COVER STORY

GOTTA GO RIGHT NOW

New remedies are coming to rescue women with overactive bladder or urinary stress incontinence

With the approval of Viagra (sildenafil, Pfizer) several years ago, the taboo surrounding impotence has largely subsided for men. If only the same were true for urological disorders that plague women. Overactive bladder (OAB) and stress urinary incontinence (SUI) are still subjects of acute embarrassment for the fairer sex.

Two million people around the world are affected by OAB, including one in three women over the age of 18 years in the United States. Roughly 90% of OAB sufferers are women. Yet, studies show that only one out of every 12 women discusses this problem with her physician. Women are too embarrassed to bring their condition to the attention of their healthcare providers, and a recent survey conducted by the National Women's Health Resource Center (NWHRC) found that 70% of women claimed their doctor had never brought the subject up with them, either.

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When most people hear the term overactive bladder, they think of elderly women wearing protective undergarments. In fact, those unaffected by the condition tend to minimize the disorder. Having an overactive bladder might cause a little embarrassment, even be a bit messy at times. But, since it's not a life-threatening disease, it's not really that big of a deal. Right? Wrong!

Here are the facts. Contrary to what is commonly believed, the term overactive bladder doesn't necessarily indicate urinary incontinence at all. In fact, overactive bladder, instead, refers to an incredible urge to use the bathroom. OAB is a bladder condition associated with urinary urgency—urgency that is also usually accompanied by urinary frequency and nocturia. In other words, those with OAB are plagued with an overactive detrusor muscle.

As a brief review of physiology, the detrusor is the muscle that surrounds the entire balloon portion of the bladder. Of course, the other important muscle in the bladder is the sphincter. Using the balloon analogy, the sphincter can be thought of as the knot in the bottom of the balloon that keeps air inside.

In order for us to void urine under normal circumstances, the detrusor muscle must contract at the same time the sphincter relaxes. In individuals with OAB, the detrusor muscle is prone to involuntary muscle contractions, while the bladder is still filling with urine. It is these involuntary muscle spasms that cause the symptoms of urinary urgency, frequency, and nocturia. Certainly, there are times when patients cannot suppress those muscle contractions. This is where urine leakage or incontinence sometimes enters into the OAB picture. However, many individuals with OAB never have incontinence episodes. It is important to recognize that OAB and incontinence do not always go hand-in-hand. Many individuals suffer from one condition, but not the other.

From a physiologic standpoint, OAB still doesn't sound so bad. Just the minor inconvenience of a muscle spasm, right? Well, let's consider OAB from a patient's viewpoint. As soon as the bladder begins to fill with urine, even just a teaspoonful, the bladder begins to contract and spasm, sending messages that urination is imminent. This essentially means that OAB sufferers feel as if they need to urinate 100% of the time.

Think about that for a moment. How would you be able to do your job if you always felt the incredible urge to run to the bathroom? Some patients with OAB find themselves in the rest room more than 20 times each day. Even when they feel as if they cannot hold their urine for another instant due to the incredible bladder spasms, when they reach the toilet, it often turns out that there is only one or two ounces of urine to void. For the OAB sufferer, sleeping at night becomes nearly impossible. Because of the way our bodies are wired, we awaken from our sleep as soon as the bladder sends the "urge" signals to urinate. OAB sufferers may find themselves in the bathroom seven or more times every night!

Consider also how daunting it is for those who have to "map rest rooms" each time they step out the door. A 30-minute jaunt across town may require several additional stops to find bathrooms. Surveys indicate that those with OAB often try to cope with their situation by limiting fluid intake and curtailing shopping trips. Eventually, OAB patients become reclusive since their urinary frequency and "finding a bathroom" become major sources of anxiety. As you are probably beginning to see, OAB negatively impacts the quality of one's life in numerous ways: socially, emotionally, and sexually. Those suffering from OAB deal with irritability, frustration, anger, sleep deprivation, and depression. Some OAB sufferers even report unemployment and divorce as a result of their medical condition.

