19. Macaulay, A. J., Stern, R. S., Holmes, D. M. and Stanton, S. L.: Micturition and the mind: psychological factors in the aetiology and treatment of urinary symptoms in women. Brit. Med. J., 294: 540, 1987. 20. Pinder, R. M., Brogden, R. N., Speight, T. M. and Avery, G. S.: Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Drugs, 13: 161, 1977.
THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
Urological Neurology and Urodynamics DOXEPIN IN THE TREATMENT OF FEMALE DETRUSOR OVERACTIVITY: A RANDOMIZED DOUBLE-BLIND CROSSOVER STUDY GUNNAR LOSE, LISBETH J0RGENSEN
AND
PER THUNEDBORG
From the Department of Uro/,ogy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
ABSTRACT
A total of 19 women with detrusor overactivity and associated symptoms completed a doubleblind placebo-controlled crossover study of doxepin. All patients had previously failed to respond to conventional pharmacotherapy. Doxepin was given at bedtime in a single 50 mg. dose for the first 2 weeks and, if needed, the dose was increased with 25 mg. in the morning for the last week of the 3-week treatment period, which was followed by 2 weeks of washout before crossover. The preference for doxepin to placebo was statistically significant (p less than 0.01). Doxepin caused a significant decrease in the nighttime micturition frequency and the nighttime incontinence episodes (p less than 0.05). Urine loss at the standardized 1-hour pad weighing test decreased significantly during treatment with doxepin although statistical significance (p equals 0.07) was not obtained. Cystometric parameters (first sensation and maximum cystometric capacity) improved significantly during treatment with doxepin (p less than 0.06 and less than 0.04, respectively). Side effects were frequent but mild. Suggestions for use of this tricyclic antidepressant in women with detrusor overactivity and possible mechanisms of action are discussed. (J. Urol., 142: 1024-1026, 1989}
The management of detrusor overactivity remains a challenge to the physician. Oral durg therapy still is the most common form of treatment and many compounds have been used in an attempt to treat storage failure by decreasing bladder contractility. 1• 2 However, the need for effective drugs with few side effects is recognized widely. The tricyclic antidepressant imipramine has been demonstrated to be useful clinically in the treatment of overactive detrusor function. 3- 6 However, scant data exist concerning the effect of other tricyclic antidepressants on the lower urinary tract. Recently, doxepin* was found in an in vitro study using bladder strips from the rabbit to be more potent than other tricyclic compounds, including imipramine with respect to antimuscarinic and musculotropic relaxant activity.7 From a clinical viewpoint doxepin may seem to have a more ideal profile of effects and side effects than imipramine for treatment of patients with detrusor overactivity. We assessed the effect of doxepin on cystometrically demonstrated detrusor overactivity in women and the associated symptoms compared to placebo in a randomized, double-blind, crossover study. PATIENTS AND METHODS
A total of 20 female outpatients (median age 53 years, range 29 to 78) with detrusor overactivity during sitting medium-fill (50 ml. per minute) water cystometry accompanied by either frequency, urgency or urge incontinence entered the trial after providing informed consent. Detrusor overactivity was defined as involuntary detrusor contractions exceeding 15 cm. water during cystometry. All patients had previously failed to respond to conventional drug therapy (table 1). Sixteen patients had previously undergone a urogenital operation, including a suprapubic anti-incontinence procedure in 12, vaginal repair in 9 and hysterectomy in 7. One patient had neurogenic bladder dysfunction secondary to myelitis of the spinal cord. Accepted for publication May 3, 1989. * Ercopharm A/8, Copenhagen, Denmark.
Exclusion criteria were acute cystitis, pregnancy, genital prolapse or cystocele indicating an operation, diseases contraindicating tricyclic antidepressant medication and the use of drugs that affected the lower urinary tract. Before entry into the study all patients underwent a routine clinical examination, urine culture, pelvic examination and cystoscopy. Design of trial (see figure). After an initial run-in period of 1 week the patients were randomized to receive either doxepin or placebo in 3-week periods followed by 2 weeks of wash-out before crossover. During the first 2 weeks of treatment 2 tablets (50 mg. doxepin or placebo) were given 1 hour before bedtime. If the effect was unsatisfactory and the patient was free of side effects the dose was increased in the last week of treatment to 1 tablet in the morning and 2 in the evening. Study measurements. The patients were evaluated initially and at the end of each period with an interview, 3-day micturition/incontinence chart, urine culture, cystometry, 1-hour pad weighing test using a standardized bladder volume8 and electrocardiography. Blood pressure and heart rate were measured with the patient in the supine and standing positions. Statistics. For comparison of subjective preferences the sign test was used. For comparison of the quantitative data Wilcoxon's test for paired differences was used. A p value of less than 0.05 was considered statistically significant. RESULTS
One patient withdrew from the study for personal reasons. Thus, the series comprised 19 women. The dose of doxepin was increased from 50 to 75 mg. in 17 women after 2 weeks of treatment. Two patients did not increase the dose although the effect of 50 mg. was unsatisfactory. The placebo dose was increased in 14 patients. Three women forgot to increase the dose despite unsatisfactory effect and 2 did not increase it due to side effects. Treatment with doxepin was preferred by 14 patients, while 2 preferred placebo. This difference was statistically significant (p <0.01). Three patients had no preference. Of the 14 patients
1024
1025
DOXEPIN IN TREATMENT OF FEMALE DETRUSOR OVERACTIVITY TABLE 1.
