Chronic Pelvic Pain Associated with Bladder Origin Disorder

Chronic pelvic pain is a significant problem affecting over 11 million women, of whom nearly three-quarters have urinary symptoms. At a symposium held in conjunction with the Annual Meeting of the American Society for Reproductive Medicine,
experts reviewed the current information about bladder origins for these symptoms in women. .

This program was supported by an unrestricted educational grant from Ortho-McNeil Pharmaceutical, Inc.

Epidemiology and Etiology of Interstitial Cystitis

“In a gynecologist’s practice where you are dealing with women who have chronic pelvic pain, you probably see interstitial cystitis every week, not just once every other year,” began Peter K. Sand, MD, Professor, Department of Obstetrics and Gynecology, and Director, Division of Urogynecology, Director, Evanston Continence Center, Northwestern University, Feinberg School of Medicine, Evanston, Illinois. He noted that gynecologists probably see early forms of the condition more often than they recognize.

Interstitial cystitis (IC) is defined as urgency and frequency with or without pelvic pain and with or without nocturia, in the absence of other pathologies. Several disorders have overlapping symptoms and can be mistakenly diagnosed instead of IC, including endometriosis, chronic pelvic pain syndrome, vestibulitis, recurrent UTI, and irritable bowl syndrome in women and chronic prostatitis in men.

Dr. Sand explained that IC begins with neural activation and nociceptive input into the dorsal horns of the spinal cord, leading to upregulation and consequently increased urgency and pain. It may begin with misdiagnosed “recurrent UTIs” (without significant bacteriuria). This can progress to “urethral syndrome” (chronic urethrotrigonitis), and then to mild, early IC, and finally to advanced cases, which are difficult to treat.

“It’s very important that we find these women early to try to reverse this vicious cycle and make these women better,” said Dr. Sand.

There are two main theories about the pathogenesis of IC. One proposes a defect in the glycosaminoglycans (GAGs) layer of the bladder. “This layer is like a trash can liner that prevents urine from coming into contact with the bladder wall,” said Dr. Sand. The other theory involves the mast cells triggering an allergic immunologic response (bladder mastocytosis).

Regardless of which theory is true, most IC begins with some sort of bladder insult (e.g., bacterial infection, catheter placement) that changes the milieu of the urothelium of the bladder and leads to damage of the GAG layer. The increased permeability allows potassium ions to leak into the interstitium and activate C-fibers, causing a sense of urgency and pain and upregulation at the spinal cord level where there will be antidromal release of substance P. With this release, there is an activation of mast cells, which release bradykinin and histamine that cause edema, inflammation, and more damage. This further activates C-fibers, perpetuating the cycle.

Dr. Sand described the process for making the diagnosis of IC. Take the patient’s history of urgency, pain, and nocturia; perform a physical exam; have the patient keep a voiding diary; and get a urine culture (to rule out bacterial UTIs). Also, get a urinalysis to make sure the patient doesn’t have microscopic hematuria

A patient questionnaire, called the Pelvic Pain and Urgency-Frequency Patient Symptom (PUF) questionnaire is a simple symptom scale that measures the presence and severity of pain, urgency, and frequency. It can effectively be used as an effective screener for IC.

If the GAG layer is deficient, it will allow potassium to cross into the interstitium; therefore, a potassium sensitivity test can be used. Dr. Sand cited a literature review of IC studies by Parsons, in which he identified 1,550 subjects who had been given a potassium sensitivity test; 79% of those with a positive test met the NIH criteria for IC. In none of the studies were there more than 2% of normal controls that tested positive on the potassium sensitivity test.

“While it’s not a perfect test in terms of sensitivity, it is a very specific test,” said Dr. Sand.

Dr. Sand went on to discuss the overlap of IC with gynecologic pelvic pain conditions. He cited work by Parsons who examined patients in four gynecologic centers that specialize in endometriosis, vestibulitis, and/or vulvo- dynia (Am J Obstet Gynecol 2002; 187:1395-1400). He found that 84% of the patients had symptoms of urgency and frequency and 81% of them had a positive potassium sensitivity test. None of the 48 control subjects had positive tests.

A study by Clemons and colleagues looked at women undergoing laparoscopy for chronic pelvic pain, and found that 38% of them met the NIH criteria for IC (Obstet Gynecol. 2002; 100:337-341). They also found some overlap between conditions. One-half of the 38% with IC also had positive findings on laparoscopy for endometriosis.

In a retrospective trial by Chung and associates, they found that 78% of 60 women undergoing laparoscopy for chronic pelvic pain met the NIH criteria for IC and 80% of them had biopsy-proven endometriosis (JSLS 2002;6:311-314). “There is tremendous concordance between these two conditions,”
remarked Dr. Sand.

