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Multimodal hypersensitivity derived from quantitative sensory testing predicts pelvic pain outcome: an observational cohort study
Abstract
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.
Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulatory technique with the potential to provide pain relief. However, tDCS effects on pain are variable across existing studies, possibly related to differences in stimulation protocols and expectancy effects. We investigated the independent and joint effects of contralateral motor cortex tDCS (anodal vs cathodal) and socially induced expectations (analgesia vs hyperalgesia) about tDCS on thermal pain. We employed a double-blind, randomized 2 × 2 factorial cross-over design, with 5 sessions per participant on separate days. After calibration in Session 1, Sessions 2 to 5 crossed anodal or cathodal tDCS (20 minutes 2 mA) with socially induced analgesic or hyperalgesic expectations, with 6 to 7 days between the sessions. The social manipulation involved videos of previous “participants” (confederates) describing tDCS as inducing a low-pain state (“analgesic expectancy”) or hypersensitivity to sensation (“hyperalgesic expectancy”). Anodal tDCS reduced pain compared with cathodal stimulation (F(1,19.9) = 19.53, P < 0.001, Cohen d = 0.86) and analgesic expectancy reduced pain compared with hyperalgesic expectancy (F(1,19.8) = 5.62, P = 0.027, Cohen d = 0.56). There was no significant interaction between tDCS and social expectations. Effects of social suggestions were related to expectations, whereas tDCS effects were unrelated to expectancies. The observed additive effects provide novel evidence that tDCS and socially induced expectations operate through independent processes. They extend clinical tDCS studies by showing tDCS effects on controlled nociceptive pain independent of expectancy effects. In addition, they show that social suggestions about neurostimulation effects can elicit potent placebo effects.
Nociplastic pain is a mechanistic term used to describe pain that arises or is sustained by altered nociception, despite the absence of tissue damage. Although nociplastic pain has distinct pathophysiology from nociceptive and neuropathic pain, these pain mechanisms often coincide within individuals, which contributes to the intractability of chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, depression and anxiety. Individuals with nociplastic pain are often diffusely tender - indicative of hyperalgesia and/or allodynia - and are often more sensitive than others to non-painful sensory stimuli such as lights, odours and noises. This Review summarizes the risk factors, clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity.
Every day our sensory systems perceive and integrate a variety of stimuli containing information vital for our survival. Pain acts as a protective warning system, eliciting a response to remove harmful stimuli; it may also be a symptom of an illness or present as a disease itself. There is a growing need for additional pain-relieving therapies involving the multisensory integration of smell and taste in pain modulation, an approach that may provide new strategies for the treatment and management of pain. While pain, smell, and taste share common features and are strongly linked to emotion and cognition, their interaction has been poorly explored. In this review, we provide an overview of the literature on pain modulation by olfactory and gustatory substances. It includes adult human studies investigating measures of pain threshold, tolerance, intensity, and/or unpleasantness. Due to the limited number of studies currently available, we have structured this review as a narrative in which we comment on experimentally induced and clinical pain separately on pain–smell and pain–taste interaction. Inconsistent study findings notwithstanding, pain, smell, and taste seem to interact at both the behavioral and the neural levels. Pain intensity and unpleasantness seem to be affected more by olfactory substances, whereas pain threshold and tolerance are influenced by gustatory substances. Few pilot studies to date have investigated these effects in clinical populations. While the current results are promising for the future, more evidence is needed to elucidate the link between the chemical senses and pain. Doing so has the potential to improve and develop novel options for pain treatment.
In the last decade, machine learning has been widely used in different fields, especially because of its capacity to work with complex data. With the support of machine learning techniques, different studies have been using data-driven approaches to better understand some syndromes like mild cognitive impairment, Alzheimer’s disease, schizophrenia, and chronic pain. Chronic pain is a complex disease that can recurrently be misdiagnosed due to its comorbidities with other syndromes with which it shares symptoms. Within that context, several studies have been suggesting different machine learning algorithms to classify or predict chronic pain conditions. Those algorithms were fed with a diversity of data types, from self-report data based on questionnaires to the most advanced brain imaging techniques. In this study, we assessed the sensitivity of different algorithms and datasets classifying chronic pain syndromes. Together with this assessment, we highlighted important methodological steps that should be taken into account when an experiment using machine learning is conducted. The best results were obtained by ensemble-based algorithms and the dataset containing the greatest diversity of information, resulting in area under the receiver operating curve (AUC) values of around 0.85. In addition, the performance of the algorithms is strongly related to the hyper-parameters. Thus, a good strategy for hyper-parameter optimization should be used to extract the most from the algorithm. These findings support the notion that machine learning can be a powerful tool to better understand chronic pain conditions.
Purpose
Some individuals with chronic pain find daily life sensations (eg, noise, light, or touch) aversive. This amplification of multisensory sensations has been associated with centrally mediated plasticity; for example, greater multisensory sensitivity (MSS) occurs in patients with fibromyalgia than rheumatoid arthritis. However, whether MSS preferentially relates to pain measures which reflect central influences (eg, dynamic quantitative sensory testing (QST) or referred pain), or whether the MSS-pain relationship requires priming from chronic pain, is unknown. Thus, this cross-sectional study investigated the relationships between MSS assessed in a pain-free state and evoked pain sensitivity.
Methods
Experimental intramuscular infusion pain and multiple static and dynamic QST were assessed in 465 healthy, pain-free adults: pain thresholds using pressure (PPTs) and heat (HPTs), temporal summation of pain (TSP) using pressure, heat or punctate stimuli, and conditioned pain modulation (CPM) using pressure or heat test stimuli. MSS was assessed using 7 items from Barsky’s Somatosensory Amplification Scale. Differences in pain and QST between sex-specific MSS quartiles were assessed, adjusting for multiple comparisons. All participants completed at least one intramuscular infusion condition, but not all were asked to complete each QST (n=166-465).
Results
Both static and dynamic QST differed between highest and lowest MSS quartiles using pressure stimuli: lower PPTs (adjusted-p<0.01); increased pressure TSP (adjusted-p=0.02); lower pressure CPM (adjusted-p=0.01). However, none of the heat or punctate QST measures (HPTs, TSP, or CPM) differed between MSS quartiles (adjusted-p>0.05). Odds of experiencing TSP or referred pain was not greater, whereas CPM was 8-fold less likely, in those with highest MSS.
