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Urinary urge incontinence: randomised crossover trials of penthienate versus placebo and propantheline

Graham M Coombes and Richard J Millard
Med J Aust 1996; 165 (9): 473-476.
Published online: 9 September 1999
Research

Urinary urge incontinence: randomised crossover trials of penthienate versus placebo and propantheline

Graham M Coombes and Richard J Millard

MJA 1996; 165: 473-476

Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details
- - More articles on Obstetrics & gynaecology and women's health


Abstract Objective: To compare the efficacy of penthienate with that of propantheline and placebo for treatment of primary idiopathic detrusor instability.
Design: Two prospective, randomised, crossover trials (double-blind for penthienate versus placebo and non-blinded for penthienate versus propantheline).
Setting: Urology Clinic of Prince Henry Hospital, Sydney, NSW (an outpatient clinic of a tertiary referral hospital), in 1993-1994.
Participants: Neurologically intact patients with urodynamically proven detrusor instability, urgency and urge incontinence, but no stress incontinence (20 participated in the penthienate/placebo trial and 23 in the penthienate/propantheline trial).
Outcome measures: Cystometrography results before and after treatment; frequency and volumes of urine voided in weeks 1 and 4 of treatment; and patient scores for degree of continence, side effects, efficacy and acceptability of treatment.
Interventions: Penthienate (5 mg), propantheline (15 mg) or placebo (all three times a day) for 4 weeks.
Results: Penthienate produced significantly greater improvements than placebo in frequency (daytime, P = 0.002; and night-time, P = 0.02), incontinence scores (P = 0.002) and amplitude of unstable detrusor contractions, when present (P = 0.01), and significantly increased diurnal and nocturnal bladder capacity, both on cystometrography (P = 0.003) and by voiding-diary records (P < 0.001). It also increased residual urine volume over the baseline level, but not significantly. Side effects, especially dry mouth, were common with penthienate, and one patient developed urinary retention. Penthienate was significantly better than propantheline in improving cystometric capacity (P = 0.03), and reducing the amplitude of unstable detrusor contractions (P = 0.01), and was perceived as more effective by patients for frequency, nocturia and incontinence.
Conclusions: Penthienate (5 mg three times a day) was objectively and subjectively significantly better than both placebo and propantheline (15 mg three times a day) for treatment of primary idiopathic detrusor instability.


Introduction Detrusor instability is a common urologic problem, causing symptoms of urgency, frequency and urge incontinence. It is defined by the International Continence Society as the presence of detrusor contractions with pressure greater than 15 centimetres of water during the filling phase of cystometrography while the patient is trying to inhibit micturition.1 Although detrusor instability may result from neuropathy (e.g., after spinal injury and in multiple sclerosis, where it is best termed detrusor hyperreflexia), in most patients it is primary and idiopathic.2

Many treatments have been used, including bladder training, biofeedback, anticholinergics, analgesics, muscle relaxants, tricyclic antidepressants and acupuncture.2-7 More invasive, surgical procedures, such as subtrigonal phenol injections, neuromodulation and bladder augmentation, are less commonly required. Success rates are variable, and depend partly on the cause of the instability, but are usually no higher than 70%.8,9

The anticholinergic propantheline bromide is used worldwide for detrusor instability and, along with oxybutynin, is among the most often studied anticholinergic agents. However, penthienate bromide, which was originally marketed in Australia for gastrointestinal spasm, has been in clinical use for detrusor instability at Prince Henry Hospital, Sydney, NSW, and, in our clinical experience, may be more effective than propantheline. It is a quaternary ammonium antimuscarinic that inhibits parasympathetic, postganglionic bladder smooth muscle receptors, has a short half-life and is optimally absorbed from the gastrointestinal tract on an empty stomach. However, its comparative efficacy has not been established. We therefore undertook randomised trials of penthienate versus placebo and penthienate versus propantheline in primary idiopathic detrusor instability.


