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Year : 2011  |  Volume : 1  |  Issue : 2  |  Page : 67-70  

Intradetrusor botulinum toxin type A in refractory overactive bladder: A potential future treatment

1 Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda - 151101, India
2 Department of Pharmacology, Government Medical College, Amritsar, Panjab, India

Date of Web Publication26-Dec-2011

Correspondence Address:
Rajiv Mahajan
Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda - 151101
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2229-516X.91144

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How to cite this article:
Mahajan R, Singh NR. Intradetrusor botulinum toxin type A in refractory overactive bladder: A potential future treatment. Int J App Basic Med Res 2011;1:67-70

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Mahajan R, Singh NR. Intradetrusor botulinum toxin type A in refractory overactive bladder: A potential future treatment. Int J App Basic Med Res [serial online] 2011 [cited 2022 Jan 17];1:67-70. Available from: https://www.ijabmr.org/text.asp?2011/1/2/67/91144

As defined by the Standardization Subcommittee of the International Continence Society (ICS), overactive bladder (OAB) is a symptom syndrome characterized by urinary urgency with or without urinary incontinence, usually accompanied by urinary frequency and nocturia but with no proven infection or other obvious pathology. [1] Thus, individuals with neurologic diseases such as multiple sclerosis, spinal cord injury, and myelodysplasia may have neurogenic OAB but they cannot be classified as having characteristic OAB. OAB symptoms are often associated with detrusor overactivity (DO) [2] but can also be associated with other forms of urethrovesical dysfunction. The symptoms of OAB are storage-phase symptoms. [1]

The terminology used is still confusing at times and therefore various terms have been redefined by the ICS. 'Urgency,' the major symptom of OAB, is characterized by a sudden compelling desire to pass urine, which is difficult to defer. Incontinence associated with urgency is referred to as 'urge urinary incontinence (UUI).' Eight or more episodes of micturition per day is defined as 'urinary frequency,' while 'nocturia' is the complaint that the individual has to awaken from sleep at night to void. [3]

The prevalence of OAB ranges from 11% to 17% in the general population. The National Overactive Bladder Evaluation Study reported a prevalence for OAB of 16% in men and 17% in women, thus affecting approximately 33.3 million adults. [4] A European study, in an evaluation of 16000 patients, demonstrated a similar prevalence of 17% in individuals older than 40 years of age. [5] Another study reported a prevalence of 11.8% in both men and women, with an increase in prevalence of OAB with age. [6] OAB is not a fatal disease but it affects the quality of life (QoL) of the patient. It has major negative impact on the psychological, social, domestic, sexual, and physical domains of the patient. From a psychological viewpoint, individuals suffering from OAB may have a loss of self-esteem, feel guilty, fear being a burden to their family and friends, and fear the odor of urine. These individuals may decrease their social interactions. Up to 65% of men and 67% of women who suffer from OAB noted that their symptoms had an effect on daily living. [7] OAB is often associated with comorbidities such as increased risk of falls and fractures, increased urinary tract and skin infections, sleep disturbances, depression, and decreased sexual health. [8] The economic burden of OAB is huge. In USA alone, OAB attributed a cost of $12.02 billion in the year 2000 only. [9]

The exact cause(s) of idiopathic OAB is/are not well defined. Many factors such as damaged neurons in the spinal cord, decreased suprapontine inhibition, increased lower urinary tract afferent input, and enhancement of excitatory neurotransmission in the micturition reflex pathways have been implicated. [10] The myogenic theory implicates the micro-motions developed in the detrusor muscle due to partial denervation of bladder as the cause of OAB. [11] Recently, the urothelium has been implicated; it has been suggested that increased release of acetylcholine from the urothelium or increased sensitivity of the sensory receptors in it may be responsible for OAB. [12]

The initial treatment of OAB is determined by the etiology and the severity of the symptoms. The aim is improvement of the symptoms and the QoL of the patient. Behavioral therapy and pharmacotherapy with antimuscarinic drugs (generally a combination of both) are by far the most popular initial treatments. [7] Behavioral interventions for treating OAB such as bladder training (patient education, schedule voiding, and positive reinforcement) and pelvic floor exercises are often the first-line therapy for mild symptoms of urge, frequency, and/or incontinence. [13] Antimuscarinic agents are the only pharmacotherapy approved by the Food and Drug Administration (FDA). The antimuscarinic agents/formulations currently approved by the FDA for OAB include extended-release oxybutynin, transdermal oxybutynin, 10% oxybutynin chloride gel, extended-release tolterodine tartrate, immediate-release trospium chloride, extended-release trospium chloride, solifenacin, darifenacin, and fesoterodine. Fesoterodine and 10% oxybutynin chloride gel are the latest approved antimuscarinic agents. [7]

As with other antimuscarinic agents, dryness of mouth, constipation, headache, and blurred vision are the most common adverse effects with the antimuscarinic agents used in the treatment of OAB, and these effects can limit their use. [13] Additionally, these drugs may cause dizziness, somnolence, and insomnia and, in some individuals, cognitive impairment. A slight increase in heart rate and prolongation in the QT interval has also been observed with some of the agents used in the treatment of OAB. [7] Some individuals remain refractory to therapy or are unable to tolerate the side effects of the therapy. For such individuals, neuromodulation is the only FDA-approved second-line therapy for the management OAB. A variety of forms of neuromodulation have been used, including intravesical stimulation, pudendal nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation. [7] Nonapproved interventions include augmentation cystoplasty surgery and neobladder construction. [13] These interventions have their own limitations: they are either costly (neurostimulations) or carry the risk of infections and the other potential risks of surgeries.

