- Email: [email protected]
A PROSPECTIVE, RANDOMIZED, PLACEBO CONTROLLED, DOUBLE-BLIND STUDY OF AMITRIPTYLINE FOR THE TREATMENT OF INTERSTITIAL CYSTITIS
0022-5347/04/1722-0533/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 533–536, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000132388.54703.4d
Infection/Inflammation A PROSPECTIVE, RANDOMIZED, PLACEBO CONTROLLED, DOUBLEBLIND STUDY OF AMITRIPTYLINE FOR THE TREATMENT OF INTERSTITIAL CYSTITIS ARNDT
VAN
OPHOVEN,* SASA POKUPIC, ACHIM HEINECKE
AND
LOTHAR HERTLE
From the Department of Urology, Universita¨tsklinikum Mu¨nster and Department of Medical Informatics and Biomathematics (AH), University of Mu¨nster, Mu¨nster, Germany
ABSTRACT
Purpose: We conducted a prospective study to examine the safety and efficacy of the tricyclic antidepressant amitriptyline in patients with interstitial cystitis (IC). Materials and Methods: The study comprised 44 women and 6 men who all met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases for IC. The patients were randomly assigned to amitriptyline or placebo. Patients were prospectively treated for 4 months with a self-titration protocol that allowed them to escalate drug dosage in 25 mg increments in 1 week-intervals (maximum dosage 100 mg). The change from baseline in the O’Leary-Sant IC symptom and problem index was the primary outcome parameter. Changes in functional bladder capacity and frequency (48-hour voiding log), and intensity of pain and urgency (visual analog scales) were chosen as secondary outcome parameters. Results: Two patients (1 on amitriptyline, 1 on placebo) dropped out of the study due to side effects. Thus, the data of 48 patients (24 patients in each group) were available for evaluation. Mean symptom score decreased from 26.9 to 18.5 in the amitriptyline group compared with 27.6 to 24.1 in the placebo group (p ⫽ 0.005). Pain and urgency intensity improved statistically significantly in the amitriptyline group compared with the placebo group (p ⬍0.001). The frequency and functional bladder capacity improved to a much greater degree in the amitriptyline group but the differences were not statistically significant (p ⫽ 0.063, p ⫽ 0.083). Anticholinergic side effects were reported by all except 2 patients in the amitriptyline group (92%) and by 5 patients in the placebo group (21%). Mouth dryness was the most frequent side effect reported in the amitriptyline group (79%). Conclusions: Amitriptyline therapy for 4 months is safe and effective for treating IC. A statistically significant change in the symptom score and statistically significant improvement of pain and urgency intensity compared with placebo were observed. Anticholinergic side effects constitute the major drawback of amitriptyline treatment for IC. KEY WORDS: cystitis, interstitial; clinical trials; amitriptyline; antidepressive agents, tricyclic
Interstitial cystitis (IC) is a chronic and debilitating bladder syndrome, primarily affecting women, characterized by pelvic/perineal/bladder pain associated with urinary urgency, frequency and sterile, cytologically normal urine. Despite a large number of purported therapeutic approaches,1 the treatment of interstitial cystitis remains suboptimal and the data regarding the efficacy of the majority of those treatment modalities are derived primarily from nonevidence based trials or case series.2 Hanno and Wein in 1987 first reported on the use of the tricyclic antidepressant amitriptyline3 and, although amitriptyline has subsequently become the most frequently prescribed oral drug for IC within the patient population of the
IC database,1 its efficacy has never been assessed in a randomized, placebo controlled, double-blind study. PATIENTS AND METHODS
The study used a randomized, placebo controlled, doubleblind design and was conducted at 1 institution (University of Mu¨nster Hospital). The study protocol was approved by the Institutional Review Board of the University Hospital of Mu¨nster and written informed consent was obtained from all patients. The study drug was supplied by Bayer Pharmaceutical, Germany. The placebo was supplied by the pharmacy of the University Hospital of Mu¨nster, which packed and blinded placebo and drug tablets. The study comprised 44 women and 6 men who all met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases for IC.4 All patients had received previous conservative medical treatment, including hydrostatic distension, intravesical instillations (eg dimethylsulfoxide, hyaluronic acid) or oral medication (eg antiallergics, sodium pentosanpolysulfate), which at best achieved