Methods Approval for the trials was given by the Eastern Sydney Area Health Service Ethics Committee. The trials were independent of drug company participation or sponsorship, apart from the manufacture and supply of placebo and penthienate tablets (for the first trial).

Penthienate versus placebo
The first trial was a prospective, randomised, double-blind crossover trial of penthienate versus placebo. Participants were 20 neurologically intact patients recruited from the outpatient Urology Clinic and Urodynamic Service of Prince Henry Hospital, Sydney, NSW.

Inclusion criteria. These were:

  • Age over 18 years;

  • Presence of symptomatic urgency or urge incontinence;

  • Detrusor instability (shown on medium-fill, room-temperature, videourodynamic studies);

  • No history of neurologic disease, narrow-angle glaucoma or severe cardiac disease (American Heart Association Grade 3 or 4);

  • No stress incontinence, bladder-outlet obstruction, significant postvoid residual urine (residuum greater than 10% of voided volume), current urinary tract infection or interstitial cystitis;

  • No current gastrointestinal obstruction;

  • No allergy or sensitivity to anticholinergic agents;

  • Not pregnant; and

  • Patient gave informed consent to active and placebo treatment.

First phase. The trial began with a one-week run-in period in which patients kept charts of frequency and volume of urine voided. Informed consent was then obtained and patients were randomised in a double-blind fashion to placebo or penthienate. Codes were generated from randomisation tables in blocks of ten, and provided in sealed envelopes by the Pharmacy Department; neither patients nor investigators knew the code until after collection of all follow-up data.

Patients received either placebo or penthienate (5 mg three times a day before meals) for four weeks. Dosage reduction was ethically necessary if the patient developed blurred vision, severe constipation, or excessive mouth dryness that interfered with nutrition. Placebo and penthienate tablets were made to the same size, shape and colour specifications by the manufacturer and stored in the refrigerator.

Assessment. All patients were asked to keep records of frequency and volume of urine voided for two 72-hour periods in the first and fourth weeks of treatment. A visual analogue score for continence was also kept (from 1 [nil leakage], to 5 [wet all the time]) and episodes of incontinence were noted. Apart from keeping voiding diaries at the set times, patients were taught no formal bladder- training techniques.

In the final (fourth) week of treatment, patients attended the outpatient clinic for assessment. History was taken and time/volume charts collected. Medium-fill room-temperature saline-filling cystometrography was performed by the urology registrar, and residual urine volume, flow rate, cystometric capacity and incidence and amplitude of any unstable detrusor contractions were recorded. Urodynamic methods, definitions and units conformed to the standards recommended by the International Continence Society.1In addition, patients scored side effects, efficacy of treatment and willingness to have that treatment in the future on a scale of 1-100.

Second phase. After a five-day washout period, patients crossed to the other arm of the trial. As it was not considered ethical to subject patients to a further urodynamic study during this period (to prove stable disease course), treatment-period interaction could not be totally excluded. Again, treatment was for four weeks, with the same assessment as previously.

Penthienate versus propantheline
The second trial was an unblinded, prospective, randomised crossover trial of penthienate and propantheline in 23 patients with detrusor instability. Inclusion criteria, run-in period and randomisation were the same as those in the first trial, except that neither patients nor observers were blinded to the treatment. Patients received either penthienate (5 mg three times a day) or propantheline (15 mg three times a day) for four weeks. There was no placebo arm. All patients were then assessed as outpatients, with the same outcome measures as those in the first trial. After a five-day drug washout period, patients crossed over to receive the other medication for a further four weeks before reassessment.

Statistical analyses
Analysis of paired data was by the Wilcoxon matched-pairs signed-rank test. Unpaired group data were analysed with the Mann-Whitney U test.


Results

Penthienate versus placebo
Patients comprised 16 women and four men, with median age 63.5 years (range, 36-85). Urological baseline characteristics are shown in Box 1. There were no significant differences in baseline data between those patients receiving placebo first and those receiving penthienate first.

