Objective
We sought to evaluate candidate mechanisms underlying the pelvic floor dysfunction in women with chronic pelvic pain (CPP) and/or painful bladder syndrome (PBS)/interstitial cystitis. Notably, prior studies have not consistently controlled for potential confounding by psychological or anatomical factors.
Study Design
As part of a larger study on pelvic floor pain dysfunction and bladder pain sensitivity, we compared a measure of mechanical pain sensitivity, pressure pain thresholds (PPTs), between women with pelvic pain and pain-free controls. We also assessed a novel pain measure using degree and duration of postexam pain aftersensation, and conducted structural and functional assessments of the pelvic floor to account for any potential confounding. Phenotypic specificity of pelvic floor measures was assessed with receiver operator characteristic curves adjusted for prevalence.
Results
A total of 23 women with CPP, 23 women with PBS, and 42 pain-free controls completed the study. Women with CPP or PBS exhibited enhanced pain sensitivity with lower PPTs (1.18 [interquartile range, 0.87–1.41] kg/cm 2 ) than pain-free participants (1.48 [1.11-1.76] kg/cm 2 ; P < .001) and prolonged pain aftersensation (3.5 [0-9] vs 0 [0-1] minutes; P < .001). Although genital hiatus ( P < .01) was wider in women with CPP there were no consistently observed group differences in pelvic floor anatomy, muscle tone, or strength. The combination of PPTs and aftersensation duration correlated with severity of pelvic floor tenderness (R 2 , 41-51; P < .01). Even after adjustment for prevalence, the combined metrics discriminated pain-free controls from women with CPP or PBS (area under the curve, 0.87).
Conclusion
Both experimental assessment of pelvic floor pain thresholds and measurement of sustained pain are independently associated with pelvic pain phenotypes. These findings suggest systematic clinical assessment of the time course of provoked pain symptoms, which occurs over seconds for mechanical pain thresholds vs minutes for aftersensation pain, would be helpful in identifying the fundamental mechanisms of pelvic floor pain. Longitudinal studies of therapies differentially targeting these discrete mechanisms are needed to confirm their clinical significance.
Chronic pelvic pain (CPP) is a highly prevalent (14-25%) condition, and pelvic floor myofascial dysfunction is increasingly recognized as a key contributor. Even among visceral CPP conditions such as painful bladder syndrome (PBS)/interstitial cystitis presumed bladder pain may actually arise from alterations in mechanical sensitivity of the pelvic floor musculature.
Although diagnosis of CPP/PBS is primarily dependent on self-report of symptoms that are confounded by psychological factors, recent guidelines suggest that palpation can identify patients with pelvic floor dysfunction. Work by our group and others suggests CPP patients exhibit enhanced pelvic floor pain sensitivity, using transvaginal pressure pain threshold (PPT) measurement. However, additional research is needed to verify whether palpation-induced pain is related to pelvic mechanical thresholds and not confounded by psychological, anatomical, and muscular factors. Indeed, gynecologists have been publicly challenged recently to prove the value of pelvic exam-based biomarkers following a Department of Veterans Affairs panel report that questions the utility of routine pelvic examination.
Since multiple nerve fiber types provide sensory innervation of the pelvic floor, identification of dysfunction within specific fiber types could identify mechanisms that can be used for diagnosis and evaluation with greater specificity. Prior reports of reduced pelvic floor pain thresholds may reflect reduced mechanical thresholds in type A fibers (mechanoreceptive nerves). However, differences in electrical and heat thresholds in male CPP suggested that CPP is associated with reduced thresholds in C fibers (multimodal pain nerves). Since A fibers primarily mediate “first pain” and C fibers mediate a delayed secondary pain, temporal characteristics of evoked pain may help resolve the distinct contribution of A vs C fibers.
Current guidelines for CPP/PBS recommend multidimensional management, which may include physical therapy in patients with pelvic palpation pain. Indeed, a randomized controlled trial combining external and pelvic floor manual physical therapy for PBS showed >2-fold reduction of global pain assessment compared with global therapeutic massage. Standardized examination of pelvic floor tenderness could improve appropriate identification of candidates for such physical therapy.