Accepted for publication March 12, 2004. The study protocol received Institutional Review Board of the University Hospital of Mu¨nster. * Correspondence: Klinik und Poliklinik fu¨r Urologie, Universita¨tsklinikum Mu¨nster, Albert Schweitzer-Str. 33, 48129 Mu¨nster, Germany (telephone: ⫹⫹-49-251-8347466; FAX: ⫹⫹-49-251-8345279; e-mail: [email protected]). 533
534
AMITRIPTYLINE FOR INTERSTITIAL CYSTITIS TABLE 1. Baseline patient demographic and clinical characteristics by treatment group Characteristic
Amitriptyline
Placebo
No. pts randomized No. females (%) No. males (%) Mean age ⫾ SD (yrs) Mean symptom duration before treatment ⫾ SD (yrs) Mean age at onset of symptoms ⫾ SD (yrs) Mean pain intensity ⫾ SD (mm on VAS) Mean urgency intensity ⫾ SD (mm on VAS) Mean 24-hr frequency ⫾ SD Mean functional bladder volume ⫾ SD (ml) Mean score-sum ⫾ SD
25 22 (88) 3 (12) 50.5 ⫾ 14.4 3.1 ⫾ 5.0 44.7 ⫾ 15.8 52.7 ⫾ 24.6 70.5 ⫾ 12.7 18.4 ⫾ 8.1 124 ⫾ 79 26.9 ⫾ 4.8
25 22 (88) 3 (12) 60.2 ⫾ 17.5 4.4 ⫾ 4.9 52.9 ⫾ 15.9 52.6 ⫾ 28.4 63.3 ⫾ 19.6 16.6 ⫾ 5.7 127 ⫾ 61 27.6 ⫾ 5.6
TABLE 2. Changes in symptoms from baseline to 4 months Characteristic Mean Mean Mean Mean Mean
score-sum ⫾ SD pain intensity ⫾ SD (mm on VAS) urgency intensity ⫾ SD (mm on VAS) 24-hr frequency ⫾ SD functional bladder volume ⫾ SD (ml)
Amitriptyline
Placebo
p Value
⫺8.4 ⫾ 7.2 ⫺22.8 ⫾ 26.1 ⫺43.8 ⫾ 23.5 ⫺4.0 ⫾ 5.1 19.0 ⫾ 54.62
⫺3.5 ⫾ 5.4 1.0 ⫾ 14.8 ⫺0.1 ⫾ 3.2 ⫺0.6 ⫾ 5.8 ⫺7.7 ⫾ 47.5
0.005 ⬍0.001 ⬍0.001 0.063 0.083
short symptomatic relief. Previous or current intake of amitriptyline was considered an exclusion criterion for study enrollment. The patients were equally assigned to amitriptyline or placebo using a block randomization design. Patients were subsequently treated prospectively for 4 months with a selftitration protocol. They were instructed to take 25 mg of amitriptyline at bedtime. If after 1 week they were not symptom-free, they increased the dosage to 50 mg. The same alteration was allowed for weeks 3 and 4, taking 75 mg and 100 mg (maximum allowed dosage), respectively. If patients experienced satisfactory relief of symptoms they were to maintain the individual lowest effective dose and not increase the dose further. The change from baseline in the O’Leary-Sant IC symptom and problem index was the primary outcome parameter for this study. This validated, self-administered index comprises 8 questions assessing major pain and voiding symptoms. The maximum index score-sum of 36 reflects maximum symptom and problem severity and the lowest possible score-sum is 0.5 Secondary outcome measures included patient reported symptoms of pain and urgency (visual analog scales, VAS), and changes in functional bladder capacity and frequency (48-hour voiding log). Additionally, patients were requested to rate satisfaction with the therapeutic outcome as either excellent, good, fair or poor (Patient Global Assessment Form). Outcomes were evaluated at baseline and in 4-week intervals after randomization. All adverse events were reported and graded according to the Common Toxicity Criteria on a scale of 0 to 5.6 The study sample size of 50 patients (25 per group) was powered for a difference of approximately 1 standard deviation between the amitriptyline and placebo group with a 95% confidence interval (␣ ⫽ 0.05) and a statistical power of 85% ( ⫽ 0.15). Baseline factors were compared between the 2 groups using Fisher’s exact and Mann-Whitney-U tests. Statistical comparisons were made using the Mann-Whitney-U test for changes in symptom score (primary outcome parameter), changes in pain and urgency intensity, and changes in voiding patterns (frequency, functional bladder volume). Chisquare statistics were calculated to compare proportion of responders between treatment groups, with p ⬍0.05 considered significant. All statistical tests were 2-tailed, and calculations were performed using SPSS and SAS statistical software packages (SAS Institute, Carey, North Carolina).
