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Noninvasive experimental bladder pain assessment in painful bladder syndrome

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Objective: To compare bladder sensitivity between patients with pelvic pain and patients who were pain free, undergoing noninvasive, controlled bladder distension via diuresis. We also sought to measure potential mechanisms underlying bladder sensitivity. Design: Prospective observational study. Setting: Community teaching hospital. Population: Reproductive-age women with non-bladder chronic pelvic pain (CPP, n = 23), painful bladder syndrome (PBS, n = 23), and pelvic pain-free controls (n = 42) METHODS: Participants were compared on cystometric capacity, pelvic floor pressure-pain thresholds (PPTs), pelvic muscle function, O'Leary-Sant bladder questionnaire, and psychosocial instruments using Wilcoxon rank-sum tests. Multivariate regression was used to identify factors underlying bladder pain phenotypes. Main outcome measures: Pelvic floor pain thresholds; self-reported bladder distension pain. Results: Participants with PBS exhibited higher bladder distension pain than those with CPP, with both groups reporting higher pain levels than controls (P < 0.05). No significant associations were found between bladder distension pain and pelvic muscle structure or pain sensitivity measures; however, bladder distension pain positively correlates with both vaginal PPTs adjacent to the bladder (r = 0.46) and pain with transvaginal bladder palpation (r = 0.56). Pain at maximal distension was less influenced by somatic sensitivity than bladder symptoms (r = 0.35 versus r = 0.59; P < 0.05). Multivariate regression identified three independent components of bladder symptoms in PBS: bladder distension pain, bladder sensation, and somatic symptoms. Conclusions: Diuresis-induced bladder pain differentiates CPP from PBS. Experimental bladder pain is not predicted by pelvic floor sensitivity. Compared with patient-reported outcomes it appears less influenced by psychological factors. Further study is needed to determine whether screening for experimental bladder pain sensitivity could predict future risk of PBS. Tweetable abstract: Controlled, water ingestion-provoked bladder pain can objectively identify visceral pain sensitivity.
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Non-invasive experimental bladder pain assessment in painful
bladder syndrome
Frank F. Tu, MD, MPH1,2,3, Julia N. Kane, MA1,2, and Kevin M. Hellman, PhD1,2,3
1Department of Obstetrics and Gynecology, University of Chicago Medical Center, Chicago, IL,
USA
2Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL,
USA
3University of Chicago, Pritzker School of Medicine, Chicago, IL, USA
Abstract
Objective—To compare bladder sensitivity between pelvic pain and pain-free patients
undergoing noninvasive, controlled bladder distension via diuresis. We also sought to measure
potential mechanisms underlying bladder sensitivity.
Design—prospective observational study
Setting—community teaching hospital
Population—Reproductive-age women with non-bladder chronic pelvic pain (CPP, n=23),
painful bladder syndrome (PBS, n=23) and pelvic pain-free controls (n=42)
Methods—Participants were compared on cystometric capacity, pelvic floor pressure-pain
thresholds (PPTs), pelvic muscle function, O’Leary-Sant bladder questionnaire, and psychosocial
instruments using Wilcoxon rank-sum tests. Multivariate regression was used to identify factors
underlying bladder pain phenotypes.
Main outcome measures—self-reported bladder distension pain, pelvic floor pain thresholds
Results—Participants with PBS exhibited higher bladder distension pain than those with CPP,
with both groups reporting pain higher than controls (p’s <0.05). No significant associations were
found between bladder distension pain and pelvic muscle structure or pain sensitivity measures.
However, bladder distension pain positively correlates with both vaginal PPTs adjacent to the
bladder (r=0.46), and pain with transvaginal bladder palpation (r=0.56). Pain at maximal
Editorial Correspondence (and address for all authors): Frank F. Tu, M.D., M.P.H., Division of Gynecological Pain and Minimally
Invasive Surgery, 2650 Ridge Avenue, Suite 1530, Evanston, IL 60201, ftu@northshore.org, 847-570-2520 (office), 847-570-1846
(fax).
Presented in poster format at 15th annual meeting of the International Association for the Study of Pain in Buenos Aires, Argentina
October 6–11, 2014
Disclosure of interests: none to report. The ICMJE disclosure forms are available as online supporting information.
Contribution to authorship: FT conceived/designed experiment, performed experiments, analyzed data, wrote the paper; KH
conceived/designed experiment, performed experiments, analyzed data, wrote the paper; JK performed experiments, analyzed data,
wrote the paper
Details of ethics approval: NorthShore University HealthSystem IRB approval (EH 08-073) 8/1/08
HHS Public Access
Author manuscript
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Published in final edited form as:
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. 2017 January ; 124(2): 283–291. doi:10.1111/1471-0528.14433.
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distension was less influenced by somatic sensitivity than bladder symptoms (r=0.35 vs. r=0.59,
p<0.05). Multivariate regression identified three independent components of bladder symptoms in
PBS: bladder distension pain, bladder sensation, and somatic symptoms.
Conclusions—Diuresis-induced bladder pain differentiates CPP from PBS. Experimental
bladder pain is not predicted by pelvic floor sensitivity. Compared to patient-reported outcomes it
appears less influenced by psychological factors. Further study is needed to determine screening
for experimental bladder pain sensitivity could predict future risk of PBS.
Tweetable abstract
Controlled, water ingestion-provoked bladder pain can objectively identify visceral pain sensitivity
Keywords
Pelvic Pain; Painful Bladder Syndrome; Pressure Pain Threshold; Quantitative Sensory Testing
Introduction
Painful bladder syndrome/interstitial cystitis (PBS) is a poorly understood chronic pain state
arising in part from an amalgam of disrupted peripheral and central pain regulatory circuits.
Since few treatments are consistently effective, preventative strategies are urgently needed.
A well-recognized finding in PBS is increased bladder pain with bladder filling.1 Although
self-report of distress in PBS appears to reflect both urgency/frequency (International
Continence Society [ICS] terms this
increased bladder sensation)
and pain, the physiological
basis for these dual contributions is not precisely known.2 In a preliminary study, during a
standardized cystometry task, PBS patients report prolonged and more intense discomfort
compared to healthy controls.3
The induction of pain at low filling volumes in patients with PBS parallels findings showing
that many irritable bowel syndrome patients also report pain at lower distension pressures
during anal manometry.4 In functional bowel disorders, standard assays of visceral
hyperalgesia are well-recognized research tools and have been used to characterize the
relevant nerve pathways and molecular underpinnings of these symptoms.5,6 Targeting the
bladder for visceral pain testing is limited by discomfort from urethral catheterization and
infectious risk. Validating more comfortable, non-invasive tests could enhance research
participation.
The present study extends our prior studies of non-invasive bladder distension in studying
menstrual pain and cross-organ visceral sensitivity in otherwise healthy controls, with the
objective of determining if bladder distension pain differs between CPP and PBS patients
(vs. healthy controls).7 Since patients with PBS have widespread reduced pain tolerance and
report more somatic symptoms, we also explored secondarily if non-specific factors and
psychological distress might affect experimental bladder pain testing.1,8 In particular, we
specifically assessed whether pelvic floor sensitivity predicts bladder distension pain, as
pelvic physical therapy reduces bladder pain symptoms, but the underlying mechanism for
this efficacy is unknown.9
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Methods
Overview
This study was a planned analysis for one aim of an overall study of pelvic floor function
and bladder pain sensitivity. We prospectively recruited chronic pelvic pain (CPP) and PBS
patients, as well as pain-free controls prospectively for a cross-sectional study at Evanston
Hospital (Evanston, Illinois) between July 2010 and September 2013 from nearby clinics
and community advertisements.
