Refractory Overactive Bladder: A common problem? Beyond the Abstract

Adherence to the standard anticholinergic treatment of overactive bladder (OAB) is surprisingly poor, considering the psychosocial impact of the disease. For example, only 25% of OAB patients still take their long-term anticholinergic medication one year after prescription, independent of which anticholinergic drug is used.

In clinical practice, these cases are often subsumed under the term “refractory OAB” (overactive bladder syndrome, overactive bladder). This designation, which has become established in clinical parlance for very different situations, implies a search for alternatives to the standard treatment of overactive bladder. Another surprising fact is that no authoritative definition for the concept of “refractory overactive bladder” exists. Therefore, cases in which treatment is discontinued by the patient due to intolerable (anticholinergic) side effects, or by the patient or physician due to the, in their opinion, absence of therapeutic effects or inadequate therapeutic effects also fall under this term.

To systematically review the term “refractory overactive bladder”," we performed a search of the literature from 2000 to 2014 using the search keywords “overactive bladder/OAB”, “detrusor overactivity” or “antimuscarinic” in association with the terms “non-responder”, “refractory”, “fail” “persistent” or “dissatisfied”. The results can be divided into five categories, as described below.

1. THE DEFINITION PROBLEM
Neither the national nor international guidelines contain a definition of the term “refractory OAB”. Non-response as well as the occurrence of intolerable side effects are used synonymously. In the case of “non-response”, it often remains unclear whether this assessment is founded on the subjective opinion of the patient or on the subjective or objective opinion of the attending physician. The switch from one anticholinergic drug to another, the discontinuation of anticholinergic therapy to switch to a non-pharmacological alternative, or purely subjective assessments, such as “did not work as expected” are given in the literature as reasons for classifying overactive bladder cases as refractory.

2. EXPECTATIONS OF THE PHYSICIAN
The criteria used to diagnose refractory OAB vary greatly among different studies, and the subjective and objective measures of treatment failure differ from one author to another. Interestingly, the criteria for failure of first-line treatment differ from those for failure of the investigated alternative treatments in the studies. The latter criteria are often less strictly formulated. If, for example, the persistence of daytime urge incontinence episodes were equally applied as the measure of failure of both first- and second-line treatment, almost no patient could be considered a responder to an anticholinergic alternative.

3. MOTIVATION AND EXPECTATIONS OF THE PATIENT
It is well established that information and guidance improves patient adherence to anticholinergic therapy. This helps to dispel exaggerated patient expectations or fears of side effects, which keep some patients from even starting to take a prescribed anticholinergic drug; moreover, the chances of dose titration are often neglected. Failure to provide information on relevant measures, such as behavioral interventions including smoking cessation and reduction of the intake or caffeinated beverages and citrus fruit juices, means that an opportunity to improve the response rates of anticholinergic therapy alone has been neglected.

4. PATHOPHYSIOLOGICAL REASONS
Overactive bladder syndrome can be triggered by a wide range of pathophysiological cofactors. Chronic infections, changes in the anatomy of the urinary tract due to prostate enlargement or prolapse, mucosal atrophy associated with estrogen deficiency, neurological disorders, undetected drug-related detrusor stimulation, pelvic floor relaxation due to substances in co-medications, or renal disease-related polyuria can be contributing causes of OAB symptoms. Although the International Continence Society’s 2003 definition of OAB excludes the presence of “infection or other obvious pathology”, the question is, up to what level of investigation does this apply? Histological studies and studies that use biochemical markers for inflammation in serum or urine clearly show that particularly inflammatory processes play an important role in overactive bladder – beyond the limits of the standard routine urine culture.

5. PHARMACOLOGICAL PHENOMENA
Individual resorption differences such as those due to simultaneous food intake, cytochrome p450 drug interactions, genetic differences in cytochrome p450 enzyme system activity, gender- and age-related differences, changes in kidney function, liver function, and the receptor status of the various detrusor and urothelial muscarinic receptor subtypes are possible reasons for a patient’s non-response to anticholinergic drugs. Frequently, these phenomena cannot be measured in routine clinical tests, but nevertheless can be offset by adjusting the anticholinergic dosage.

CONCLUSIONS
The non-response to standard anticholinergic therapy in patients with overactive bladder may be due to a variety of reasons. Before looking for treatment alternatives, the clinician should realistically assess the expectations of the patient and, after evaluating the patient’s co-medications and co-morbidities, the patient’s first-line drug treatment should be supplemented with behavioral interventions and other measures, as appropriate. If the peculiarities of anticholinergic therapy are then taken into account (in terms of cytochrome interactions, renal function or banal things such as impaired absorption due to simultaneous food intake, etc.), the response rates to standard anticholinergic therapy may be improved without a premature shift to (invasive) treatment alternatives. The term “refractory OAB” should only be used in such cases when the aforementioned steps have confirmed the patient´s nonresponse to first-line treatment.

Written by:
Andreas Wiedemann, Department of Urology, Evangelisches Krankenhaus Witten gGmbH, University Witten/Herdecke, 58455 Witten, Germany.
Joachim Grosse, Urological Clinic, University Clinic Aachen, 52074 Aachen, Germany
Ulrich Schwantes, Department of Medical Science / Clinical Research, Dr. R. Pfleger GmbH, 96045 Bamberg, Germany.

AbstractRefractory overactive bladder: A common problem?