Chronic Pelvic Pain and the “New IC”:
Insights in the Neuropathology, Diagnosis, and Treatment

Charles W. Butrick, MD, Director, The Urogynecology Center, Overland Park, Kansas, discussed new insights into the neuropathology of pelvic pain disorders.

Regardless of the trigger of IC, the patient ends up with disruption of the processing of the sensory input coming from the bladder, leading to urgency, frequency, and pain. According to Gate Control theory, there is a sensory input, which travels up C-fibers, goes into the sacral spinal cord and then the brain stem, and finally up into the cortex. Along those pathways, there are modulating influences that help to process and control pain. In IC, the sensory input rises from the bladder.

“Many things can affect how well the gates work,” said Dr. Butrick. For example, estrogen plays a role in the ability to modulate pain, which may explain why some women with IC have peri-menstrual flares.

Modulation of pain may also be affected by the fact that urothelial cells have neuronal-like properties. They release ATP and nitrous oxide (NO), they respond to neurotransmitters, and they express vanilloid receptors (e.g., capsaicin). Urothelial cells, therefore, have a sensory function and interact chemically with afferent nerves that send nerve signals to the dorsal horn.

The dorsal horn is a major site of modulation of pain input, and acute and chronic pain produce different physiologic enzymatic receptor changes. With chronic pain, glutamate is released in greater amounts and there is more glutamate in the cleft between the primary neuron and the dorsal horn neuron. In addition, N-methyl-D-asparate (NMDA) receptors become activated, which opens calcium channels, activating NK1 receptors and gene fos expression, and substance P is released.

Under normal conditions, many visceral afferent nerves (such as those in the bladder) are turned off. However, in the environment of prolonged stimulation and inflammation, these “silent” afferent nerves become active. The bladder has the highest neural density of any organ within the pelvis and it has the highest proportion of silent C-fibers. “Therefore, the bladder is a classic organ to become turned on if anything in the pelvis becomes upregulated,” said Dr. Butrick.

This process of upregulation not only is occurring at the level of visceral afferents (the nerves within the bladder, colon, uterus), but it is also occurring elsewhere, such as within the spinal cord. When the spinal cord becomes upregulated, there is an exaggerated reflex output, which initiates a process involving not only the original offending site (e.g., the bladder or implants of endometriosis) but the surrounding areas.

The resulting neuropathic output states include visceral hyperalgesia (the organ becomes hypersensitive), viscerosomatic hyperalgesia (referral neurogenic inflammation), viscerovisceral hyperalgesia (referral sensitization to second viscera; e.g., IC with irritable bowel syndrome, endometriosis with IC), viscero-muscular reflex (visceral pain from IC or endometriosis causes pelvic floor muscle hypertonicity and painful trigger points).

This entire process describes a visceral pain syndrome. “According to urologist Dr. Grannun Sant, IC is not an end-organ disease; it is a visceral pain syndrome,” said Dr. Butrick. “Visceral pain syndromes involve chronic neurogenic inflammation, primary afferent overactivity, and central sensitization which interact to perpetuate pain,” he said.

Dr. Butrick continued with a discussion of diagnosing IC. He believes the potassium sensitivity test has many advantages. In this test, the patient is catheterized and then a comparison is made between filling the bladder with water and then with a potassium chloride solution. If the bladder has a disruptive GAG layer, the patient will feel more urgency and pain with the potassium solution.

One advantage of this test is that it reproduces the pain; another is that it is predictive of the response to treatment with pentosan polysulfate sodium. Dr. Butrick also noted problems with the test. If the test is positive, it is painful for the patient. There can be false negatives and false positives (due to detrusor instability, UTI, or radiation cystitis).

It’s possible to avoid the potassium sensitivity test in many patients, said Dr. Butrick, by using the PUF questionnaire, which Dr. Sand described. For example, a patient with a score of 20 or more on the PUF questionnaire has a 94% likelihood of having IC.

Dr. Butrick echoed Dr. Sand’s comments about the potential overlap between IC and other causes of pelvic pain, such as endometriosis and vulvodynia. Studies have found that many patients with pelvic pain have a positive potassium sensitivity test. “In the management of chronic pain, we have to treat all pain generators,” he said.

“The take home message,” he said, “is that given the new concepts of visceral pain syndrome, the urologist sees the end of the spectrum—advanced IC—while the gynecologist is more likely to see the earlier part of the spectrum, which may include patients with recurrent UTIs that are culture negative, endometriosis, vulvodynia, urethral syndrome, pain with intercourse, and problems with urgency and frequency.” Therefore, gynecologists and other physicians should keep IC in mind when evaluating patients who complain of chronic pelvic pain. IC may be present alone or with one of these other conditions.

