Minimally Invasive Therapies for Chronic Pelvic Pain Syndrome

Transcription

1 Curr Urol Rep (2010) 11: DOI /s x Minimally Invasive Therapies for Chronic Pelvic Pain Syndrome Salim A. Wehbe & Jennifer Y. Fariello & Kristene Whitmore Published online: 7 May 2010 # Springer Science+Business Media, LLC 2010 Abstract Chronic pelvic pain syndrome (CPPS) is a common problem among men and women worldwide. It is a symptoms-complex term for interstitial cystitis/painful bladder syndrome in women and chronic prostatitis/chronic pelvic pain syndrome in men. Patients often present with a combination of lower urinary tract symptoms with pelvic pain and sexual dysfunction. No gold standard exists for diagnosis or treatment of CPPS. The diagnosis is often challenging and is determined by elimination. Multiple treatment modalities exist, ranging from physical therapy to surgery. We discuss minimally invasive therapies for treatment of this complex of symptoms. Although data suggest reasonable efficacy of several medications, multimodal therapy remains the mainstay of treatment. We review the following minimally invasive therapeutic modalities: dietary modifications, physical therapy, mind-body therapies, medical therapy, intravesical therapies, trigger point injections, botulinum toxin injections to the pelvic floor, and neuromodulation. We report data supporting their use and efficacy and highlight the limitations of each. Keywords Chronic pelvic pain syndrome. Interstitial cystitis. Minimally invasive therapy. Chronic prostatitis Introduction Interstitial cystitis/painful bladder syndrome (IC/PBS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) S. A. Wehbe (*) : J. Y. Fariello : K. Whitmore Department of Obstetrics and Gynecology, Drexel University College of Medicine, Pelvic and Sexual Health Institute, 207 North Broad Street, 4th Floor, Philadelphia, PA 19107, USA swehbe@drexelmed.edu are pelvic pain conditions with typical complaints of similar symptoms including pain, lower urinary tract symptoms (LUTS), and sexual dysfunction. These two conditions, which compose the urologic chronic pelvic pain syndromes (UCPPS), have unknown etiologies and share similarities in symptoms and treatment modalities. Currently, no consistently effective treatments are available for either. It is believed that IC/PBS and CP/CPPS share a common pathophysiological pathway, and several theories are evolving [1]. The etiology of this syndrome is thought to be multifactorial and involves a cascade of events: damage to the urogenital epithelium followed by neurogenic inflammation [2]. The National Institutes of Health (NIH) recently formed the Urologic Pelvic Pain Collaborative Research Network to study UCPPS that are characterized by a constellation of symptoms including urgency, frequency, nocturia, and occasionally obstructive symptoms associated with pelvic pain in the absence of bacterial infection or other definable pathological characteristics [3, 4]. IC/PBS symptoms usually begin with transient flares and remissions before progressing to severe, continuous, and quality-of-life (QOL) altering symptoms. The Rand Interstitial Cystitis Epidemiology study recently reported a prevalence of 3% to 6% of the population [5], which suggests that IC/PBS is considerably more common than previously thought, particularly because previous studies used stringent diagnostic criteria [3, 6]. CP/CPPS, which is associated with white cells in the prostatic secretions (inflammatory; NIH category IIIA) or the absence thereof (noninflammatory; NIH category IIIB), affects approximately 10% to 16% of men [7, 8]. CP/CPPS typically presents with symptoms affecting urinary and sexual functioning. Historically, it was thought that the etiology of CP/CPPS stemmed from inflammation of the prostate; thus, treatments were anti-inflammatory and produced limited symptomatic relief [9]. Neurogenic inflammation involves

