In a prior article for AUANews, Dr. Quentin Clemens described the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health–sponsored Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.¹ MAPP Network studies are completing this year, and after 14 years a logical question to ask is, how will this affect our evaluation and treatment of patients with urological chronic pelvic pain?

Clinical Evaluation of Patients With Urological Chronic Pelvic Pain Syndrome

Attention to overlapping conditions. MAPP was set up to compare urological chronic pelvic pain syndrome (UCCPS) patients with those having other chronic pain conditions including fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome.¹ The overlap in all of these syndromes has led to the term “chronic overlapping pain conditions” (COPC). These patients need to be evaluated for conditions outside of those that may be usually associated with urological disease and referred to the appropriate specialists.

Widespread pain. Patients who had pain in sites outside the pelvis, ie widespread pain,² had brain functional MRI finding signatures similar to patients with fibromyalgia, a systemic pain condition characterized by centralized pain, and different from pain-free controls.³ The implication is that these patients may benefit from interventions targeting the central nervous system. A body map similar to that used in MAPP Network Studies (Figure 1) is a valuable tool for evaluation.

Pelvic floor dysfunction. All MAPP Network study participants underwent a standardized pelvic examination. Trained examiners palpated 6 locations evaluating the pelvic musculature for tenderness. Of UCPPS participants, 81% had pelvic floor tenderness on exam compared to 9% of controls. Participants with greater tenderness had more severe disease burden, including worse pelvic pain and urinary symptoms, worse quality of life, and more widespread distribution of nonpelvic pain.⁴ Given these findings, one may need to consider that a patient presenting with UCCPS has pelvic floor dysfunction until proven otherwise. A potentially important finding from MAPP Network researchers is that the pelvic floor muscles can be stimulated not only by the brain areas directly innervating them, but also are activated in synergy with the gluteal muscles.⁵ Therefore, pelvic muscular abnormalities that involve the gluteal muscles, such as gait problems, could potentially also lead to abnormal pelvic floor activation. Consideration of ongoing structural pelvic abnormalities in these patients may be important.

Bladder symptoms in men. One of the long-held tenets of UCCPS was that women were much more likely to be diagnosed with interstitial cystitis/bladder pain syndrome than men. The findings from MAPP Network studies showed that 42% of men enrolled with a presumptive diagnosis of chronic prostatitis/chronic pelvic pain syndrome also met criteria for a diagnosis of interstitial cystitis.¹ Thus, men should be queried about pain related to the bladder. This has important implications for treatment.

Future Clinical Trials

The finding that urinary and pain symptoms do not always correlate with each other and therefore should not be combined into 1 composite score⁶ has profound implications for clinical trials. We have often relied on composite scores to determine response to therapies. Also, the phenotyping data from MAPP Network studies showing the difference between patients with widespread compared to localized pelvic pain also mean that we have likely been combining dissimilar patient types in trials, and who likely would respond differently to different therapies. There has yet to be a positive large-scale, double-blind, placebo-controlled trial in men or women with UCCPS, despite numerous attempts in past National Institutes of Health–funded studies. Future trials will need to address these issues in patient selection and outcome measures.

Targets for Future Therapy

A major rationale for initiating the MAPP Network was that several decades of trials of therapies for UCCPS had not identified a generally effective intervention. The decision was made to go back to further examine this group of patients in depth, involving researchers with expertise outside of urologists, to try to identify new therapeutic targets. Given the complexity of the condition and the heterogeneity of the patient phenotypes, no single clear option has emerged, but several areas may be targets for multidisciplinary treatment:

Psychological. The impact of psychological factors is well known in the pain field. In the MAPP Network study, pain catastrophizing and self-reported stress were associated with pain outcome.⁷ Thus, addressing these areas could reduce pain. Intervening on psychological symptoms can be difficult but there are efforts ongoing to do just this.⁸

TLR-4 receptor. The TLR-4 receptor is the binding site for lipopolysaccharide, a component of gram-negative bacteria, but also binds other compounds and then activates the innate immune system. In a MAPP Network study, patients whose peripheral blood mononuclear cells demonstrated a more robust inflammatory reaction to TLR-4 stimulation also demonstrated more widespread pain.⁹ Thus, the TLR-4 receptor could be a site for targeting therapy.

Pelvic floor dysfunction/neuromodulation. The data implicating the pelvic floor in UCCPS are very strong. How to treat pelvic floor dysfunction beyond pelvic floor physical therapy is unclear. However, the data from MAPP Network on the areas of the central nervous system that control the pelvic floor provided evidence for testing the idea of targeting these brain areas with transcranial magnetic stimulation. Repetitive transcranial magnetic stimulation at specific frequencies leads to an inhibitory influence of the supplemental motor area on pelvic floor tone.¹⁰ Trials in this area are ongoing.

Conclusions and Future Directions

The MAPP Network study is a great model of team science. Our understanding of the complex interplay of the factors that can affect urinary pain and voiding symptoms would not be possible without assistance from nonurological experts in those fields. One of the best examples is the contribution of neuroscientists who performed the functional MRI studies and showed differences in central nervous system connectivity in individuals with and without pain (Figure 2). The amount of data are vast and, with deposition into the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository, will provide a source to study for many researchers to come. They also show that we likely need to be teaching the next generation of urologists about disciplines that would not have been imagined 50 years ago.