The limited availability of treatment options, compounded by the problem of the adverse effects of the available drugs, the high cost of the secondary interventions, and the potential risk of surgeries, has always forced researchers to look for better and more affordable treatment options in patients with OAB refractory to antimuscarinic drugs. Botulinum toxin-A (BoNTA) is one such drug that has been tried out over the last 10-11 years in patients with refractory OAB as 'off-label' drug. BoNTA is derived from different strains of the bacterium Clostridium botulinum through proprietary manufacturing processes. It acts by producing a chemodenervation of muscle by preventing both the release of acetylcholine as well as its binding at the neuromuscular endplate. The paralytic effect of BoNTA produces a relaxation of the muscle. [14] Current FDA-approved indications for BoNTA include cervical dystonia, strabismus, blepharospasm, hemifacial spasm, and glabellar wrinkles. [15]

A PubMed search for 'BoNTA in OAB' showed 208 results, while a search for 'BoNTA in DO' showed 226 results. By applying the limit of 'clinical trials', the search results scaled down to 39 and 43 for BoNTA in OAB and BoNTA in DO, respectively. Further applying the limit of 'in the last 1 year' showed nine results of clinical trials for BoNTA in OAB and seven results for BoNTA in DO. The first documented report of use of BoNTA in OAB dates back to the year 2000, when 200-300 units of BoNTA was injected into the detrusor muscle under cystoscopic guidance in 31 patients with spinal cord injury, detrusor hyperreflexia, and urge incontinence resistant to anticholinergic drugs. This study revealed encouraging results: the dose of the anticholinergic drugs could be markedly decreased and the symptoms were improved in these patients. A dose of 300 units of BoNTA was adjudged to be needed to counteract an overactive detrusor, with the improvement persisting for at least 9 months, when repeat injections were advised. [16] Subsequent studies have provided corroborative evidence to support this claim.

Retrospective data obtained from a European multicenter study enrolling 231 patients with neurogenic DO who received 300 units of BoNTA injected under cystoscopic guidance into the detrusor muscle at 30 different locations showed significant increase in cystometric bladder capacity and mean reflex volume, and a significant decrease in mean voiding pressure at 36 weeks' follow-up. The requirement of anticholinergics decreased considerably in these patients. [17] In another study, intradetrusor injection of 300 units of BoNTA was shown to decrease the incidence of urinary infections in patients with neurogenic DO refractory to anticholinergics. After 6-months of follow-up, the incidence of symptomatic urinary infections came down from a pre-treatment rate of 1.75±1.87 to a post-treatment rate of 0.2±0.41 (P=.003). [18] In a long-term (6 years) follow-up study in 17 spinal cord-injured (SCI) patients with refractory DO managed with repeated intradetrusor injections of 300 units of BoNTA, significant improvement in urinary symptoms and QoL was observed. A significant decrease in the frequency of daily incontinence episodes and a significant increase in first uninhibited detrusor contraction and in maximum bladder capacity were observed. Fifteen patients (88.2%) were completely continent. [19]

None of the studies reported above had a comparative arm and all were nonrandomized. In the first ever double-blind, placebo-controlled, randomized trial, 16 patients receiving intradetrusor injection of 200 units of BoNTA were compared with 18 patients receiving placebo for change in maximum cystometric capacity, changes in overactive bladder symptoms, post-void residual, maximum detrusor pressure during filling cystometry, and reflex detrusor volume. All these parameters improved significantly in the BoNTA arm. However, this was a single-center study and the patients were followed up for 12 weeks only. [20]

In a recent prospective, double-blind, multicenter, 36-week follow-up study (with an extension of 36 weeks by giving open-label injection of BoNTA after completion of the double-blind period of first 36 weeks), 57 patients of 18-75 years of age with refractory neurogenic DO secondary to spinal cord injury or multiple sclerosis and urinary incontinence were randomized to receive either 300 units of BoNTA (n=28) or placebo (n=29) via cystoscopic injection into the detrusor muscle. As compared to placebo, the mean daily frequency of urinary incontinence episodes was significantly lower for the BoNTA-treated group. There was also significant improvement in urodynamic and QoL parameters for the treatment group as compared to the placebo group. It was concluded by the authors that in adults with antimuscarinic-refractory neurogenic DO or multiple sclerosis, BoNTA is well tolerated and provides clinically beneficial improvement for up to 9 months. [21] This multicenter study clearly established the long-term efficacy of BoNTA in refractory DO and OAB. Another study has reported recently that urodynamic improvement can be maintained for at least 6 months with 100 units of intradetrusor injections of BoNTA in patients with refractory OAB. [22]

Though no serious adverse effect has been reported with the 'off-label' use of BoNTA in patients with refractory OAB, there are reports of botulinum toxin spreading from the area of injection to other areas of the body and causing symptoms similar to those of botulism in children with cerebral palsy being treated with BoNTA for muscle spasticity. Such symptoms include unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision, and drooping eyelids. In view of such reports the FDA has directed safety label changes, including a boxed warning, for all botulinum toxin products. [23] However, despite the boxed warning, once it is approved, intradetrusor injection of BoNTA is going to be the treatment of choice in patients with OAB refractory to anticholinergic drugs or in patients who have known contraindication to anticholinergic drugs; this is because of the nonavailability of other easier and cheaper treatment options and due to the established advantages of BoNTA therapy, such as the persistence of its effect for relatively long periods, improvement in urodynamic parameters and QoL, decrease in the requirement of anticholinergic drug dosage (with consequent decrease in the side effects), and the proven efficacy and few side effects of a dose of 100 units of BoNTA.

   References Top

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