Although surveys indicate that many women are uncomfortable talking with their doctor about OAB, and many incorrectly assume this situation is a normal part of the aging process, this topic is unlikely to remain a taboo for much longer since several new drugs are on track for launch within the year. New therapeutic advances will undoubtedly help to bring the topic into the limelight.

Existing drug treatments

There are several approved therapies on the market for treating OAB. Oral oxybutynin (Ditropan and Ditropan XL, ALZA) has been considered by many as the gold standard for efficacy in OAB treatment. But, since its launch in January 2001, tolterodine (Detrol and Detrol LA, Pfizer) has become the treatment most often prescribed in the United States for OAB and has been used by more than seven million patients around the world.

Unfortunately, many individuals cannot tolerate the anticholinergic side effects associated with these therapies. Oxybutynin and tolterodine both cross the blood brain barrier and bind to muscarinic receptors in the central nervous system, leading to sedation. Additionally, dry mouth, dry eyes, and constipation occur frequently. It has been said that less than 50% of patients continue therapy with oral oxybutynin for more than three months.

And while tolterodine may be more specific for bladder muscarinic receptors than receptors in the salivary glands, according to Mark Ruscin, Pharm.D., associate professor with the department of clinical pharmacy at University of Colorado, whose specialty is long-term care, "Geriatric patients are very sensitive to anticholinergic effects, especially cognitive issues and constipation." High rates of noncompliance and anticholinergic adverse effects are what make new therapeutic options so attractive.

Just one year ago, in February 2003, Watson Pharmaceuticals added a new twist to OAB therapy when the company's oxybutynin transdermal system, Oxytrol, received Food & Drug Administration approval. This transdermal formulation controls OAB symptoms all day and all night by releasing 3.9 mg of oxybutynin consistently and continuously, while minimizing anticholinergic side effects. "We've had good results with the patch," said Ruscin. "Patients are tolerating it well. The patch has some advantages. Because of the way the patch is absorbed, the drug bypasses liver metabolism. As a result, there is a favorable ratio between oxybutynin and its active metabolite, desethyloxybutynin."

It is the metabolite of oxybutynin that is thought to be responsible for much of the drug's anticholinergic side effects. With the patch carrying lower plasma levels of the metabolite, dry mouth and other anticholinergic side effects are less problematic. In fact, in clinical trials, there were no statistical differences between Oxytrol and placebo with respect to anticholinergic side effects. Ruscin did say, however, that the problems he sees with the patch tend to be rash and irritation at the application site.

Roger Dmochowski, M.D., a urologist at Vanderbilt University, uttered similar sentiments: "Patients who experience lots of anticholinergic side effects with oral therapies seem to do well with the patch." And he added, "Patients are gradually becoming more accepting of patches" as drug delivery systems. However, despite the advantages that Oxytrol appears to bring to OAB therapy, surprisingly few physicians seem to know about it. In fact, Dmochowski indicated that the product's "overall impact, educationally, has been rather restricted to date" for reasons that are not entirely clear.

What's in the pipeline?

• Trospium chloride: A leading therapy for OAB in Europe for the past six to eight years, trospium chloride (Indevus Pharmaceuticals) is an anticholinergic compound currently under review by the FDA that has been shown to reduce both urinary urgency and frequency in patients with OAB. Around the world, the drug has been studied in clinical trials and postmarketing surveillance studies involving more than 10,000 patients.

Like other anticholinergic compounds, trospium acts as an antagonist at muscarinic receptors in the bladder, to decrease bladder contractions. Unlike currently available anticholinergics, trospium possesses a quaternary amine structure. With a positively charged nitrogen atom, trospium is not as lipid soluble as oxybutynin and tolterodine, and it is not expected to cross the blood brain barrier very easily. This reduces the likelihood of unwanted sedative effects. The drug is also not metabolized by the hepatic P450 microsomal isoenzymes, so clinically relevant drug-drug interactions are not anticipated.