2 Curr Urol Rep (2010) 11: upregulation of the sensory nerves in the end organ to the spinal cord and central nervous system. This process results in pain wind-up so that pain is perceived as visceral allodynia and hyperalgesia in the bladder and adjacent pelvic organs, defining a visceral pain syndrome [10]. Because of the prevalence of UCPPS, the direct costs are greater than the mean yearly costs reported for many other chronic pain conditions. The substantial costs associated with UCPPS support ongoing efforts to educate physicians about these conditions and to identify effective treatments. Using Medicare rates to do the calculations of tests and procedures, the annual per person costs increased substantially to $7043 for IC/PBS and $6534 for CP/CPPS [11]. The clinically practical UPOINT phenotyping classification system for patients diagnosed with UCPPS was recently described as a six-point system that categorizes the phenotype of patients with UCPPS into six clinically identifiable domains including urinary, psychosocial, organ specific, infection, neurological/systemic, and tenderness (levator ani muscle). This system was proposed as a clinical tool to help health care providers direct therapy to specific symptoms [12 ]. Treatment for these conditions is often multimodal, with therapy commonly targeting all pain triggers simultaneously to be effective. In this review, we discuss all treatment modalities separately (Table 1). Dietary Modification Dietary restriction has been recommended as a first line of therapy in patients with IC/PBS. However, until now, evidence supporting the efficacy of dietary management has been lacking. Many modifications are recommended including a decrease in acidic foods that include coffee and other caffeinated beverages, alcoholic beverages, tomatoes, and spices. Occasionally, some patients do respond to urinary alkalinization provided by an antacid such as Prelief (AkPharma, Pleasantville, NJ). Other nutraceutical and oral antacids are available. Herati et al. [13] established the prevalence and characteristics of food sensitivities in patients with IC/PBS and CP/ CPPS. Validated questionnaires containing a list of 175 comestibles and pain questions were mailed to 325 patients with IC/PBS and 286 patients with CP/CPPS. The researchers found that whereas patients with IC/PBS were more likely to be food sensitive than patients with CP/CPPS, the symptoms of patients with both IC/PBS and CP/CPPS were aggravated by similar comestibles such as grapefruit juice, spicy foods, alcohol, and caffeinated coffee. Their findings also revealed that the symptoms of both groups of patients were improved by certain comestibles, namely water and Prelief [13]. Food restrictions have not been scientifically proven to help slow the progression of the disease or to improve the Table 1 Minimally invasive therapeutic modalities for the treatment of urologic chronic pelvic pain syndromes Behavioral therapy Dietary modifications Mind-body therapy Psychotherapy Acupuncture Meditation Relaxation techniques Medical therapy a Antibiotics Anti-inflammatory agents Glycosaminoglycans α-blockers Antihistamines Oral neuromodulators Phytotherapy Muscle relaxants Nonpharmacological therapy to pelvic floor Biofeedback Global therapy massage Myofascial massage Thiele massage Pharmacological therapy to pelvic floor Trigger-point injections with local anesthetics and anti-inflammatory agents Botulinum toxin A Bladder instillations Dimethyl sulfoxide Resiniferatoxin Alkalinized lidocaine Cocktails (heparin+lidocaine + glucocorticoids+gentamicin) Neuromodulation Sacral Posterior tibial Pudendal Perineal electromagnetic a Further elucidated in Table 2 course of the disease. Usually, food restriction should be weighed against the decrease in the QOL of the patients. After 2 weeks, patients are usually asked to start adding back into their diet one food item every 3 days to identify any specific alimentary sensitivity. Physical Therapy Whereas theories abound about the source of pain in patients with UCPPS, a common finding in the pelvic floor is hypertonic, hyperspastic myofascial tissue. Chronic pain and tension in the pelvic floor can stem

3 278 Curr Urol Rep (2010) 11: from a variety of causes: reflex and voluntary muscle contraction, muscle abnormalities from poor posture, chronic stress injuries, neurological abnormalities or sensitization, and convergence from other damaged tissues [14 ]. These abnormalities in the pelvic floor musculature may be a significant contributor to the pain of UCPPS. Adaptive shortening, weakness, and strain of the pelvic floor muscles along with dysfunction of the psoas muscles and hip adductors may contribute to pelvic floor, genital, and rectal pain [15]. The NIH Chronic Prostatitis Cohort Study, a seven-center study, examined and followed 488 men with CP/CPPS and 121 asymptomatic controls for 3 years. They found that 194 of the 488 (51%) men with CPPS and 8 of the 121 (7%) controls had extraprostatic muscle tenderness on physical examination [16]. Hetrick et al. [17] reported that when compared with healthy controls, men with CP/CPPS had a