The present study objective was to determine whether specific variations in myofascial anatomy, function, or sensitivity differentiate CPP, PBS, and pain-free patients and how these relate to the simple binary construct of clinical tenderness. These findings also extend our prior work on quantitative sensory testing in undifferentiated CPP to a primarily visceral condition, PBS, and for the first time are extrapolated to testing in the general population with Monte Carlo simulations.
Materials and Methods
Study design
To test our primary hypothesis that pelvic floor PPTs would be lower (indicative of increased pain sensitivity) in CPP and PBS patients vs pain-free controls, we conducted a cross-sectional study from July 2010 through September 2013. Secondary analyses subsequently estimated the discriminatory value of pelvic floor sensitivity for CPP and PBS, adjusting for potential epidemiological, anatomical, physiological, and psychological factors.
Setting and participants
Cases included women with CPP or PBS recruited from Chicago area clinics, community advertisements, and mailed invitations to patients in our system’s electronic health record databases. CPP was defined as pain lasting ≥3 months in the area between the umbilicus and inguinal ligament. Symptoms could not solely be perceived on the skin (as in vulvodynia), only involve the hip or back, or only occur with menses (isolated dysmenorrhea). PBS patients met the CPP criteria and also reported urgency or frequency for at least 3 months’ duration ( Appendix ; Supplemental Material presents detailed criteria). Controls were healthy, pelvic pain-free, PBS cohort age-matched patients (±5 years) recruited from the same population as above.
Cases were limited to ages 18-55 years. Exclusion criteria included: pregnancy, active urogenital infection, prior urogenital malignancy, unexplained hematuria, active nephro/ureterolithiasis, vaginal prolapse exceeding second degree, refusal of vaginal examination, and unwillingness to avoid short-acting opioids prior to examination. All participants received a stipend of $50. The NorthShore University HealthSystem Institutional Review Board approved the study.
Study procedure
At the screening visit, 1 examiner (F.F.T.) conducted a complete abdominopelvic examination. We used the vaginal palpometer described below to calibrate exam palpation pressure to 0.4-0.6 kg/cm 2 , and asked participants to rate tenderness at multiple palpation sites using a numeric rating scale (0, no pain, to 10, worst imaginable pain). Vaginal tissue compliance, voluntary pelvic floor contractility, and pelvic floor gross muscle strength were quantified on exam using Likert scales (clinical exam scoring criteria is presented in the Supplemental Material). We diagnosed pelvic organ prolapse using standard POP-Q criteria (except isolated cervical elongation >2 cm was not treated as prolapse).
Participants completed medical history questionnaires covering prior surgery, medication use, other treatments, and menstrual history. They also completed the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression survey, and Patient-Reported Outcomes Measurement Information System computer adaptive tests for fatigue, anxiety, depression, pain behavior, pain interference, and sleep impairment. Pain patients also completed the McGill Pain Questionnaire–short form.
Experimental pain measurement was performed at 2 subsequent visits in a temperature-controlled research examination room. The sessions were planned for 1 month apart, although repeat sessions were adjusted due to personal circumstances in 4 participants (participant flow chart, Figure 1 ). We assessed pelvic floor sensitivity at the bilateral iliococcygeus, anteriorly under the bladder and posteriorly against the anorectal raphe using our previously validated vaginal pressure algometer in a randomized order (Supplemental Material, algometer, presents details).
Both post-PPT pain (numeric rating scale 0-10) and duration were recorded to evaluate the safety and comfort of PPT testing. Post hoc, we recognized these recorded safety data are a measure of sustained pain. Following prior work in neuropathic pain we conducted post hoc analysis of these results to characterize sustained pain (hereafter referred to as “aftersensation pain”).
Study size
Our initial sample size requirements were based on preliminary data suggesting a 0.5-kg/cm 2 difference between PBS patients and pain-free controls (α = 0.01, β = 0.2), and were estimated at 22 participants per group. It was assumed the CPP group had similar sample size requirements. We specify 3 primary contrasts for formal hypothesis testing: determining if group differences exist for pelvic floor PPTs, self-reported pain with clinical palpation, and duration of time for pain to return to baseline after clinical assessment between the CPP/PBS and the HC population. All other contrasts are considered exploratory.