Additionally, trospium is excreted largely unchanged—80%—by the kidneys, an effect that has been postulated to result in a favorable therapeutic ratio when comparing beneficial effects of the drug in the bladder with its unwanted effects on salivary glands.

In clinical trials, trospium improves symptoms of OAB within three days. Compared with placebo, trospium significantly reduces voiding frequency and urge incontinent episodes, and it significantly increases the volume of urine voided with each micturition, all within the first week of therapy. During clinical trials, patients also reported fewer lifestyle restrictions while taking the drug and significant improvements in their quality of life. The most common side effects are associated with the drug's anticholinergic activities and include dry mouth and constipation. In head-to-head comparison trials, trospium is at least as efficacious as oral oxybutynin and tolterodine.

Because trospium is already available in other countries, clinical trial data are readily available. However, information is a bit harder to come by for two other novel anticholinergic compounds currently under review by the FDA. In fact, according to Dmochowski, there are virtually "no published data" available for solifenacin and darifenacin, as the pharmaceutical companies pursuing these drugs are keeping the data "very close to their vests."

• Solifenacin succinate and darifenacin hydrobromide: When asked to comment on the key features of solifenacin and darifenacin, Dmochowski indicated that neither drug possesses a quaternary structure so both can penetrate the central nervous system. However both drugs are unique from other existing therapies because they may exhibit some selectivity for the M3 muscarinic receptor. As with oxybutynin and tolterodine, both solifenacin and darifenacin are metabolized by hepatic P450 microsomal enzymes and may result in drug-drug interactions.

Solifenacin succinate (Vesicare; Yamanouchi Pharma America) received an approvable letter from the FDA for treatment of OAB in October 2003. It is anticipated that the drug will be launched in 2004 after further clinical data are submitted to the FDA.

In trials, solifenacin has been used by more than 3,000 patients. In a 12-week, double-blinded study presented at the American Geriatric Society in May 2003, solifenacin significantly improved urgency, urge incontinence, and frequency associated with OAB. The volume of urine voided with each micturition also improved with solifenacin. Not surprisingly, dry mouth and constipation are the adverse effects most commonly reported by patients during clinical trials.

Darifenacin hydrobromide (Enablex, Novartis) also received an approvable letter in October 2003 for treatment of OAB. According to Novartis, darifenacin is a selective antagonist at M3 muscarinic receptors, a receptor subtype believed to play a major role in detrusor muscle contraction.

More than 5,000 patients have participated in clinical trials assessing the safety and efficacy of darifenacin. According to data presented at the International Continence Society's 33rd Annual Congress in Italy in October 2003, darifenacin prolongs "warning time"—the time between the first sensation of urgency and urination. According to Dmochowski, side effects with darifenacin include dry mouth and constipation. As with solifenacin, approval and launch of darifenacin are anticipated sometime in 2004.

Stress urinary incontinence

Tackling taboo topics is nothing new for Gail Sheehy, author of Passages, the book that broke the taboo surrounding menopause. Now she is treading on new ground as she seeks to educate women about another taboo—that of stress urinary incontinence. SUI is not synonymous with OAB. In fact, it is a completely different medical condition. However, SUI may accompany OAB.

SUI is accidental urinary leakage that occurs while coughing, sneezing, laughing, exercising, or performing any other activity that increases abdominal pressure. SUI is the most common cause of urinary incontinence. One out of every three women over 18 years of age indicated in a recent survey that she has been affected by SUI, but this condition should definitely not be accepted as a normal part of the aging process.

SUI occurs when the bladder's sphincter cannot withstand increases in abdominal pressure. The problem may be due to a combination of factors including an incompetent sphincter or weakened pelvic floor muscles. Triggers for SUI include childbirth, obesity, chronic constipation, chronic cough or allergies, and estrogen deficiencies. In fact, just being of the female gender is considered a risk factor for SUI. Ruscin indicated that this is a condition that affects many postmenopausal women. Muscle tone in the pelvic floor and urethral tone diminish postmenopausally.