greater incidence of pelvic floor muscle instability on pelvic floor muscle electromyograms. The use of manual therapy of the pelvic floor in 10 patients with IC/PBS and 42 patients with frequency/ urgency was reported by Weiss [18] with significant results. Out of 10 patients with IC/PBS, seven reported moderate to marked improvement in their symptoms. Similar results were obtained by Oyama et al. [19], who performed transvaginal Thiele massage twice a week for 5 weeks on 21 symptomatic women with IC/PBS and high-tone pelvic floor dysfunction. They concluded from this pilot study that Thiele massage improved IC/PBS symptoms and decreased hypertonicity of the pelvic floor [19]. FitzGerald et al. [20] published the first prospective, randomized, multicenter clinical trial comparing myofascial physical therapy and global therapy massage for the treatment of UCPPS. They recruited 23 men and 24 women and randomized them to either global therapy massage (24 patients) or myofascial physical therapy (23 patients). Patients in the myofascial physical therapy arm demonstrated a response rate of 57% compared to 21% of those in the global therapy massage arm (P=0.03) as evidenced by the global assessment response rate [20]. Biofeedback is another aspect of pelvic floor physical therapy that can provide beneficial results for the UCPPS patient. Through biofeedback, the patient can learn to control the pelvic floor muscles by visualizing the activity of the muscle on the computer and use the visual feedback to achieve conscious control over contraction of the pelvic floor muscle, thus breaking the cycle of spasm. Ger et al. [21] studied 60 patients with intractable rectal pain, 70% of whom were diagnosed with levator spasm. Biofeedback was performed on 14 of the 60 patients for 30-minute to 60-minute sessions weekly for 6 weeks. In 6 of the 14 patients (43%), pain relief was rated as good or excellent at 15-month follow-up [21]. A prospective trial using biofeedback included 16 patients with levator ani syndrome using a rectal manometric balloon. The median pain score before biofeedback therapy was 8 (on a 0 to 10 linear analog scale) and significantly improved to a median score of 2 after therapy. All patients reported nontender musculature after treatment [22]. Physical therapy, including manual therapy and myofascial release, learning specific stretching exercises, and incorporating biofeedback, offers a safe and effective form of evaluation and treatment for the patient with UCPPS. Properly executed pelvic floor reeducation has the potential to yield great benefit with minimal risk. Mind-Body Therapies for UCPPS Aside from the traditional therapies used to treat UCPPS, mind-body therapies such as psychotherapy, acupuncture, meditation, and relaxation techniques are being used more frequently. Astin [23] calls such therapies mind-body as opposed to alternative because the interventions discussed are used primarily as complements, rather than alternatives, to conventional medicine. It is reported in the literature that mind-body therapy reduces pain and improves QOL in patients with other pain-related conditions such as rheumatoid arthritis, fibromyalgia, back pain, migraine and tension headaches, and dyspareunia [24, 25]. Men with CP/CPPS report an increased incidence of avoidance or absence of sexual relationships and psychological symptoms such as depression and suicidal ideations [26]. In an NIH meeting on pelvic pain, experts discussed the biopsychosocial aspects of UCPPS. A survey of 253 men with CP/CPPS found worsened urinary symptoms in those who reported greater pain. Even stronger positive predictors of pain were increased self reports of depression, helplessness, and catastrophizing [14 ]. Through cognitive behavioral therapy, patients can develop better coping strategies and alter their pain beliefs for their chronic pain. Studies have shown that these changes can predict positive treatment outcomes by reducing helplessness, increasing perceived control, and decreasing catastrophizing [27, 28]. A review of the literature demonstrated that wellcontrolled studies examining the effects of sex therapy on CPPS are lacking. However, it was found that the techniques used in sex therapy, which include cognitive behavioral therapy, correlated positively with decreased CP/ CPPS symptoms and other sexual pain disorders [29, 30]. A literature review provided four studies on the use of acupuncture for treatment of CP/CPPS. Chen et al. [31] conducted a pilot study of 12 men diagnosed with refractory CP/CPPS who underwent a minimum of twice weekly acupuncture treatments for 6 weeks, during which time they received three sets of acupuncture points for a

