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

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.

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.

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.

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.

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.

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