Unlike OAB, there are no FDA-approved pharmacologic therapies for treating SUI at the present time. According to Ruscin, vaginal estrogens may be tried as a first-line therapy in postmenopausal women. Additionally, he finds pseudoephedrine fairly effective. However, he cautioned that pseudoephedrine might increase blood pressure, especially among geriatric patients who frequently have hypertension already.

Urologists and patients alike are excited about duloxetine (Eli Lilly and Boehringer Ingelheim), a drug that, if approved, would be the first pharmacologic therapy to receive the FDA's blessing for SUI. Duloxetine is a dual norepinephrine and serotonin reuptake inhibitor. To date, the drug has received an approvable letter from the FDA for treating both depression and SUI.

According to urologist Mary Jane Minkin, M.D., clinical professor of obstetrics and gynecology at Yale University School of Medicine, researchers have identified a unique area in the central nervous system, called Onuf's nucleus, which controls the urethral sphincter. Onuf's nucleus is rich in serotonin and norepinephrine receptors. When these receptors are stimulated, the urethral sphincter contracts and prevents urine leakage, even when abdominal pressure increases. By enhancing noradrenergic and serotonergic neurotransmission, duloxetine helps to keep the sphincter competent and tight.

"Duloxetine has both a physical and a psychological effect," said Timothy Garnett, M.D., a medical director with Eli Lilly & Co. "It works well in treating SUI, a physical condition, because it increases the levels of serotonin and norepinephrine in the spinal cord region, and this results in increased muscle activity that allows the urethra to remain closed more effectively during physical activities."

In a recent phase III clinical trial, 683 women with SUI received either duloxetine or placebo for 12 weeks. According to study results, 40 mg of duloxetine twice daily reduced the number of incontinence episodes by 50% versus 27% for placebo. The most common side effects with duloxetine are nausea, fatigue, dry mouth, insomnia, constipation, and dizziness. Dmochowski reported, "Despite a high placebo effect, duloxetine clearly reduces incontinence episodes and improves the quality of life" for women affected by SUI.

It is anticipated that duloxetine will reach the market first as an antidepressant under the trade name of Cymbalta, and Lilly has asked the FDA to accept Yentreve as duloxetine's trade name for treating SUI. Final approval could come by the end of 2004 or early 2005.

Within the next two years, therapeutic options for managing both OAB and SUI are anticipated to change dramatically. For patients who quietly suffer from these conditions, this is welcome news and long overdue.

Kelly Dowhower Karpa, Ph.D., R.Ph.

What the terms mean

• Urinary frequency: the need to urinate more than eight times in a 24-hour period

• Urinary urgency: a compelling need to pass urine

• Urinary incontinence: involuntary urine leakage immediately preceded by urgency

• Nocturia: waking from sleep one or more times during the night to urinate

Treatments for OAB and SUI

Approved drug therapies for OAB Dosage

Oxybutynin (Ditropan) 5 mg 2-4 times daily

Oxybutynin, extended release (Ditropan XL) 5 mg-30 mg once daily

Oxybutynin, transdermal (Oxytrol) 1 patch applied twice weekly

Tolterodine (Detrol) 1 mg-2 mg twice daily

Tolterodine, extended release (Detrol LA) 2 mg-4 mg once daily

Drug therapies in the pipeline for OAB Tentative dosage

Trospium 20 mg-40 mg twice daily

Solifenacin (Vesicare) 5 mg-10 mg once daily

Darifenacin (Enablex) 30 mg once daily

Drug therapies in the pipeline for SUI Tentative dosage

Duloxetine (Yentreve) 40 mg twice daily

 

Kelly Karpa. Cover Story: GOTTA GO RIGHT NOW. Drug Topics Mar. 8, 2004;148:60.