Conclusion
Normal variation in non-noxious MSS is related to both static and dynamic pain sensitivity, without sensitization associated with chronic pain, but is dependent on the QST stimulus. Thus, common influences on MSS and pain sensitivity may involve central mechanisms but are likely more complex than previously recognized.
Background
Because the development of neuropathic symptoms contributes to pain severity and chronification after surgery, their early prediction is important to allow targeted treatment.
Objectives
We longitudinally investigated trajectories of signs and symptoms in patients undergoing thoracotomy and assessed whether and at which time they were related to the development of neuropathic pain symptoms six months after surgery.
Methods
Presurgical and six, monthly postsurgical assessments included questionnaires for mental and physical well‐being (e.g. depression/anxiety, pain catastrophizing, sleep quality, neuropathic pain symptoms), and quantitative sensory testing (QST).
Results
QST trajectories indicated nerve impairment of the surgery site with predominant loss of function. Signs of recovery towards the end of the assessment period were observed for some tests. Unsupervised cluster analysis with NPSI scores six months after surgery as clustering variable identified one group with no/low levels of neuropathic symptoms and one with moderate levels. The two groups differed w.r.t. several signs and symptoms already at early time points. Notably, neuropathic pain anywhere in the body differed already preoperatively and sleep impairment differentiated the two groups at all time points. Regression analysis revealed three factors that seemed particularly suited to predicted six months NPSI scores, namely preoperative neuropathic pain symptoms, with contributions from sleep impairment one month after surgery and the presence of dynamic mechanical allodynia three months after surgery.
Conclusions
Clinical routine should focus on the individual’s physiological state, including pre‐existing neuropathic pain and sleep quality to identify patients early who might be at risk to develop chronic post‐surgical neuropathic pain.
Objective:
This study sought to characterize central sensitization further among women with chronic pelvic pain by identifying temporal summation using a cotton swab (Q-tip) test that can be used at the bedside.
Method:
A total of 36 women (18 with chronic pain and allodynia; 18 without pain) were recruited. Both groups were randomized to receive three strokes of a benign stimulus on the abdomen at differing frequencies: 10, 30, or 100 seconds. Each group included six women. Pain was assessed using a rating scale from 1 to 10. Data were analyzed using the multivariate approach to repeated measures analysis of variance.
Results:
The pattern of pain scores differed significantly between women with and without chronic pain (P = 0.002). Women with chronic pelvic pain and allodynia showed a statistically significant increase in pain with successive strokes of the Q-tip (P = 0.012 for stroke 1 vs. 2, P = 0.026 for stroke 2 vs. 3, and P = 0.005 for stroke 1 vs. 3).
Conclusion:
Women with chronic pelvic pain and allodynia show significant worsening of pain with successive strokes of a cotton-tip applicator, thus indicates that wind-up and central sensitization are present in women with chronic pelvic pain and allodynia. Identification of summation is further evidence of neuroplasticity, which is helpful in innovative therapies for chronic pelvic pain.
Sensory modulation disorder (SMD) affects sensory processing across single or multiple sensory systems. The sensory over-responsivity (SOR) subtype of SMD is manifested clinically as a condition in which non-painful stimuli are perceived as abnormally irritating, unpleasant, or even painful. Moreover, SOR interferes with participation in daily routines and activities (Dunn, 2007; Bar-Shalita et al., 2008; Chien et al., 2016), co-occurs with daily pain hyper-sensitivity, and reduces quality of life due to bodily pain. Laboratory behavioral studies have confirmed abnormal pain perception, as demonstrated by hyperalgesia and an enhanced lingering painful sensation, in children and adults with SMD. Advanced quantitative sensory testing (QST) has revealed the mechanisms of altered pain processing in SOR whereby despite the existence of normal peripheral sensory processing, there is enhanced facilitation of pain-transmitting pathways along with preserved but delayed inhibitory pain modulation. These findings point to central nervous system (CNS) involvement as the underlying mechanism of pain hypersensitivity in SOR. Based on the mutual central processing of both non-painful and painful sensory stimuli, we suggest shared mechanisms such as cortical hyper-excitation, an excitatory-inhibitory neuronal imbalance, and sensory modulation alterations. This is supported by novel findings indicating that SOR is a risk factor and comorbidity of chronic non-neuropathic pain disorders. This is the first review to summarize current empirical knowledge investigating SMD and pain, a sensory modality not yet part of the official SMD realm. We propose a neurophysiological mechanism-based model for the interrelation between pain and SMD. Embracing the pain domain could significantly contribute to the understanding of this condition’s pathogenesis and how it manifests in daily life, as well as suggesting the basis for future potential mechanism-based therapies.
Abstract
Hypersensitivity due to central pain mechanisms can influence recovery and lead to worse clinical outcomes, but the ability of quantitative sensory testing (QST), an index of sensitisation, to predict outcomes in chronic musculoskeletal disorders remains unclear. We systematically reviewed the evidence for ability of QST to predict pain,
disability and negative affect using searches of CENTRAL, MEDLINE, EMBASE, AMED, CINAHL and PubMed databases up to April 2018. Title screening, data extraction, and methodological quality assessments were performed independently by 2 reviewers. Associations were reported between baseline QST and outcomes
using adjusted (β) and unadjusted (r) correlations. Of the 37 eligible studies (n=3860 participants), 32 were prospective cohort studies and 5 randomised controlled trials. Pain was an outcome in 30 studies, disability in 11 and negative affect in 3. Meta-analysis revealed that baseline QST predicted musculoskeletal pain (mean r=0.31, 95%CI: 0.23 to 0.38, n=1057 participants) and disability (mean r=0.30, 95%CI: 0.19 to 0.40, n=290 participants). Baseline modalities quantifying central mechanisms such as temporal summation (TS) and conditioned pain modulation (CPM) were associated with follow-up pain (TS: mean r=0.37, 95%CI: 0.17 to 0.54; CPM: r=0.36, 95%CI: 0.20
to 0.50), whereas baseline mechanical threshold modalities were predictive of follow-up disability (mean r=0.25, 95%CI: 0.03 to 0.45). QST indices of pain hypersensitivity might help develop targeted interventions aiming to improve outcomes across a range of musculoskeletal conditions.
Chronic pain, one of the most common reasons adults seek medical care (1), has been linked to restrictions in mobility and daily activities (2,3), dependence on opioids (4), anxiety and depression (2), and poor perceived health or reduced quality of life (2,3). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% (5), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions (5). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.