To investigate the possibility of a carryover effect of penthienate in patients who received placebo second, the data were analysed initially in groups according to which drug had been given first. In the placebo arm of the trial there were no significant differences in cystometric capacity, residual postvoid volume, amplitude of unstable detrusor contractions, flow rate, frequency, nocturia or subjective incontinence scores between patients who took placebo first and those who took it second. Thus, five days was adequate for washout of penthienate. Thereafter, data were analysed without regard to which drug was taken first.

Continence and urodynamic characteristics after penthienate and placebo treatment are shown in Box 1. After penthienate treatment, there were increases over the baseline in daytime voiding interval, mean voided volume (daytime and night-time) and cystometric capacity, and decreases in night-time frequency and subjective incontinence score. Values for all these parameters were significantly "better" after penthienate than after placebo. The decrease in median incontinence score with penthienate was dramatic, from a baseline of 5 ("wet all the time") to 1 ("nil leakage"), compared with 4 for placebo. Ten of 20 patients taking penthienate became dry (incontinence score of 1, 50% cure rate), compared with only two patients taking placebo.

The same 10 patients taking penthienate were also completely stable (detrusor pressure < 15 cm H2O) to a capacity of 500 mL on cystometrography. Among the other 10, the median amplitude of unstable detrusor contractions was reduced from 40 to 27 cm H2O. However, with placebo only four patients (20%) tested stable and the other 16 had unstable detrusor contractions, with a median pressure of 30 cm H2O. The difference between the penthienate and placebo groups in detrusor pressures in those patients who remained unstable was significant (P = 0.05).

Residual urine volume increased from the baseline level in the penthienate group and decreased in the placebo group, but neither change was significant. However, the resulting difference between penthienate and placebo residual volumes was significant (P = 0.02).

Urine flow rate increased significantly in both the penthienate and placebo group over the baseline level (P = 0.01), but did not differ significantly between the two groups. The increase in flow rate appeared to be related to the increase in voided volume, as there was no change in percentile performance on the Haylen Liverpool flow nomogram.10

Side effects of treatment were common with penthienate (Box 2). All patients mentioned a dry mouth, and in one elderly patient this led to difficulty swallowing, which necessitated reducing the penthienate dose. Although 11 of 20 patients taking placebo also mentioned mouth dryness, the scores for degree were significantly less than for penthienate. A patient taking penthienate complained of diarrhoea, but there was no evidence of faecal impaction to suggest spurious diarrhoea caused by decreased gastrointestinal motility. Another patient taking penthienate in the second phase of the trial developed chronic urinary retention (with a residual postvoid volume of 550 mL). This patient's results were excluded from the analysis.

Patients' subjective impressions of treatment are also shown in Box 2. There was a significant preference for penthienate compared with placebo in both perceived efficacy and willingness for retreatment (P = 0.002). Penthienate was considered beneficial by 17 (85%), but placebo by only five (25%). Two patients preferred placebo to penthienate; their cystometric capacities and filling pressures on testing differed little between penthienate and placebo, but their voiding diaries showed greater daytime and night-time voided volumes during the penthienate arm.

Penthienate versus propantheline
Patients comprised 18 women and five men, with median age 63 years (range, 34-85). Propantheline was given first to 12 patients and penthienate to 11.

Baseline characteristics are compared with those after propantheline and penthienate treatment in Box 3. Both penthienate and propantheline significantly increased daytime voiding interval, cystometric capacity and flow rate over baseline figures. However, the improvements in cystometric capacity were significantly greater with penthienate than with propantheline. Furthermore, penthienate, but not propantheline, significantly increased voided volume (both daytime and night-time) and decreased night-time frequency and the incidence of incontinence (by patient score). Consequently, daytime voided volume and incontinence score were significantly "better" for penthienate than for propantheline. The difference in incontinence score was dramatic -- 1.5 after penthienate (where 1 = "nil leakage"), but 5 ("wet all the time") after propantheline.

