INCONTINENCE (URINARY)

What is urinary incontinence?

Incontinence is an inability to control the bladder, resulting in involuntary leakage of urine. The processes controlling urination are complex, involving the brain, nervous system and various muscles in the bladder itself. Common types of incontinence are stress incontinence (leakage on coughing, laughing, physical exertion), due to physically increased abdominal pressure without detrusor muscle contraction, urge incontinence (sudden voiding), as a result of detrusor muscle spasm, mixed incontinence, with features of both of the above, and overactive bladder (OAB), in which feelings of urgency may cause someone to urinate more frequently without resulting in incontinence. Treatment should address any physical cause of loss of control where possible.

Who does incontinence affect and what does it cost?

The number of people with urinary incontinence is not accurately known, but the Continence Foundation has estimated that as many as 6 million adults in the UK may be affected. Among adults living in the community, women are affected more often than men and are more likely to experience stress incontinence. Overactive bladder accounts for 50 per cent of incontinence in men.

The proportion of people with incontinence increases with age. Cerebrovascular disease (stroke, dementia), impaired mobility and multiple medication are associated with incontinence and it is the most common triggering factor for an elderly person being admitted to residential care. It has been estimated that over half of UK nursing home residents are incontinent.

Incontinence remains a taboo topic and a survey found that of the 14 per cent of men aged 40-79 years who reported continence problems, only 25 per cent had sought medical help. The Continence Foundation has estimated that the cost to the NHS of treating incontinence in England in 1998 exceeded £350 million, of which £23 million were related to medicines and £128 million were for appliances and containment products.

Present treatments and shortcomings

Bladder retraining and pelvic floor exercises help some of those affected but, in addition, medicines acting on the bladder may be helpful. Anticholinergic compounds, such as oxybutynin (Cystrin/Ditropan, sanofi-aventis), propiverine (Detrunorm, Amdipharm), solfenacin (Vesicare, Astellas) and trospium (Regurin, Galen) work on the detrusor muscle of the bladder to reduce spasms by blocking muscarinic receptors of the M3 subtype. They are prescribed for the treatment of overactive bladder and urge incontinence. The alternative anticholinergic tolterodine (Detrusitol, Pfizer) acts selectively on other muscarinic receptors regulating bladder relaxation (M2 receptors). Anticholinergic medicines are helpful but can induce side-effects such as dry mouth, constipation, headaches and, in those with Alzheimer's disease, impaired cognition, so new treatments would be valuable.

Only one medicine is available for the treatment of stress incontinence. This is duloxetine (Yentreve, Lilly), a noradrenaline and serotonin (5HT) reuptake inhibitor. By contrast with muscarinic antagonists, it is thought to act on nerves in the spinal cord that control the urethral sphincter muscle, increasing its tone and thus preventing leakage. Its main side-effects include nausea, dry mouth, constipation, fatigue and insomnia.

What's in the development pipeline?

Darifenacin (Emselex, Novartis) is an M3 selective anticholinergic that is not yet available in the UK. Another anticholinergic at an advanced stage of development is fesoterodine (Pfizer). Other anticholinergics in early clinical research include SMP-986 (Dainippon-Sumitomo, Phase 2) and KRP-197 (Kyorin, Phase 1).

Several new medicines for overactive bladder are under study that act by stimulating the beta-3 subtype of adrenergic receptors. These are found in detrusor muscle, where they are believed to be important for its relaxation, and also in certain other tissues, including the heart and on adipose tissue cells. Companies exploring compounds with this activity are Astellas (YM-178, Phase 2), Boehringer Ingelheim (KUC-7483, Phase 1), GlaxoSmithKline (solabegron, Phase 1) and MediciNova (MN-246, Phase 1).

Another process being explored is inhibition of the type-1 neurokinin (NK-1) receptors found within the spinal cord and in the nerves that control the bladder. These nerves are involved in the impulse that initiates bladder spasm in overactive bladder. GlaxoSmithKline has an agent (casopitant) in Phase 2 trial for overactive bladder that is a specific NK-1 antagonist, as do sanofi-aventis (SSR 240600) and Tanabe (TA-5538).

A variety of other compounds is also being researched. At the Phase 2 stage are elocalcitol (BioXell), DDP200 (Dynogen), two compounds (MK-0594 and MK-0634), from Merck Sharp & Dohme and cizolirtine (Lab. Dr. Esteve). This last compound is also being studied for its usefulness in stress incontinence. Also at Phase 1 are two potassium channel opening compounds, ABT-598 (Abbott) and GSK 366074 (GlaxoSmithKline).

The longer-term future

With this range of new medicines being explored, it seems likely that new compounds will emerge that avoid the side-effects of present anticholinergics. Alternatives to duloxetine for stress incontinence would also be of value. With the ageing of the population, the need for new treatments for urinary incontinence will increase and intensive research seems sure to continue.

FOR FURTHER INFORMATION CONTACT:

The Continence Foundation
307 Hatton Square, 16 Baldwin's Gardens
London, EC1N 7RJ
Phone: 020 7831 9831 (Helpline)
Website: www.continence-foundation.org.uk