Interstitial Cystitis (IC), also called Painful Bladder Syndrome (PBS), is a disease syndrome characterized by pain in the region of the bladder, along with urgency, and frequency in the context of sterile, uninfected urine. The diagnosis is made by symptoms and exam, without needing any other tests such as cystoscopy or hydrodistension.
Classic symptoms of IC include pelvic pain, especially with a full bladder, urgency, frequency, and pain with intercourse, but over time, the pain can become more constant. Certain foods, like spicy or acidic foods or alcohol, can worsen symptoms, as can the time around the menstrual flow. The pain typically begins at the suprapubic region (the mid – low abdomen just above the pubic bone) and can radiate towards the groin or the low back.
Initially, many patients feel like they have a bladder infection, although if the urine is cultured, no bacteria will grow. Typically these patients are prescribed antibiotics and a local anesthetic for the bladder (like pyridium or azo). As there is no infection the antibiotics will be useless, but some will get some relief from the pyridium, leading them to believe they actually had an infection because they feel better during the treatment. As time goes on, the symptoms will wax and wane, mimicking recurring bladder infections and confusing some physicians until they check the urine cultures and find no bacteria.
IC was first named as a disease in 1887 by Dr. AJC Skene who described inflammation of the bladder in the absence of infection. In 1915, Dr. Guy Hunner described the details of ulcers that are sometimes found in IC patients and now carry his name. Despite these early recognitions of the disease, for many years, even into the early 1980s, IC was considered a psychosomatic disease, caused by emotional disturbances. Thanks to a young doctor who had IC, Dr. Vicki Ratner, the Interstitial Cystitis Association was started in 1984 and began crusading for more research and funding for investigation into the causes and treatments of IC. After 30 years of research, we are still just beginning to learn about what causes the initial insult that results in the syndrome we call IC, as well as how to treat the disease and not just the symptoms.
IC affects nearly 1 in 5 women in the US, and although it can occur in men, over 95% of IC patients are women. The typical age of onset is in the 30s and 40s, but certainly can occur at younger or older ages. IC is frequently associated with other causes of pelvic pain, especially endometriosis and pelvic floor muscle spasm, also irritable bowel syndrome, fibromyalgia, and vulvar vestibulitis.
IC is diagnosed predominantly by symptoms of bladder pain, urgency, and frequency. Cystoscopy (looking in the bladder with a scope) is sometimes performed to look for Hunner’s ulcers, although these small ulcerated areas are only present in about 10% of patients with IC. Sometimes hydrodistension (inflating the bladder with saline under pressure) is used as a diagnostic adjunct as well as a therapeutic procedure. Glomerulations, or small areas of hemorrhage within the wall of the bladder that manifest themselves after the hydrodistension, are diagnostic for IC, and are seldom seen in patients without IC. Some patients get symptomatic relief after the hydrodistension that lasts for a variable amount of time, but there can be some immediate bladder pain and spasm for the first day or 2 after the procedure. Cysto with hydro is not as frequently performed now as it was even 10 years ago, and current recommendations are that cystoscopy is only necessary for patients with blood in the urine.
Dr. Lowell Parsons, one of the first urologists to dedicate his practice to IC research, found that potassium is a common substance that is very irritating to the bladder of women with IC, but not to normal bladders. He then developed the “potassium sensitivity test” (PST), which is an in-office diagnostic test for IC. The patient is catheterized to drain the bladder, then a solution containing a high concentration of potassium is instilled into the bladder for several minutes. If the patient feels pain, then the bladder is drained (again by catheterization) and a “rescue solution” of local anesthetic is instilled, and for patients with IC, they should have resolution of their pain. As you can imagine, most women with bladder pain aren’t jumping up and down to volunteer for more bladder pain, so there is hesitancy among some doctors and quite a few patients to perform the PST. Dr. Parsons then developed a questionnaire (PUFF) that correlates well with the PST, such that patients that score over a certain number on the questionnaire would have an 80% likelihood of having a positive PST. Currently, we use the PUFF questionnaire as well as local anesthetic instilled into the bladder to help diagnose women with IC. We think it’s better to prove the bladder is the source of pain by making it better rather than aggravating it!
What causes this odd disease that feels like a bladder infection that won’t go away? There are various theories on this subject, some better documented than others, but we’ll discuss the most accepted ones.