4 Curr Urol Rep (2010) 11: total of 30 points. At the end of 6 weeks, 92% of patients had more than a 50% decrease from the baseline NIH Chronic Prostatitis Symptom Index (NIH-CPSI) total score, and 83% of patients had more than 75% subjective global improvement. The response rate was unchanged during 33 weeks of follow-up [31]. Honjo et al. [32] studied 10 men diagnosed with CP/CPPS. Each of the patients received weekly acupuncture treatments for 5 weeks. When the treatments ended, the average pain and QOL scores on the NIH-CPSI decreased significantly (P<0.05 and P< 0.01, respectively) [32]. The first NIH-funded randomized, blinded, comparative study of acupuncture versus sham acupuncture for CP/ CPPS was published in Ninety patients were divided between acupuncture at traditional points and sham acupuncture. The patients were treated for 30 minutes twice weekly for 10 weeks, then followed for an additional 24 weeks. Using NIH-CPSI as their validated symptom tool, the researchers found that acupuncture was twice as effective as sham acupuncture, that more acupuncture patients had a complete resolution of symptoms, and that those patients who received acupuncture had better longterm response rates at 20 weeks after completing treatment [33]. In a three-arm study from 2009, Lee and Lee [34] compared advice and exercise alone; advice, exercise, and sham acupuncture; and advice, exercise and acupuncture needles that were electrically stimulated. Each group had 13 men. The NIH-CPSI scores of the men who received acupuncture showed a significant reduction in pain, but no change in urinary symptoms or QOL. The pretreatment and posttreatment scores remained the same [34]. In some patients with refractory UCPPS, it may be helpful for providers to integrate mind-body therapies into conventional treatment plans. Although few randomized controlled trials have been done in this area, anecdotal evidence shows promising results in the amelioration of chronic pain through the use of these therapies. Medical Therapy Treatments for UCPPS include medical therapy that is usually multimodal and involves a systematic approach targeting all pain generators simultaneously. A patient diagnosed with CP/CPPS should be treated initially with a prolonged course of an antibiotic such as a quinolone in combination with an anti-inflammatory agent [35 ]. This standard therapeutic approach works for some patients. If first-line therapy fails, several other medications can be used as adjunct therapy. Adjunct therapy helps maximize the effect of the initial therapy and aims at improving the patient s QOL. Such therapies include glycosaminoglycans, α-blockers, antihistamines, neuropathic pain modulators, phytotherapy, and muscle relaxants (Table 2). Antibiotics The response of patients with CP/CPPS to antibiotic therapy depends on the duration of symptoms at the time of presentation. Patients with symptoms of short duration (median 4 weeks) not previously treated with antibiotics demonstrate response rates of up to 75% [36]. In patients with long-term CP/CPPS symptoms (median 6.5 years), antimicrobials appear to have no significant benefit [37]. Patients with a recent onset of symptoms are treated with a 4-week to 6-week course of a fluoroquinolone or trimethoprim/sulfamethoxazole (co-trimoxazole). Anti-inflammatory Agents Anti-inflammatory therapy apparently has minimal effect on UCPPS. However, some immunomodulators should be considered for patients with documented bladder inflam- Table 2 Oral therapy for urologic chronic pelvic pain syndromes Antibiotics Quinolones Cotrimoxazole Anti-inflammatory agents Rofecoxib Immunomodulators Prednisone Cyclosporine Glycosaminoglycans Pentosan polysulfate sodium Antihistamines Hydroxyzine Montelukast α-blockers Tamsulosin Terazosin Alfuzosin Phytotherapy Quercetin Cernilton Neuropathic Pain Modulators Amitriptyline Nortriptyline Gabapentin Pregabalin Muscle Relaxants Cyclobenzaprine Tizanidine Clonazepam