Stable cystometrograms were seen in 13 of the 23 patients (56%) after penthienate, but in only 10 (43%) after propantheline. In the patients with residual unstable detrusor contractions, the amplitude of these contractions decreased with penthienate but increased with propantheline, which led to a significant difference between the two treatments (P = 0.01).

Although residual urine volume increased over the baseline value with penthienate, the change was not significant. Similarly, although detrusor compliance (detrusor pressure at a given bladder volume, which measures bladder-wall stiffness) increased after penthienate but decreased after propantheline, none of the changes were significant and did not lead to significant differences between the two drug treatments.

Side effects and subjective response to treatment are shown in Box 4. Mouth dryness was significantly worse with penthienate, but patients believed that it had significantly greater efficacy and were more willing to repeat penthienate treatment.


Discussion Our trials showed a significantly greater response to penthienate than to placebo or propantheline treatment, both objectively and subjectively, in primary idiopathic detrusor instability. For drug therapy to be useful in this condition, it needs to be more effective than placebo, which can produce significant improvement11 (up to 43%, or as high as that of some active drug therapies).12 In addition, results should be at least as good as those that can be achieved with non-invasive therapies such as bladder training, without intolerable side effects. The Urology Clinic at Prince Henry Hospital has previously shown that bladder training and/or biofeedback gives up to 74% cure or improvement in symptoms of detrusor instability.5 In this study, we found that after penthienate there were objective improvements in bladder capacity, stability and amplitude of unstable detrusor contractions and 50%-56% of patients became objectively dry. There were also improvements in subjective criteria for continence after penthienate, with 85% feeling subjectively cured or improved. These subjective criteria were included to assess clinical worth from the patients' perspective, as statistical significance may not necessarily equate with clinical significance.4

There have been no previous comparative trials of the relative efficacy of penthienate and propantheline for detrusor instability. We found that, in the doses studied (manufacturer's recommended starting doses), both produced some urodynamic and symptomatic improvements, but that penthienate was significantly better than propantheline in improving cystometric capacity and reducing the amplitude of unstable detrusor contractions, and was perceived as more effective by patients for frequency, nocturia and incontinence.

Most recent studies on propantheline in detrusor instability have compared it with another anticholinergic, oxybutynin, which has been found to produce response rates of up to 60% and a median increase in cystometric capacity of 104 mL;13 it was more effective than propantheline in some studies,12,14 but not others.15 Similarly as for penthienate, the price of its therapeutic effect was a higher residual urine volume and higher rate of side effects.12 However, as we found for penthienate, the anticholinergic side effects were generally tolerable and, if the treatment was discontinued, short-lived. Nevertheless, in detrusor hyperreflexia caused by multiple sclerosis oxybutynin and propantheline treatment had to be discontinued because of side effects in 22% and 27% of patients, respectively.15

We conclude that penthienate bromide has a significant place in the management of detrusor overactivity. It has been our practice to use penthienate as first-line drug treatment in those patients with idiopathic detrusor instability not responsive to conservative measures such as bladder training and biofeedback. Unfortunately, it is currently unavailable in Australia as it is no longer manufactured locally.

The side effects of anticholinergic treatment are well recognised and occurred with both penthienate and propantheline. With appropriate modifications of dosage (e.g., in the elderly, who are more likely to have side effects, and in those with neurogenic bladders and detrusor hyperreflexia caused by multiple sclerosis, who are more sensitive to penthienate), most patients can tolerate these side effects and still benefit from therapy. Treatment should start with the lowest therapeutic dose and be monitored closely to maximise patient compliance if long term use is considered.