First, there’s the permeability theory. Think of your bladder as the kitchen garbage can that stores the garbage for a while until it can be taken out to the big outside trash can (the toilet). This trash can has a liner, made out of huge sugar molecules (GlycosAminoGlycans, or the GAG layer) that form a mucousy-slimy layer that protects the cells of the bladder lining (urothelium) from irritating substances, primarily potassium, in the urine. In patients with IC, there are “holes” in this mucous lining that allow contact between the urine and the urothelium, where the nerve endings live. This theory has been supported by research by Dr. Parsons and others who documented increased uptake of substances within urine by the urothelium, as well as lower levels of certain molecules within the GAG layer in women with IC. Unfortunately, there are no defects in that layer that are visible, and other research on this subject has been contradictory, so some researchers are still skeptical. Nevertheless, this is a widely accepted theory of IC.
Next, there is the mast cell/ inflammation theory. Mast cells are inflammatory cells that can be activated to “degranulate” and release granules containing histamine and other substances that effect a local inflammatory response. Histamine is what causes your skin to turn red after a bug bite, or even when blushing. It opens up the small blood vessels, causes itching and pain, and attracts white blood cells. These responses activate nerve fibers, especially the ones that transmit pain (c-fibers). So, to summarize, mast cells release histamine and other mediators that cause inflammation. Next, the inflammation can increase the levels of NGF (Nerve Growth Factor), which has several actions, the most obvious of which is to increase the density and conductivity of nerves in the bladder, which eventually (through a complex series of events in the spinal cord) decreases the voiding threshold, causing the bladder to empty at smaller volumes, resulting in urgency and frequency. NGF also increases the sensitivity of the sensory nerves that run from the bladder to the brain, causing pain. Wow, that sounds like IC – urgency, frequency, and pain; but what causes the mast cells to degranulate in the first place? There is relatively new and exciting research pertaining to this subject, and it mostly points to something known as “neurogenic inflammation”.
Normally, pain signals travel from receptors in the pelvis to the spinal cord and then synapse (connect) with other nerves that carry the signal up to the brain. Neurogenic inflammation happens when sensory nerves receive a painful stimulus for an extended period of time, and this can cause the nerve impulse to essentially hit a “backstop”, and travel backwards towards the sensory nerve ending that is not used to receiving signals, only sending them. The terminal of the sensory neuron then releases substances called neuropeptides that cause edema (swelling), vasodilation (relaxation of the small blood vessels that causes redness), and hyperalgesia, or a hyperactive response to a painful stimulus – essentially creating a self-perpetuating cycle of pain. Most likely it is the neurogenic inflammation that causes the degranulation of the mast cells causing more inflammation and pain, again fueling the vicious circle.
But what causes the initial painful stimulation that starts the cascade of neurogenic inflammation and self-perpetuating pain? There are various theories on this, but most likely any pain in the pelvis can start the ball rolling, whether it be from endometriosis, GI issues, pelvic floor spasm, or possibly even chronic UTIs. “Pelvic Crosstalk” is the idea that the nerves in the pelvis are organized in such a way that each nerve cell that lives in the spinal cord sends out multiple projections (axons) into different organs – ie the same nerve cell can innervate the rectum, bladder, vagina, etc. This allows for the complex reflexes that go on without our knowledge so that we don’t pee when we have a bowel movement or have sex, and lets certain muscles relax while others contract to facilitate either storage or emptying of urine and stool. It also means that the potential exists for pain starting in one organ (such as endometriosis of the pelvis or chronic muscle spasm of the pelvic floor muscles) to send impulses up that organ’s axon to the spinal cord, then rebound into a different axon of the same nerve cell traveling backwards down to another pelvic organ such as the bladder, causing neurogenic inflammation at that site.
This theory may sound complicated (and it is), but it explains a lot of previously unexplained facts. It makes sense of the high incidence of IC and IBS in patients with endometriosis, because the initial pain source could be the endometriosis, and then the neurogenic inflammation winds up in the bowel or bladder with subsequent pain there. It also explains the higher than normal incidence of sexual abuse in populations of women with IC – sexual abuse can cause spasm of the levator muscles which serves as the initial pain generator, causing the same pattern of inflammation in other organs.