Participants
CPP was defined as pain lasting three months or longer in the area between the umbilicus
and inguinal ligament. Symptoms could not solely be perceived on the skin, only involve the
hip or back, or only occur with menses. PBS patients were defined by International
Continence Society (ICS) criteria: complaint of pelvic pain related to bladder function,
accompanied by other symptoms such as increased daytime and nighttime frequency, in the
absence of proven urinary infection or other obvious pathology reported urgency or
frequency symptoms,2 Controls were pelvic pain-free, PBS cohort age-matched patients (±5
years) and recruited from the same population. Cases were limited to ages 18–55 years old.
Exclusion criteria included: pregnancy, active urogenital infection, prior urogenital
malignancy, unexplained hematuria, active nephro/ureterolithiasis, vaginal prolapse
exceeding second degree, and unwillingness to avoid short-acting opioids prior to
examination. All participants received modest stipends. The NorthShore University Health
System Institutional Review Board approved the study, and all participants gave informed
consent.
Study procedure
All examinations and tests were performed in a research examination room. Participants
were asked to complete a screen visit and two assessment visits.
Screen Visit
All participants signed consent before any study procedures were executed. A complete
abdominopelvic examination was performed by the primary author. The exam included
asking participants to rate pain from palpation at multiple sites using a 0–10 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 (for more details see Appendix S1). Participants also completed the O’Leary-Sant
Interstitial Cystitis Symptom (ICSI) and Problem Indices (ICPI) and University of
Wisconsin (UW) Interstitial Cystitis questionnaires of bladder function.10,11 They also
completed Patient Reported Outcomes Measurement Information System (PROMIS)
computer adaptive tests for anxiety and depression.12 A somatic symptom score was derived
as the total score of non-bladder symptoms (dizziness, chest pain, nausea, feelings of
suffocation, and tingling in fingers and toes) each rated on a 0–6 Likert scale from selected
UW reference scale questions, similar to those on the Brief Symptom Inventory assessing
somatization.11
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Assessment Visit 1
On the first assessment visit, external and internal pressure-pain thresholds (PPT) and
bladder testing were performed using our prior published standardized protocols.13 The
order of PPT and bladder testing was randomized, except for the PBS participants, who all
underwent bladder filling first. For pressure-pain threshold assessment, we first tested the
four external sites (shoulder, forehead, hip and knee), applying pressure at a rate between 0.5
and 1.0 kg/cm2/s using a pain pressure algometer with a 1 cm2 circular cap. The same
approach was next applied to test four transvaginal pelvic floor sites (right and left
iliococcygeus, anterior bladder, and posterior anorectal raphe) using a specially designed,
fingertip-mounted algometer. Averaged thresholds from two trials were used for the final
analysis. Extended details are presented in Appendix S1.
Participants were asked to hydrate with 12 ounces of water one hour before the visit and
abstain from caffeine the day of testing. After an initial void, participants had baseline
volume measurement of the bladder while supine. Bladder volume was measured using a
Voluson 730 three-dimensional transabdominal 5.0 MHz ultrasound transducer (GE
Healthcare, Wauwatosa, WI). Measurement of bladder volumes was performed using the
scanner’s onboard Virtual Organ Computer-aided Analysis (VOCAL™) software with the
transducer oriented sagittally above the symphysis pubis. Volume was calculated from the
perimeter measurements of six serial plane sections separated by 30°. Validation and
reliability of this method by our research team has been previously published.7
Following the initial scan, participants were asked to drink 20 ounces of water within 5
minutes to further encourage diuresis. While participating they were offered light reading
and were asked not to do other distracting tasks such as making phone calls or engaging in
regular conversation. Participants were asked to report awareness upon reaching three levels
of bladder urgency: first sensation, first desire to void, and maximal capacity. At each of
these three thresholds, we measured bladder volume and then asked the participant to rate
their level of bladder pain and urgency (10 cm visual analogue scale [VAS]). The urgency
scale was anchored at opposite ends with the descriptors “no urgency” and “worst urgency
imaginable.” Similarly, the pain scale was anchored at opposite ends with the descriptors
“no pain” and “worst pain imaginable.” Additionally, every 15 minutes from the time that
participants finished drinking the priming dose of water, they were instructed to evaluate
their current level of pain and urgency using the same VAS measures. If a participant did not
reach maximum capacity by 45 and 60 minutes, she was asked to drink an additional ten
ounces of water (maximum of twenty additional ounces) to encourage diuresis. The bladder
testing was capped at two hours. Bladder filling rates were estimated by calculating the
change in volumes estimated at each cystometric threshold, divided by the elapsed time.
Assessment Visit 2
This visit was conducted approximately one month after assessment visit 1. All participants
underwent internal and external pressure testing and completed a similar battery of
questionnaires assessing pain levels and mental health as was collected during the screen
visit.
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Study Size
The study aim when the study was initially funded targeted a primary hypothesis that
bladder sensation and pelvic floor sensitivity are positively associated. Prior published data
suggested a Cohen’s d effect size of 1.1 for this association.1,3,14 A power analysis estimated
that to achieve that effect size with 80% power, we would need 38 CPP and/or PBS patients
(28 enhanced bladder sensation, and 10 with normal bladder sensation) to significantly
resolve a group difference (p<0.05). An additional aim was to assess if there were
differences in self-reported bladder sensation between pain groups and pain-free controls.
Statistical Analysis
For this paper we addressed three primary pre-defined contrasts: between diagnostic groups
we compared bladder pain at maximum capacity and a time series variable capturing overall
change in bladder pain during the experimental bladder task. We also compared average
pelvic floor pressure pain thresholds between pain patients exhibiting lower vs. higher first
sensation thresholds (≥100 mL cutoff).14 We had complete case data for all bladder testing
and accompanying ratings. Based on Shapiro-Wilk determinations of normality of variables,
group differences were evaluated with Wilcoxon rank-sum tests (followed by post-hoc
Dunn’s tests with Holm-Sidak corrections for multiple comparisons), repeated measures
ANOVA on the ranks, or chi-squared tests with STATA 13.0 (College Station, TX).
Relationships between bladder distension pain, somatic pain sensitivity, the ICSI and other
candidate contributing factors (pelvic floor tone, strength, flexibility and voluntary control;
anxiety; depression; and somatic symptoms) were analyzed with Spearman rank-order
correlation. Significant differences between correlation coefficients were verified with
Fisher-to-z transforms. To verify whether bladder distension pain or other factors were
independently related to bladder pain phenotypes, we performed multivariate linear
regression and determined receiver operating characteristic curves.
Results
Demographic Profile
As expected, the PBS group reported higher bladder distress on both the UW and ICSI
bladder-specific measures compared to pain-free controls (p’s<0.01, Table 1). Women with
CPP had intermediate UW and ICSI scores that were significantly higher than healthy
controls, but lower than participants with PBS (p<0.05). Diary data supported that both CPP
and PBS patients had more voids per day compared to healthy controls (p<0.05). Consistent
with prior published findings, both pain groups had significant duration of ongoing
symptoms, significant rates of comorbid diagnoses (IBS, endometriosis, fibromyalgia, abuse
history), and heightened levels of depression and anxiety.
Bladder Testing Flow Rate
An important consideration in replacing pain measurements obtained with retrograde
bladder filling with natural diuresis is that different flow rates could affect sensation or pain
report. To determine the impact of natural variation in flow rate on perception we analyzed
empirical differences of average flow on sensation and pain. There were no significant
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differences in flow rate between groups (Healthy: 6.6 [5.6–8.0] ml/min, CPP: 6.6 [5.4–9.0].