Central sensitization refers to the amplification of pain by central nervous system mechanisms. Classically described as a consequence of ongoing nociceptive input, it is increasingly recognized that central sensitization also occurs independent of peripheral injury or inflammation. Features of central sensitization have been identified in nearly all chronic pain conditions, and it is considered the primary underlying cause of pain in conditions such as fibromyalgia. Central sensitization is characterized in these conditions by widespread pain and multisite hyperalgesia/allodynia. Co‐occurring symptoms include fatigue, mood and cognitive problems, sleep disturbances, and multisensory hypersensitivity. Individuals with central sensitization often report previous exposure to psychosocial or physical stressors, and a higher personal lifetime and family history of pain, with the latter findings supported by genetic studies. Neuroimaging studies of central sensitization show evidence of: changes in brain gray matter in pain processing regions; neurochemical imbalances; and altered resting brain‐network connectivity between pronociceptive and antinociceptive brain areas. Immune system abnormalities have also been demonstrated in individuals with central sensitization. The recognition of central sensitization, and whether it is being driven by ongoing nociceptive input or it is occurring in the absence of a peripheral driver, is critical for effective pain management.
To study the characteristics of temporal summation (TS) and conditioned pain modulation (CPM) in fibromyalgia (FM) patients, we systematically searched Pubmed and EMBASE for studies using TS or CPM comparing FM patients to healthy controls. We computed Hedge's g, risk of bias, sensitivity analysis and meta-regression tests with 10000 Monte-Carlo permutations. Twenty-three studies (625 female/23 male FM patients and 591 female/81 male healthy controls) were included. The meta-analyses showed an effect size of 0.53 for TS (p<0.001; 95% CI 0.23 to 0.83), which is a 68% relative difference between patients and controls, and of 0.57 for CPM (p<0.001; 95% CI -0.88 to -0.26), representing a 65% relative difference between the groups. The qualitative analyses revealed large heterogeneity between study protocols. Although studies were of low risk of bias, lack of blinding was substantial. Sensitivity analysis and meta-regression identified type and site of stimulation, age, lab, sample size, and medication control as important sources of between study variability. We demonstrate a significant alteration of pain modulation mechanisms in FM patients.
Perspective
: This novel meta-analysis provides evidence for defective endogenous pain modulation in fibromyalgia patients. We explored the impact of covariates on between study variability in these paradigms. These biomarkers may aid in diagnosis, and treatment of patients. However, validation requires further investigation under strict methodological settings, and into individual patient covariates.
According to empirical studies and recent theories, people differ substantially in their reactivity or sensitivity to
environmental influences with some being generally more affected than others. More sensitive individuals have been described as orchids and less-sensitive ones as dandelions. Applying a data-driven approach, we explored the existence of sensitivity groups in a sample of 906 adults who completed the highly sensitive person (HSP) scale. According to factor analyses, the HSP scale reflects a bifactor model with a general sensitivity factor. In contrast to prevailing theories, latent class analyses consistently suggested the existence of three rather than two groups. While we were able to identify a highly sensitive (orchids, 31%) and a low-sensitive group (dandelions, 29%), we also detected a third group (40%) characterised by medium sensitivity, which we refer to as tulips in keeping with the flower metaphor. Preliminary cut-off scores for all three groups are provided. In order to characterise the different sensitivity groups, we investigated group differences regarding the Big Five personality traits, as well as experimentally assessed emotional reactivity in an additional independent sample. According to these follow-up analyses, the three groups differed in neuroticism, extraversion and emotional reactivity to positive mood induction with orchids scoring significantly higher in neuroticism and emotional reactivity and lower in extraversion than the other two groups (dandelions also differed significantly from tulips). Findings suggest that environmental sensitivity is a continuous and normally distributed trait but that people fall into three distinct sensitive groups along a sensitivity continuum.
Primary dysmenorrhea (PD) has been the focus of a number of experimental pain studies. Although a number of reviews exist, few have critically evaluated the existing body of research on PD and experimental and procedural pain. Data from 19 published research articles that include women with PD and responses to an experimental or procedural pain stimulus (or stimuli) suggest that women with PD may have elevated pain reactivity, as compared to women without PD. This pattern appears to be true across different phases of the menstrual cycle. However, there is an abundance of conflicting findings, which may be due to significant methodological issues such as inconsistent definitions of PD, wide variation in experimental pain methodologies, and inaccurate assessment of the menstrual cycle. Future research should focus on identifying specific symptoms (i.e., pain threshold ratings) to more clearly define what constitutes PD, establish reliable and valid laboratory testing protocols, and assess the menstrual cycle with greater precision.
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.
BACKGROUND Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological
condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly
treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a
normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and
consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea.
To evaluate candidate mechanisms underlying the pelvic floor dysfunction in women with chronic pelvic pain and/or painful bladder syndrome/interstitial cystitis. Notably, prior studies have not consistently controlled for potential confounding by psychological or anatomical factors.
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, between women with pelvic pain and pain-free controls. We also assessed a novel pain measure using degree and duration of post-exam 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.
A total of 23 women with chronic pelvic pain, 23 painful bladder syndrome, and 42 pain-free controls completed the study. Women with chronic pelvic pain or painful bladder syndrome exhibited enhanced pain sensitivity with lower pressure pain thresholds (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<0.001) and prolonged pain aftersensation (3.5 [0-9] vs 0 [0-1] minutes; p< 0.001). Although genital hiatus (p<0.01) was wider in women with chronic pelvic pain there were no consistently observed group differences in pelvic floor anatomy, muscle tone or strength. The combination of pressure pain thresholds and aftersensation duration correlated with severity of pelvic floor tenderness (R(2) =41-51, p's< 0.01). Even after adjustment for prevalence, the combined metrics discriminated pain-free controls from women with chronic pelvic pain or painful bladder syndrome (area under the curve=0.87).
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Patient-reported outcomes (PRO) are questionnaire measures of patients' symptoms, functioning, and health-related quality of life. They are designed to provide important clinical information that generally cannot be captured with objective medical testing. In 2004, the National Institutes of Health launched a research initiative to improve the clinical research enterprise by developing state-of-the-art PROs. The NIH Patient-Reported Outcomes Measurement System (PROMIS) and Assessment Center are the products of that initiative. Adult, pediatric, and parent-proxy item banks have been developed by using contemporary psychometric methods, yielding rapid, accurate measurements. PROMIS currently provides tools for assessing physical, mental, and social health using short-form and computer-adaptive testing methods. The PROMIS tools are being adopted for use in clinical trials and translational research. They are also being introduced in clinical medicine to assess a broad range of disease outcomes. Recent legislative developments in the United States support greater efforts to include patients' reports of health experience in order to evaluate treatment outcomes, engage in shared decision-making, and prioritize the focus of treatment. PROs have garnered increased attention by the Food and Drug Administration (FDA) for evaluating drugs and medical devices. Recent calls for comparative effectiveness research favor inclusion of PROs. PROs could also potentially improve quality of care and disease outcomes, provide patient-centered assessment for comparative effectiveness research, and enable a common metric for tracking outcomes across providers and medical systems.
Conditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM.
The main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction.
The reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation.
Objective
Fibromyalgia (FM) is a disorder characterized by chronic pain and enhanced responses to acute noxious events. However, the sensory systems affected in FM may extend beyond pain itself, as FM patients show reduced tolerance to non-nociceptive sensory stimulation. Characterizing the neural substrates of multisensory hypersensitivity in FM may thus provide important clues about the underlying pathophysiology of the disorder. The aim of this study was to characterize brain responses to non-nociceptive sensory stimulation in FM patients and their relationship to subjective sensory sensitivity and clinical pain severity.Methods
Functional magnetic resonance imaging (MRI) was used to assess brain response to auditory, visual, and tactile motor stimulation in 35 women with FM and 25 matched controls. Correlation and mediation analyses were performed to establish the relationship between brain responses and 3 types of outcomes: subjective hypersensitivity to daily sensory stimulation, spontaneous pain, and functional disability.ResultsPatients reported increased subjective sensitivity (increased unpleasantness) in response to multisensory stimulation in daily life. Functional MRI revealed that patients showed reduced task-evoked activation in primary/secondary visual and auditory areas and augmented responses in the insula and anterior lingual gyrus. Reduced responses in visual and auditory areas were correlated with subjective sensory hypersensitivity and clinical severity measures.ConclusionFM patients showed strong attenuation of brain responses to nonpainful events in early sensory cortices, accompanied by an amplified response at later stages of sensory integration in the insula. These abnormalities are associated with core FM symptoms, suggesting that they may be part of the pathophysiology of the disease.
Central sensitization elicits pain hypersensitivity and is thought to be causally implicated in painful temporomandibular disorder (TMD). This causal inference is based on cross-sectional evidence that people with TMD have greater sensitivity than controls to noxious stimuli. We tested this inference in the OPPERA prospective cohort study of 3,258 adults with no lifetime history of TMD when enrolled (Visit 1). During five years of follow-up, one group labelled "persistent TMD cases" (n=72) developed first-onset TMD by Visit 2 that persisted ⩾6 months until Visit 3. Another group labelled "transient TMD cases" (n=75) developed first-onset TMD at Visit 2 which resolved by Visit 3. Randomly sampled "controls" (n=126) remained TMD-free throughout all three visits. At each visit, pressure pain thresholds (PPTs) were measured by algometry at 10 cranial and bodily sites. In persistent TMD cases, mean PPTs reduced 43 kPa (P<0.0001) between Visits 1 and 2 and thereafter did not change significantly. In transient TMD cases, mean PPTs reduced 41 kPa (P<0.001) between Visits 1 and 2, and then increased 20 kPa (P<0.001) by Visit 3. These patterns were similar after excluding cranial sites symptomatic for TMD. Importantly, Visit 1 PPTs had no clinically useful prognostic value in predicting first-onset TMD (odds ratio [OR] =1.07, P=0.15). Among first-onset cases, Visit 2 PPTs were modest predictors of persistent TMD (OR=1.36, P=0.002). In this longitudinal study, PPTs reduced when TMD developed then rebounded when TMD resolved. However, pre-morbid PPTs poorly predicted TMD incidence, countering the hypothesis that they signify mechanisms causing first-onset TMD.
Dysmenorrhea is characterized by high rates of transition to chronic pain. In a previous study using structural equation modeling we demonstrated that several symptom domains associated with the emerging concept of nociplastic pain can be described using two symptom groups: generalized sensory sensitivity (GSS; composed of widespread pain, interceptive sensitivity, and environmental sensitivity) and SPACE (composed of unrefreshing Sleep, Pain, Affective disturbances, Cognitive issues, and reduced Energy). Here we perform a secondary cross-sectional analysis examining the same symptoms groups in a cohort of dysmenorrhea patients without a diagnosis of chronic pain. Our purpose is to determine if the same symptom patterns are apparent, and if they are associated with the presence and severity of comorbid pain. Participants were 201 women with dysmenorrhea. We replicated the hypothesized two-factor structure in this cohort (comparative fit index = .971, root mean square error of approximation =.055; 90% CI: .000, .097). GSS was associated with the severity of bladder, bowel, and overall pain in multivariable models including SPACE, patient age, and BMI (all β > .32, all p < .05). SPACE was associated with menstrual pain during NSAID use, while GSS was associated with the same in the absence of NSAID use (both p < .05). This two-factor model of symptoms appears to be replicable and valid in a cohort of women at risk for developing chronic pain conditions. These symptom groups are promising potential markers of future pain chronification and may point to patients in need of earlier or more aggressive intervention.
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.
Objectives:
Youth with functional abdominal pain (FAP) experience significant pain-related distress and functional impairment. Although quantitative sensory testing protocols have identified alterations in pain modulatory systems that distinguish youth with FAP from healthy controls, the extent to which evoked pain responses predict subsequent trajectories of pain symptoms and disability over and above established psychosocial risk factors is unclear.
Methods:
The present study included 183 adolescents with FAP who were enrolled in a randomized controlled trial comparing an 8-week, internet-delivered program of cognitive behavior therapy (n=90) or pain education (n=93). Participants completed a quantitative sensory testing protocol prior to the intervention and were followed for 12-months post-treatment.
Results:
Whereas adolescents with FAP who exhibited stronger baseline conditioned pain modulation reported decreases in pain-related interference over follow-up (b=-0.858, SE=0.396, P=0.032), those with weaker conditioned pain modulation exhibited high, relatively stable levels of pain-related interference over time (b=-0.642, SE=0.400, P=0.110). Conditioned pain modulation status predicted changes in pain-related interference after controlling for the effects of treatment condition and psychosocial risk factors. Static measures of pain sensitivity (i.e., pain threshold, pain tolerance) and temporal summation of second pain were not associated with changes in measures of abdominal pain, gastrointestinal symptom severity, or pain-related interference over follow-up.