Statistical analysis
Software (STATA 13.1; StataCorp LP, College Station, TX) was used for statistical analysis. We had complete case data for the first session of clinical palpation and PPT testing. Since the pain data were not normally distributed as confirmed by Shapiro-Wilk tests, group differences were evaluated with Dunn test with Šidák correction for multiple comparisons. Bonferroni adjustments were made for variables evaluated with χ 2 tests. We used Spearman correlations to identify potential confounders of the group and pressure pain sensitivity relationship, among pain-free participants, and verified this with stepwise linear regression. Coefficients from this regression model were used to standardize PPT estimates, ultimately including age and genital hiatus for subsequent modeling. To further evaluate the clinical significance of palpation pain, PPT, and aftersensations in the general population, we adjusted for prevalence using a biased-bootstrap Monte Carlo resampling method. Biased resampling was performed such that the simulated population contained 15% pain subjects, assuming combined prevalence of 11% CPP only and 4% with PBS. The model also incorporated a 15% random Poisson noise to account for measurement error. As an alternative verification for correct prevalence adjustment, we performed binomial regression with sample weighting. Receiver operating characteristics were tabulated to determine the area under the curve (AUC) for both Monte Carlo simulations and sample weighting results.
Results
Initially, 93 study participants were recruited, with 42 pain-free controls and 46 patients with either CPP or PBS completing at least 1 PPT testing session ( Figure 1 ). Women with CPP and PBS had comparable demographic factors, anatomy, and peripheral sensitivity ( Tables 1 and 2 ). However, women with PBS reported more pain when the bladder or adjacent regions were palpated ( P < .05) ( Table 2 ). Women with and without CPP/PBS in the study had similar age, weight, pregnancy history, and marital status ( Table 1 ). Women with CPP were more likely to be college educated than pain-free women. As anticipated, higher levels of psychological distress and prior diagnosis of endometriosis and dysmenorrhea were also more common among CPP/PBS patients ( Table 1 ). Significant differences in demographic factors were not observed between women with CPP and PBS.
| Controls n = 42 | CPP n = 23 | PBS n = 23 | |
|---|---|---|---|
| Age, y | 32 (23–44) | 35 (29–44) | 31 (27–39) |
| Weight, lb | 146 (127–192) | 170 (140–199) | 145 (128–183) |
| Marital status | |||
| Married/committed | 20/42 (48%) | 15/23 (65%) | 14/23 (61%) |
| Single | 21/42 (50%) | 5/23 (22%) | 7/23 (30%) |
| Divorced/separated/widowed | 1/42 (2%) | 3/23 (13%) | 2/23 (9%) |
| Race | |||
| Caucasian | 30/41 (73%) | 15/23 (65%) | 21/23 (91%) |
| African American | 8/41 (20%) | 4/23 (17%) | 2/23 (9%) |
| Other | 3/41 (7%) | 4/23 (17%) | 0/23 (0%) |
| Education level | |||
| ≤High school equivalent | 4/41 (10%) | 2/22 (9%) | 3/23 (13%) |
| Some college | 20/41 (49%) | 3/22 (14%) a | 10/23 (43%) |
| Associate degree | 2/41 (5%) | 0/22 (0%) | 1/23 (4%) |
| College/bachelor degree | 12/41 (29%) | 13/22 (59%) a | 7/23 (30%) |
| Postgraduate degree | 3/41 (7%) | 4/22 (18%) | 2/23 (9%) |
| Parous | 12/42 (29%) | 10/23 (43%) | 11/23 (48%) |
| PROMIS physical functioning | 59 (56–62) | 43 (38–54) | 42 (38–48) |
| Depression | 8/42 (19%) | 10/23 (43%) | 12/23 (52%) a |
| CES-D score | 2 (0–4) | 13 (3–21) a | 15 (8–23) a |
| Anxiety | 8/42 (19%) | 8/23 (35%) | 13/23 (57%) a |
| STAI score | 27 (24–32) | 38 (29–48) a | 43 (36–50) a |
| Abuse | 6/42 (14%) | 12/23 (52%) a | 15/23 (65%) a |
| Dyspareunia | 3/35 (9%) | 8/13 (62%) a | 10/11 (91%) a |
| Prior abdominal/pelvic surgeries | 16/42 (38%) | 17/23 (74%) a | 18/23 (78%) a |
| Dysmenorrhea | 15/35 (43%) | 14/15 (93%) a | 18/19 (95%) a |
| Endometriosis | 0/42 (0%) | 5/23 (22%) a | 8/23 (35%) a |
| Fibromyalgia | 0/42 (0%) | 3/23 (13%) a | 2/23 (9%) |
| Chronic headaches | 4/42 (10%) | 2/23 (9%) | 5/23 (22%) |
| Irritable bowel syndrome | 1/42 (2%) | 3/23 (13%) | 9/23 (39%) a |
| Duration of pelvic pain, y | 4 (2–7) a | 6 (1–9) a |
a Significant differences ( P < .05) between healthy vs CPP or healthy vs PBS (significant differences between CPP and PBS were not observed).