PBS: 6.0 [5.0 – 6.8] mL/min, p=0.45). However, there was a significant positive correlation
between flow rate and maximum tolerance bladder volume (r=0.73, p<0.001). This is
potentially due to the fact that women with low bladder capacity drink less to improve
tolerability.15 Also flow rates increased over time. Across all participants, there was a
significant increase in flow rate from first sensation (4.3 [2.5–6.6] mL/min) to first urge (6.9
[5.3–9.2], p<0.001) and again from first urge to maximum tolerance (8.7 [7.0–10.8],
p<0.001). To account for any potential confounding, we examined tolerances across the
groups with a general linear model accounting for flow rate. In the general linear model,
there was a significant effect of rate on maximum tolerance (p<0.001), but women with PBS
still had a 112 [44 – 181] ml lower volume at maximal capacity compared to control women
or women with CPP (p<0.001).
Controlled bladder filling elicits greater pain in PBS
Women with PBS reached all cystometric thresholds (first sensation, first desire to void, and
maximal capacity) at significantly lower volumes and time-to-threshold than healthy
controls (Fig 1A, Table S1;p’s<0.05). The mean bladder volume and time-to-threshold was
significantly lower in PBS compared to the CPP group at maximal capacity only. Volume
and time-to-threshold at each cystometric threshold did not differ between CPP and healthy
controls. However, women with CPP reported more pain than healthy controls at all sensory
thresholds (Fig 1B, Table S1;p’s<0.05). Furthermore, women with PBS had higher bladder
pain than those with CPP at first sensation and first desire to void (Fig 1B, Table
S1;p’s<0.05).
Longitudinal report of bladder urgency and pain ratings are shown in Fig 1C–D, with a
significant effect of both time and group observed (p’s<0.001). Nested group×time
interactions indicated that women with CPP have significant increasing pain over time
compared to healthy participants, and PBS participants have worsening pain over time
compared to CPP participants (p’s<0.001).
Potential factors influencing bladder volume tolerance and pain report
In our prior work, full data was not available to evaluate potential predictors of either evoked
bladder pain or bladder volume sensitivity. We found some positive associations between
pelvic floor mechanical sensitivity and evoked bladder pain report. Pressure pain threshold
under the bladder and pain at first sensation was inversely correlated (Table 2, r=−0.46;
p<0.01). Pain evoked by clinical bladder exam was also correlated to bladder distension pain
at all cystometric thresholds (r=0.51–0.56; p<0.01). All other PPTs (transvaginal or
external), as well as pelvic floor anatomy and functional assessments (Table S2) were not
associated with bladder distension pain. For predictors of volume sensitivity, we had one
planned comparison of average pelvic floor PPT for only women with pain, to determine if
mechanical sensitivity was higher in women with volume sensitivity. No difference in
pressure thresholds were observed (high volume sensitive < 100 mL first sensation (1.19
kg/cm2 [1.00–1.44];n=21 vs. low volume sensitivity (1.00 kg/cm2 [0.85–1.23], n=25, p =
0.13). Likewise, no significant associations were seen between any volume sensitivity
threshold with any PPTs. As with pain, pelvic floor tone, strength, flexibility and voluntary
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control did not predict volume sensitivity (Table S2). Interestingly, prolonged duration of
pain report (aftersensation) following mechanical pressure testing (Table 2) correlated with
both bladder distension pain (r=0.50–0.55) and first desire (0.39) and maximal capacity
volumes (0.40, all p < 0.05).
Psychological factors have more impact on bladder symptom reporting than bladder
distension pain
Finally, we examined the associations of psychological factors and bladder distension pain
or volume sensitivity (Table 2). At first sensation, moderate positive correlations were
observed between bladder distension pain, somatic symptom reporting, depression, and
anxiety (0.4–0.48 p<0.05), while depression correlated with bladder pain similarly at first
urge and maximal capacity. We did not observe significant associations between volume
sensitivity and psychological factors, just as we found with mechanical sensitivity and pelvic
anatomy factors (Table S2).
Associations between physiological constructs, psychological profiles and disease-
specific outcomes measures
We also characterized how the combination of functional bladder pain, capacity and
psychosomatic factors influences bladder specific symptom reporting in PBS. Maximal
distension pain (r=0.56), maximal capacity volume (r=−.44), palpation evoked bladder pain
(r=0.60) and somatic symptoms (r=.59) were associated with clinical bladder
symptomatology (ICSI, Table 2). Interestingly, this general somatic symptom report
association with bladder symptom report, tis stronger than its relationship with cystometric
measures of sensitivity (maximal distension pain r=0.35 and capacity r=−0.18, respectively,
p<0.05 Fisher to Z transform). We next explored the distribution of these variables for each
group, to better understand the weight of bladder factors vs. somatic symptoms. We plotted
the summed standardized values for these three variables for each individual participant
adjusting for the general prevalence of CPP and PBS (Fig 2). Although significant bladder
distension pain was rare in the general population, half of patients with CPP had bladder
distension pain, but not necessarily accompanied by filling sensitivity. In patients with PBS,
19/23 had summed standardized scores for bladder pain, bladder sensation, and somatic
symptoms that exceeded 2 standard deviations from median values of a general population.
However, there was seemingly little relationship between the amount of bladder pain or
enhanced bladder sensation and somatic symptoms among patients with PBS. Multivariate
linear regression further identifies that maximal capacity pain, bladder sensitivity, and
somatic symptom reporting are each independent factors contributing to ICSI scores (Table
S3;R2=0.54, p<0.001). A receiver operating characteristics curve showed that the three
factor model generated an area under the curve (AUC) of 0.90 for identifying participants
with an ICSI score ≥6, the threshold for PBS diagnosis suggested in the original ICSI
validation paper (Fig 2).10 The three factor model was superior to a bladder factors-only
(AUC=0.83, p<0.05) or a somatic complaint-only model (AUC=0.74, p<0.01).
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Discussion
Main Findings
We applied a standardized protocol for measuring bladder pain and sensation exploiting the
simplicity of provoked diuresis and confirm distension-induced bladder pain is present in
both classic PBS as well as in half of CPP patients not meeting PBS criteria. Our non-
invasive measure empirically differentiates between relative degrees of visceral sensitivity
(CPP vs. PBS) and is less sensitive to non-specific somatic/psychological factors. The
simplicity of this measure could make it attractive as a general measure of visceral
hypersensitivity, with research applications beyond the urological field.5,6
Another key finding was that pelvic floor pain sensitivity did not predict visceral sensitivity.