Previous drug therapy in 19 women who completed the trial Drug Emepronium bromide lmipramine Estrogen Terodiline Ephedrine Phenoxybenzamine
14 6 4 2 2
somg
Wash out
Period 2
1smg
somg
3 weeks
t
2 weeks
t
1smg
3 weeks
EVALUATION
t
t
Design of trial
who preferred doxepin 12 claimed to have become continent during treatment, while 2 were improved. The 2 patients who preferred placebo were improved. The number of nighttime voidings and incontinence episodes decreased significantly during treatment with doxepin compared to the run-in period and placebo treatment (table 2). When one considers the daytime frequency there was no significant decrease during doxepin treatment. The number of daytime incontinence episodes decreased significantly during treatment with doxepin as judged from the micturition chart and the 1-hour pad weighing test. The difference between the doxepin and placebo treatments was not statistically significant. The cystometric data are given in table 3. Uninhibited detrusor contractions disappeared in 5 women during treatment with doxepin versus 3 with placebo. The median volume at first TABLE 2.
Day: Voidings Incontinence episodes Urine loss (gm.) Night: Voidings Incontinence episodes
Doxepin
Placebo
14
3 2 2
8 8 4 1
1 0 0
1
1
active drug/placebo
Period 1
Side effects in 19 women who completed the trial
Total No. women Fatigue Dryness of mouth Dizziness Weakness Blurred vision
RANDOMIZED
Run in
TABLE 4.
No. Women Treated
sensation increased by 117% (p <0.02) and the median maximum cystometric capacity increased by 58% (p = 0.08) during doxepin treatment compared to the run-in period, while the corresponding values were 33 and 21 %, respectively, during placebo treatment, which was not statistically significant (p = 0.79 and 0.84). The difference between the median volume at first sensation and maximum cystometric capacity during doxepin versus placebo was significant (p = 0.06 and 0.04, respectively). During doxepin treatment residual urine was unchanged compared to the run-in period but it was significantly greater compared to the placebo group (p <0.05). Side effects occurred in 14 women during treatment with doxepin versus 3 during placebo treatment (table 4). These side effects were well tolerated and did not deter 17 patients from requesting continued treatment with doxepin after the randomization code was broken. No patient ceased treatment because of side effects. Five women stated spontaneously that their sleep was significantly improved during treatment with doxepin. No significant changes occurred in the blood pressure, heart rate and electrocardiogram in any of the treatment groups. No case of orthostatic hypotension was seen during treatment with doxepin. DISCUSSION
Our study demonstrates that the well known tricyclic antidepressive drug doxepin is significantly better than placebo in improving the symptoms and urodynamic parameters of female detrusor overactivity. Statistical significance in favor of doxepin was not obtained for all test parameters. However, it should be considered that our series was small and comprised patients who had been treated unsuccessfully in the past with other drugs. Furthermore, in most of the patients detrusor overactivity developed or persisted after an anti-incontinence operation, which implies a poor response to drug treatment. 9 We chose the crossover design to save patients well aware of the methodological problems in the form of period effect and carry-over effect, which have led to some skepticism concerning this
Frequency of voiding and leaking episodes per 3 days, and urine loss at the I -hour pad weighing test Run-In*
P Value (run-in versus doxepin)
Doxepin*
P Value (doxepin versus placebo)
Placebo*
P Value (placebo versus run-in)
26 (4-99) 4 (0-26) 39 (0-101)
0.15 Not significant 0.07
22 (9-78) 1 (0-28) 6 (0-95)
Not significant Not significant 0.17
22 (10-63) 3.5 (0-19) 40 (0-114)
Not significant Not significant Not significant
4 (0-16) 1 (0-5)
0.01 <0.01
1 (0-6) 0 (0-6)
<0.001 <0.05
4 (0-13) 1 (0-5)
Not significant <0.01
* Median (range). TABLE 3.