| Variable | Healthy | CPP | PBS |
|---|---|---|---|
| Introitus flexibility, 0–3 | 2 (1–2) | 2 (1–2) | 2 (2–2) |
| Pelvic floor relaxation, 0–2 | 0 (0–0) | 0 (0–0) | 0 (0–0) |
| Pelvic floor strength, 0–5 | 2 (1–3) | 2 (1–3) | 2 (2–3) |
| Pelvic floor tone, –9 to +9 | 0 (0–2) | 0 (–2 to 3) | 0 (–2 to 2) |
| Genital hiatus, cm | 1.5 (1.0–2.0) | 2.0 (1.8–2.5) a | 2.0 (1.5–2) |
| POP-Q stage | |||
| 0 | 32/42 (76%) | 21/23 (91%) | 19/23 (83%) |
| 1 | 8/42 (19%) | 1/23 (4%) | 2/23 (9%) |
| 2 | 2/42 (5%) | 1/23 (4%) | 2/23 (9%) |
| Right SI joint | 0.0 (0.0–0.0) | 0.0 (0.0–1.5) a | 0.0 (0.0–1.5) a |
| Left SI joint | 0.0 (0.0–0.0) | 0.0 (0.0–0.0) | 0.0 (0.0–0.5) a |
| Right pubococcygeus | 0.0 (0.0–0.0) | 0.0 (0.0–3.0) a | 3.0 (1.0–5.5) a , b |
| Left pubococcygeus | 0.0 (0.0–0.0) | 1.0 (0.0–3.0) a | 3.0 (0.5–5.0) a |
| Right iliococcygeus | 0.0 (0.0–0.0) | 0.0 (0.0–3.0) a | 1.0 (0.0–5.0) a |
| Left iliococcygeus | 0.0 (0.0–0.0) | 0.0 (0.0–3.0) a | 2.0 (0.5–5.0) a , b |
| Right obturator | 0.0 (0.0–0.0) | 0.0 (0.0–1.5) a | 1.0 (0.0–4.5) a |
| Left obturator | 0.0 (0.0–0.0) | 1.0 (0.0–3.5) a | 2.0 (0.0–3.5) a |
| Bladder | 0.0 (0.0–0.0) | 0.0 (0.0–2.5) a | 5.0 (3.0–6.0) a , b |
| Urethra | 0.0 (0.0–0.0) | 0.0 (0.0–1.0) | 4.0 (0.0–5.0) a , b |
| Uterus | 0.0 (0.0–0.0) | 1.5 (0.0–5.0) a | 4.0 (0.0–6.0) a |
| Uterosacral ligaments | 0.0 (0.0–0.0) | 0.0 (0.0–4.0) a | 1.5 (0.0–5.0) a |
| Right vaginal fornix | 0.0 (0.0–0.0) | 0.0 (0.0–4.5) a | 4.0 (0.0–6.5) a , b |
| Left vaginal fornix | 0.0 (0.0–0.0) | 2.0 (0.0–5.0) a | 4.0 (0.5–6.0) a |
| Vaginal tenderness | 0.0 (0.0–0.0) | 0.0 (0.0–0.0) | 0.0 (0.0–1.8) a |
| Vaginal PPT values, kg/cm 2 | |||
| Right sidewall | 1.5 (1.2–1.9) | 1.2 (0.9–1.4) a | 1.4 (0.8–1.6) a |
| Left sidewall | 1.2 (1.0–1.6) | 1.1 (0.9–1.3) | 0.9 (0.7–1.2) a |
| 12 o’clock | 1.5 (1.1–1.8) | 1.1 (0.8–1.3) a | 0.9 (0.7–1.2) a |
| 6 o’clock | 1.5 (1.2–1.8) | 1.2 (0.9–1.5) a | 1.2 (0.9–1.4) a |
| Aftersensation, NRS | 0.0 (0.0–0.5) | 1.0 (0.0–1.5) a | 1.0 (0.5–1.8) a |
| Aftersensation, min | 0.0 (0.0–1.0) | 2.0 (0.0–9.5) a | 1.0 (0.0–9.0) a |
a Significant differences ( P < .05) after corrections for multiple comparisons between CPP and PBS vs healthy controls
b Significant differences between subjects with CPP and PBS.