Our original hypothesized relationship was based on previous clinical observations that
targeted pelvic floor physical therapy can improve bladder pain symptoms and can reduce
general pelvic floor sensitivity.9,16 In contrast, we found localized mechanical hyperalgesia
during palpation or vaginal pressure pain thresholds predicted bladder distension pain and
sensation, but only at the bladder site. We can thus conclude that somatovisceral
convergence is not a major contributor to bladder filling pain, yet pelvic floor dysfunction
could still incrementally influence inputs into brainstem descending inhibition and increase
overall bladder pain symptomatology.17 Since as many as 43% of patients do not
significantly respond to manual therapy, and questionnaire based studies are vulnerable to
somatization, quantitative sensory evaluation of the bladder and pelvic floor may be
necessary to elucidate the mechanisms modifiable through physical therapy. One likely
possibility is that PBS represents heterogeneous groupings of patients, some with
predominantly pelvic floor dysfunction, others mainly expressing dysfunctions in central
pain processing, and still others exhibiting predominantly pure bladder mechanical
hyperalgesia.18 A factorial approach to unpackaging pain mechanisms has been used to
identify patients with diabetic neuropathy that respond to duloxetine, a drug also used off-
label to treat PBS.19
Strengths
Several strengths of our study support diuresis-provoked bladder testing as a valid visceral
sensitivity task. First, we controlled for sociodemographic features within a reproductive age
cohort on bladder distension pain and found no influence. Our extensive demographic
characterization, including medical comorbidities (endometriosis, dysmenorrhea,
fibromyalgia, abuse exposure) will allow future studies to contrast their findings using these
parameters, as our sample is typical of a referral population of significantly distressed
women. Second, we controlled for potential psychological confounders with standardized
patient reported outcomes instruments, as studies of rectal distension have implied that
heightened sensation is entirely mediated by anxiety or somatization.20,21 This allowed us to
show that bladder distension pain may be a less biased outcome measure, perhaps reflecting
the lack of perceived threat (no catheter or manometry balloon insertion) presented by a
noninvasive test. Since self-reported symptom indices are vulnerable to somatization and
psychological factors, complete phenotypic assessment of pain states ideally includes
symptom-based and unbiased experimental visceral pain assessment.8,22,23 Third, we used a
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positive control group without significant bladder symptoms to untangle potential pain and
urgency relationships on visceral pain sensitivity.
Limitations
The primary limitation of a naturalistic study is the inability to precisely control the
experimental stimulus. However, when we controlled for estimated filling rates, we found no
difference between diagnostic groups, and likewise no relationship to distension provoked
pain. Although impairments in compliance accounting for limitations in maximal capacity
are not associated with PBS, future studies using ultrasonographic elastography could
confirm this non-invasively.24,25 We acknowledge this is a modest sized study, but we were
adequately powered for our primary contrasts. Future replication of our results in larger
cohorts is obviously needed.
Interpretation
How should we investigate the utility of distension-mediated pain as a risk marker for future
PBS? We are still quite far from understanding the trajectory that leads from asymptomatic
bladder sensitivity to overt bladder pain symptoms. Large scale studies, like the ongoing
National Institutes of Health-funded Multidisciplinary Approach to Pelvic Pain network and
its predecessors, have not longitudinally characterized the changes in visceral pain
sensitivity in healthy participants, perhaps since catheterization elicits more apprehension
and pain particularly in younger populations.26,27 Our tool could be used to follow the
transition to chronic bladder pain if employed following cases of acute cystitis, focusing
selectively on patients exhibiting generalized somatic symptoms. Given that a key role has
been identified for somatization in temporomandibular joint disorder risk in a large-scale
longitudinal study, assessing visceral sensitivity and somatization simultaneously could be
quite enlightening.28
Conclusion
We show preliminary validity for diuresis-induced bladder pain as a visceral pain measure
reflecting local mechanical sensitivity. As an assessment tool for mechanism-based study of
CPP states, it may be less influenced by psychological factors than patient-reported
outcomes. The benefit of our visceral distension measure remains to be fully appreciated, as
this task can be studied in ambulatory settings, may be a marker for the emergence of PBS,
and potentially could be comingled with other therapeutic trials as an objective marker of
disease change following treatment.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We thank Dr.’s Daniel Clauw, Adam Gafni-Kane, Joel Greenspan, and James W. Griffith for valuable comments on
our manuscript.
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Funding: F.F.T. was supported by NIH grant K23HD054645, K.M.H. was supported by a Research Career
Development Award from the NorthShore University HealthSystem Research Institute, Evanston, IL. The content is
solely the responsibility of the authors and does not necessarily represent the official views of the National
Institutes of Health
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Figure 1.
Time course of provoked diuresis and evoked bladder pain by pain diagnostic category.
Panel A: The median volume and time are shown for first sensation (S), first desire (D), and
maximal capacity (M) for each of the 3 groups with error bars indicating 25–75th
percentiles. Panel B shows the relationship between volume and pain. C and D show
evolution of reported bladder and urgency (VAS 0–10) obtained every 15 minutes regardless
of cystometric thresholds.
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Figure 2.
Stacked bar chart of standardized relative severity of bladder pain, bladder capacity and
somatic complaint, individual level data. Results scaled for estimated frequency of CPP and
PBS in the general population (e.g. 0 = mean, 1 = 1 standard deviation higher than the
general population). A–C: Scores of individual participants were z-scored to represent the
prevalence using weighted-average scaling assuming 11% CPP only and 4% CPP with
PBS.29,30 Each bar represents a single subject. The total height or depth of the bar represents
the number of standard deviations above or below the population average. D: ROC curve for
using these three parameters to predict an ICSI score ≥6.
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Table 1
Sociodemographic and medical history profiles between controls and women with chronic pelvic pain (CPP) or painful bladder syndrome (PBS).
Variable Controls
n=42 CPP
n=23 p for
CPP
vs
Control
PBS
n=23 p for
PBS
vs
Control
p for
PBS
vs
CPP
Age 32 (23–44) 35 (29–44) .279 31 (27–39) .694 .185
Weight (lb) 146 (127–192) 170 (140–199) .244 145 (128–183) .814 .390
Married/Committed 20/42 (48%) 15/23 (65%) .519 14/23 (61%) .31 .999
Caucasian 30/41 (73%) 15/23 (65%) .999 21/23 (91%) .219 .096
Parous 12/42 (29%) 10/23 (43%) .684 11/23 (48%) .369 .999
UW Bladder 0 (0–2) 11 (4.5–17) .001 22 (19–31)
*
.001 .025
UW Reference 2 (0–5) 6.5 (3–19) .001 21 (4–30.5) .001 .468
ICSI 2 (1–3) 7 (3–9) .001 13 (10–14)
*
.001 .007
ICPI 0 (0–0) 4 (2–10) .001 11 (9–13)
*
.001 .007
Voids per day 7 (5–8) 9 (6–12) .030 10 (7–14) .011 .702
History of abuse 6/42 (14%) 12/23 (52%) .003 15/23 (65%) .003 .999
Dysmenorrhea 15/35 (43%) 14/15 (93%) .003 18/19 (95%) .003 .999
Endometriosis 0/42 (0%) 5/23 (22%) .003 8/23 (35%) .003 .972
Fibromyalgia 0/42 (0%) 3/23 (13%) .033 2/23 (9%) .117 .999
Irritable bowel syndrome 1/42 (2%) 3/23 (13%) .285 9/23 (39%) .003 .112
Pelvic pain (VAS 10 cm) 0 (0–0) 4.1 (2.7–6.5) .001 6.2 (3.4–7.2) .001 .554
Days in bed (last 3 months) - 4 (0–30) - 5 (0–20) - .423
Pain duration (years) - 3 (2–18) - 3.6 (1.4–9.5) - .151
CES-D score 2 (0–4) 13 (3–21) .001 15 (8–23) .001 .191
STAI score 27 (24–32) 38 (29–48) .001 43 (36–50) .001 .118
SF12 Physical Component 56 (56–59) 42 (31– 51) .001 37 (27–47) .001 .339
SF12 Mental Component 55 (49–57) 46 (36–55) .001 42 (35–51) .001 .578
Data are specified as median (interquartile range), or as a proportion (percent) for each group. Significance of exploratory analysis differences pain groups vs. pain free groups using a Dunn test with a
Holm-Sidak correction or a chi square with a Bonferroni correction.