RESULTS
Two patients (1 on amitriptyline, 1 on placebo) dropped out of the study due to adverse side effects. Thus, the data on 48 patients (24 patients in each group) were available for evaluation. Selected baseline characteristics are shown in table 1. For the primary outcome there was a highly statistically significant difference between the study groups (table 2). Mean symptom score-sum decreased from 26.9 to 18.5 in the amitriptyline group compared with 27.6 to 24.1 in the placebo group (p ⫽ 0.005). Of the patients in the amitriptyline group 10 (42%) had a greater than 30% decrease in the symptom score compared with 3 (12.5%) in the placebo group (p ⬍0.001). For the secondary end points there were highly statistically significant differences between the study groups for several outcome parameters (table 2). Pain and urgency intensity improved statistically significantly in the amitriptyline group compared with the placebo group (p ⬍0.001). The frequency and functional bladder capacity improved to a much greater degree in the amitriptyline group but the differences were not statistically significant (p ⫽ 0.063 for comparison of frequency and p ⫽ 0.083 for comparison of functional bladder capacity between treatment groups). Of the 24 patients receiving amitriptyline 15 (63%) rated satisfaction with the therapeutic outcome as either good or excellent compared to 1 patient (4%) in the placebo group (p ⬍0.001, table 3). At the end of 4 months of treatment the effective daily treatment dose in the drug group was 50 mg amitriptyline in 9 of the 24 patients (37.5%). Seven patients (29%) took 25 mg amitriptyline at bedtime, 5 (21%) took 75 mg and 3 (12.5%) took the maximum dose of 100 mg daily. Anticholinergic side effects were noted by all except 2 patients in the amitriptyline group (92%) and by 5 patients in the placebo group (21%). A dry mouth was the most frequent side effect in the amitriptyline group (79%, table 4). No adverse side effects of grade 3 or higher were reported.
TABLE 3. Patient satisfaction with therapeutic outcome after 4 months treatment period Poor Fair Good Excellent
No. Amitriptyline (%)
No. Placebo (%)
3 (13) 6 (25) 10 (42) 5 (21)
21 (88) 2 (8) 1 (4) 0
535
AMITRIPTYLINE FOR INTERSTITIAL CYSTITIS TABLE 4. Reported adverse side effects (worst reported) Adverse Side Effect
No. Grade 0, None (%) Amitriptyline
Placebo
Mouth dryness 5 (21) 22 (92) Wt gain 9 (37) 22 (92) Sedation 15 (62.5) 21 (87.5) Constipation 13 (54) 22 (92) Nausea/vertigo 21 (87.5) 21 (87.5) Blurred vision/diplopia 20 (83) 24 (100) Erectile dysfunction 23 (96) 24 (100) Numbers include report of multiple concurrent side effects.
DISCUSSION
Normal bladder function is generally understood as the organ’s competence to store a sufficient amount of urine followed by a painless urge to void and finally almost complete emptying. This complex ability, which is severely impaired in patients with IC, is based on activation and maintenance of sophisticated reflex mechanism involving sympathetic, parasympathetic and somatic control of the lower urinary tract. The spinal and supraspinal neuronal pathways involved are modulated by activation and/or inhibition of neurons in the periphery, at spinal levels and at supraspinal regulatory sites. Serotonergic (5-hydroxitryptamine [5-HT]) pathways and receptor mechanisms have a crucial role within this neuronal network. The mechanism of action of serotonergic drugs, such as the wellknown 5-HT reuptake inhibitor amitriptyline used in this study, is to modulate this neuronal network resulting in an ameliorating impact on the impaired bladder function of patients with IC. de Groat recently reviewed the effects of serotonergic drugs on central nervous system control of the lower urinary tract and underscored that in vitro data indicate that activation of the central serotonergic system can suppress voiding and urge to void by enhancing efferent control of the urethral outlet and inhibiting the parasympathetic excitatory input to the bladder.7 Burgard et al reviewed serotonergic modulation of bladder afferent pathways pointing out that sufficient data show that multiple 5-HT receptors are located within the lumbosacral spinal cord.8 In addition, various 5-HT receptor subtypes are present in centrally located neuronal nuclei as well as sacral parasympathetic nuclei. These nuclei contain autonomic and somatic bladder efferent fibers, indicating that 5-HT may modulate efferent as well as afferent processing in the spinal cord. Additional animal derived data suggest that 5-HT receptors mediate an increase in sensory threshold for micturition without inhibiting visceral motor response.8 The mechanism of analgesic action of amitriptyline in general,9, 10 and particularly for IC, is not fully understood. 