Detrusor instability (No. women) First sensation (ml.)* Maximum cystometric capacity (ml.)* Residural urine (ml.)* * Median (range).
Results of cystometric measurements after each treatment period Run-In
Doxepin
Placebo
P Value (doxepin versus placebo)
19 60 (25-212) 144 (55-300) 5 (0-75)
14 112 (20-24 7) 227 (29-365) 5 (0-25)
16 80 (18-264) 175 (34-316) 0 (0-75)
Not significant 0.06 0.04 0.014
1026
LOSE, J0RGENSEN AND THUNEDBORG
design. 10' 11 We have included a washout period to counteract the carry-over effect. Our results are in agreement with previous studies on imipramine. 3 - 6 Doxepin has been shown in vitro to possess a more pronounced detrusor inhibiting effect than imipramine. 7 However, it is not possible to extrapolate from such data to the in vitro potencies. This problem must be elucidated in a clinical trial. Tricyclic antidepressants possess a wide spectrum of effects and these drugs also are used to treat certain nonpsychiatric disorders, such as chronic pain syndromes, the irritable colon syndrome and peptic ulcer disease. 12- 14 The precise mode of action oftricyclic antidepressants on the bladder still is unclear. Many mechanisms may be proposed, including a central possible antidepressant effect,1 5 a peripheral anticholinergic effect,7' 15 ' 16 a direct musculotropic relaxant effect, 16 an a-adrenergic potentiating or a-adrenolytic effect,1 6 a local anesthetic effect, 17 a histamine antagonistic effect (Hl and H2),1 4 a calcium antagonistic effect18 or an enkephalin-like activity. 13 Since the etiologies of detrusor overactivity remain unclear it is impossible to know which mechanisms are the most relevant. Doxepin may improve storage failure by decresing bladder contractility and/or decreasing sensory input. A central, possibly antidepressive effect, via an increase in the level of biogenic amines in the central nervous system, also may be relevant. In this context it is interesting to note that women with detrusor overactivity seem to be more depressed than the normal population. 19 However, it may be difficult to assess what comes first, detrusor overactivity or the psychological symptoms. Our patients were not examined by a psychiatrist but none had overt signs of a psychiatric disorder. However, the proved anxiolytic and antidepressive actions of doxepin certainly should be considered in the selection of treatment for patients with detrusor overactivity who are depressed or anxious. It is important to inform the patient that doxepin is used to treat psychiatric disorders when prescribing the drug. Tricyclic antidepressants differ in the profile of their effects and side effects. Doxepin is well tolerated also in the elderly and in patients with cardiovascular disease. 20 Generally, it has caused fewer or less troublesome side effects than imipramine. 20 Side effects tend to be dose-related in female patients. 20 In this context it should be considered that the dose used in psychiatric conditions usually is about 150 to 300 mg. per day which is more than double the dose used in this study. Dry mouth, drowsiness or sedation and constipation are the most commonly reported side effects but they often are mild. 20 This finding is in accordance with our results. The sedative effect, however, may be helpful to treat sleep disturbances that often accompany severe detrusor overactivity with nocturia. This particular impact of doxepin on the nighttime problems seems to be unique compared to conventional anticholinergic and calcium blocking agents. Daytime drowsiness can be counteracted by giving the major portion or the total daily dose at bedtime, as done in our study. Postural hypotension and cardiotoxicity seem to be minor problems with doxepin compared to imipramine. 20 The median volume of residual urine was 5 ml. during doxepin treatment versus O ml. during placebo treatment. Although this difference was statistically significant it seems of no clinical importance, since in no patient was a marked increase noted. Doxepin is well absorbed from the gut. 20 The bioavailability is variable owing to extensive first-pass metabolism in the liver. 15 The plasma half-time is 8 to 24 hours, which allows for once daily administration. Therapeutic response appears to correlate with plasma level of the active metabolite desmethyldoxepin or of doxepin plus desmethyldoxepin. Monitoring of plasma concentration is easy to perform. Finally, the cost of
doxepin is low compared to widely used detrusor inhibitor drugs, such as emepronium bromide and terodiline. Based on our data and that of the literature doxepin seems to have a favorable profile of effects and side effects for treatment of female detrusor overactivity and associated symptoms. Doxepin should be considered particularly in the treatment of patients with nighttime problems and possibly in patients who are depressed or anxious. Advantages compared to conventional drugs include once-daily administration, lower cost and ease of serum monitoring. In conclusion, doxepin seems to offer a new alternative in the pharmacological treatment of detrusor overactivity and associated symptoms. REFERENCES
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