*
differences between pain groups p < 0.05. As an exploratory analysis for potential group differences, reported significance should not be construed as formal hypothesis tests.
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UW – University of Wisconsin Symptom Scale, ICSI/ICPI – Interstitial Cystitis Symptom Index/Problem Index, CESD - Center for Epidemiologic Studies Depression survey, STAI -State-Trait Anxiety
Inventory, VAS – Visual Analog Scale, SF12- Short Form 12 Health Survey.
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Table 2
Spearman correlations of factors affecting bladder sensitivity, volume, and the Interstitial Cystitis Symptom Index (ICSI).
Bladder Pain Bladder Volume ICSI
First
sensation First
desire Maximal
capacity First
sensation First
desire Maximal
capacity
ICSI 0.54
*
0.53
*
0.56
*
−0.28 −0.34 −0.44
*
Pressure Sensitivity
Right PPT −0.30 −0.18 −0.19 0.00 −0.02 0.03 −0.21
Left PPT −0.26 −0.15 −0.16 0.14 0.06 0.09 −0.17
Bowel PPT −0.23 −0.16 −0.21 0.02 −0.05 0.01 −0.27
Bladder PPT −0.46
*
−0.32 −0.37 0.07 0.03 0.06 −0.32
Body PPT −0.18 −0.18 −0.13 0.15 0.13 0.09 −0.10
Pain Report
Aftersensation 0.55
*
0.50
*
0.51
*
−0.32 −0.39
*
−0.40
*
0.49
*
Bladder Palpation 0.56
*
0.51
*
0.55
*
−0.01 −0.10 −0.17 0.60
*
Psychological
Somatic Symptoms 0.40
*
0.36 0.35 −0.13 −0.13 −0.18 0.59
*
Depression 0.48
*
0.43
*
0.42
*
−0.14 −0.14 −0.17 0.49
*
Anxiety 0.40
*
0.35 0.37 −0.13 −0.21 −0.19 0.50
*
*
designates p<0.05 after Holm-Sidak corrections for multiple comparisons.
PPT – pelvic floor pain thresholds
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... 37,39,56,77 Given that visceral and widespread somatic hypersensitivity are CPP hallmarks, understanding the neural mechanisms responsible could identify therapeutic targets. 65,88,97 Prior work suggests that central nervous system mechanisms of pain sensitization 5,15,80 involving broad abnormalities in gray matter volume, function, and connectivity 12,51-54,64,68 may underlie multimodal hypersensitivity. 24 For example, patients with fibromyalgia report increased unpleasantness during visual or multimodal stimulation with greater insula activation 36,60 and decreased visual cortex activity 60 compared with pain-free controls. ...
... Notably, they have visceral hypersensitivity and mechanical hypersensitivity in nonpelvic sites 39 that correlate with mild preclinical symptoms of CPP. 38,96,97 We evaluated participants' visceral sensitivity using our validated noninvasive bladder-filling task, 96 and menstrual pain was assessed through self-report. We evaluated visual sensitivity by presenting participants with an aversive but nonpainful visual stimulus while recording scalp electroencephalography (EEG) and perceived unpleasantness. ...
... Provoked bladder pain was also related to mechanical and thermal hypersensitivity across nonpelvic sites and correlated with the severity of self-reported bladder pain, bowel pain, and intercourse pain in this cohort 39 and in participants with severe chronic pain. 97 Given the relationship between bladder pain and other sensory modalities, including vision, we recommend expanding the modalities comprising multimodal hypersensitivity to include the viscera (eg, bladder pain). ...
Article
Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n=147) that had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. We administered two experimental tasks to evaluate the cross-modal relationship between visual and visceral sensitivity. Visual sensitivity was probed by presenting participants with a periodic pattern-reversal checkerboard stimulus presented across five brightness intensities during EEG recording. Self-reported visual unpleasantness ratings for each brightness intensity were simultaneously assessed. Visceral sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visually evoked cortical activity increased with brightness intensity across the entire scalp, especially at occipital electrode sites. Visual stimulation-induced unpleasantness was associated with provoked bladder pain and evoked primary visual cortex activity. However, the relationship between unpleasantness and cortical activity was moderated by provoked bladder pain. These results demonstrate that activity in primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.
... 6,30,57 This task has been validated in participants with bladder pain syndrome and chronic pelvic pain. 91 Notably, even in participants without bladder pain conditions, elevated pain during this task was associated with more frequent report of daily bladder symptoms. 49 After voiding their bladder, participants ingested 20 fluid ounces of water. ...
... Like previous QST studies, 39,47 a PCA of these 40 QST measures resulted in modality-specific components: PPT S-R 79 and bladder hypersensitivity. 91 By contrast, the largest source of underlying QST variability was MMH, a component that was not modality specific. Although previous studies have conjectured that centralized hypersensitivity (eg, generalized sensory sensitivity, somatization, somatic symptoms disorders, sensory modulation disorder, etc.) 8,14,23,85 underlies chronic pain conditions, our results provide evidence of MMH being a broad construct that correlates with affective symptoms, somatic symptoms, genitourinary pain, menstrual pain, and overall pain and health. ...
Article
Multimodal hypersensitivity (MMH)—greater sensitivity across multiple sensory modalities (eg, light, sound, temperature, pressure)—is associated with the development of chronic pain. However, previous MMH studies are restricted given their reliance on self-reported questionnaires, narrow use of multimodal sensory testing, or limited follow-up. We conducted multimodal sensory testing on an observational cohort of 200 reproductive-aged women, including those at elevated risk for chronic pelvic pain conditions and pain-free controls. Multimodal sensory testing included visual, auditory, and bodily pressure, pelvic pressure, thermal, and bladder pain testing. Self-reported pelvic pain was examined over 4 years. A principal component analysis of sensory testing measures resulted in 3 orthogonal factors that explained 43% of the variance: MMH, pressure pain stimulus response, and bladder hypersensitivity. The MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Over time, MMH increasingly predicted pelvic pain and was the only component to predict outcome 4 years later, even when adjusted for baseline pelvic pain. Multimodal hypersensitivity was a better predictor of pelvic pain outcome than a questionnaire-based assessment of generalized sensory sensitivity. These results suggest that MMHs overarching neural mechanisms convey more substantial long-term risk for pelvic pain than variation in individual sensory modalities. Further research on the modifiability of MMH could inform future treatment developments in chronic pain.
... This is why this prospective, singleblind, comparative study was designed to highlight decreased nociceptive thresholds (primary objective) and spatial and temporal diffusion of pain in HS-CPP compared with LS-CPP women. Furthermore, correlations were found in previous studies between the decrease in pain thresholds of pelvic or perineal organs and anxiety, 5,6 catastrophizing thinking 7,8 and depression, 9 whereas others did not show that link. 10 We therefore evaluated the psychological state of the participants to investigate the correlation with the decrease in sensory thresholds. ...
... Bladder sensory test A noninvasive bladder test was performed in accordance with the method described by Tu et al 9,12 and Hellman et al 13 This validated technique enables bladder sensitivity to be assessed without retrograde catheterization, which is uncomfortable and induces a source of stimulation onto the bladder's afferent nerves. The bladder test protocol is shown in Supplemental Figure 2, with AJOG at a Glance Why was this study conducted? ...