5 280 Curr Urol Rep (2010) 11: mation [38]. One open-label study of 14 IC/PBS patients with Hunner s ulcers using prednisone, 25 mg, daily for 2 months reduced the O Leary-Sant Interstitial Cystitis Symptom and Problem Indices (ICSI/ICPI) by 22% (P< 0.02) and pain by 69% (P<0.001) [39]. Additionally, a randomized study of 64 patients with IC/PBS treated with cyclosporine produced a 75% response rate [40]. Nickel et al. [41] randomized 161 patients with CP/CPPS to 6 weeks of the cyclooxygenase-2 selective rofecoxib; a dosage of 50 mg once daily provided a modest benefit compared with placebo. Glycosaminoglycans Pentosan polysulfate (PPS) is a polysaccharide originally synthesized as a low molecular weight heparin substitute. It is thought to replenish the glycosaminoglycan layer and is the only oral drug approved for interstitial cystitis. In a study by Nickel et al. [42], 100 men with CP/CPPS were randomized to oral PPS, 300 mg, three times daily or placebo for 16 weeks. PPS had a favorable effect but failed to show a statistically significant improvement in the total NIH-CPSI scores ( 5.9 with PPS vs 3.2 with placebo), clinical global improvement assessment (37% vs 18%, respectively), and improvement in QOL compared with those in the placebo group ( 2.0 vs 1.0, respectively) [42]. α-blockers Patients with UCPPS, LUTS, and obstructive symptoms may benefit from less selective α-blockers such as alfuzosin. These medications are not approved by the U.S. Food and Drug Administration (FDA) for use in patients with UCPPS but can be considered first-line or part of multimodal therapy in patients who are naïve to α-blocker therapy. Men with more severe symptoms at baseline are significantly more likely to show improved urinary symptoms and pain reduction. A long course of 12 weeks to 14 weeks of α-blockers provides modest benefits when prescribed to α-blocker naïve patients with CP/CPPS with shorter duration of disease [43]. Antihistamines Due to the increased incidence of allergies and high number of bladder mast cells in patients with UCPPS, the histamine-1 receptor antagonist hydroxyzine has been used because it also exhibits anticholinergic, sedative, anxiolytic, and bladder mast cell inhibitory properties. Hydroxyzine, 75 mg, four times a day titrated over 1 month to 4 months reduced symptoms by 55% in patients with IC/PBS [44]. Montelukast is a leukotriene antagonist that binds to the cysteinyl leukotriene receptor type 1. It is commonly used by patients with asthma because it reduces inflammation in the lungs and has been described for use in UCPPS [45]. At doses of 10 mg daily, it has few side effects and anecdotally has been effective in some men with CP/CPPS. Medication to Treat Neuropathic Pain Evidence is mounting that the pain of UCPPS may be neuropathic and associated with central nervous system sensitization. This pattern is similar to those of other complex regional chronic pain syndromes. Several classes of medications have been useful in treating neuropathic pain, and they may be used alone or in combination. Tricyclic antidepressants such as nortriptyline and amitriptyline have shown to be effective in treating neuropathic pain. Their effects are produced by serotonin and noradrenaline reuptake inhibition. They may also block sodium channels, known to be upregulated in some neuropathic pain syndromes. The anticonvulsants gabapentin and pregabalin act at voltage-gated calcium channels, reducing neurotransmitter release. Pregabalin has a higher affinity for the channel than does gabapentin and is considered by some as the drug of choice due to its lower side effect profile [14 ]. Phytotherapy Phytotherapy is not approved for the treatment of UCPPS. Quercetin, commonly found in red wine, green tea, and onions, is a polyphenol bioflavonoid with reported antioxidant, antihistamine, and anti-inflammatory properties. In a double-blind, placebo-controlled trial using quercetin, 500 mg, twice daily for 1 month, 82% of 17 men experienced a 25% reduction in NIH-CPSI scores. However, quercetin needs to be used with caution with fluoroquinolones because it decreases their efficacy [46]. Cernilton (now PollenAid; Graminex, Saginaw, MI) is an extract of bee pollen and is presumed to have anti-inflammatory and antiandrogenic activity. Open-label studies have reported some symptomatic improvement in patients with CP/CPPS [47]. Muscle Relaxants Secondary to the presence of increased pelvic floor muscle spasticity associated with UCPPS, muscle relaxants appear to have a beneficial effect. Cyclobenzaprine is a medication closely related to the tricyclic antidepressants. It is used with starting doses of 10 mg daily, which can be prescribed up to three times daily. Tizanidine is a centrally acting α 2 - agonist shown to be superior to placebo in treating spasticity for several conditions. In addition, clonazepam has been useful in treating neuropathic pain [14 ].