Discussion:
The present findings contribute to a growing literature on the predictive utility of quantitative sensory testing indices and suggest that conditioned pain modulation may complement existing psychosocial risk measures in determining individualized pain-related risk profiles.
Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.
Background: Chronic pelvic pain (CPP) is a complex pain syndrome. Since its pathogenesis is still poorly understood and structural alterations in pain related brain regions may be present, there is a greater acceptance that sensitization of the central nervous system (CNS) plays an important role in the development and maintenance of chronicity. Objective: The purpose of this study is to systematically review the scientific evidence regarding central sensitization (CS) in female patients with urogynecological CPP. Study Design: Systematic review of the literature. Methods: A systematic literature search was conducted in PubMed and Web of Science using different keyword combinations related to urogynecological CPP and central sensitization. Full text clinical reports addressing CS in adult women with urogynecological CPP were included and assessed for methodological quality by 2 independent reviewers. Results: After screening for the eligibility, a total of 29 full-text articles with low to good methodological quality were retained. All studies were observational, 27 of which were casecontrol and 2 of which were cohorts. Sensitivity of the CNS was investigated by using a variety of methods. Although different central mechanisms seem to be involved in pain processing, the present evidence suggests hyperexcitability of the CNS in patients with urogynecological CPP. Altered brain morphology and function, generalized hyperalgesia to different type of stimuli, overactive bottom-up nociceptive mechanisms, and autonomic dysregulation were established in patients with urogynecological CPP. Nevertheless, diffuse noxious inhibitory control seemed normal, and therefore the contribution of an impaired endogenous pain inhibition mechanism to CPP requires further study. The same goes for the contribution of psychological factors. Limitations: The level of evidence of retained studies is low due to the observational study designs and a wide range of diagnoses and assessment methods. Conclusion: Although the majority of the literature provides evidence for the presence of CS in urogynecological CPP with changes in brain morphology/function and sensory function, it is unclear whether these changes in central pain processing are secondary or primary to CPP, especially since evidence regarding the function of endogenous pain inhibition and the role of psychosocial pain facilitation is scarce. Further studies with good methodological quality are needed in order to clarify exact mechanisms. Key words: Urogynecological pain, pelvic pain, chronic pelvic pain, hyperalgesia, sensitization, central sensitization, pain processing, pain modulation, pain inhibition, systematic review
Aims:
To investigate associations between experimental pain sensitivity and five chronic pain conditions among 655 participants in the OPPERA study.
Methods:
Quantitative sensory tests were used to measure sensitivity to three modalities of nociception: blunt pressure pain, mechanical pinprick pain, and thermal heat pain. Participants were also classified according to the presence or absence of five chronic pain conditions: temporomandibular disorders, headache, low back pain, irritable bowel syndrome, and fibromyalgia.
Results:
Univariate analyses found each modality to be significantly associated with at least one pain condition, most consistently for pressure pain sensitivity (8 of 15 instances) and least consistently for heat pain sensitivity (5 of 35 instances). Yet, multivariable analyses that evaluated the independent contributions of all five pain conditions found few significant associations (12 of 75 instances). Instead, pain sensitivity consistently varied according to the total number of pain conditions a person experienced, implying that the combination of pain conditions influences each nociceptive modality.
Conclusion:
When evaluating nociceptive sensitivity in a chronic pain patient, comorbid pain conditions should be considered, as the more salient feature underlying sensitivity is likely the number rather than the type(s) of pain conditions.
The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet, it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire.A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia is just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy whereas hyperalgesia was more frequent in painful mononeuropathy (compared to painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions.Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide, and that painful and painless neuropathic conditions may mechanistically blend into one another.
Improving the ability to predict persistent pain after spine surgery would allow identification of patients at risk and guide treatment decisions. Quantitative sensory tests (QST) are measures of altered pain processes, but in our previous study, preoperative QST did not predict pain and disability at single time-points. Trajectory analysis accounts for time-dependent patterns. We hypothesized that QST predict trajectories of pain and disability during 1 year after low back surgery. We performed a trajectory analysis on the cohort of our previous study (n = 141). Baseline QST included electrical, pressure, heat, and cold stimulation of the low back and lower extremity, temporal summation, and conditioned pain modulation. Pain intensity and Oswestry Disability Index were measured before, and 2, 6, and 12 months after surgery. Bivariate trajectories for pain and disability were computed using group-based trajectory models. Multivariable regressions were used to identify QST as predictors of trajectory groups, with sociodemographic, psychological, and clinical characteristics as covariates. Cold pain hypersensitivity at the leg, not being married, and long pain duration independently predicted worse recovery (complete-to-incomplete, incomplete-to-no recovery). Cold pain hypersensitivity increased the odds for worse recovery by 3.8 (95% confidence intervals 1.8-8.0, P < 0.001) and 3.0 (1.3-7.0, P = 0.012) in the univariable and multivariable analyses, respectively. Trajectory analysis, but not analysis at single time-points, identified cold pain hypersensitivity as strong predictor of worse recovery, supporting altered pain processes as predisposing factor for persisting pain and disability, and a broader use of trajectory analysis. Assessment of cold pain sensitivity may be a clinically applicable, prognostic test.
Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.
OBJECTIVE
To synthesize the epidemiological findings for the associations between dysmenorrhea, including primary dysmenorrhea and endometriosis-associated dysmenorrhea, and any chronic pain conditions, including chronic pelvic pain, and chronic non-pelvic pain.
DATA SOURCES
PubMed, Embase, and CINAHL from inception to December 2019.
STUDY ELIGIBILITY CRITERIA
Observational population-based studies in which the relationship between dysmenorrhea and the presence or severity of chronic pain was examined.
STUDY APPRAISAL AND SYNTHESIS METHODS
Each study was double-coded and evaluated for bias based on the modified Newcastle and Ottawa Scale. Random-effect meta-analyses were conducted to quantify the associations between dysmenorrhea and the presence of chronic pelvic and non-pelvic pain.
RESULTS
Out of 9,452 records, 32 studies were included, with 14 reporting associations between dysmenorrhea and chronic pelvic pain, and 20 for dysmenorrhea and chronic non-pelvic pain. Primary dysmenorrhea and endometriosis-associated dysmenorrhea were examined in 7 studies, respectively. Over 30% of the studies were categorized as poor quality, 56% as moderate, and 12.5% as high. Dysmenorrhea was positively associated with both the presence and severity of chronic pelvic and non-pelvic pain conditions. Based on 6,689 women from 8 studies, those with chronic pelvic pain had 2.43 (95% confidence interval = 1.98, 2.99, I² = 42%) times the odds of having dysmenorrhea compared to those without. Based on 3,750 women from 11 studies, those with chronic non-pelvic pain had 2.62 (95% confidence interval = 1.84, 3.72, I² = 72%) times the odds of having dysmenorrhea compared to those without. Overall, dysmenorrhea was associated with 2.50 (95% confidence interval = 2.02, 3.10) times the odds of chronic pain, which did not differ by chronic pelvic vs chronic non-pelvic pain, community vs clinical populations, or different geographical regions.