5-HT is known to have a role in the transmission of nociceptive signals at various neuronal levels, ie at spinal cord, brainstem and thalamic sites.11 Additionally, the presynaptic inhibition of 5-HT re-uptake induced by amitriptyline is thought to be involved in its analgesic activity.12 Collectively, current data from functional studies and clinical observations indicate that 5-HT receptor activation induced by amitriptyline appears to act as a pharmacological neuromodulation of afferent and efferent neuronal pathways that signal and regulate pain and urgency sensations from the bladder. Additionally, amitriptyline also may improve symptoms of IC through its known antihistamine properties. In fact, amitriptyline is one of the most potent tricyclic antidepressants in terms of blocking H1-histaminergic receptors13 and inhibition of histamine secretion from mast cells.14, 15 However, probably due to its aforementioned characterized strong neuromodulating activity amitriptyline shows efficacy irrespective of increased mast cell density within the detrusor muscle or lamina propria, as reported for the so called classical, late stage disease.16 Based on the histopathological characteris-
No. Grade 1, Mild (%)
No. Grade 2, Moderate (%)
Amitriptyline
Placebo
Amitriptyline
Placebo
19 (79) 10 (42) 9 (37.5) 8 (33.3) 3 (12.5) 4 (17) 1 (4)
2 (8) 2 (8) 3 (12.5) 2 (8) 3 (12.5) – –
– 5 (21) – 3 (12.5) – – –
– – – – – – –
tics of our own and externally taken bladder biopsies (we did not receive informed consent from all patients for a repeated bladder biopsy and pathology at our institution), all patients with late stage histological features were equally distributed among the amitriptyline responder and nonresponder group. In this study treatment with amitriptyline significantly improved the primary and most of the secondary outcome parameters in patients suffering from IC compared to placebo. Adverse events, although mostly mild and similar to those in previous reports, constitute the major drawback of this therapeutic approach to IC. The primary reason given by 1 patient on amitriptyline who withdrew from the study and by 5 of 9 others who rated their therapeutic outcome as either poor or fair (table 3) were exclusively anticholinergic side effects. Comparison of our study with previous studies of amitriptyline for IC is difficult because the drug has not been previously evaluated using a prospective, randomized, placebo controlled, double-blind method. The 4 previously reported studies all used an open label design3, 17–19 and 1 did not allow the patient to self-titrate the drug to the individual response dose.19 However, all 4 reports were in strong favor of amitriptyline for IC based on remarkable clinical response regarding amelioration of pelvic pain and frequency. Our study confirms these findings and provides additional data that amitriptyline also shows significant efficacy regarding amelioration of urinary urgency. In contrast to previous studies also assessing readily available agents for the treatment of IC, we did not encounter recruitment difficulties.20 Although Hanno et al already reported on the beneficial effect of amitriptyline for patients with IC, including a comprehensive discussion of potential mechanisms of drug action,18 amitriptyline was at no time well received among German urologists as a therapeutic option for IC. Thus, amitriptyline is still rarely prescribed for the disease and only few patients referred to our institution had been on amitriptyline medication before study recruitment. However, considering the evidence of its efficacy observed in our study amitriptyline has become the first line therapeutic approach to IC at our institution. CONCLUSIONS
Amitriptyline therapy for 4 months is safe and effective for treating IC. A statistically significant change in the O’LearySant symptom score and statistically significant improvement of pain and urgency intensity compared with placebo was observed. Anticholinergic side effects constitute the major drawback of amitriptyline treatment for IC. REFERENCES
1. Rovner, E., Propert, K. J., Brensinger, C., Wein, A. J., Foy, M., Kirkemo, A. et al: Treatments used in women with interstitial cystitis: the Interstitial Cystitis Data Base (ICDB) study experience. The Interstitial Cystitis Data Base Study Group. Urology, 56: 940, 2000 2. Propert, K. J., Payne, C., Kusek, J. W. and Nyberg, L. M.: Pitfalls in the design of clinical trials for interstitial cystitis. Urology, 60: 742, 2002
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AMITRIPTYLINE FOR INTERSTITIAL CYSTITIS
3. Hanno, P. M. and Wein, A. J.: Medical treatment of interstitial cystitis (other than Rimso-50/Elmiron). Urology, suppl., 29: 22, 1987 4. Hanno, P. M., Landis, J. R., Matthews-Cook, Y., Kusek, J., Nyberg, L., Jr. and The Interstitial Cystitis Database Study Group: The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol, 161: 553, 1999 5. O’Leary, M. P., Sant, G. R., Fowler, F. J., Jr., Whitmore, K. E. and Spolarich-Kroll, J.: The interstitial cystitis symptom index and problem index. Urology, suppl., 49: 58, 1997 6. NIH Common Toxicity Criteria. http://www.fda.gov/cder/cancer/ toxicityframe.htm. 2003 7. de Groat, W. C.: Influence of central serotonergic mechanisms on lower urinary tract function. Urology, suppl., 59: 30, 2002 8. Burgard, E. C., Fraser, M. O. and Thor, K. B.: Serotonergic modulation of bladder afferent pathways. Urology, suppl., 62: 10, 2003 9. Carasso, R. L., Yehuda, S. and Streifler, M.: Clomipramine and amitriptyline in the treatment of severe pain. Int J Neurosci, 9: 191, 1979 10. Pilowsky, I., Hallett, E. C., Bassett, D. L., Thomas, P. G. and Penhall, R. K.: A controlled study of amitriptyline in the treatment of chronic pain. Pain, 14: 169, 1982 11. Richardson, B. P.: Serotonin and nociception. Ann N Y Acad Sci, 600: 511, 1990 12. Tura, B. and Tura, S. M.: The analgesic effect of tricyclic anti-
