Infection/Inflammation Association of Neuropathic Pain With Bladder, Bowel and Catastrophizing Symptoms in Women With Bladder Pain Syndrome Lori Cory,* Heidi S. Harvie, Gina Northington, Anna Malykhina, Kristene Whitmore† and Lily Arya‡ From the University of Pennsylvania School of Medicine (LC), Department of Gynecology, Chestnut Hill Hospital (HSH), Department of Obstetrics and Gynecology (GN, LA), and Department of Surgery (AM), University of Pennsylvania and the Pelvic and Sexual Health Institute (KW), Philadelphia, Pennsylvania Purpose: In this study we determined if there is an association of neuropathic pain with urinary, bowel and catastrophizing symptoms in women with bladder pain syndrome. Materials and Methods: Female patients with a diagnosis of bladder pain syndrome completed validated questionnaires to assess neuropathic pain, urinary and bowel symptoms, quality of life and pain catastrophizing. Women were dichotomized into neuropathic pain and nonneuropathic pain groups. Urinary and bowel symptoms, pain catastrophizing and quality of life scores were compared between the 2 groups using parametric and nonparametric tests. Results: Of 150 women with bladder pain syndrome 40 (27%) had features of neuropathic pain while 110 (73%) did not. Women with features of neuropathic pain had significantly worse urinary urgency (mean ⫾ SD 3.1 ⫾ 3.1 vs 2.1 ⫾ 1.7, p ⬍0.001), bladder pain (3.0 ⫾ 1.1 vs 2.0 ⫾ 1.3, p ⬍0.001), bowel pain (8.8 ⫾ 4.0 vs 5.3 ⫾ 3.6, p ⬍0.001), diarrhea (7.8 ⫾ 6.1 vs 4.1 ⫾ 4.3, p ⬍0.001), quality of life (12.2 ⫾ 5.5 vs 9.8 ⫾ 3.8, p ⬍0.001) and higher pain catastrophizing (32.2 ⫾ 12.4 vs 23.1 ⫾ 14.3, p ⬍0.001) scores than those without neuropathic pain. Conclusions: In women with bladder pain syndrome the presence of neuropathic pain is significantly associated with the severity of bladder and bowel pain, urinary urgency and diarrhea. Women with features of neuropathic pain also have worse pain catastrophizing and quality of life than those without features of neuropathic pain. Key Words: cystitis, interstitial; neuralgia; catastrophization; irritable bowel syndrome; questionnaires BLADDER pain syndrome, formerly known as painful bladder syndrome/interstitial cystitis, is defined as a clinical syndrome of chronic pain, pressure or discomfort that is perceived by the patient to originate from the bladder and is associated with other urinary symptoms such as frequency or urgency.1 Although BPS has a significant negative impact on patient well-being and quality of life,2,3 little is known about the pathogenesis of this disorder. Animal studies have implicated a neurogenic mechanism for BPS.4,5 Subjects with BPS report somatosensory symptoms such as burning pain and hypersensitivity to touch in the lower abdomen, urethra, lower back, rec- 0022-5347/12/1872-0503/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION Vol. 187, 503-507, February 2012 Printed in U.S.A. DOI:10.1016/j.juro.2011.10.036 AND RESEARCH, INC. Abbreviations and Acronyms BMI ⫽ body mass index BPS ⫽ bladder pain syndrome IBS ⫽ Birmingham Irritable Bowel Syndrome symptom questionnaire ICPI ⫽ O’Leary-Sant Interstitial Cystitis Problem Index ICSI ⫽ O’Leary-Sant Interstitial Cystitis Symptom Index VAS ⫽ visual analog scale Submitted for publication June 8, 2011. Study received institutional review board approval. Supported by a FOCUS Medical Student Fellowship in Women’s Health supported by Patricia Kind. * Correspondence: Department of Urogynecology, Hospital of the University of Pennsylvania, 1000 Courtyard, 3400 Spruce St., Philadelphia, Pennsylvania 19104 (telephone: 610-715-0305; FAX: 215-662-7929; e-mail: lori.cory@gmail.com). † Financial interest and/or other relationship with Ortho-McNeill, Coloplast and Allergan. ‡ Financial interest and/or other relationship with Pfizer. See Editorial on page 381. For other articles on a related topic see pages 715 and 725. www.jurology.com 503 504 NEUROPATHIC PAIN OF BLADDER PAIN SYNDROME tum and vagina.6,7 Neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.”8 Somatosensory neuropathic pain, perceived by the peripheral nervous system, is clinically characterized by the presence of a variety of sensory symptoms and pain qualities. Using cluster analysis, prior studies have demonstrated a characteristic sensory profile and a typical constellation of neuropathic symptoms such as radiating pain, pain attacks and hypersensitivity to touch (allodynia) in subjects