CONCLUSIONS
Dysmenorrhea may be a general risk factor for chronic pain, although whether primary dysmenorrhea increases the risk for chronic pain is unclear. Given that adolescence is a sensitive period for neurodevelopment, elucidating the role of primary dysmenorrhea in pain chronicity in future longitudinal studies is important for preventing both chronic pelvic and non-pelvic pain.
Background:
Although adults are known to have sensory sensitivity differences, existing sensitivity scales have been mostly developed for children. The limited number of adult scales measure social/emotional features and modalities together.
Aims:
To develop scales for adults that evaluate visual, auditory and somatosensory sensitivities as separate domains and independent of social/emotional features.
Methods and procedures:
Two consecutive studies (visual-auditory part and somatosensory part) were conducted using the same methods. Both studies included a pilot (n1 = 405 and n2 = 294) and a main group (n1 = 425 and n2 = 603). An exploratory factor analysis produced a single-factor solution for the visual and auditory domains and a three-factor solution for the somatosensory domain (touch, pain, and itch) of Sensory Sensitivity Scales.
Outcomes and results:
A confirmatory factor analysis revealed good construct validity in the the visual (CFI = .973, TLI = .965, and RMSEA = .075) auditory (CFI = .943, TLI = .927, and RMSEA = .074) and somatosensory (CFI = .955, TLI = .946, and RMSEA = .048) scales. The categories were internally consistent (αv = .86, αa = .79, αs = .69). As an indicator of convergent validity, higher autistic traits were related to higher sensitivity (rs-v = .17, rs-a = .25, rs-s = .14).
Conclusions and implications:
Sensory Sensitivity Scales (SeSS) can be used to screen sensory sensitivity variability or identify and follow up the outcome of sensory interventions in adults.
Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms since it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear to what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area, in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported non-significant correlations between CPM efficiency and clinical manifestations of pain, while the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need of future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.
Background
The Pain Sensitivity Questionnaire (PSQ) is a self‐rating instrument developed as a time‐ and cost‐saving alternative to quantitative sensory testing (QST). The aims of the study were to assess 1) the associations between PSQ scores and QST in women with persistent pelvic pain and in pain‐free controls, and 2) to what extent demographic variables and psychological distress influenced PSQ scores.
Methods
Fifty‐five healthy women and 37 women with persistent pelvic pain participated. All filled in the PSQ and Hospital Anxiety and Depression Scale and had QST (heat, cold, and pressure pain thresholds) performed on six locations on the body. Information on age, body mass index, smoking habits, and pain duration were collected. Principal component analysis and orthogonal partial least square regressions were used.
Results
The patients scored significantly higher on PSQ than the controls. Significant multivariate correlations between pain thresholds and PSQ scores were found only in the patient group. In the patient group, the heat and cold pain thresholds correlated more strongly with PSQ scores than the pressure pain threshold.
Conclusions
The PSQ score was significantly higher in pelvic pain patients, and correlations between QSTs and the PSQ were only found for patients.
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Quantitative sensory testing (QST) is a formal variant of a time-honoured clinical examination technique in neurology, the sensory examination. Prototypical QST profiles have been found in human surrogate models of peripheral sensitization, central sensitization, and deafferentation. Probabilistic sorting of individual patients to any combination of these profiles has been developed, and there is emerging evidence for the predictive value of such sensory profiles for treatment efficacy. This way, QST aids in diagnostics of individual patients and may help guide their care in the future. Deficits in "dynamic" QST have been proposed as predictors of chronic pain (impaired descending inhibition and delayed recovery from central sensitization). Several psychological factors had previously been found to be predictors of pain chronicity (catastrophizing, self-efficacy, and neuroticism). The relative importance of psychological vs sensory testing predictors has not been evaluated. It is likely that both will have differential roles in clinical practice.
Chronic widespread pain (CWP) is common and associated with loss of functioning and health. Subjects with chronic nonwidespread pain (CnWP) are at increased risk of developing CWP, but few studies have described the nature of the development over time. We followed a random sample of 3105 participants from the population-based HUNT 3 study with 5 annual measurements of pain over 4 years. Although 29% reported CWP on at least 1 occasion, only 7% reported it consistently on 4 or 5 occasions. The average annual cumulative incidence was 5%, and the recovery rate was 38%. In mutual adjusted analysis, the risk of developing CWP from 1 year to the next was higher in subjects with chronic pain (relative risk [RR] = 2.4; 95% confidence interval [CI]: 1.8-3.4), 2 or more pain regions (RR = 3.3; 95% CI: 2.5-4.4), moderate pain or more (RR = 1.8; 95% CI: 1.5-2.6), and with comorbid chronic disease (RR = 1.6; 95% CI: 1.3-1.9). Developing CWP was associated with a modest concurrent change in self-reported mental and physical health. The risk of developing CWP between the fourth and fifth occasions was 80% lower for subjects without a history of CWP, compared to those with a history of CWP. For subjects without previous CWP, the development was associated with previously reported CnWP, but not with the number of occasions with CnWP, in analyses adjusted for sex, age, and pain severity. A substantial proportion of the new cases of CWP originates from subjects floating below and above the definition for CWP over time and, thus, does not seem to involve major transitions in health.
Background:
Menstrual symptoms such as dysmenorrhea, heavy menstrual bleeding, and perimenstrual mood disorders are known to be widespread among the general population. From studies in patients with endometriosis and premenstrual disorder, it has been shown that these symptoms can have a large impact on women's quality of life and account for substantial health care use. Furthermore, it is estimated that many women initially do not consult a doctor while facing menstrual symptoms. Consequently, the impact of menstrual symptoms on daily activities in the general population is unknown.
Objective:
To obtain a nationwide overview of menstrual symptoms and their impact on everyday activities.
Study design:
Nationwide, cross-sectional, internet-based survey among 42,879 women aged 15-45 years, conducted from July to October 2017.
Outcome measures:
presence of menstrual symptoms, pain or intensity score, impact on daily activities.
