Multimodal Hypersensitivity Predicts Pelvic Pain Outcome 4 Years Later

Abstract

Background and Aims: Multimodal hypersensitivity (MMH) is a hallmark symptom associated with chronic pain conditions [3–5,8,10,12,14] and mechanisms responsible for MMH may be a key reason why individuals develop chronic pain [2,7] or a determinant of treatment response [6,9]. MMH is increased sensitivity across multiple sensory modalities (e.g., light, sound, temperature, pressure) common in “centralized” or nociplastic pain conditions [1,13]. Individuals with chronic pelvic pain conditions, like irritable bowel syndrome and bladder pain syndrome, similarly exhibit MMH despite not having any outward pelvic pathology (e.g., infection, endometriosis, etc.) [11,13]. However, our understanding of MMH is limited given previous investigations’ reliance on subjective self-report questionnaires, unidimensional quantitative sensory testing (QST), and limited longitudinal follow-up. A synergistic approach exploiting multiple forms of QST with longitudinal data could improve our understanding of MMH to identify an individual's susceptibility to developing chronic pain and accelerate the advancement of proactive preventative measures and treatments.
Methods: We conducted multimodal QST on a cohort of 200 reproductive age women at elevated risk for developing chronic pelvic pain conditions and pain-free controls. Multimodal QST comprised visual, auditory, bodily pressure, pelvic pressure, thermal, and bladder testing. Pelvic pain outcome was examined over a four-year follow-up period using self-report questionnaires and was defined by participants’ rating their average feeling of 1) menstrual and non-menstrual pelvic pain, 2) pain with urination, and 3) pain with bowel movements during the past week using a 0-100 VAS. Statistical analyses included principal components analysis (PCA) to assess QST variability, and multiple regression to identify predictors of longitudinal pelvic pain outcome.
Results: A PCA of 40 QST measures resulted in three orthogonal factors that explained 43% of the variance: MMH (21%), pressure pain threshold stimulus-response (PPT S-R; 12%), and bladder hypersensitivity (10%). The MMH and bladder hypersensitivity factors correlated with several self-report measures, including affective symptoms, somatic symptoms, genitourinary pain, menstrual pain, and overall pain and health. In the longitudinal regression models, baseline pelvic pain provided a diminishing degree of predictive power annually. In contrast, MMH provided an increasing degree of predictive power over time and was the only predictor of pelvic pain four years later (η_p^2 = .15, p < .001). The bladder hypersensitivity and PPT S-R components did not predict pelvic pain outcome at any year.
Conclusions: This investigation provided crucial experimental evidence of MMH, a hypothesized construct underlying “centralized” mechanisms of pain sensitivity, and its ability to predict worse pelvic pain outcome. Prior QST studies implicate specific peripheral hyperalgesic or descending modulatory pathways mediating sensitization; however, we suggest that these interpretations underestimate the risk for developing chronic pain because previous studies fail to quantify MMH, a broader multimodal mechanism responsible for sensory unpleasantness. Future research is needed to clarify the mechanisms underlying MMH to develop preventative strategies for chronic pelvic pain.
Conflicts of Interest: The authors report no direct conflicts of interest.
Source of Financial Support for the Project: This study was funded by the National Institute of Child and Human Development (R01HD098193) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100368).
Ethical Permissions: All participants provided informed consent and followed protocols approved by NorthShore University HealthSystem's Institutional Review Board.
Relevance for Patient Care: Further research on the detectability and modifiability of multimodal hypersensitivity could provide options for future diagnostic and treatment avenues for chronic pain.
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Full text

