Inserting a half-speculum into the vagina, displace the rectum away from the bladder. As the patient performs a Valsalva maneuver or coughs forcefully, evaluate the support of the anterior vaginal wall. Then turn the speculum 180 degrees and displace the bladder anteriorly, examining the posterior pelvic wall for any signs of prolapse. Also note any urogenital atrophy.
Finally, use a full speculum to evaluate the vaginal apex and cervix (if the patient has not had a hysterectomy). Bimanual and abdominal examinations also are important to rule out any abdominal or pelvic mass that could be irritating or causing pressure on the bladder.
Reexamine the patient for evidence of prolapse when she is standing. Some cases are difficult to detect when the patient is supine.
Step 4Begin multipronged therapy
Bladder retraining. Review the patient’s history, voiding diary, and findings from the physical exam to identify an appropriate treatment. After sharing all findings with the patient, instruct the patient on bladder retraining, which has 3 main components: education, scheduled voiding, and positive reinforcement. (Bladder retraining can be an extremely successful modality.)
Education consists of explaining the pathophysiology of overactive bladder and answering any questions the patient may have, so she understands why she is having the problem.
For scheduled voiding—also known as bladder retraining—examine the voiding diary to determine the approximate length of time between voids in a day. For instance, if the patient voids every hour, we generally ask her to continue doing so for the first week of retraining. The following week, we increase the interval to an hour and 15 minutes, the third week to 1.5 hours, and so on, with an ultimate goal of 3 hours between voids.
We also give instructions on pelvic floor rehabilitation or Kegel exercises. If the patient is able to voluntarily contract her pelvic floor muscles adequately, we recommend an exercise regimen that involves contracting her muscles numerous times a day for at least 10 seconds each time. If she is unable to contract her muscles or has a “dead” pelvic floor, she is referred to a physical therapist for biofeedback and possibly electrical stimulation.
We also instruct the patient to avoid racing to the bathroom when she feels an urge to void. Instead, have her stop, contract her pelvic floor muscles, and allow the urge to pass. She can then walk comfortably to the bathroom.
As mentioned earlier, the voiding diary may highlight problems such as excessive intake of fluids.
Local estrogen therapy can be added if there are signs of urogenital atrophy.
Medical therapy. In addition to education, timed voids, pelvic floor rehabilitation, and estrogen therapy, we usually start the extended-release form of tolterodine (4 mg) or oxybutynin (10 mg), which are antimuscarinic agents. (See “Treating overactive bladder: An expanding ‘pharmacopeia’”).
We ask her to return for a follow-up visit in 4 to 6 weeks to inquire about her symptoms and any significant side effects. We ask the patient to prepare another voiding diary for that visit so we can objectively measure decreases in frequency, urgency, and urge incontinence.
Dose adjustment is very important in patients with overactive bladder. If the woman is experiencing minimal effect with no side effects, titrate the dosage upward. If she is having good effect with significant side effects, decrease the dosage or consider switching to the transdermal form of oxybutynin.
When all these conditions are met and the patient remains severely affected, we perform multichannel urodynamic testing along with cystoscopy. If the testing supports the diagnosis of overactive bladder, and all other mechanisms for improvement have been exhausted, we counsel the patient about intravesical administration of botulism toxin, which relaxes skeletal and smooth muscle by preventing release of acetocholine from nerve terminal endings. Another option is sacroneuromodulation (InterStim therapy).
Treating overactive bladder: An expanding ‘pharmacopeia’
Antimuscarinic medications have been the mainstay of pharmacologic therapy for overactive bladder. In fact, the 2 most commonly prescribed drugs for overactive bladder are antimuscarinics: oxybutynin and tolterodine. Other medications also are available that affect different aspects of the neurophysiology of micturition.
Oxybutynin. The bladder contains 5 subtypes of muscarinic receptors, with a predominance of M2 and M3 subtypes. Oxybutynin has some selectivity for M3 receptors. It has been shown to inhibit bladder contractions, but because of muscarinic blockade in other parts of the body, it can have bothersome side effects. For example, oxybutynin has shown a higher affinity for muscarinic receptors in the parotid gland than the bladder, leading to dry mouth. In addition, the active metabolite of oxybutynin, N-Desethyl-oxybutynin, can reach concentrations that are 6 times the parent compound after oral administration.9 Other side effects include constipation, gastrointestinal upset, and blurry vision.
Alternate routes of administration have been developed to improve tolerability, including extended-release oral formulations, rectal administration, and a transdermal patch. Oxybutynin XL is the extended-release form, which incorporates a push-pull osmotic system. In parallel randomized, controlled clinical trials comparing immediate- and extended-release oxybutynin, oxybutynin XL was just as effective as the immediate-release formulation but had fewer side effects.10-12 Absorption of oxybutynin XL may occur to a larger degree in the colon than in the stomach and proximal small intestine, thereby decreasing conversion to N-Desethyl-oxybutynin. Oxybutynin XL comes in 3 doses (5, 10, and 15 mg) and offers the advantage of dose titration, a very important aspect of management.