Acknowledgements
Winthrop Laboratories manufactured and supplied the penthienate (Monodral) and placebo tablets for the first crossover trial. We thank Dorothy Wheeler, RN, and Marilynne Berg, RN, of the Urology Training Unit, Prince Henry Hospital, for their help in the follow-up studies.


References
  1. Abrams P, Blaivas JG, Stanton SL, Andersen JT. The standardisation of terminology of lower urinary tract function. Scand J Urol Nephrol 1988; Suppl 114: 5-19.
  2. Tapp AJS, Cardozo LD, Versi E, Cooper D. The treatment of detrusor instability in controlled study postmenopausal women with oxybutynin chloride: a double blind placebo. Br J Obstet Gynaecol 1990; 97: 521-526.
  3. Blaivas JG, Labib KB, Michalik SK, Zayed AAH. Cystometric response to propantheline in detrusor hyperreflexia: therapeutic implications. J Urol 1980; 124: 259.
  4. Wein AJ. Pharmacologic treatment of incontinence. J Am Geriatr Soc 1990; 38: 317-328.
  5. Millard RJ, Oldenburg BF. The symptomatic, urodynamic and psychodynamic results of bladder re-education programs. J Urol 1983; 53: 565-566.
  6. Chang PL. Urodynamic studies in acupuncture for women with frequency, urgency and dysuria. J Urol 1988; 140: 563-566.
  7. Burgio KL, Engel BT. Biofeedback-assisted behavioural training for elderly men and women. J Am Geriatr Soc 1990; 38: 338-340.
  8. Koldewijn EL, Rijkhoff NJM, van Kerrebroeck PE, et al. Selective stimulation of sacral nerves for bladder control: a computer model. Neurourol Urodyn 1992; 11: 328-330.
  9. Mundy AR. Detrusor instability. Br J Urol 1988; 62: 393-397.
  10. Haylen BT, Ashby D, Sutherst JR, et al. Maximum and average urine flow rates in normal male and female populations -- the Liverpool nomograms. Br J Urol 1989; 64: 30-38.
  11. Benson H, Epstein MD. The placebo effect. JAMA 1975; 232: 1225.
  12. Thuroff JW, Bunke B, Ebner A, et al. Randomized, double blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 1991; 145: 813-817.
  13. Moore KH, Hay DM, Imrie AE, et al. Oxybutynin Hydrochloride (3 mg) in the treatment of women with idiopathic detrusor instability. Br J Urol 1990; 66: 479-485.
  14. Gajewski JB, Awad SA. Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperreflexia. J Urol 1986; 135: 966-968.
  15. Holmes DM, Montz FJ, Stanton SL. Oxybutynin versus propantheline in the management of detrusor instability. A patient-regulated variable dose trial. Br J Obstet Gynaecol 1989; 96: 607-612.
(Received 22 Jun, accepted 20 Jul 1996)


Authors' details Department of Urology, Prince Henry Hospital, Sydney, NSW.
Graham M Coombes, FRACS, Urology Registrar. Currently, Royal North Shore Hospital, Sydney, NSW; Richard J Millard, FRACS, FRCS, Associate Professor of Urology, University of NSW, Sydney, NSW.
Reprints: Dr G M Coombes, 74 Osborne Road, Lane Cove, NSW 2066.






1: Continence and urodynamic characteristics before and after treatment with penthienate and placebo (median and range)*

Baseline (n = 20)Penthienate (n = 19)†Placebo (n = 19)†P‡

Daytime voiding interval (hours)2 (1-5)3 (2-6)2 (1-4)0.002
Night-time frequency (times)2.5 (1-6)1 (0-5)2 (0-4)0.02
Mean daytime voided volume (mL)200 (75-400)270 (125-400)168 (50-300)0.0002
Mean night-time voided volume (mL)250 (50-650)300 (195-740)275 (50-700)0.02
Incontinence score§5 (2-5)1 (1-5)4 (1-5)0.002
Urodynamic testing
Cystometric capacity (mL)283 (150-450)500 (225-600)400 (200-500)0.003
Amplitude of unstable detrusor contractions (cm H2O)¶40 (16-80)27 (16-40)30 (20-45)0.05
Residual postvoid volume (mL)30 (0-160)40 (0-150)15 (5-50)0.02
Flow rate (mL/s)14 (6-25)17 (10-30)20 (15-45)0.68
Number of patients
With stable cystometrogram**0104NA
"Dry" (incontinence score of 1)0102NA