depressants. Brain Res, 518: 19, 1990 13. Baldessarini, R. J.: Drugs and the treatment of psychiatric disorders. In: The Pharmacological Basis of Therapeutics, 7th ed. Edited by A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad. New York: Macmillan Publishing Co., chapt. 19, pp. 387– 445, 1985 14. Ferjan, I. and Erjavec, F.: Changes in histamine and serotonin secretion from rat peritoneal mast cells caused by antidepressants. Inflamm Res, 45: 141, 1996 15. Irman-Florjanc, T.: Amitriptyline changes the pharmacokinetic profile of histamine in rat blood. Inflamm Res, suppl., 51: S23, 2002 16. Peeker, R. and Fall, M.: Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J Urol, 167: 2470, 2002 17. Pranikoff, K. and Constantino, G.: The use of amitriptyline in patients with urinary frequency and pain. Urology, suppl., 51: 179, 1998 18. Hanno, P. M., Buehler, J. and Wein, A. J.: Use of amitriptyline in the treatment of interstitial cystitis. J Urol, 141: 846, 1989 19. Kirkemo, A. K., Miles, B. J. and Peters, J. M.: Use of amitriptyline in interstitial cystitis. J Urol, suppl., 143: 279A, abstract 364, 1990 20. Sant, G. R., Propert, K. J., Hanno, P. M., Burks, D., Culkin, D., Diokno, A. C. et al: A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol, 170: 810, 2003
Vol. 172, 533–536, August 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000132388.54703.4d
Infection/Inflammation A PROSPECTIVE, RANDOMIZED, PLACEBO CONTROLLED, DOUBLEBLIND STUDY OF AMITRIPTYLINE FOR THE TREATMENT OF INTERSTITIAL CYSTITIS ARNDT
VAN
OPHOVEN,* SASA POKUPIC, ACHIM HEINECKE
AND
LOTHAR HERTLE
From the Department of Urology, Universita¨tsklinikum Mu¨nster and Department of Medical Informatics and Biomathematics (AH), University of Mu¨nster, Mu¨nster, Germany
ABSTRACT
Purpose: We conducted a prospective study to examine the safety and efficacy of the tricyclic antidepressant amitriptyline in patients with interstitial cystitis (IC). Materials and Methods: The study comprised 44 women and 6 men who all met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases for IC. The patients were randomly assigned to amitriptyline or placebo. Patients were prospectively treated for 4 months with a self-titration protocol that allowed them to escalate drug dosage in 25 mg increments in 1 week-intervals (maximum dosage 100 mg). The change from baseline in the O’Leary-Sant IC symptom and problem index was the primary outcome parameter. Changes in functional bladder capacity and frequency (48-hour voiding log), and intensity of pain and urgency (visual analog scales) were chosen as secondary outcome parameters. Results: Two patients (1 on amitriptyline, 1 on placebo) dropped out of the study due to side effects. Thus, the data of 48 patients (24 patients in each group) were available for evaluation. Mean symptom score decreased from 26.9 to 18.5 in the amitriptyline group compared with 27.6 to 24.1 in the placebo group (p ⫽ 0.005). Pain and urgency intensity improved statistically significantly in the amitriptyline group compared with the placebo group (p ⬍0.001). The frequency and functional bladder capacity improved to a much greater degree in the amitriptyline group but the differences were not statistically significant (p ⫽ 0.063, p ⫽ 0.083). Anticholinergic side effects were reported by all except 2 patients in the amitriptyline group (92%) and by 5 patients in the placebo group (21%). Mouth dryness was the most frequent side effect reported in the amitriptyline group (79%). Conclusions: Amitriptyline therapy for 4 months is safe and effective for treating IC. A statistically significant change in the symptom score and statistically significant improvement of pain and urgency intensity compared with placebo were observed. Anticholinergic side effects constitute the major drawback of amitriptyline treatment for IC. KEY WORDS: cystitis, interstitial; clinical trials; amitriptyline; antidepressive agents, tricyclic
Interstitial cystitis (IC) is a chronic and debilitating bladder syndrome, primarily affecting women, characterized by pelvic/perineal/bladder pain associated with urinary urgency, frequency and sterile, cytologically normal urine. Despite a large number of purported therapeutic approaches,1 the treatment of interstitial cystitis remains suboptimal and the data regarding the efficacy of the majority of those treatment modalities are derived primarily from nonevidence based trials or case series.2 Hanno and Wein in 1987 first reported on the use of the tricyclic antidepressant amitriptyline3 and, although amitriptyline has subsequently become the most frequently prescribed oral drug for IC within the patient population of the
