New Pharmacologic and Minimally Invasive Therapies for the Overactive Bladder

Michael Franks, MD, Emmanuel Chartier-Kastler, MD, Michael B. Chancellor, MD

Disclosures
In This Article

New Delivery Tools

Intravesical therapy with anticholinergic drugs is effective, but this method of delivery is cumbersome since it requires repeated manipulation of the lower urinary tract. However, if constant therapeutic levels of oxybutynin in the bladder without repeated instrumentation can be achieved, this would provide an extremely effective regimen to OAB. The key to this intravesical regimen is a long-lasting intravesical pump to deliver the desired drug dose. This technology, called UROSTM, is currently under development by Situs Corp of San Diego, Calif. The concept involves a reservoir that can be easily inserted into the bladder and filled with the desired drug. The reservoir size must be balanced so that it is not too small to be voided out, yet not too large to cause bladder irritation. The reservoir will be able to constantly release a precise drug quantity into the bladder. When the reservoir is empty -- for example, after 30 days -- a flexible cystoscope can be used to retrieve the empty reservoir and a new reservoir can be inserted. Drugs to treat bladder spasms, pain, and even bladder cancer may all be delivered by this technique in the future.

Capsaicin, a substance P antagonist, recently has been tried, with limited success. First, capsaicin causes stimulation of the unmyelinated C fibers and myelinated A delta fibers within the urinary bladder. This results in severe discomfort or pain with release of the neurotransmitters substance P or neurokinin A in the bladder. Functional desensitization of C fiber afferent neurons may decrease detrusor instability. The use of this substance is still largely experimental, and it is given to patients with detrusor hyperreflexia. However, some trials are ongoing with the use of capsaicin for detrusor instability, especially when the patient has not benefited from other forms of treatment. In a recent capsaicin study of detrusor hyperreflexia, 44% of patients had satisfactory continence, 36% were improved, and treatment failed in only 20%.[43]

Resiniferatoxin (RTX) is a much more potent sensory antagonist than capsaicin. Like capsaicin, it possesses a vanilloid receptor agonist. RTX acts without the excitatory effect of capsaicin and therefore elicits less discomfort. This regimen promises an alternative to capsaicin, potentially for use in bladder instability and detrusor hyperreflexia. However, formal controlled trials still have to be performed to determine the precise use and dosage for this agent. Initial results in a human trial revealed that 1 month after a single instillation of resiniferatoxin, 25% of the patients maintained an increased bladder volume with decreased symptoms, and all the patients had increased bladder capacity immediately after instillation.[44] The key advantage of RTX is that it is at least as effective as capsaicin, without the local side effect. For a detailed review of intravesical capsaicin and resiniferatoxin, see the review article by Chancellor and de Groat.[45]

Intrathecal administration of clonidine has been found an effective treatment of severe acute or chronic pain and, more recently, of spasticity. There is some evidence for a spinal adrenergic control of micturition. Clonidine activates noradrenergic receptors in the CNS and is widely used as an hypotensive drug. In cats with chronic spinal lesions, intravenous clonidine improves the micturition reflex by enhancing detrusor contraction and by decreasing bladder sphincter dyssynergia.[46] Clonidine has already been tested orally in patients with spinal lesions but has shown no significant clinical effect.[47] Intrathecal clonidine may represent a useful conservative treatment of both severe bladder hyperactivity and spinal spasticity.[48] The effect occurred very shortly after injection (5 min), and lasted at least 3 hours. Its long-term effect, via a subcutaneous implantable pump, as with intrathecal baclofen, should now be evaluated.[49]

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