NA=not assessed. *Unless otherwise stated. †One patient was excluded because of chronic urinary retention. ‡ For difference between penthienate and placebo. § On analogue scale, with range 1 ("nil leakage") to 5 ("wet all the time"). ¶ n = 10 for penthienate and n = 16 for placebo, after exclusion of subjects with stable cystometrogram. ** Detrusor pressure < 15 cm H2O on filling cystometrography to a capacity of 500 mL.
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2: Side effects and subjective patient impressions of penthienate and placebo
PenthienatePlacebo

Dry mouth
Number of patients20 (100%)11 (55%)
Mean score (range)*65 (25-95)25 (0-80)
Nasal dryness2 (10%)0
Constipation/lower abdominal pain1 (5%)0
Upper abdominal pain1 (5%)0
Blurred vision1 (5%)0
Chronic urinary retention1 (5%)0
Mean subjective efficacy (range)*80 (10-95)23 (0-95)
Number of patients
 Improved17 (85%)5 (25%)
 Willing to repeat treatment12 (60%)5 (25%)

* Subjective score on scale of 0-100. Patient had diagnosed hiatus hernia, but no documented peptic ulcer or reflux oesophagitis.
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3: Continence and urodynamic characteristics before and after treatment with penthienate and propantheline (median and range)*

Baseline (n = 23)Penthienate (n = 23)Propantheline (n = 23)P †

Daytime voiding interval (hours)2 (1-5)3 (2-6)3 (2-4)0.53
Night-time frequency (times)2 (1-6)1 (0-5)2 (1-6)0.07
Mean daytime voided volume (mL)200 (75-400)260 (125-400)200 (125-450)0.001
Mean night-time voided volume (mL)250 (50-650)300 (195-740)325 (230-550)0.17
Incontinence score‡5 (2-5)1.5 (1-5)5 (1-5)0.001
Urodynamic testing
Cystometric capacity (mL)280 (150-450)500 (225-600)470 (275-550)0.03
Amplitude of unstable detrusor contractions (cm H2O)40 (15-80)27 (16-40)50 (20-75)0.01
Residual postvoid volume (mL)25 (0-160)37 (0-150)17.5 (0-100)0.1
Flow rate (mL/s)15 (6-29)20 (10-50)20 (15-35)0.48
Compliance (mL/cmH2O)70 (12-210)100 (23-600)55 (14-166)0.08
Number with stable cystometrogram§01310NA

NA=not assessed. * Unless otherwise stated. † For difference between penthienate and propantheline. ‡ On analogue scale, with range 1 ("nil leakage") to 5 ("wet all the time"). § Detrusor pressure < 15 cm H2O on filling cystometrography to a capacity of 500 mL.
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4: Side effects and subjective patient impressions of penthienate and propantheline
Penthienate PropanthelineP*

Mean score for subjective efficacy† (range)83 (10-95)38 (5-90)0.002
Mean score for mouth dryness† (range)73 (25-45)55 (30-90)0.05
Mean score for constipation† (range)5 (0-50)7 (0-75)0.73
Number of patients "dry" (incontinence score, 1)1310 NA
Number of patients improved1913NA
Number of patients willing to repeat treatment1211 NA

NA=not assessed. * By Wilcoxon matched-pairs signed-rank test. † Subjective score on scale of 0-100.
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Received 22 November 2018, accepted 22 November 2018

  • Graham M Coombes
  • Richard J Millard


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