Urinary incontinence is the involuntary leakage of urine. The embarrassment of this condition means that many people don't receive treatment. Research-based companies are developing promising medicines to help improve the lives of incontinence sufferers.
Incontinence is an inability to control the bladder, resulting in involuntary leakage of urine. Common forms are stress incontinence (leakage on coughing, laughing, physical exertion), due to increased abdominal pressure, and urge incontinence, as a result of spasm. The latter is the most responsive to medication.
The mechanisms controlling normal urination are complex, involving the brain, nervous system and various muscles in the bladder itself. Treatment for incontinence should address any organic cause of loss of control where possible.
In Europe, more than 16 per cent of men and women aged 40 or older experience some symptoms of overactive bladder, giving a total of 25 million people. Patients usually complain about episodes of incontinence several times in the last month and having to get up twice or more during the night to urinate (nocturia).
The proportion of people affected by incontinence episodes, an increased rate of urinations per day and a decreased average volume of urine passed per urination increases with age. There are thought to be about 65 million women with stress urinary incontinence worldwide. Many patients never seek medical help because they are embarrassed to admit they are suffering from incontinence.
Cerebrovascular disease (stroke, dementia), impaired mobility and multiple medication are associated with incontinence in the elderly and it is the most common triggering factor for an elderly person being admitted to residential care. Incontinence remains a taboo topic and it is estimated that only 10 to 20 per cent of people with an unstable or overactive bladder receive any kind of treatment; only one fifth of those are on medication.
To date, treatment options have been limited. Teaching muscle control and retraining of the bladder (pelvic floor exercises) help some of those affected. In addition, medicines acting on the bladder may be helpful. Several medicines, called anti-cholinergic compounds, work on the contractile muscle of the bladder (the detrusor muscle) to reduce spasms by selectively blocking muscarinic receptors of the M3 subtype.
Several M3 receptor-specific compounds are available to treat overactive bladder (both urge and frequency incontinence). The newer molecules have an improved side effect profile and less potential for medicine-medicine interactions than older anticholinergic compounds.
Extended-release versions have been developed that are taken once daily. There is also a patch applied twice weekly that provides an alternative to existing oral medicines. It is said to have a lower anti-cholinergic side effect profile.
Such unwanted effects, including dry mouth, blurred vision and constipation, are common reasons for treatment discontinuation with older anti-cholinergic products. As the elderly make up a large part of the patient population for urinary incontinence, an improved side-effect profile would be beneficial for patients taking multiple medicines.
In addition, there is a different type of anti-cholinergic medication, which acts selectively on muscarinic receptors regulating bladder relaxation (M2 receptors).
In 2004, the first stress incontinence medicine was launched in the EU. The compound is a serotonin and noradrenaline reuptake inhibitor (SNRI) and is approved for moderate to severe cases. Increased concentrations of serotonin and noradrenaline act on the nerve that stimulates the urethral sphincter. This is believed to increase the tone of the urethral sphincter at the exit of the bladder, helping to prevent accidental urine leakage.
Stress urinary incontinence is almost twice as prevalent as urge urinary incontinence, which has many more treatment options. Up to now, the disorder has been treated with behavioural therapy, pelvic floor exercises and surgery. The SNRI is particularly useful in women who find it difficult in keeping to physiotherapy exercises or those who are not candidates for surgery.
While medicines to treat overactive bladder are now intensively researched, there are only a few medications approved for the other common form of incontinence, stress incontinence. Therefore, researchers are exploring further compounds which act in the central nervous system by inhibiting reuptake of the neurotransmitters serotonin and norepinephrine in nerves involved in controlling bladder function.
Another urinary incontinence compound, a modulator of substance P and calcitonin gene-related peptide (CGRP), is being studied in Phase 3 trials. So far, it has been well tolerated. Also in development is a compound which is believed to be an inhibitor of C-fibre nerves.
Compounds interacting with neurokinin (NK) receptors are exciting most interest at present. The furthest advanced compound with this mode of action, which targets NK-1 receptors in the central nervous system, is in Phase 3 trials. The advantage of this approach is that the medicine works on the nerves controlling the urination process and does not inhibit the functioning of the detrusor muscle itself, which should reduce the risk of urinary retention.
There would seem to be limited scope for improving clinical results by developing more specific muscarinic receptor blockers which act on the muscle itself; instead, progress is likely to come from investigating alternative mechanisms of action.
Other neurokinin antagonists are under development either in Phase 1 trial or still in the preclinical stage. Approaches being explored in preclinical development include inhibitors of central nervous system alpha1-adrenoceptors for stress incontinence, and a potassium channel opener, in Phase 2 trials for overactive bladder.
The modulation of potassium channels of small and intermediate conductance of nerves affecting the bladder muscle may be such a promising pathway. So far, molecules with this profile have shown promise by increasing the time between urination and the amount of urine in the bladder.
Other research is being devoted to temporarily restricting urine production. Research groups are studying new pathways to develop incontinence products targeting the kidney. Such compounds belong to the class of second-generation orally active non-peptide vasopressin agonists.
The research project further includes the principles that have emerged from research with aquaporins, a family of proteins that form channels through which water enters cells. The idea is to develop a product that will manipulate urine production and turn it off for a short time so that patients can go to the cinema or attend meetings.