6 Curr Urol Rep (2010) 11: Bladder Instillations Intravesical agents are instilled when the etiology of UCPPS is believed to be from the bladder. A variety of intravesical agents are used, often as an adjunct to oral treatment, especially during symptoms flares. Dimethyl Sulfoxide Dimethyl sulfoxide (DMSO) is the only FDA-approved intravesical agent for the treatment of IC/PBS. DMSO has multiple mechanisms of actions including antiinflammatory, analgesic, collagen dissolution, muscle relaxant, and histamine-release inhibitor from mast cells [48]. In a study of 28 patients with IC/PBS, DMSO was given weekly for 6 weeks. Symptoms reduction was reported by 13 of the 28 patients at the end of the 6 weeks [49]. Although DMSO has been shown to provide moderate symptomatic relief, its unpleasant garlic odor makes it an undesirable treatment option for many patients [50]. Resiniferatoxin Resiniferatoxin (RTX) is a vanilloid receptor agonist that desensitizes the C fibers that transmit pain. Because it desensitizes the afferent bladder innervations, it was thought that it would decrease the pain that leads to urinary urgency and frequency. A prospective, double-blind, placebo-controlled study was done on 163 patients who each received a single instillation of RTX. The study failed to show that RTX was effective in improving overall pain, urgency, frequency, and nocturia; in fact, it was associated with dose-dependent instillation pain, bladder pain, and pain during urination [51]. Pentosan Polysulfate Sodium When PPS is taken orally, only 1% to 3% of the active drug reaches the bladder. An 18-week, double-blind, placebocontrolled clinical trial randomized 20 patients to the treatment group, which received both oral and intravesical PPS; another 20 patients were randomized to the placebo group, which received oral PPS and intravesical sterile water. The researchers reported that the treatment group had a twofold reduction of the severity of symptoms compared to the placebo group (P=0.04). The treatment group also showed improvement in all health-related QOL domains compared with pretreatment [52]. Alkalinized Lidocaine Local anesthetics penetrate tissue when the anesthetic is buffered by the surrounding tissue. Because the ph of urine is usually acidic (5 to 6), local anesthetics are not easily absorbed. In 2009, Nickel at al. [53] assessed the immediate and sustained relief of IC/PBS symptoms after a consecutive 5-day course of treatment with intravesical alkalinized lidocaine and characterized the pharmacokinetics of single and multiple doses of intravesical therapy. Patients (n=102) were randomized to receive a daily intravesical instillation of alkalinized lidocaine, 200 mg (with 8.4% sodium bicarbonate solution), or placebo for 5 consecutive days. Patients were followed at intervals of up to 29 days after the first instillation. Efficacy was assessed by changes in the global response assessment; Likert scales for bladder pain, urgency, and frequency; and ICSI/ICPI. The study showed that patients treated with lidocaine rated their overall bladder symptoms as moderately or markedly improved on the global response assessment scale 3 days after completing the 5-day course of treatment (30% and 9.6% for patients treated with PSD597 and placebo, respectively; P=0.012). The peak serum lidocaine concentration during the study was less than 2 μg/ml and well below the toxic level (>5 μg/ml) [53]. Cocktails Various intravesical cocktails use combinations of heparin, lidocaine, sodium bicarbonate, gentamicin, and glucocorticoids for the treatment of patients with IC/PBS [54]. Pelvic Floor and Trigger Point Injections The pelvic floor diaphragm muscles are commonly affected by the surrounding visceral structures. Embryological development of the urogenital system has shared innervations and muscular support of the bladder and pelvis, resulting in shared symptoms. UCPPS flares are often associated with pelvic floor muscle dysfunction [55]. Perception of pain, no matter what its cause, can lead to both reflex and voluntary muscle contraction, which may result in more pain and dysfunction. Treatment of CP/CPPS with physical therapy and trigger point release is still empirical. However, if physical therapy fails to be effective in relieving muscle pain and tenderness, other treatment modalities involving trigger point injections or botulinum toxin injections to pelvic floor muscles might be beneficial for patients with UCPPS. Kang at al. [56] used a mixture of triamcinolone acetonide, 40 mg, and 1 ml of 2% lidocaine injected into the most tender point transanally in 104 patients (mean age, 51 years) with levator syndrome. Patients responses at 6 months were pain-free in 30.1%, good in 46.5%, fair in 18.2%, and no response in 5.2% [56]. Langford et al. [57] studied the role of trigger point injections in 18 women with chronic pelvic pain and levator