Results:
Dysmenorrhea was the most common symptom, with a prevalence of 85%, followed by psychological complaints (77%), and tiredness (71%). During their menstrual period, 38% of all women reported not to be able to perform all their regular daily activities. From the women that had to skip tasks because of their symptoms, only 48.6% told their family that menstrual symptoms were the reason for the transfer of tasks.
Conclusion:
Menstrual symptoms are widespread among the general population. One in 3 women quit daily activities owing to menstrual symptoms. Half of all women did not mention menstrual complaints being the reason for transferring tasks in a family setting. These results must be interpreted with caution owing to the potential for selection bias. However, considering the impact of menstrual symptoms on daily activities in a large group of women, it is time to open the societal dialogue and improve education for both patients and doctors.
Abstract Primary dysmenorrhea (PD; menstrual pain without an underlying medical condition) is associated with enhanced pain sensitivity and temporal summation in adult women, which may reflect the presence of central pain processes. Research in this area has been limited by focusing on only adult populations and incomplete assessments of central sensitization. The current study explored both excitatory and inhibitory measures of pain processing in girls and young adult women with and without PD. Thirty-two girls with PD and 34 healthy controls underwent laboratory pain testing during each of three menstrual cycle phases (menstrual, ovulatory, and mid-luteal), which included measures of pain tolerance and threshold, temporal summation, and conditioned pain modulation. Results indicated enhanced pain sensitivity in girls with PD as measured by heat pain tolerance and threshold, compared to healthy controls. These group differences were evident at all phases of the menstrual cycle. No group differences in cold pain tolerance, temporal summation, or conditioned pain modulation were evident at any phase of the menstrual cycle. These data suggest some evidence of central sensitization in girls with PD, although no evidence of deficient pain modulation was observed. Future research should focus on identifying other potential phenotypes for PD to identify those at risk for developing other pain problems.
Abstract Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in UCPPS participants was compared to healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from six participating MAPP testing sites were pooled for analysis. UCPPS participants (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in UCPPS patients was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in UCPPS participants revealed that pain sensitivity increased during periods of urological symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement one year later. The finding that individuals with UCPPS demonstrate non-pelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.
Painful temporomandibular disorders (TMD) are both consequence and cause of change in multiple clinical, psychosocial, and biological factors. While longitudinal studies have identified antecedent biopsychosocial factors that increase risk for TMD onset and persistence, little is known about long-term change in those factors after TMD develops or remits. During a 7.6-year median follow-up period, we measured change in psychosocial characteristics, pain sensitivity, cardiovascular indicators of autonomic function, and clinical jaw function among 189 participants whose baseline chronic TMD status either persisted or remitted and 505 initially TMD-free participants, 83 of whom developed TMD. Among initially TMD-free participants who developed TMD, symptoms and pain sensitivity increased while psychological function worsened. In contrast, participants with chronic TMD at baseline tended to show improved TMD symptoms, improved jaw function, reduced somatic symptoms, and increased positive affect. In general, clinical and psychosocial variables more frequently changed in parallel with TMD status compared to pain sensitivity and autonomic measures. These findings demonstrate a complex pattern of considerable changes in biopsychosocial function associated with changes in TMD status. In particular, several biopsychosocial parameters improved among participants with chronic TMD despite pain persisting for years, suggesting considerable potential for ongoing coping and adaptation in response to persistent pain.
Chronic Overlapping Pain Conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This 'centralized pain' phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here we used three cohorts, including patients with Urologic Chronic Pelvic Pain Syndrome (UCPPS), a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified two general factors in all three cohorts, one characterized by a broad increased sensitivity to internal somatic sensations and environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity (GSS), and one characterized by constitutional symptoms - Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the UCPPS cohort found the same two factor structure at month six and one year, suggesting that the two factor structure is reproducible over time. In secondary analyses we found that GSS particularly is associated with the presence of comorbid COPCs, while SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.
Background:
Dysmenorrhea is a common risk factor for chronic pain conditions including bladder pain syndrome. Few studies have formally evaluated asymptomatic bladder pain sensitivity in dysmenorrhea, and whether this largely reflects excess pelvic symptom reporting due to comorbid psychological dysfunction.
Objective:
We sought to determine whether bladder hypersensitivity is more common among women reporting moderate or greater dysmenorrhea, without chronic pain elsewhere, after accounting for anxiety and depression. Demonstrating this would suggest that dysmenorrhea might be an early clue for visceral or widespread pain hypersensitivity and improve understanding of potential precursors to bladder pain syndrome.
Study design:
We compared cohorts of regularly menstruating women, without complaints of chronic pain elsewhere, a) reporting moderate-to-severe dysmenorrhea (n=98) and b) reporting low levels or no menstrual pain (n=35). Participants underwent rapid bladder filling following a standard water ingestion protocol, serially rating bladder pain and relative urgency during subsequent distension. Potential differences in bladder volumes were controlled for by sonographic measurement at standard cystometric thresholds. Bladder sensitivity was also measured with complementary measures at other times separately including a simplified rapid filling test, palpation of the bladder wall, and through ambulatory self-report. Anxiety and depression were evaluated with the National Institute of Health Patient-Reported Outcomes Measurement Information System measures.
Results:
Women with moderate-to-severe dysmenorrhea reported more urinary symptoms than controls and had a lower maximum capacity (498 ± 18 mL vs. 619 ± 34 mL, p<0.001) and more evoked bladder filling pain (0-100 visual analog scale: 25 ± 3 vs. 12 ± 3, p<0.001). The dysmenorrhea-bladder capacity relationship remained significant irrespective of menstrual pain severity, anxiety, depression, or bladder pain (R2=0.13, p=0.006). Severity of menstrual pain predicted evoked bladder pain (R2=0.10, p=0.008) independent of anxiety (p=0.21) and depression (p=0.21). Women with moderate-to-severe dysmenorrhea exhibiting provoked bladder pain (24/98, 24%) also reported higher pain during the screening rapid bladder test (p<0.001), in response to transvaginal bladder palpation (p<0.015), and on prospective daily diaries (p<0.001) than women with dysmenorrhea without provoked bladder pain.
Conclusions:
Women experiencing moderate-to-severe dysmenorrhea also harbor a higher pain response to naturally evoked bladder distension. Non-invasive bladder provocation needs to be tested further longitudinally in dysmenorrhea sufferers to characterize the course of visceral sensitivity and determine if it may help predict individuals at risk for developing subsequent pain in the bladder or elsewhere.