• 200 reproductive-age women (age M=24.9, SD=6.4 years) from the
Chronic Pain Risk Associated with Menstrual Period Pain study
(NCT02214550)
• Groups: n=132 dysmenorrhea (66%), 30 pain-free controls (15%), 22
chronic pain (11%), 16 bladder pain syndrome (8%)
Multimodal Sensory Testing
• Pressure Pain Thresholds (PPTs) • Bladder Filling Test
• Visual & Auditory Stimulation • Temporal Summation (TS)
• Conditioned Pain Modulation (CPM) • Cold Pain
Self-Report Questionnaires
• ICSI + ICPI •GUPI • CMSI • BSI • Menstrual Pain
• PROMIS anxiety, depression, pain interference, pain behavior, global
physical health, global mental health
Sensory Composite Variables
Sensory testing variables were Z-scored and summed to form:
• Traditional QST = PPTs + TS + CPM + cold pain
• Bladder Test = bladder pain + urgency + descriptors
• Audio/Visual = unpleasantness + stimulus-response slope
Outcome: Pelvic Pain Composite (0-100 VAS)
Annually participants rated their average feeling, in the past week, of:
• menstrual and non-menstrual pelvic pain,
• pain with urination,
• and pain with bowel movements
Statistical Analysis
• A principal component analysis (PCA) of
40 sensory testing measures resulted in
3 PCs that were further explored
• Annual pelvic pain outcome was
regressed on PCs and composites
Matthew J. Kmiecik1,2, Frank F. Tu1,2, Daniel J. Clauw3 & Kevin M. Hellman1,2
1NorthShore University HealthSystem, 2The University of Chicago Pritzker School of Medicine, 3The University of Michigan Medical School
References
[1] Fitzcharles M-A, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Nociplastic pain: towards an
understanding of prevalent pain conditions. Lancet 2021;397:2098–110.
[2] Iacovides, S., Avidon, I. & Baker, F. C. What we know about primary dysmenorrhea today: a critical
review. Hum. Reprod. Update 21, 762–778 (2015).
Acknowledgements
We thank Dr. GF Gebhart for his sage advice and lab staff for performing sensory testing
assessments. The data and code used in data processing and analysis are available on Open
Science Framework. FFT reports personal fees from Myovant, Tremeau Pharmaceuticals, and
UroShape, royalties from Wolters Kluwer, and grant support from Dot Laboratories and Eximis
outside this presented work. The remaining authors report no additional conflicts of interest.
Three components are explored from PCA Distributions of sensory testing composites and PCs
Multimodal hypersensitivity (PC1) is the best predictor
of current and future pelvic pain
• Multimodal hypersensitivity (MMH)—greater sensitivity across multiple
sensory modalities (e.g., light, sound, temperature, pressure)—is
associated with the development of chronic pain [1]
• To quantify the risk of MMH on the development of chronic pain we
conducted multimodal sensory testing in a cohort of at-risk women
• This at-risk cohort included varying degrees of menstrual pain, an
extremely prevalent (45-95%) risk factor for chronic pain [2]
Introduction
Contact
0
25
50
75
100
Baseline 1 2 3 4
Year
Mean Pelvic Pain
Composite (VAS)
0
5
10
15
20
010 20 30 40
Component
% Variance Explained
Permutation Testing
(2,000 iterations)
ns p < .001
-10
-5
0
5
10
Multimodal Hypersensitivity (PC1)
Factor Scores
0
25
50
75
100
Baseline 1 2 3 4
Year
Pelvic Pain Outcome
(0-100 VAS)
> 75%
< 25%
25-75%
< 25%
> 75%
25-75%
-1 -0.5 0 0.5 +1
r
PC 1
MMH
PC 2
PPT S-R
PC 3
Bladder Hypersensitivity
BSI (Somatic Symptoms)
CMSI 3 Months (Last Year)
CMSI 3 Months (Lifetime)
Global Mental Health
Global Physical Health
GUPI Total
GUPI Pain Subscale
GUPI QOL Subscale
GUPI Urinary Subscale
Interstitial Cystitis Problem Index
Interstitial Cystitis Symptom Index
Menstrual Pain
PROMIS Anxiety
PROMIS Depression
PROMIS PB
PROMIS PI
Bootstrapped 95% CI
p < .05 ns
-5.0
-2.5
0.0
2.5
5.0
QST Bladder
Test
Audio/
Visual
Z-Score
-5.0
-2.5
0.0
2.5
5.0
MMH
(PC1)
PPT S-R
(PC2)
Bladder
Hyper. (PC3)
Bladder
Hyper.
.00
.05
.10
.15
.20
.25
1 2 3 4
Year
.00
.05
.10
.15
.20
.25
1 2 3 4
Year
p
2
η
(Pelvic Pain Outcome)
p
2
η
(Pelvic Pain Outcome)
Baseline
Pelvic Pain
QST
Bladder
Test
Audio/
Visual
Baseline
Pelvic Pain
MMH
PPT S-R
ns
p < .05
← PC1 Multimodal Hypersensitivity →
𝜎2 = 20.6%, p=.005
← PC2 PPT Stimulus-Response →
𝜎2 = 12.4%, p = .005
← PC1 Multimodal Hypersensitivity →
𝜎2 = 20.6%, p=.005
← PC3 Bladder Hyper. →
𝜎2 = 9.5%, p = .005
← PC2 PPT Stimulus-Response →
𝜎2 = 12.4%, p = .005
← PC3 Bladder Hyper. →
𝜎2 = 9.5%, p = .005
After Pain
TS
PPTs
CPM
Bladder
Task
Auditory
Visual
Pelvic
Desc.
Cold
Pain
Bladder
Desc.
After Pain
TS
PPTs
CPM Bladder
Task
Auditory
Visual Pelvic
Desc.
Cold
Pain
Bladder
Desc.
PPTs
After Pain
TS
Bladder
Task
Bladder
Desc.
Pelvic
Desc.
Visual
CPM
Auditory
p < .05
Bootstrapped Significance
Axis: X Y Both None
PC1 vs. PC2 PC1 vs. PC3
PC2 vs. PC3
Cold
Pain
Multimodal (PC1) and bladder hypersensitivity (PC3)
correlate with self-report measures
Method
Aims
1. Quantify multimodal hypersensitivity in an at-risk cohort
2. Compare multimodal hypersensitivity to traditional sensory tests
3. Identify the best predictor of future pelvic pain (four-year follow up)
Multimodal hypersensitivity (PC1) distinguishes
pelvic pain outcome
Preprint Here!
mkmiecik14@gmail.com
@mattkmiecik14
Matthew J Kmiecik, PhD
• Data support multimodal hypersensitivity as 1) a construct distinct from
modality-specific nociception and 2) important to pelvic pain outcome
• Multimodal sensory testing improves the prediction of pain outcome
over unimodal approaches ubiquitous in pain research (i.e., QST)
CONCLUSIONS
Multimodal Hypersensitivity Predicts Pelvic Pain Outcome 4 Years Later (PTU343)