Article
Background: Central sensitization is frequently associated with chronic pelvic pain and requires specific management. The pain is described as hypersensitivity to an innocuous stimulus that is both widespread and persistent. However, no study has evaluated if central sensitization can be measured objectively with neurophysiological tests in the pelvic and perineal area to prove this concept in women with chronic pelvic pain. Objective: To evaluate nociceptive thresholds (primary objective) and spatial and temporal diffusion of pain among women with chronic pelvic pain and high or low scores of central sensitization STUDY DESIGN: This prospective, assessor-blinded, comparative study compared a cohort of women with chronic pelvic pain and a high (>5/10, n=29) versus low (<5/10, n=24) score of sensitization according to the Convergences PP criteria. Participants underwent a non-invasive bladder sensory test, a rectal barostat and a muscular (algometer) and a vulvar (vulvagesiometer) sensory test. Post-stimulation pain (minutes), quality of life (SF-36) and psychological state, comprising anxiety (State-Trait Anxiety Inventory), depression (Beck Depression Index Short Form) and catastrophizing (Pain Catastrophizing Scale), were assessed. Results: The participants mostly suffered from endometriosis (35.8%), irritable bowel syndrome (35.8%), bladder pain syndrome (32.1%) and vestibulodynia (28.3%). Baseline characteristics were similar. Women with a high sensitization score had more painful diseases diagnosed (2.7 ± 1.3 vs. 1.6 ± 0.8, p = 0.002) and suffered for longer (11 ± 8 vs. 6 ± 5 years, p = 0.028) than participants with a low score. The bladder maximum capacity was equivalent between participants (399 ± 168 vs. 465 ± 164 mL, p = 0.18). However, the pain felt at each cystometric threshold was significantly increased in women with a high sensitization score. No difference was identified for the rectal pain pressure step (29.3 ± 5.5 vs. 30.7 ± 6.5 mmHg, p = 0.38). The rectal compliance was decreased in women with a high sensitization score with a significant increase in pain felt. The average of pain pressure thresholds at the 5 vulvar sites tested was decreased in these participants (162.5 ± 90.5 vs. 358.7 ± 196.5 g, p = 0.0003). Similar results were found for the average of the pain pressure thresholds at 6 muscles tested (1.34 ± 0.41 vs. 2.63 ± 1.52 kg/m2, p = 0.0002). A longer period was needed for patients with high sensitization score to obtain a VAS <3/10 after the stimulation of the bladder (4.52 ± 5.26 vs. 1.27 ± 2.96 minutes, p = 0.01), the rectum (3.75 ± 3.81 vs. 1.19 ± 1.23 minutes, p = 0.009) and the muscles (1.46 ± 1.69 vs. 0.64 ± 0.40 minutes, p = 0.002). The psychological state was equivalent between groups. No association was found between the sensory thresholds and the psychological state results. The physical component of the quality of life was reduced in women with high sensitization score (p = 0.0005) with no difference in the mental component. Conclusions: Using neurophysiological tests, this study shows that there are objective elements to assess for the presence of central sensitization, independently of psychological factors.
... 6,30,57 This task has been validated in participants with bladder pain syndrome and chronic pelvic pain. 91 Notably, even in participants without bladder pain conditions, elevated pain during this task was associated with more frequent report of daily bladder symptoms. 49 After voiding their bladder, participants ingested 20 fluid ounces of water. ...
... Like previous QST studies, 39,47 a PCA of these 40 QST measures resulted in modality-specific components: PPT S-R 79 and bladder hypersensitivity. 91 By contrast, the largest source of underlying QST variability was MMH, a component that was not modality specific. Although previous studies have conjectured that centralized hypersensitivity (eg, generalized sensory sensitivity, somatization, somatic symptoms disorders, sensory modulation disorder, etc.) 8,14,23,85 underlies chronic pain conditions, our results provide evidence of MMH being a broad construct that correlates with affective symptoms, somatic symptoms, genitourinary pain, menstrual pain, and overall pain and health. ...
Article
Multimodal hypersensitivity (MMH)—greater sensitivity across multiple sensory modalities (eg, light, sound, temperature, pressure)—is associated with the development of chronic pain. However, previous MMH studies are restricted given their reliance on self-reported questionnaires, narrow use of multimodal sensory testing, or limited follow-up. We conducted multimodal sensory testing on an observational cohort of 200 reproductive-aged women, including those at elevated risk for chronic pelvic pain conditions and pain-free controls. Multimodal sensory testing included visual, auditory, and bodily pressure, pelvic pressure, thermal, and bladder pain testing. Self-reported pelvic pain was examined over 4 years. A principal component analysis of sensory testing measures resulted in 3 orthogonal factors that explained 43% of the variance: MMH, pressure pain stimulus response, and bladder hypersensitivity. The MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Over time, MMH increasingly predicted pelvic pain and was the only component to predict outcome 4 years later, even when adjusted for baseline pelvic pain. Multimodal hypersensitivity was a better predictor of pelvic pain outcome than a questionnaire-based assessment of generalized sensory sensitivity. These results suggest that MMHs overarching neural mechanisms convey more substantial long-term risk for pelvic pain than variation in individual sensory modalities. Further research on the modifiability of MMH could inform future treatment developments in chronic pain.
... All QST measures and self-report questionnaires are detailed in the Supplementary Materials and are briefly explained here. We measured bladder sensitivity using our validated non-invasive bladder filling test that measures urgency, pain, volume, and pain descriptors across a range of thresholds (Hellman et al., 2018;Tu et al., 2013;Tu et al., 2017). Body and pelvic pain sensitivity was assessed as pressure pain thresholds (PPTs) across four body and four transvaginal sites using a digital algometer (Wagner Instruments, Greenwich, CT) and finger mounted forcesensing resistor (Trossen Robotics, Downers Grove, IL), respectively (Hellman et al., 2015;Hellman et al., 2020). ...
... The current investigation improves upon these previous attempts by administering a broader panel of nociceptive sensory tests (PPTs, CPM, TS, cold pressor, bladder provocation) and non-nociceptive supraspinal tests (visual and auditory sensitivity). Like previous QST studies (Greenspan et al., 2011;Hastie et al., 2005), a PCA of these 40 QST measures resulted in modality-specific components: PPT S-R (PC2; similar to Santana et al., 2020) and bladder hypersensitivity (PC3; similar to Tu et al., 2017). In contrast, the largest source of underlying QST variability was MMH, a component that was not modality specific. ...
Preprint
Full-text available
Multimodal hypersensitivity (MMH)---greater sensitivity across multiple sensory modalities (e.g., light, sound, temperature, pressure)---is a mechanism hypothesized to be responsible for the development of chronic pain and pelvic pain. However, previous studies of MMH are restricted given their reliance on biased self-report questionnaires, limited use of multimodal quantitative sensory testing (QST), or limited follow-up. Therefore, we conducted multimodal QST on a cohort of 200 reproductive age women at elevated risk for developing or maintaining chronic pelvic pain conditions and pain-free controls. Pelvic pain self-report was examined over a four-year follow-up period. Multimodal QST was comprised of visual, auditory, bodily pressure, pelvic pressure, thermal, and bladder testing. A principal component analysis of QST measures resulted in three orthogonal factors that explained 43\% of the variance: MMH, pressure stimulus-response, and bladder hypersensitivity. MMH and bladder hypersensitivity factors correlated with several self-report measures related to pain at baseline. Baseline self-report pain ratings were significant predictors of pelvic pain up to three years after assessment but decreased in their predictive ability of pelvic pain outcome over time. In contrast, MMH increased its predictive ability of pelvic pain outcome over time and was the only factor to predict outcome up to four years later. These results suggest that a "centralized" component of MMH is an important long-term risk factor for pelvic pain. Further research on the modifiability of MMH could provide options for future treatment avenues for chronic pain.