The upregulation of pain signals by the nervous system causes “Neurogenic Pain”. The most commonly recognized type of neurogenic pain is that of phantom limb pain, where the patient feels pain in their arm or leg that was previously amputated, typically in a traumatic fashion. Essentially what this means is that instead of shutting down stimuli that don’t signal any danger (ie touching a hot stove, being bit by a snake, etc), the brain increases the perception of pain above what is normal for any given stimulus.
Now that we know what the possible causes of IC are, what can we do to make the pain go away? There is unfortunately not a “magic bullet” that cures IC, and not many viable surgical options. What we do have is a multifaceted approach that can at least keep the symptoms controlled for most patients. The goal of treatment is suppression of symptoms, rather than a “cure”. Based on this, with the idea that each patient is unique and has slightly different symptoms, I prefer to individualize treatment in order to address the issues of each patient, rather than use a shotgun approach. Let’s look at all the different approaches first, then dissect them one by one.
The initial intervention for most patients with IC is modifying their dietary intake. It is well known that certain substances in foods will irritate the bladder and worsen both pain and urgency/frequency. The biggest offenders are acid, caffeine, alcohol, and spice (i.e. hot peppers). Acid lives in most fruit juices especially citrus, tomato based sauces, vinegar (in most salad dressings), and other things. Caffeine is pretty self explanatory, and even decaf tea can be irritating, but herbal teas are usually fine. Capsaicin is the substance in hot peppers, Tobasco and Sriracha that makes them hot, and it is severely irritating to the bladder. A full listing of foods to avoid can be found at ica.org. Most experts recommend starting by cutting out all potentially irritating foods, then adding back things one by one to see how much it affects their symptoms. This approach will hopefully result in each patient understanding their own personal triggers, and should give them the ability to choose between eating clean and feeling good, vs giving in to a craving of a trigger with the understanding that they’ll have an increase in their symptoms. Most of my patients appreciate this understanding and gives them control over their disease rather than it controlling them.
Because IC and pelvic floor dysfunction frequently coexist, PT is usually quite helpful for calming down the symptoms of IC. The AUA recently upgraded appropriate manual physical therapy techniques that resolve abdominopelvic muscular trigger points and improve connective tissue restrictions as a standard of care with grade A evidence. (Hanno PM, Erickson D, Moldwin R, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol 2015;193:1545-53.) These recommendations are based on a randomized clinical trial by Fitzgerald and colleagues that tested ten 60-minute sessions over 12 weeks of myofascial physical therapy (MPT) compared to global therapeutic massage (GTM) in IC patients. At 3 months, significantly more patients in the MPT group reported moderate or marked improvement compared to GTM group (59% versus 26%). (FitzGerald MP, Payne CK, Lukacz ES, et al. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. J Urol 2012;187:2113-8.) It should also be noted that these therapies are not pelvic floor strengthening therapy, and that such exercises may actually worsen IC symptoms, so it is important that your physical therapist is skilled in treating patients with pelvic floor pain and spasm.
Over the Counter (OTC) Meds and Supplements:
Prelief is usually found next to Beano in the supermarket or drug store. It is a substance that neutralizes acid in urine, thereby lessening the irritation from acidic foods. Many people feel that it helps them significantly.
Aloe Vera capsules have also been found in some small studies to help IC symptoms. The effect seems to be related to the formulation and the purity, so remember the old adage, “you get what you pay for” and don’t try to get the bargain basement brand. There tends to be large variation in the quality of supplements as they’re not regulated well.
Elmiron is the trade name of the only FDA approved medication to treat interstitial cystitis. It is a substance that looks a little like heparin (a blood thinner that is used in the bladder to rebuild the lining – see the bladder instillations section) and is excreted into the urine where it can theoretically bind to the the GAG layer that lines the bladder. Since IC is thought to result from holes in this GAG layer, Elmiron can relieve the pain of IC by essentially filling the holes and preventing the potassium in the urine from irritating the cells of the bladder wall. That’s the good news. The bad news is that Elmiron takes from 3-6 months to work because most of it is excreted in the GI tract with very little making it to the bladder. Most studies show that 40-60% of women eventually get relief from it. The most common side effect is stomach irritation (nausea or diarrhea), which can be caused more from the capsule containing the drug than the drug itself. Some hair loss has been noted, and there is a theoretical risk of increased bruising from the blood thinning effect.