IC database,1 its efficacy has never been assessed in a randomized, placebo controlled, double-blind study. PATIENTS AND METHODS
The study used a randomized, placebo controlled, doubleblind design and was conducted at 1 institution (University of Mu¨nster Hospital). The study protocol was approved by the Institutional Review Board of the University Hospital of Mu¨nster and written informed consent was obtained from all patients. The study drug was supplied by Bayer Pharmaceutical, Germany. The placebo was supplied by the pharmacy of the University Hospital of Mu¨nster, which packed and blinded placebo and drug tablets. The study comprised 44 women and 6 men who all met the symptom criteria of the National Institute of Diabetes, Digestive and Kidney Diseases for IC.4 All patients had received previous conservative medical treatment, including hydrostatic distension, intravesical instillations (eg dimethylsulfoxide, hyaluronic acid) or oral medication (eg antiallergics, sodium pentosanpolysulfate), which at best achieved
Accepted for publication March 12, 2004. The study protocol received Institutional Review Board of the University Hospital of Mu¨nster. * Correspondence: Klinik und Poliklinik fu¨r Urologie, Universita¨tsklinikum Mu¨nster, Albert Schweitzer-Str. 33, 48129 Mu¨nster, Germany (telephone: ⫹⫹-49-251-8347466; FAX: ⫹⫹-49-251-8345279; e-mail: [email protected]). 533
534
AMITRIPTYLINE FOR INTERSTITIAL CYSTITIS TABLE 1. Baseline patient demographic and clinical characteristics by treatment group Characteristic
Amitriptyline
Placebo
No. pts randomized No. females (%) No. males (%) Mean age ⫾ SD (yrs) Mean symptom duration before treatment ⫾ SD (yrs) Mean age at onset of symptoms ⫾ SD (yrs) Mean pain intensity ⫾ SD (mm on VAS) Mean urgency intensity ⫾ SD (mm on VAS) Mean 24-hr frequency ⫾ SD Mean functional bladder volume ⫾ SD (ml) Mean score-sum ⫾ SD
25 22 (88) 3 (12) 50.5 ⫾ 14.4 3.1 ⫾ 5.0 44.7 ⫾ 15.8 52.7 ⫾ 24.6 70.5 ⫾ 12.7 18.4 ⫾ 8.1 124 ⫾ 79 26.9 ⫾ 4.8
25 22 (88) 3 (12) 60.2 ⫾ 17.5 4.4 ⫾ 4.9 52.9 ⫾ 15.9 52.6 ⫾ 28.4 63.3 ⫾ 19.6 16.6 ⫾ 5.7 127 ⫾ 61 27.6 ⫾ 5.6
TABLE 2. Changes in symptoms from baseline to 4 months Characteristic Mean Mean Mean Mean Mean
score-sum ⫾ SD pain intensity ⫾ SD (mm on VAS) urgency intensity ⫾ SD (mm on VAS) 24-hr frequency ⫾ SD functional bladder volume ⫾ SD (ml)
Amitriptyline
Placebo
p Value
⫺8.4 ⫾ 7.2 ⫺22.8 ⫾ 26.1 ⫺43.8 ⫾ 23.5 ⫺4.0 ⫾ 5.1 19.0 ⫾ 54.62
⫺3.5 ⫾ 5.4 1.0 ⫾ 14.8 ⫺0.1 ⫾ 3.2 ⫺0.6 ⫾ 5.8 ⫺7.7 ⫾ 47.5
0.005 ⬍0.001 ⬍0.001 0.063 0.083
short symptomatic relief. Previous or current intake of amitriptyline was considered an exclusion criterion for study enrollment. The patients were equally assigned to amitriptyline or placebo using a block randomization design. Patients were subsequently treated prospectively for 4 months with a selftitration protocol. They were instructed to take 25 mg of amitriptyline at bedtime. If after 1 week they were not symptom-free, they increased the dosage to 50 mg. The same alteration was allowed for weeks 3 and 4, taking 75 mg and 100 mg (maximum allowed dosage), respectively. If patients experienced satisfactory relief of symptoms they were to maintain the individual lowest effective dose and not increase the dose further. The change from baseline in the O’Leary-Sant IC symptom and problem index was the primary outcome parameter for this study. This validated, self-administered index comprises 8 questions assessing major pain and voiding symptoms. The maximum index score-sum of 36 reflects maximum symptom and problem severity and the lowest possible score-sum is 0.5 Secondary outcome measures included patient reported symptoms of pain and urgency (visual analog scales, VAS), and changes in functional bladder capacity and frequency (48-hour voiding log). Additionally, patients were requested to rate satisfaction with the therapeutic outcome as either excellent, good, fair or poor (Patient Global Assessment Form). Outcomes were evaluated at baseline and in 4-week intervals after randomization. All adverse events were reported and graded according to the Common Toxicity Criteria on a scale of 0 to 5.6 The study sample size of 50 patients (25 per group) was powered for a difference of approximately 1 standard deviation between the amitriptyline and placebo group with a 95% confidence interval (␣ ⫽ 0.05) and a statistical power of 85% ( ⫽ 0.15). Baseline factors were compared between the 2 groups using Fisher’s exact and Mann-Whitney-U tests. Statistical comparisons were made using the Mann-Whitney-U test for changes in symptom score (primary outcome parameter), changes in pain and urgency intensity, and changes in voiding patterns (frequency, functional bladder volume). Chisquare statistics were calculated to compare proportion of responders between treatment groups, with p ⬍0.05 considered significant. All statistical tests were 2-tailed, and calculations were performed using SPSS and SAS statistical software packages (SAS Institute, Carey, North Carolina).