reporting neuropathic pain.9,10 PainDETECT is a validated questionnaire to measure neuropathic symptoms, and has been used in various chronic pain disorders including shoulder impingement syndrome,11 fibromyalgia,12,13 diabetic neuropathy and postherpetic neuralgia.14 Visceral pain is perceived in organs such as the bladder or the bowel and is transmitted via silent, unmyelinated C fibers.15,16 Instruments such as the ICSI17 and the IBS18 have been validated to measure visceral pain such as bowel and bladder pain as well as other visceral symptoms such as urgency and diarrhea. Prior studies suggest that subjects with neuropathic pain have a greater emotional reaction to pain and worse quality of life than those with nociceptive pain.9,13 However, the relationship among neuropathic pain, bladder and bowel symptoms, coping and quality of life in women with BPS is not known. The aim of our study was to determine the association of neuropathic pain with urinary, bowel and catastrophizing symptoms in women with bladder pain syndrome. Our hypothesis was that in women with BPS the presence of neuropathic pain is associated with more severe urinary and bowel symptoms as well as worse coping and quality of life than in women without neuropathic pain. MATERIALS AND METHODS This was a prospective cross-sectional study of 150 consecutive women presenting with urinary symptoms in a urology practice (KW) between July and September 2010. Institutional review board approval was obtained from the University of Pennsylvania. Study Participants Patients 18 years old or older with a diagnosis of BPS as defined by the ESSIC (European Society for the Study of Interstitial Cystitis) criteria were eligible for the study.1 Diagnostic criteria for study inclusion were chronic (more than 6 months) pelvic pain, pressure or discomfort perceived to be related to the bladder, accompanied by at least 1 other urinary symptom (ie urgency or frequency). Women were asked specific questions on each of these symptoms and were enrolled in the study only if they met inclusion criteria. All women had documented negative urine culture at the time of diagnosis. Women who had undergone cystoscopy were included only if cystoscopy findings were negative for tumors, stones, polyps and foreign bodies. Exclusion criteria were failure to meet the ESSIC diagnostic criteria,1 known neurological disorders (multiple sclerosis, Parkinson disease, spina bifida, spinal cord injury/trauma), diabetes mellitus, history of pelvic floor malignancy treated with chemotherapy and/or radiation, and recent pregnancy. Measures After informed consent demographic data were collected on current medications for BPS, coexistent medical conditions and prior pelvic surgeries. All women completed the ICSI, ICPI, PainDETECT neuropathic pain questionnaire, IBS and Pain Catastrophizing Scale. PainDETECT is a validated 9-item instrument used as a screening tool for the detection of neuropathic pain.9 The instrument includes a VAS to measure the overall intensity of pain and a body map to mark the site of pain. The remaining 9 items measure neuropathic characteristics of pain and comprise the neuropathic pain score. Of these items 1 characterizes the course of pain (persistent pain with slight fluctuations, persistent pain with pain attacks, pain attacks without pain between them, pain attacks with pain between them), 1 assesses radiation and 7 evaluate the quality of pain (burning sensation, paresthesias, pain induced by light touch, pain with characteristics mimicking electric shocks, thermal hyperalgesia, numbness and pain induced by light pressure). Total scores range from ⫺1 to 38, and scores of 19 or greater indicate the presence of a neuropathic component (greater than 90% probability) while a score of less than 12 makes the probability of neuropathic pain unlikely. In a validation study comparing patients with neuropathic and nociceptive pain, PainDETECT was shown to have a sensitivity and specificity of 85% and 80%, respectively, for the diagnosis of neuropathic pain.9 The O’Leary-Sant questionnaire, comprised of the ICSI and the ICPI,17 was used to measure the severity of urinary symptoms and their impact on quality of life. Each index contains 4 items assessing lower urinary tract symptoms (urgency, frequency, nocturia and pain associated with the bladder). Index scores range from 0 to 20 and 0 to 16 for the ICSI and the ICPI, respectively.17 The IBS was used