Elmiron can also be instilled directly into the bladder to speed relief and also avoid systemic side effects. The other bad news is that there are no generic versions available, it is quite expensive, and some drug plans don’t cover it well or at all. Thus, I think it is most cost effective to use Elmiron in bladder instillations where more of the drug is useful to correct the defects in the GAG layer, and much less drug needs to be purchased.
TCAs, as they are called, are typically a mainstay of treatment for any chronic pain syndrome, of which IC is one of the most well-defined. These drugs were originally created back in the 1950s and 60s as the first medications available to treat depression, but they are rarely used for this today. Amitryptaline has been studied quite extensively, and provides significant benefit to decrease neurogenic pain. The downside is that oftentimes the side effects of sleepiness and dopiness limit the ability to reach a therapeutic dose, and some patients cannot take even small amounts because of this. Starting with a very low dose and increasing it very slowly can improve tolerance and lessen the side effects.
These drugs block the histamine release from the mast cells, thus decreasing the local inflammation in the bladder wall. Many different formulations exist but the most common used for IC is hydroxyzine or Atarax. Some patients find them extremely helpful, others not so much.
These medications also slow down transmission of nerve impulses within the central nervous system. They are commonly used for any chronic pain syndromes, especially those with a neurogenic component. Most have similar side effects and tolerance issues as the TCAs.
These are especially useful in patients with a significant component of pelvic floor muscle spasm to their pelvic pain. Valium can be placed directly into the vagina in pill or suppository form, providing better spasm relief with less systemic effects. We can also use compounded creams in the vagina that will work on the bladder and the pelvic floor that contain various medications on this list, oftentimes with less of the side effects than when they’re taken orally.
As alluded to above, some medications are more effective when placed directly into the bladder, such as Elmiron. We can also use heparin, a cheap and commonly available blood thinner in the bladder to do the same function as Elmiron for those who don’t have a phenomenal drug plan. We combine either Elmiron or heparin with a local anesthetic to numb the bladder, and these can be done either in the office once or twice a week, or by the patient at home as often as every day. Most patients start with treatments 2-3 times a week, then taper down as their bladder pain lessens.
I believe that the first thing that needs to be done in women with IC is to identify what is the underlying (original if you will) pain generator. For most of the patients I see (with IC, get it…) that underlying source of pain is endometriosis. Approximately half of my patients with endo and IC have spontaneous relief of their bladder symptoms after excision surgery. The other half have to work at getting the IC under control, but it generally responds better after excision than before. It seems that those with worse bladder symptoms (pain, urgency, frequency), more pelvic floor spasm, and more of a neurogenic component to their pain (ie fibromyalgia, chronic migraines, IBS, etc) have a greater chance of the IC symptoms persisting after removing the endo.
Interstim (Sacral Neuromodulation) is a procedure where we implant electrodes near the S3 nerve root (the main sensory nerve from the bladder). These are stimulated for a week or 2 to see if it works, then if the test is successful as it is 80-90% of the time, we implant a little battery that looks like a pacemaker in the buttock. While Interstim is not approved for treatment of IC, it is approved for treating urgency and frequency, and those are the main symptoms that improve. I have seen about half of my IC patients have pain relief as well, but if you mostly have pain with a full bladder and your bladder feels full half as often as it did, most people think that’s a pretty good improvement. The lead with the electrodes is permanent and the battery needs to be changed every 3-5 years. Currently it is incompatable with MRIs, but they are working on a unit that is OK with MRIs and can be recharged so the battery won’t have to be changed either.
IC can be a debilitating condition when it is not recognized or treated appropriately. Unfortunately there are still many physicians, even urologists and gynecologists, who don’t understand IC, or maybe they do but they don’t want to treat it so they brush off the patient’s complaints. Despite this, I believe that overall awareness and recognition of IC is improving, and with appropriate interventions the symptoms can be well controlled. I like to tell my patients that when they understand the condition and the treatments, especially which foods are their own personal triggers and what to do for an acute flare, then they can control their bladder rather than their bladder controlling them. Knowledge is power, especially when it comes to IC, and our goal is to empower our patients so they feel less like victims and more in control of their health.