7 282 Curr Urol Rep (2010) 11: ani muscle spasm of at least 6 months duration. A mixture of 0.25% bupivacaine, 10 ml; 2% 10 ml of lidocaine; and 1 ml of triamcinolone, 40 mg, was used for injection of 5 ml per trigger point. Three months after trigger point injections, 13 of 18 women improved, resulting in a comprehensive success rate of 72%; 6 of 18 women (33%) were completely pain free [57]. Based on the premise that paralysis of a spastic levator muscle will relieve pain, an increasing number of investigators are studying the effectiveness of transvaginal trigger-point injection of botulinum toxin A (BTX) for relief of levator ani muscle spasm [58, 59]. In a trial by Abbot et al. [58], BTX injections were more effective than placebo in reducing pain and pelvic floor pressure in 30 women with chronic pelvic pain and pelvic floor muscle spasm. Participants had 80 units of BTX injected into the pelvic floor muscles. The change from baseline in the treatment group was significant for dyspareunia (P<0.001), pelvic pain (P=0.009), and reduction in pelvic floor pressure on perineometry (P<0.001) [58]. Preliminary data show that a BTX injection into the prostate might help relieve symptoms, but large randomized trials are needed to determine the efficacy [60]. Patients with severe hypertonus and voiding dysfunction who fail to respond to pharmacological and behavioral therapies are candidates for pelvic floor injection therapy. However, no strong scientific evidence exists for treating patients with CP/CPPS with trigger point injections. Neuromodulation As previously mentioned, patients with UCPPS appear to have an abnormal hypersensitivity component that results from neurogenic inflammation and central sensitization involving C fibers. Visceral pain syndromes involve perpetual neurogenic inflammation, primary afferent overactivity, and central sensitization. Neuromodulation is believed to affect the afferent and efferent nerve fibers passing through pelvic nerves, resulting in a modification of the function of the bladder, urethra, pelvic floor muscles, and rectum. Neuromodulation reportedly balances the neurological stimuli between the viscera and somatic muscles of the pelvis and likely downregulates the C fibers, which are a crucial component of the allodynia found in these patients [61, 62]. This modulation would result in a decrease of the painful stimuli. Sacral Neuromodulation Sacral neuromodulation (SNM) is an FDA-approved modality for the treatment of refractory overactive bladder. SNM is a potential therapy for UCPPS associated with pelvic floor dysfunction. Small studies have demonstrated this fact through the stimulation of afferent pathways of sacral roots and of motor fibers innervating pelvic floor muscles [63]. SNM lessened intractable pelvic pain in these patients [64, 65]. It is thought that by reestablishing pelvic floor muscle awareness, pelvic floor hypertonus can be decreased, which not only reduces symptoms of pelvic pain but also helps relieve symptoms such as daytime frequency and nocturia [63]. SNM is a promising new avenue for the treatment of refractory UCPPS [66]. Comiter [67] prospectively examined the efficacy of SNM on 17 patients with refractory IC/PBS. The patients were evaluated at a mean of 14 months. Mean daytime frequency and nocturia improved, mean voided volume increased, and the average pain decreased from 5.8 to 1.6 points on a 0-point to 10- point pain scale. Of these patients, 94% reported sustained improvement at the last postoperative visit [67]. Peters et al. [68] examined the effect of SNM on pain secondary to IC/ PBS. Inclusion criteria included symptoms of urgency, frequency, and pelvic pain and failing six previous IC/PBS treatments. Overall, participants reported a 36% decrease in the use of narcotics (morphine dose equivalents) from 81.6 mg/day to 52 mg/day. With continuous stimulation, 95% of participants reported a moderate to marked improvement in their pain. At a mean of greater than 15 months postimplantation, 25% of the participants remained narcotic-free [68]. In a multicenter prospective study done by Whitmore et al. [69], a total of 33 patients were enrolled; SNM appeared to be effective in reducing symptom severity and increasing voided volumes in patients previously unresponsive to standard therapy. A large study by Everaert et al. [64] showed that SNM relieved pain in both men and women, leading researchers to hypothesize that it may also be an optional treatment for men with pelvic pain associated with chronic prostatitis. Hellstrom et al. [70] reported a case series of three men with intractable pelvic pain who did not respond to conventional medical therapy. SNM successfully relieved pain and decreased voiding dysfunction in patients with CP/CPPS [70]. A multicenter clinical trial by Siegel et al. [65] recruited patients with chronic intractable pelvic or urogenital pain (n=10), all of whom failed conventional treatment. SNM decreased the amount of time the patient reported being in pain and the severity of pain from 9.7 to 4.4 on a 0-point to 10-point pain scale. Patients also reported improved QOL at their 19-month follow-up visit [65]. Peripheral Neuromodulation Promising treatment modalities regarding peripheral pelvic neuromodulation include posterior tibial nerve and pudendal nerve modulation (PNM), both of which are derived