... To evaluate provoked bladder pain, we used a previously validated bladder test [37,38]. Participants were asked to avoid caffeine and hydrate with 12 ounces of water 1 h before their scheduled study visit. ...
Article
Full-text available
Background: Although dysmenorrhea is a highly prevalent risk factor for irritable bowel syndrome (IBS), the factors underlying this risk are not fully understood. Prior studies support a hypothesis that repeated distressing menstrual pain promotes cross-organ pelvic sensitization with heightened visceral sensitivity. Aims: To further explore cross-organ pelvic sensitization we examined the association of dysmenorrhea, provoked bladder pain, and other putative factors with self-reported IBS-domain pain frequency and new onset after 1-year follow up. Methods: We measured visceral pain sensitivity with a noninvasive provoked bladder pain test in a cohort of reproductive-aged women, enriched for those reporting moderate-to-severe menstrual pain intensity but without any prior IBS diagnosis (n = 190). We analyzed the relationship between menstrual pain, provoked bladder pain, pain catastrophizing, anxiety, and depression with primary outcomes: (1) frequency of self-reported IBS-domain pain and (2) new onset of IBS-domain pain after 1-year follow up. Results: All hypothesized factors correlated with the frequency of IBS-domain pain (p's ≤ 0.038). In a cross-sectional model, only menstrual pain (standardized adjusted odds ratio 2.07), provoked bladder pain (1.49), and anxiety (1.90) were independently associated with IBS-domain pain ≥ 2 days/month (C statistic = 0.79). One year later, provoked bladder pain (3.12) was the only significant predictor of new onset IBS-domain pain (C statistic = 0.87). Conclusion: Increased visceral sensitivity among women with dysmenorrhea could lead to IBS. Because provoked bladder pain predicted subsequent IBS, prospective studies should be performed to see if the early treatment of visceral hypersensitivity mitigates IBS.
... The study of Anderson et al. shows that, despite describing the presence of MTrPs in the coccygeus and anal sphincter muscles in patients with chronic prostatitis, the prevalence rates are much lower than those of the levator ani muscle [45]. In general, more studies support the relationship between PF muscle dysfunction and CPP patients [121][122][123], in addition to the efficacy of treatment directed at these structures, which provides benefits, relieving pain in patients with CPP after infiltration of lidocaine in the levator ani muscle; for example, the study of Langford et al. [60]. ...
Article
Full-text available
There is limited information on myofascial trigger points (MTrPs) and specific symptoms of chronic pelvic pain and, more specifically, dysmenorrhea. The objective of this study was to determine whether patients suffering from primary dysmenorrhea present alterations in mechanosensitivity and pain patterns, and greater presence of MTrPs in the abdominal and pelvic floor muscles. A case-control study was carried out with a total sample of 84 participants distributed based on primary dysmenorrhea and contraceptive treatment. The sample was divided into four groups each comprising 21 women. Data on pain, quality of life, and productivity and work absenteeism were collected; three assessments were made in different phases of the menstrual cycle, to report data on pressure pain threshold, MTrP presence, and referred pain areas. One-way ANOVA tests showed statistically significant differences (p < 0.01) between the groups, for the Physical Health domain and the total score of the SF-12 questionnaire, and for all the domains of the McGill questionnaire; but no significant differences were found in the data from the WPAI-GH questionnaire. Statistically significant data (p < 0.01) were found for mechanosensitivity in the abdominal area and limbs, but not for the lumbar assessment, within the group, with very few significant intergroup differences. The frequency of active MTrPs is higher in the groups of women with primary dysmenorrhea and during the menstrual phase, with the prevalence of myofascial trigger points of the iliococcygeus muscle being especially high in all examination groups (>50%) and higher than 70% in women with primary dysmenorrhea, in the menstrual phase, and the internal obturator muscle (100%) in the menstrual phase. Referred pain areas of the pelvic floor muscles increase in women with primary dysmenorrhea.
Article
Pain with bladder filling remains an unexplained clinical presentation with limited treatment options. Here, we aim to establish the clinical significance of bladder filling pain using a standardized test and the associated neural signature. We studied individuals diagnosed with urologic chronic pelvic pain syndrome (UCPPS) recruited as part of the multidisciplinary approach to the study of chronic pelvic pain (MAPP) study. Patients with urologic chronic pelvic pain syndrome (N = 429) and pain-free controls (N = 72) underwent a test in which they consumed 350 mL of water and then reported pain across an hour-long period at baseline and 6 months. We used latent class trajectory models of these pain ratings to define UCPPS subtypes at both baseline and 6 months. Magnetic resonance imaging of the brain postconsumption was used to examine neurobiologic differences between the subtypes. Healthcare utilization and symptom flare-ups were assessed over the following 18 months. Two distinct UCPPS subtypes were identified, one showing substantial pain related to bladder filling and another with little to no pain throughout the test. These distinct subtypes were seen at both baseline and 6 month timepoints. The UCPPS subtype with bladder-filling pain (BFP+) had altered morphology and increased functional activity in brain areas involved in sensory and pain processing. Bladder-filling pain positive status predicted increased symptom flare-ups and healthcare utilization over the subsequent 18 months when controlling for symptom severity and a self-reported history of bladder-filling pain. These results both highlight the importance of assessing bladder filling pain in heterogeneous populations and demonstrate that persistent bladder-filling pain profoundly affects the brain.
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Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.
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Somatization disorder has been described in several comorbid functional syndromes of urological chronic pelvic pain syndrome, such as irritable bowel syndrome. We investigated whether a subset of patients with urological chronic pelvic pain syndrome may have the polysymptomatic, polysyndromic presentation pattern that is common in somatization disorder. A total of 70 male and female patients with urological chronic pelvic pain syndrome and 35 age matched controls without the syndrome completed a 59-item symptom checklist to assess the classic polysymptomatic, polysyndromic symptom pattern. The 2 operational tools used were the Perley-Guze derived symptom checklist and the somatic symptom algorithm used for Diagnostic and Statistical Manual, 4th Edition, Text Revision somatization disorder criteria. Female patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome) reported significantly more nonpain symptoms and pain symptoms outside the pelvis than control female urology patients (p=0.0016 and 0.0018, respectively). Female patients with urological chronic pelvic pain syndrome were more likely to endorse a polysymptomatic, polysyndromic symptom pattern than female controls (27% vs 0%, p=0.0071). In contrast, male patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome and/or chronic prostatitis/chronic pelvic pain syndrome) did not report more extrapelvic pain than male controls (p=0.89). Male patients with urological chronic pelvic pain syndrome were not more likely than male controls to have a polysymptomatic, polysyndromic symptom pattern. A subset of female patients with urological chronic pelvic pain syndrome endorses numerous extrapelvic symptoms across multiple organ systems. The checklist may be valuable to assess patients for this polysymptomatic, polysyndromic symptom pattern, which is common in somatization disorder. Recognizing this polysymptomatic, polysyndromic presentation will prompt clinicians to investigate further to determine whether somatization disorder may be an underlying diagnosis in a small subset of patients with urological chronic pelvic pain syndrome who complain of numerous extrapelvic symptoms.
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This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy.