A transdermal version of oxybutynin was recently released. In theory, transdermal treatment offers potential advantages such as more stable plasma concentrations and lower presystemic metabolism, which may decrease the primary active metabolite of N-Desethyl-oxybutynin. In a randomized, placebo-controlled trial of 3 doses of transdermal oxybutynin (1.3, 2.6, and 3.9 mg daily), only the highest dose out-performed placebo for median changes in incontinence episodes, frequency, and normal void volume.13 Quality of life also was significantly improved with the 3.9-mg dose. Anticholinergic side effects were comparable between active and placebo groups.
Tolterodine is a potent muscarinic-receptor antagonist without selectivity for particular subtypes. It is marketed in both immediate- and extended-release (tolterodine LA) formulations. A recent series compared both forms of the drug with placebo in 1,529 adults with overactive bladder.14 The primary measure of efficacy was change in the mean number of incontinent episodes weekly. Both medications showed a significantly better response than placebo. Dry mouth was significantly lower with tolterodine LA. When the authors used median values instead of mean values (because of non-normal distributed data), tolterodine LA showed improved efficacy over the immediate-release formulation. This study was sponsored by the drug’s manufacturer.
Comparisons of oxybutynin and tolterodine. In a prospective, double-blind, head-to-head study of the 2 drugs sponsored by the manufacturer of oxybutynin XL, 378 men and women were randomized to receive oxybutynin XL (10 mg daily) or tolterodine immediate-release (2 mg twice daily).15 Inclusion criteria included 7 or more episodes of urge incontinence per week and at least 10 voids per 24 hours. The Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial demonstrated greater efficacy with extended-release oxybutynin than with tolterodine, although both medications decreased weekly episodes of urge incontinence. Oxybutynin XL also showed a small but significant advantage for mixed incontinence and urinary frequency. Dry mouth and central nervous system side effects were similar for the 2 drugs.
A second head-to-head study also was sponsored by the manufacturer of oxybutynin—this one a randomized, double-blind comparison of the extended-release versions of both drugs. The Overactive Bladder: Performance of Extended Release Agents (OPERA) trial randomized 790 women to oxybutynin XL (10 mg daily) or tolterodine LA (4 mg daily).16 Inclusion criteria included at least 21 to 60 incontinent episodes per week and urgency and frequency exceeding 10 episodes per 24 hours. The drugs were similar in both measures, as well as in side effects, although dry mouth, usually mild, was more common among oxybutynin users. However, oxybutynin was significantly more effective in reducing micturition frequency, and 23% of women taking oxybutynin reported no episodes of incontinence, compared with 16.8% of women taking tolterodine. This finding was significant.
A third head-to-head study involved 2 separate trials conducted in parallel, with individual centers evaluating only 1 drug. In it, 1,289 patients were randomized to open-label treatment with either 2 mg or 4 mg of tolterodine LA in 1 trial and with 5 mg or 10 mg of oxybutynin XL in the other.17Inclusion criteria included 18 years of age or greater and symptoms of urinary urgency and frequency. After 8 weeks, tolterodine LA (4 mg) was found to be significantly more effective than either dose of oxybutynin XL, while tolterodine LA (2 mg) was similar to both doses of oxybutynin XL. This study was hampered by the fact that no data were supplied on the number of patients with isolated frequency and urgency versus those who had urge incontinence. Also, no objective parameters such as a voiding diary were utilized.
Three antimuscarinic drugs in the pipeline. Other antimuscarinic agents include trospium, a quaternary amine with some antimuscarinic activity. Because of its structure, it does not cross the brain barrier well and may thus have fewer central side effects.
Two new drugs awaiting approval from the US Food and Drug Administration are darifenacin, which has high selectivity for M3 receptors, and solifenacin, an M3 antagonist with greater selectivity for the bladder than the salivary glands in animal models.
All 3 drugs should be available in the United States some time in 2004.
Antiadrenergic medications. Because the bladder also contains alpha- and beta-adrenergic receptors, antiadrenergic medications have been developed. Currently available alpha-adrenergic agonists include ephedrine, phenyl-propanolamine, and pseudoephedrine. Beta-adrenergic agonists include isoproterenol and terbutaline.
Serotonergic agents. Both sympathetic and parasympathetic autonomic nuclei—as well as urethral sphincter motor nuclei—receive serotonergic input from the Raphe nuclei in the caudal brain stem. Serotonergic pathways generally enhance urine storage by activating sympathetic pathways and inhibiting parasympathetic pathways. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor that may be effective against both urge and stress incontinence. It is currently awaiting approval by the US Food and Drug Administration.