RESULTS
Two patients (1 on amitriptyline, 1 on placebo) dropped out of the study due to adverse side effects. Thus, the data on 48 patients (24 patients in each group) were available for evaluation. Selected baseline characteristics are shown in table 1. For the primary outcome there was a highly statistically significant difference between the study groups (table 2). Mean symptom score-sum decreased from 26.9 to 18.5 in the amitriptyline group compared with 27.6 to 24.1 in the placebo group (p ⫽ 0.005). Of the patients in the amitriptyline group 10 (42%) had a greater than 30% decrease in the symptom score compared with 3 (12.5%) in the placebo group (p ⬍0.001). For the secondary end points there were highly statistically significant differences between the study groups for several outcome parameters (table 2). Pain and urgency intensity improved statistically significantly in the amitriptyline group compared with the placebo group (p ⬍0.001). The frequency and functional bladder capacity improved to a much greater degree in the amitriptyline group but the differences were not statistically significant (p ⫽ 0.063 for comparison of frequency and p ⫽ 0.083 for comparison of functional bladder capacity between treatment groups). Of the 24 patients receiving amitriptyline 15 (63%) rated satisfaction with the therapeutic outcome as either good or excellent compared to 1 patient (4%) in the placebo group (p ⬍0.001, table 3). At the end of 4 months of treatment the effective daily treatment dose in the drug group was 50 mg amitriptyline in 9 of the 24 patients (37.5%). Seven patients (29%) took 25 mg amitriptyline at bedtime, 5 (21%) took 75 mg and 3 (12.5%) took the maximum dose of 100 mg daily. Anticholinergic side effects were noted by all except 2 patients in the amitriptyline group (92%) and by 5 patients in the placebo group (21%). A dry mouth was the most frequent side effect in the amitriptyline group (79%, table 4). No adverse side effects of grade 3 or higher were reported.
TABLE 3. Patient satisfaction with therapeutic outcome after 4 months treatment period Poor Fair Good Excellent
No. Amitriptyline (%)
No. Placebo (%)
3 (13) 6 (25) 10 (42) 5 (21)
21 (88) 2 (8) 1 (4) 0
535
AMITRIPTYLINE FOR INTERSTITIAL CYSTITIS TABLE 4. Reported adverse side effects (worst reported) Adverse Side Effect
No. Grade 0, None (%) Amitriptyline
Placebo
Mouth dryness 5 (21) 22 (92) Wt gain 9 (37) 22 (92) Sedation 15 (62.5) 21 (87.5) Constipation 13 (54) 22 (92) Nausea/vertigo 21 (87.5) 21 (87.5) Blurred vision/diplopia 20 (83) 24 (100) Erectile dysfunction 23 (96) 24 (100) Numbers include report of multiple concurrent side effects.