According to a symptom-based telephone questionnaire conducted by Sant, 1.8 million women have “classic IC,” 9 million are diagnosed with chronic pelvic pain (95% of whom have IC), all 2 million men with nonbacterial prostatitis have IC, and 4.5 million patients diagnosed with overactive bladder actually have IC. Altogether, 10.8 million patients have IC, which is many more than was previously thought.

In conclusion, Dr. Butrick stressed that “when therapy is initiated early in IC it is very easy to treat with a high response rate.” Unfortunately, many women are not diagnosed with IC for many years.

Dr. Sand returned to the podium to review treatment options for IC. “The goals of treatment,” said Dr. Sand, “are to correct the epithelial dysfunction (the defective GAG layer), inhibit neural hyperactivity, and control allergic triggers.”

Treatment begins with dietary modification, such as avoiding alcohol, caffeine, and other acidic beverages and foods that irritate the bladder. Bladder retraining with behavior modification to address urinary frequency is also possible, but it’s difficult, Dr. Sand noted. Other possibilities are physical therapy, herbal therapy, biofeedback, and acupuncture.

In terms of pharmacologic therapy, there are two approved agents to treat pelvic/bladder pain associated with IC: pentosan polysulfate sodium, the only FDA-approved oral medication, and dimethyl sulfoxide (DMSO), the only FDA-approved intravesical agent. Possible surgical treatments include hydrodistention, augmentation, neuromodulation, and urinary diversion.

Pharmacologic treatment of IC
Besides pentosan polysulfate sodium, other oral agents for IC include nociceptive blockers, antihistamines, anticholinergics, and pain medications. Among nociceptive blockers, Dr. Sand recommended the tricyclics, particularly amitriptyline and doxepin. SSRIs don’t work as well but they are an option, as is gabapentin.

The antihistamines that have been shown to work for IC are hydroxyzine pamoate and hydroxyzine hydrochloride. The H2-blocker cimetidine has had some success in patients who can’t tolerate the antihistamines. Dr. Sand referred to an open-label three-month study by Theoharides et al. using hydroxyzine therapy in 140 patients, with a 65% follow-up (Urology. 1997:49(5A suppl):108-110). There was a 40% reduction in O-Leary-Sant symptom scores and a 55% reduction in the symptom score in patients who had a history of allergies. “There was a better response in patients who had a history of allergy,” Dr. Sand remarked.

He next turned to a more detailed discussion of pentosan polysulfate, which is labeled for oral use at 100 mg t.i.d. “While it’s off label, many physicians use 200 mg b.i.d. to improve patient compliance,” said Dr. Sand. For patients with allergies or mast cells on biopsy, treatment sometimes includes hydroxyzine hydrochloride.

In a double-blind, randomized trial of pentosan polysulfate, after three months 38% of those taking the drug had a greater than 50% decrease in pain scores, compared to 17% of those taking placebo (Parsons CL, et al. J Urology. 1993;150:845-848). While this doesn’t seem like a tremendous response, Dr. Sand explained that “time is the key.”

It takes a while for this medication to work. In a dose-ranging study by Nickel and associates, at 12 weeks 44% of patients had a greater-than-50% response; at 32 weeks, 68% had such a response (AUA 2002. Abstract). This was true regardless of the dose (300 mg, 600 mg, or 900 mg daily).

To overcome the problem of having patients wait three to four months for pentosan polysulfate to begin relieving symptoms, Dr. Sand suggested multimodal therapy. For example, he begins therapy with DMSO and then starts pentosan polysulfate. The intravesical DMSO achieves a 60% to 70% immediate response; however, after six to seven months, many patients stop responding. “So, I do four to six weekly instillations of DMSO, and as that is wearing off at about six months, the pentosan polysulfate is kicking in,” he said.

For patients who don’t respond to pentosan polysulfate alone, Dr. Sand adds amitriptyline or another tricyclic. Hydroxyzine can also be added, once or twice a day, and some patients benefit from oxybutynin chloride.

Dr. Sand concluded by describing a randomized, controlled study of pentosan polysulfate (300 mg t.i.d.) in men with chronic pelvic pain by Nickel et al. (Urology. 2002;167(suppl):63. Abstract). After 16 weeks, men in the active treatment group had a significantly better response on the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) compared to placebo. They also had a greater reduction in pain and scored higher on a quality of life measurement.
A similar study in women has not yet been completed, but Dr. Sand expects similar results in women.

“Already, outside of this trial, many clinicians are using IC treatment for patients with chronic pelvic pain with remarkable responses,” said Dr. Sand. Health care providers should consider chronic pelvic pain of bladder origin, and specifically IC, when women present with symptoms of urgency, frequency, and pain. The PUF is a simple diagnostic tool that can identify IC patients at an early stage, and effective treatment is available.

All contents Copyright © 1999 - 2004 Medical Association Communications