Clinical tenderness and mechanical thresholds
On clinical examination, measures of pelvic floor flexibility, strength, and tone did not differ between groups ( Table 2 ). However, routine palpation elicited more self-reported pain (tenderness) in both CPP and PBS patients at almost every pelvic site ( Table 2 ). Aside from genital hiatus ( Table 2 ), there were no consistently observed group differences in myofascial anatomy or function between women with CPP or PBS and pain-free controls.
We next analyzed the PPT results to evaluate potential mechanisms underlying the pelvic floor tenderness reported by CPP and PBS patients. Since differences other than bladder sensitivity were not statistically significant between these 2 groups, they were grouped together for the remainder of the pelvic floor targeted analyses. Across all 4 pelvic floor sites, PPTs in women with CPP/PBS were lower (meaning higher pain sensitivity) than in pain-free participants (CPP/PBS, 1.18; interquartile range [IQR], 0.87–1.41 kg/cm 2 ; pain-free participants, 1.48; IQR, 1.11–1.76 kg/cm 2 ) (individual sites are listed in Table 2 ) ( P < .001). Reports of pain aftersensation following completion of PPT testing were more intense and prolonged in women with CPP/PBS ( Table 2 ) ( P < .001). We compared the cumulative sum of tenderness pain (all of the sites listed in Table 2 ) across participants to their average PPT and aftersensation duration with multivariate regression. Across all of the groups (R 2 , 0.51; P < .001) and within women with CPP/PBS (R 2 , 0.41; P < .001) increased tenderness was associated with lowered PPTs ( P < .01) and longer aftersensation ( P < .001).
To identify any potential confounders of pain sensitivity, we examined the correlation between candidate demographic, medical history, and pelvic floor predictors of average pelvic PPT in pain-free controls ( Table 3 ). Age (r = 0.57), genital hiatus (0.46), pelvic floor tone (–0.38), and introital flexibility (0.32) were significantly correlated with pelvic floor pain threshold. Forward stepwise regression confirmed the primary contributing factors to PPTs in pain-free participants were age and genital hiatus (R 2 , 0.42; P < .001). A 1-cm increase in genital hiatus was associated with a 0.3 ± 0.1 kg/cm 2 increase in pelvic PPT ( P < .01). Increasing participant age was associated with a reduction of 0.016 ± 0.005 kg/cm 2 /y in pelvic PPT ( P < .01). After adjusting for median age (32 years) and genital hiatus length (1.5 cm) PPT differences remained robust between women with CPP/PBS (0.98 [IQR, 0.68–1.13] kg/cm 2 ) and pain-free controls (1.36 [IQR, 1.20–1.61] kg/cm 2 , P < .001). We also confirmed that the identity of the examiner (clinician vs trained nonclinicians) had no contributing effect ( P = .85). Intraclass correlations of average PPTs across sessions were 0.86 (95% confidence interval [CI], 0.72–0.92) for pain-free subjects and 0.81 (95% CI, 0.64–0.90) for subjects with CPP/PBS suggesting PPTs were stable over a 1-month period.