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To determine predictors of physical and emotional discomfort associated with urodynamic testing in men and women both with and without neurologic conditions. An anonymous questionnaire-based study was completed by patients immediately after undergoing fluoroscopic urodynamic testing. Participants were asked questions pertaining to their perceptions of physical and emotional discomfort related to the study, their urologic and general health history, and demographics. Logistic regression was performed to determine predictors of physical and emotional discomfort. A total of 314 patients completed the questionnaire representing a response rate of 60%. Half of the respondents (50.7%) felt that the examination was neither physically nor emotionally uncomfortable, whereas 29.0% and 12.4% of respondents felt that the physical and emotional components of the examination were most uncomfortable, respectively. Placement of the urethral catheter was the most commonly reported component of physical discomfort (42.9%), whereas anxiety (27.7%) was the most commonly reported component of emotional discomfort. Presence of a neurologic problem (odds ratio, 0.273; 95% confidence interval, 0.121-0.617) and older age (odds ratio, 0.585; 95% confidence interval, 0.405-0.847) were factors associated with less physical discomfort. There were no significant predictors of emotional discomfort based on our model. Urodynamic studies were well tolerated regardless of gender. Presence of a neurologic condition and older age were predictors of less physical discomfort. These findings are useful in counseling patients regarding what to expect when having urodynamic procedures. Copyright © 2015 Elsevier Inc. All rights reserved.
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Unlabelled: Case-control studies have consistently associated psychological factors with chronic pain in general and with temporomandibular disorder (TMD) specifically. However, only a handful of prospective studies have explored whether preexisting psychological characteristics represent risk factors for first-onset TMD. The current findings derive from the prospective cohort study of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 3,263 TMD-free participants completed a battery of psychological instruments assessing general psychological adjustment and personality, affective distress, psychosocial stress, somatic symptoms, and pain coping and catastrophizing. Study participants were then followed prospectively for an average of 2.8 years to ascertain cases of first-onset of TMD, and 2,737 provided follow-up data and were considered in the analyses of TMD onset. In bivariate and demographically adjusted analyses, several psychological variables predicted increased risk of first-onset TMD, including reported somatic symptoms, psychosocial stress, and affective distress. Principal component analysis of 26 psychological scores was used to identify latent constructs, revealing 4 components: stress and negative affectivity, global psychological and somatic symptoms, passive pain coping, and active pain coping. In multivariable analyses, global psychological and somatic symptoms emerged as the most robust risk factor for incident TMD. These findings provide evidence that measures of psychological functioning can predict first onset of TMD. Future analyses in the OPPERA cohort will determine whether these psychological factors interact with other variables to increase risk for TMD onset and persistence. Perspective: This article reports that several premorbid psychological variables predict first-onset TMD in the OPPERA study, a large prospective cohort study designed to discover causal determinants of TMD pain. Measures of somatic symptoms were most strongly associated with TMD onset, but perceived stress, previous life events, and negative affect also predicted TMD incidence.
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To evaluate pain and embarrassment associated with invasive urodynamics and to determine underlying factors. One hundred seventy one consecutive patients referred to our department for invasive urodynamics were evaluated using visual numeric rating scales for sensations of apprehension, pain, and embarrassment during several steps of the procedure (scores ranging from 0 [no symptom] to 10 [worst imaginable symptom]). We also investigated the influence of sex, age, information provided before urodynamics, and medical indication on these sensations. The Spearman correlation, non-parametric test, and logistic regression analysis were performed to determine explicative factors for the most painful sensations. The mean age was 61.0 (standard deviation ± 15 years). The mean (95% confidence interval [CI]) apprehension level was 2.9/10 (2.4; 3.4). The mean (95% CI) pain levels at installation on urodynamic table, transurethral catheter insertion (cystometry), and catheter repositioning (urethral pressure profilometry) were 0.3/10 (0.1; 0.5), 1.9/10 (1.6; 2.3), and 1.3/10 (1.0; 1.7), respectively. At catheter insertion, 25% of patients reported a pain level ≥4/10. The mean embarrassment level due to urination in front of the doctor was 1.9/10 (1.4; 2.3). Painful sensations reported during the different steps were strongly correlated with each other and with levels of apprehension and embarrassment. Age <54 years (lower quartile) and apprehension level were the only factors associated with painful sensation. Our study confirms that invasive urodynamics is a well-tolerated procedure. However, some patients experience high levels of pain and embarrassment throughout the procedure. Younger age and apprehension were the most influential factors. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc.
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The factors that underlie pelvic pain are poorly understood. Specifically, the relative influence of dysmenorrhea and psychological factors in the etiology of non-cyclic pelvic pain conditions, such as interstitial cystitis and irritable bowel syndrome, is unknown. To further characterize pelvic pain, we compared the frequency of menstrual, somatosensory, and psychological risk factors between women with and without severe non-cyclic pelvic pain symptoms. 1,012 reproductive-aged women completed a 112-item questionnaire with domains including mood, fatigue, physical activity, somatic complaint, and pain. Questionnaire items included existing items for menstrual distress and newly-written items derived from qualitative interviews. The relationship of dysmenorrhea and non-cyclic pelvic pain complaints (dyspareunia, dyschezia, or dysuria) was modeled using quantile regression. Among women who menstruate regularly, those with dysmenorrhea had disproportionally more severe non-cyclic pelvic pain (54/402, 13%) than women without dysmenorrhea (5/432, 1%; OR=13, 95% CI=5-33). In a multivariate-adjusted model, dysmenorrhea (β=.17), activity capability (β=.17), somatic complaint (β=.17), and bodily pain (β=.12) and were the primary predictors of non-cyclic pelvic pain. Depression (β=.03) and anxiety (β=.01) were not significantly predictive. The presence of dysmenorrhea, somatic complaint and low activity capability predicted 90% of the cases of women with non-cyclic pelvic pain. The association between dysmenorrhea and non-cyclic pelvic pain, suggests that menstrual pain is an etiological factor in non-cyclic pelvic pain, whereas depression and anxiety may be secondary effects. Longitudinal studies are needed to determine whether dysmenorrhea causally influences development of non-cyclic pelvic pain or shares common underlying neural mechanisms.
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Objective: Catheterization to measure bladder sensitivity is aversive and hinders human participation in visceral sensory research. Therefore, we sought to characterize the reliability of sonographically estimated female bladder sensory thresholds. To demonstrate this technique's usefulness, we examined the effects of self-reported dysmenorrhea on bladder pain thresholds. Methods: Bladder sensory threshold volumes were determined during provoked natural diuresis in 49 healthy women (mean age, 24±8 y) using 3-dimensional ultrasound. Cystometric thresholds (Vfs, first sensation; Vfu, first urge; Vmt, maximum tolerance) were quantified and related to bladder urgency and pain. We estimated the reliability (1-wk retest and interrater). Self-reported menstrual pain was examined in relationship to bladder pain, urgency, and volume thresholds. Results: Average bladder sensory thresholds (mL) were Vfs (160±100), Vfu (310±130), and Vmt (500±180). Interrater reliability ranged from 0.97 to 0.99. One-week retest reliability was Vmt=0.76 (95% CI, 0.64-0.88), Vfs=0.62 (95% CI, 0.44-0.80), and Vfu=0.63 (95% CI, 0.47-0.80). Bladder filling rate correlated with all thresholds (r=0.53 to 0.64, P<0.0001). Women with moderate to severe dysmenorrhea pain had increased bladder pain and urgency at Vfs and increased pain at Vfu (P's<0.05). In contrast, dysmenorrhea pain was unrelated to bladder capacity. Discussion: Sonographic estimates of bladder sensory thresholds were reproducible and reliable. In these healthy volunteers, dysmenorrhea was associated with increased bladder pain and urgency during filling but unrelated to capacity. Plausibly, women with dysmenorrhea may exhibit enhanced visceral mechanosensitivity, increasing their risk to develop chronic bladder pain syndromes.