to characterize bowel symptoms.18 This questionnaire consists of 11 items assessing 3 internal dimensions (abdominal pain, diarrhea and constipation) and has been validated for the evaluation of irritable bowel syndrome symptoms.18 Scores for each dimension range from 0 to 15 for the pain and constipation dimensions and 0 to 25 for the diarrhea dimension. There is no cutoff score for the diagnosis of irritable bowel syndrome. A summary score is calculated as the sum of the 3 dimension scores with a range of 0 to 55. The Pain Catastrophizing Scale was used to measure the emotional reaction to pain.19 The instrument identifies subjects with a tendency to catastrophize in response to perceived pain. The scale consists of 13 questions on 3 components of rumination, magnification and helplessness. Individual questions are scored from 0 to 4 with total scores ranging from 0 to 52. Increased pain catastrophization is seen with higher scores. In validation studies the 505 NEUROPATHIC PAIN OF BLADDER PAIN SYNDROME instruments showed high internal consistency with coefficient alphas of 0.87, 0.60 and 0.79 for the rumination, magnification and helplessness components, respectively.19 Analysis Based on the PainDETECT score, women were divided into 2 groups of neuropathic pain (score 19 or greater) and nonneuropathic pain (score less than 19).9 Individual somatosensory symptoms (burning pain, prickling, allodynia, electric shocks, thermal sensitivity, numbness, pain with slight pressure) were defined as clinically significant if they were reported with a score greater than 3 (strong, very strong).9 Demographic data and the prevalence of neuropathic symptoms are presented as percentages, medians or means ⫾ SD. Categorical data were compared between women with and without neuropathic pain using the Pearson chi-square and Fisher’s exact tests as appropriate. Continuous variables were compared between the 2 groups using parametric t tests for normally distributed variables (such as age and BMI) and nonparametric t tests for independent samples (Mann-Whitney test) for variables that did not have a normal distribution (all symptoms scores). To determine if PainDETECT and ICSI measure similar or different pain constructs in women with BPS (construct validity), we assessed the relationship between neuropathic pain scores as measured by PainDETECT and urinary symptom scores as measured by the ICSI using Spearman correlation coefficients. Since we made multiple comparisons, p ⬍0.01 (rather than the usual 0.05) was considered significant. In a previous study on adults with neuropathic pain, the mean VAS score of average neuropathic pain intensity was 5.5 ⫾ 2.0.14 We fixed alpha at 0.05 and power at 90%. Based on these assumptions we estimated that we needed 40 women with neuropathic pain to detect a difference of 25% in the mean pain score of women with and those without neuropathic pain. Given that the prevalence of neuropathic pain has been previously reported as 25% to 30% in women with interstitial cystitis,6,7 we planned to identify 150 women with BPS. All reported p values were 2-sided and p ⬍0.01 was considered statistically significant. All statistical analysis was done using Stata® version 10.0. RESULTS Of the 172 women who met the inclusion criteria 150 agreed to participate and were enrolled in the study. Of those enrolled 133 (89%) had undergone cystoscopy at the time of diagnosis. Based on responses to the neuropathic pain questionnaire 40 women (27%) were included in the neuropathic pain group (score 19 or greater). There were no significant differences in age, parity, BMI or current treatment between the women with and those without neuropathic pain (table 1). The rate of fibromyalgia was significantly greater in women with than in those without neuropathic pain. Women with neuropathic pain were more likely to have undergone hysterectomy and other abdominal Table 1. Demographics Mean ⫾ SD age Median parity (range) Mean ⫾ SD kg/m2 BMI No. current treatment (%): Pentosan polysulfate sodium Tricyclic antidepressants Hydroxyzine Gabapentin Narcotics Benzodiazepenes Bladder instillation§ Sacral neuromodulation No. surgical history (%): Hysterectomy Cesarean section Appendectomy Ovarian cyst removal Anti-incontinence/prolapse procedure No. medical history (%): Endometriosis Irritable bowel syndrome Migraines Fibromyalgia Chronic fatigue syndrome Depression Anxiety Mean ⫾ SD Pain Catastrophizing Scale Median