DISCUSSION
Normal bladder function is generally understood as the organ’s competence to store a sufficient amount of urine followed by a painless urge to void and finally almost complete emptying. This complex ability, which is severely impaired in patients with IC, is based on activation and maintenance of sophisticated reflex mechanism involving sympathetic, parasympathetic and somatic control of the lower urinary tract. The spinal and supraspinal neuronal pathways involved are modulated by activation and/or inhibition of neurons in the periphery, at spinal levels and at supraspinal regulatory sites. Serotonergic (5-hydroxitryptamine [5-HT]) pathways and receptor mechanisms have a crucial role within this neuronal network. The mechanism of action of serotonergic drugs, such as the wellknown 5-HT reuptake inhibitor amitriptyline used in this study, is to modulate this neuronal network resulting in an ameliorating impact on the impaired bladder function of patients with IC. de Groat recently reviewed the effects of serotonergic drugs on central nervous system control of the lower urinary tract and underscored that in vitro data indicate that activation of the central serotonergic system can suppress voiding and urge to void by enhancing efferent control of the urethral outlet and inhibiting the parasympathetic excitatory input to the bladder.7 Burgard et al reviewed serotonergic modulation of bladder afferent pathways pointing out that sufficient data show that multiple 5-HT receptors are located within the lumbosacral spinal cord.8 In addition, various 5-HT receptor subtypes are present in centrally located neuronal nuclei as well as sacral parasympathetic nuclei. These nuclei contain autonomic and somatic bladder efferent fibers, indicating that 5-HT may modulate efferent as well as afferent processing in the spinal cord. Additional animal derived data suggest that 5-HT receptors mediate an increase in sensory threshold for micturition without inhibiting visceral motor response.8 The mechanism of analgesic action of amitriptyline in general,9, 10 and particularly for IC, is not fully understood. 5-HT is known to have a role in the transmission of nociceptive signals at various neuronal levels, ie at spinal cord, brainstem and thalamic sites.11 Additionally, the presynaptic inhibition of 5-HT re-uptake induced by amitriptyline is thought to be involved in its analgesic activity.12 Collectively, current data from functional studies and clinical observations indicate that 5-HT receptor activation induced by amitriptyline appears to act as a pharmacological neuromodulation of afferent and efferent neuronal pathways that signal and regulate pain and urgency sensations from the bladder. Additionally, amitriptyline also may improve symptoms of IC through its known antihistamine properties. In fact, amitriptyline is one of the most potent tricyclic antidepressants in terms of blocking H1-histaminergic receptors13 and inhibition of histamine secretion from mast cells.14, 15 However, probably due to its aforementioned characterized strong neuromodulating activity amitriptyline shows efficacy irrespective of increased mast cell density within the detrusor muscle or lamina propria, as reported for the so called classical, late stage disease.16 Based on the histopathological characteris-
No. Grade 1, Mild (%)
No. Grade 2, Moderate (%)
Amitriptyline
Placebo
Amitriptyline
Placebo
19 (79) 10 (42) 9 (37.5) 8 (33.3) 3 (12.5) 4 (17) 1 (4)
2 (8) 2 (8) 3 (12.5) 2 (8) 3 (12.5) – –
– 5 (21) – 3 (12.5) – – –
– – – – – – –
tics of our own and externally taken bladder biopsies (we did not receive informed consent from all patients for a repeated bladder biopsy and pathology at our institution), all patients with late stage histological features were equally distributed among the amitriptyline responder and nonresponder group. In this study treatment with amitriptyline significantly improved the primary and most of the secondary outcome parameters in patients suffering from IC compared to placebo. Adverse events, although mostly mild and similar to those in previous reports, constitute the major drawback of this therapeutic approach to IC. The primary reason given by 1 patient on amitriptyline who withdrew from the study and by 5 of 9 others who rated their therapeutic outcome as either poor or fair (table 3) were exclusively anticholinergic side effects. Comparison of our study with previous studies of amitriptyline for IC is difficult because the drug has not been previously evaluated using a prospective, randomized, placebo controlled, double-blind method. The 4 previously reported studies all used an open label design3, 17–19 and 1 did not allow the patient to self-titrate the drug to the individual response dose.19 However, all 4 reports were in strong favor of amitriptyline for IC based on remarkable clinical response regarding amelioration of pelvic pain and frequency. Our study confirms these findings and provides additional data that amitriptyline also shows significant efficacy regarding amelioration of urinary urgency. In contrast to previous studies also assessing readily available agents for the treatment of IC, we did not encounter recruitment difficulties.20 Although Hanno et al already reported on the beneficial effect of amitriptyline for patients with IC, including a comprehensive discussion of potential mechanisms of drug action,18 amitriptyline was at no time well received among German urologists as a therapeutic option for IC. Thus, amitriptyline is still rarely prescribed for the disease and only few patients referred to our institution had been on amitriptyline medication before study recruitment. However, considering the evidence of its efficacy observed in our study amitriptyline has become the first line therapeutic approach to IC at our institution. CONCLUSIONS
Amitriptyline therapy for 4 months is safe and effective for treating IC. A statistically significant change in the O’LearySant symptom score and statistically significant improvement of pain and urgency intensity compared with placebo was observed. Anticholinergic side effects constitute the major drawback of amitriptyline treatment for IC. REFERENCES
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