The visual analog scale (VAS) is a tool widely used to measure pain, yet controversy surrounds whether the VAS score is ratio or ordinal data. We studied 52 postoperative patients and measured their pain intensity using the VAS. We then asked them to consider different amounts of pain (conceptually twice as much and then half as much) and asked them to repeat their VAS rating after each consideration (VAS2 and VAS3, respectively). Patients with unrelieved pain had their pain treated with IV fentanyl and were then asked to rate their pain intensity when they considered they had half as much pain. We compared the baseline VAS (VAS1) with VAS2 and VAS3. The mean (95% confidence interval) for VAS2:1 was 2.12 (1.81–2.43) and VAS3:1 was 0.45 (0.38–0.52). We conclude that the VAS is linear for mild-to-moderate pain, and the VAS score can be treated as ratio data.
Implications: A change in the visual analog scale score represents a relative change in the magnitude of pain sensation. Use of the VAS in comparative analgesic trials can now meaningfully quantify differences in potency and efficacy.
Until recently, most clinicians and scientists believed that the experience of pain is perceptually proportional to the amount of incoming peripheral nociceptive drive due to injury or inflammation in the area perceived to be painful. However, many cases of chronic pain have defied this logic, leaving clinicians perplexed as to how patients are experiencing pain with no obvious signs of injury in the periphery. Conversely, there are patients who have a peripheral injury and/or inflammation but little or no pain. What makes some individuals experience intense pain with minimal peripheral nociceptive stimulation and others experience minimal pain with serious injury? It is increasingly well accepted in the scientific community that pain can be generated and maintained or, through other mechanisms, suppressed by changes in the central nervous system, creating a complete mismatch between peripheral nociceptive drive and perceived pain. In fact, there is no known chronic pain condition where the observed extent of peripheral damage reproducibly engenders the same level of pain across individuals. Temporomandibular disorders (TMDs) are no exception. This review focuses on the idea that TMD patients range on a continuum—from those whose pain is generated peripherally to those whose pain is centralized (i.e., generated, exacerbated, and/or maintained by central nervous system mechanisms). This article uses other centralized chronic pain conditions as a guide, and it suggests that the mechanistic variability in TMD pain etiology has prevented us from adequately treating many individuals who are diagnosed with the condition. As the field moves forward, it will be imperative to understand each person’s pain from its own mechanistic standpoint, which will enable clinicians to deliver personalized medicine to TMD patients and eventually provide relief in even the most recalcitrant cases.
Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in fibromyalgia patients as compared to healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging to endogenous MOR binding and clinical pain ratings in female opioid-naïve fibromyalgia patients (n=18) using whole-brain analyses and regions of interest (ROI) from our previous research. Within anti-nociceptive brain regions, including the dorsolateral prefrontal cortex (r = .81, p < .001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all p < .02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, p = .050). In many of these regions pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggests that dysregulation of the endogenous opioid system in fibromyalgia could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in fibromyalgia.
Pain can be elicited through all mammalian sensory pathways yet cross-modal sensory integration, and its relationship to clinical pain, is largely unexplored. Centralized chronic pain conditions such as fibromyalgia are often associated with symptoms of multisensory hypersensitivity. In the present study, female fibromyalgia patients demonstrated cross-modal hypersensitivity to visual and pressure stimuli compared to age- and sex-matched healthy controls. Functional magnetic resonance imaging (fMRI) revealed that insular activity evoked by an aversive level of visual stimulation was associated with the intensity of fibromyalgia pain. Moreover attenuation of this insular activity by the analgesic pregabalin was accompanied by concomitant reductions in clinical pain. A multivariate classification method using support vector machines (SVM) applied to visual evoked brain activity distinguished fibromyalgia patients from healthy controls with 82% accuracy. A separate SVM classification of treatment effects on visual evoked activity reliably identified when patients were administered pregabalin as compared to placebo. Both SVM analyses identified significant weights within the insular cortex during aversive visual stimulation. These data suggest that abnormal integration of multisensory and pain pathways within the insula may represent a pathophysiological mechanism in some chronic pain conditions, and that insular response to aversive visual stimulation may have utility as a marker for analgesic drug development.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
We briefly outline the information-theoretic (I-T) approaches to valid inference including a review of some simple methods for making formal inference from all the hypotheses in the model set (multimodel inference). The I-T approaches can replace the usual t tests and ANOVA tables that are so inferentially limited, but still commonly used. The I-T methods are easy to compute and understand and provide formal measures of the strength of evidence for both the null and alternative hypotheses, given the data. We give an example to highlight the importance of deriving alternative hypotheses and representing these as probability models. Fifteen technical issues are addressed to clarify various points that have appeared incorrectly in the recent literature. We offer several remarks regarding the future of empirical science and data analysis under an I-T framework.
Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but cannot be attributed to a general increase in cortical sensory processing. Here we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of brain pain-modulating systems. These individuals expressed discomfort at light levels substantially lower than healthy controls. Complementary studies in lightly anesthetized rat demonstrated that a subset of identified pain-modulating neurons in the rostral ventromedial medulla unexpectedly responds to light. Approximately half of the pain-facilitating "ON-cells" and pain-inhibiting "OFF-cells" sampled exhibited a change in firing with light exposure, shifting the system to a pro-nociceptive state with activation of ON-cells and suppression of OFF-cell firing. The change in neuronal firing did not require a trigeminal or posterior thalamic relay, but was blocked by inactivation of the olivary pretectal nucleus. Light exposure also resulted in a measurable but modest decrease in the threshold for heat-evoked paw withdrawal, as would be expected with engagement of this pain-modulating circuitry.These data demonstrate integration of information about light intensity with somatic input at the level of single pain-modulating neurons in the brainstem of the rat under basal conditions. Taken together, our findings in rodents and humans provide a novel mechanism for abnormal photosensitivity, and suggest that light has the potential to engage pain-modulating systems such that normally innocuous inputs are perceived as aversive or even painful.
Objective:
We hypothesized that change in pain threshold to pressure reflects a generalized change in the pain system affecting both tender and control points.
Methods:
We assessed 18 tender points and 4 control points using an algometer in 60 patients with generalized fibromyalgia/fibrositis syndrome, 60 patients with localized chronic pain syndromes, and in 60 pain-free subjects.
Results:
A significant correlation was found between myalgia scores at tender points and control points in these subjects.
Conclusion:
These results suggest that there is a diffuse change in pain modulation in fibromyalgia, as hypothesized, but the tender point is still clinically useful.