av pain on VAS (range) Neuropathic Pain Nonneuropathic Pain p Value 40.1 ⫾ 13.5 1 (0–4) 26.1 ⫾ 5.6 45.0 ⫾ 14.8 1 (0–7) 25.1 ⫾ 5.1 0.07* 0.26† 0.29* 12 5 3 5 18 17 1 2 50 13 7 9 33 49 11 2 (45.5) (11.8) (6.4) (8.2) (30.0) (44.6) (10.0) (1.8) 0.09 1.00‡ 0.73‡ 0.53‡ 0.09 0.82 0.18‡ 0.29‡ 10 (25.0) 9 (22.5) 7 (17.5) 2 (5.0) 2 (5.0) 15 (13.6) 14 (12.7) 12 (10.9) 2 (1.8) 1 (0.9) 0.10 0.14 0.28 0.29‡ 0.17‡ 4 (10.0) 10 (25.0) 7 (17.5) 17 (42.5) 4 (10.0) 4 (10.0) 2 (5.0) 32.2 ⫾ 12.4 16 (14.6) 22 (20.0) 20 (18.2) 15 (13.6) 5 (4.6) 9 (8.2) 10 (9.1) 23.1 ⫾ 14.3 0.59‡ 0.51 0.92 ⬍0.001 0.25‡ 0.75‡ 0.52‡ ⬍0.001† 6 (3–10) 6 (3–10) 0.85储 (30.0) (12.5) (7.5) (12.5) (45.0) (42.5) (2.5) (5.0) * Student’s t test. † Equality of medians test. ‡ Fisher’s exact test. § Containing gentamicin, heparin, sodium bicarbonate, bupivacaine and hydrocortisone sodium succinate. 储 Nonparametric t test for independent samples. or pelvic surgical procedures than those without neuropathic pain, but these differences did not reach significant levels. Subjects with neuropathic pain scored significantly higher on the Pain Catastrophizing Scale. There was no significant difference in the overall average VAS score between the 2 groups. In terms of clinically significant specific somatic sensory symptoms (score greater than 3, ie strong or very strong pain) the prevalence was burning (39%), tingling or pricking (19%), allodynia (14%), pain attacks (25%), thermal sensitivity (pain to heat or cold, 10%), numbness (9%) and pain with slight pressure (39%). Overall 103 women (69%) reported the presence of at least 1 clinically significant somatosensory symptom. We observed low correlations between the total pain score of the PainDETECT, and total ICSI (r ⫽ 0.31) and total ICPI (r ⫽ 0.28) scores The correlations of specific pain items of the PainDETECT (burning, tingling, allodynia, pain attacks, thermal sensitiv- 506 NEUROPATHIC PAIN OF BLADDER PAIN SYNDROME ity, numbness and pain with light pressure) and bladder pain (as measured by the ICSI) ranged from 0.30 to 0.36. The correlation of specific pain items on the PainDETECT with urinary urgency, frequency and nocturia (as measured by the ICSI) ranged from 0.18 to 0.28. Women with neuropathic pain had significantly worse total urinary symptom and quality of life scores than those without neuropathic pain (table 2). Women with neuropathic pain also reported significantly greater severity of individual urinary symptoms, including urgency and pain/burning in the bladder, than those without neuropathic pain. The severity of urinary frequency and nocturia was not significantly different between the groups. The total irritable bowel syndrome symptom score for women with neuropathic pain was significantly higher than for those women without neuropathic pain (table 3). Individual dimension scores for abdominal pain and diarrhea were significantly higher in women with vs without neuropathic pain. The severity of constipation was not significantly different between the groups. DISCUSSION Using a validated questionnaire to measure pain with neuropathic characteristics, we report a high prevalence of somatic sensory symptoms in women with BPS. Overall 27% of women met the criteria for neuropathic pain (score 19 or greater) and 69% of women reported the presence of at least 1 somatosensory symptom. We noted a high prevalence of pain attacks (25%) and a lower prevalence of allodynia (pain with light touch, 14%), symptoms that are considered characteristic of neuropathic pain syndromes. PainDETECT has been used to identify pain with neuropathic characteristics in several conditions including herpetic and diabetic neuropathy,14 fibromyalgia13 and low back pain.9 We observed low correlations between the total pain score of PainDETECT and total ICSI (r ⫽ 0.31) and ICPI (r ⫽ 0.28) scores. Correlations between specific pain Table 2. Comparison of urinary symptoms and quality of life Mean ⫾ SD total urinary symptom score (ICSI): Urgency (ICSI question 1) Frequency (ICSI question 2) Nocturia (ICSI question 3) Bladder pain/burning (ICSI question 4) Mean ⫾ SD total quality of life score (ICPI) Neuropathic Pain Nonneuropathic Pain p Value* 13.1 ⫾ 4.1 9.9 ⫾ 4.0 ⬍0.001 3.1 ⫾ 1.4 4.0 ⫾ 1.3 3.0 ⫾ 1.7 3.0 ⫾ 1.1 2.1 ⫾ 1.7 3.4 ⫾ 1.6 2.5 ⫾ 1.5 2.0 ⫾ 1.3 ⬍0.001 0.02 0.13 ⬍0.001 12.2 ⫾ 5.5 9.8 ⫾ 3.8 ⬍0.001 * Nonparametric t test for independent samples. Table 3. Comparison of bowel symptoms between women with and without