8 Curr Urol Rep (2010) 11: from several sacral nerve roots. A theoretical advantage of stimulation of the peripheral nerves is that more segments of the sacral cord can thus be exposed to afferent stimulation. The posterior tibial nerve has been reported to improve symptoms of voiding dysfunction and of chronic pelvic pain. It has a modest efficacy compared with SNM; the difference may be related to the intermittent rather than chronic stimulation [71]. Posterior tibial stimulation A study of 51 female patients with a mean age of 55 years who presented with LUTS and IC/PBS received a lowvoltage electric stimulation of 30 minutes for 10 weeks. QOL questionnaires and voiding diaries after treatment showed significant improvement in frequency/urgency, impact on QOL, and hypogastric pain. Afferent nerve stimulation offers an alternative treatment for managing lower urinary tract irritative symptoms [72]. Pudendal nerve neuromodulation Pudendal nerve neuromodulation is a promising new minimally invasive treatment for refractory UCPPS. A neurostimulator implanted adjacent to the pudendal nerve in a small series of patients yielded significant improvement in patients with overactive bladder, including some of whom had prior SNM [73]. Peters et al. [74] reported a possible superior effect of PNM in a series of patients simultaneously implanted with both a sacral lead and a pudendal lead. The same author reported on chronic PNM as a logical alternative, particularly in those who fail SNM, for the treatment of IC/PBS. Patients reviewed retrospectively who had a tined lead placed at the pudendal nerve via the ischial-rectal approach showed a pudendal response ( 50% improvement) in 71.4%. Almost all who had previously failed SNM (93.2%) responded to PNM. Significant improvements in frequency, voided volume, incontinence, and urgency occurred. ICSI/ICPI improved over 12 months [75]. Carmel et al. [76] reported a technique involving a two-step procedure that included electrode implantation for the treatment of chronic pelvic/perineal pain. Three women who underwent this procedure as a last resort had a significant improvement in symptoms after 2 years of follow-up [76]. Electromagnetic therapy A rapidly changing electromagnetic field noninvasively applied to the perineum may result in neural excitation and pelvic floor muscle stimulation to a degree that breaks the cycle of tonic muscular spasm and neural hypersensitivity and inflammation, thereby regulating pelvic floor muscular activity [77]. In a study by Rowe et al. [77], 21 patients with CP/CPPS were prospectively randomized to receive active electromagnetic or placebo therapy. Active electromagnetic therapy consisted of 15 minutes of pelvic floor stimulation at a frequency of 10 Hz followed by 15 minutes at 50 Hz twice weekly for 4 weeks. The mean symptom scores decreased significantly in the actively treated group at 3 months and 1 year (P<0.05); the greatest improvement was in pain-related symptoms [77]. In 2006, Paick et al. [78] showed that extracorporeal magnetic innervation combined with α-blocker therapy may be more effective than α-blocker monotherapy for patients with CP/CPPS. Conclusions Although the studies are small and limited, neuromodulation appears to be efficacious in treating refractory UCPPS. Theoretically, SNM could decrease the use of concomitant therapies for patients and could potentially decrease the cost and increase the ease of medication management. Further research is needed to gain a better understanding of the mechanisms of action of neuromodulation and to demonstrate the full effect of this therapeutic modality in treating patients with UCPPS. Acknowledgments The authors wish to thank Pamela Fried of Drexel University College of Medicine s Academic Publishing Services for editorial assistance. Disclosure No potential conflicts of interest relevant to this article were reported. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Eisenberg ER, Moldwin RM: Etiology: where does prostatitis stop and interstitial cystitis begin? World J Urol 2003, 21: Heim LJ: Evaluation and differential diagnosis of dyspareunia. Am Fam Physician 2001, 63: Metts JF: Interstitial cystitis: urgency and frequency syndrome. Am Fam Physician 2001, 64: Nickel JC: Interstitial cystitis an elusive clinical target? J Urol 2003,170: Berry SH, Stoto MA, Elliott M, et al.: Prevalence of interstitial cystitis/painful bladder syndrome in the United States. The Rand Interstitial Cystitis Epidemiology (RICE) study. Poster presented at the Annual Meeting of the American Urological Association. Chicago, IL; April 25 30, Rosenberg MT, Page S, Hazzard MA: Prevalence of interstitial cystitis in a primary care setting. Urology 2007, 69(Suppl 4):48 52.

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