neuropathic pain Mean ⫾ SD total bowel symptom score (IBS): Pain dimension Diarrhea dimension Constipation dimension Neuropathic Pain Nonneuropathic Pain p Value* 22.9 ⫾ 10.0 14.1 ⫾ 7.8 ⬍0.001 8.8 ⫾ 4.0 7.8 ⫾ 6.1 6.4 ⫾ 4.5 5.3 ⫾ 3.6 4.1 ⫾ 4.3 4.6 ⫾ 4.1 ⬍0.001 ⬍0.001 0.02 * Nonparametric t test for independent samples. items on PainDETECT and bladder pain were also low (range 0.30 to 0.36). These findings suggest that PainDETECT and the ICSI measure different constructs in women with BPS such that PainDETECT measures somatosensory symptoms while the ICSI measures visceral symptoms (eg bladder pain, urgency). The most important finding of our study is that the presence of neuropathic pain is significantly associated with the severity of urinary and bowel symptoms as well as pain catastrophizing in women with BPS. Specifically, higher neuropathic pain scores were significantly associated with worse bladder pain, urinary urgency (table 2), bowel pain and diarrhea (table 3). In BPS, urgency and bladder pain have been described as abnormal processing of sensory information related to the genitourinary tract,20,21 while frequency and nocturia result from a number of different causes including behavioral factors.22 The underlying mechanism explaining the clustering of bowel, bladder and pain catastrophizing symptoms in women with BPS and neuropathic pain is not clear. In other chronic pain conditions such as fibromyalgia and diabetic neuropathy, using cluster analysis, researchers have identified subgroups of patients with distinct clinical phenotypes.13,14 Such clinical phenotypes may have important implications for understanding the disease mechanism and treatment options. Further studies are required to determine whether such phenotypes exist in BPS as well. Our findings that women with neuropathic pain experience more severe bowel and bladder symptoms and worse pain catastrophizing are clinically significant, and suggest that women with BPS and neuropathic pain may benefit from medications that target neuropathic pain such as amitriptyline,23 as well as screening for poor coping and psychological counseling. We cannot comment on the cause-effect relationship between neuropathic pain, and visceral symptoms and pain catastrophizing because our study is cross-sectional in design. Strengths of our study include the enrollment of women with well-defined BPS using established diagnostic criteria,1 the use of validated question- NEUROPATHIC PAIN OF BLADDER PAIN SYNDROME naires to capture patient reported symptoms and the attainment of an adequate sample size. Limitations of our study should also be considered. Our study is cross-sectional in design and cannot determine the causal role of neuropathic pain. Misclassification of women with neuropathic pain is another potential limitation. We dichotomized women into 2 groups with and without neuropathic pain based on a cutoff score of 19 as described in the original validation study. However, subjects with scores ranging from 13 to 18 may have some components of neuropathic pain.9 Therefore, some women with neuropathic pain may have been included in the nonneuropathic pain group, resulting in bias toward the null hypothesis. Since we observed significant differences in urinary and bowel symptoms and 507 quality of life data between women with and those without neuropathic pain, such misclassification likely did not occur. Using patient reported instruments our study provides compelling clinical evidence of an association between neuropathic pain, and severity of urinary and bowel symptoms and pain catastrophizing in women with BPS. CONCLUSIONS In women with bladder pain syndrome the presence of neuropathic pain is significantly associated with the severity of bladder and bowel pain, urinary urgency and diarrhea. Women with neuropathic pain also have worse pain catastrophizing and quality of life than those without neuropathic pain. REFERENCES 1. van de Merwe JP, Nordling J, Bouchelouche P et al: Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008; 53: 60. 2. El Khoudary SR, Talbott EO, Bromberger JT et al: Severity of interstitial cystitis symptoms and quality of life in female patients. J Womens Health (Larchmt) 2009; 18: 1361. 3. Nickel JC, Tripp DA, Pontari M et al: Psychosocial phenotyping in women with interstitial cystitis/ painful bladder syndrome: a case control study. J Urol 2010; 183: 167. 4. 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