Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms.

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.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study.

PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

[ 11 C]-PBR28 positron emission tomography signal as an imaging marker of joint inflammation in knee osteoarthritis.

ABSTRACT: Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [ 11 C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy controls (HC) underwent positron emission tomography/magnetic resonance imaging (PET/MRI) knee imaging with the TSPO ligand [ 11 C]-PBR28. Standardized uptake values were extracted from regions-of-interest (ROIs) semiautomatically segmented from MRI data, and compared across groups (HC, KOA) and subgroups (unilateral/bilateral KOA symptoms), across knees (most vs least painful), and against clinical variables (eg, pain and Kellgren-Lawrence [KL] grades). Overall, KOA patients demonstrated elevated [ 11 C]-PBR28 binding across all knee ROIs, compared with HC (all P 's < 0.005). Specifically, PET signal was significantly elevated in both knees in patients with bilateral KOA symptoms (both P 's < 0.01), and in the symptomatic knee ( P < 0.05), but not the asymptomatic knee ( P = 0.95) of patients with unilateral KOA symptoms. Positron emission tomography signal was higher in the most vs least painful knee ( P < 0.001), and the difference in pain ratings across knees was proportional to the difference in PET signal ( r = 0.74, P < 0.001). Kellgren-Lawrence grades neither correlated with PET signal (left knee r = 0.32, P = 0.19; right knee r = 0.18, P = 0.45) nor pain ( r = 0.39, P = 0.07). The current results support further exploration of [ 11 C]-PBR28 PET signal as an imaging marker candidate for KOA and a link between joint inflammation and osteoarthritis-related pain severity.

Chronic overlapping pain conditions increase the risk of long COVID features, regardless of acute COVID status.

ABSTRACT: Chronic overlapping pain conditions (COPCs) refer to conditions that have similar central nervous system pathophysiologic mechanisms driving widespread pain as well as common comorbid symptoms such as fatigue and problems with sleep, memory, and mood. If COPCs predict the onset of long COVID, this could offer a valuable orientation for long COVID-related research and clinical care. This retrospective cohort study aimed to determine whether having a COPC predicts the onset of long COVID features using US electronic health records and 1:1 propensity score matching without replacement. The study cohorts included (1) people with acute COVID (n = 1,038,402), (2) people with acute influenza (n = 262,092), and (3) a noninfected cohort comprising people with a routine healthcare encounter (n = 1,081,593). Having a COPC increased the risk of long COVID features in all 3 study cohorts. Among those with COVID, having a pre-existing COPC increased the risk by 1.47 (95% CI = 1.46, 1.47). In the influenza cohort, COPCs increased the risk by 1.39 (95% CI = 1.38, 1.40). In the noninfected cohort, COPCs increased the risk by 1.57 (95% CI = 1.56, 1.59). These findings reinforce the likelihood that nociplastic mechanisms play a prominent role in long COVID. Recognizing that this ubiquitous nonspecific syndrome occurs frequently in the population can inform precision medicine therapies that avoid the pitfalls of viewing long COVID exclusively in the framework of postinfectious disease.

The Chronic Overlapping Pain Condition Screener.

Ten Chronic Overlapping Pain Conditions (COPCs) are currently recognized by the National Institutes of Health Pain Consortium (eg, irritable bowel syndrome, chronic migraine headache, and chronic low back pain). These conditions affect millions of Americans; however, assessing these conditions, their co-occurrence, and their relationship to treatment has proven challenging due to time constraints and a lack of standardized measures. We present a Chronic Overlapping Pain Condition-Screener (COPC-S) that is logic-driven, efficient, and freely available in electronic format to nonprofit entities. Thirty experts were convened to identify and modify self-report criteria for each COPC as well as criteria that trigger the administration of the diagnostic criteria from a body map and a brief series of questions. Their recommendations were then programmed into the Research Electronic Data Capture platform and refined for comprehensibility and ease of use by patient focus groups. The electronic screener and physician-administered criteria were both administered to patients with known COPCs in a counter-balanced fashion to determine the level of agreement between methods. The expert panel identified screening items/body map regions and diagnostic criteria for all 10 COPCs. Patients found the content comprehensible and the platform easy to use. Cohen's Kappa statistics suggested good agreement between the electronic COPC-S and criteria administered by a physician (κ = .813). The COPC-S is an efficient tool for screening multiple COPCs and has applicability to research studies, clinical trials, and clinical practice. PERSPECTIVE: Assessing COPCs remains a challenge for researchers and clinicians. The COPC-S is an efficient and logic-driven electronic tool that allows for the rapid screening assessment of 10 COPCs. The instrument may have utility in research and clinical settings.

Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

PURPOSE: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction. MATERIALS AND METHODS: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis. RESULTS: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2. CONCLUSIONS: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms.

Risk Factors for the Development of Multisite Pain in Children.

OBJECTIVE: Chronic pain has economic costs on par with cardiovascular disease, diabetes, and cancer. Despite this impact on the health care system and increasing awareness of the relationship between pain and mortality, efforts to identify simple symptom-based risk factors for the development of pain, particularly in children, have fallen short. This is critically important as pain that manifests during childhood often persists into adulthood. To date, no longitudinal studies have examined symptoms in pain-free children that presage a new, multisite manifestation of pain in the future. We hypothesized that female sex, sleep problems, and heightened somatic symptoms complaints at baseline would be associated with the risk of developing new multisite pain 1 year later. METHODS: Symptom assessments were completed by parents of youth (ages 9 to 10) enrolled in the Adolescent Brain Cognitive Development study. Multivariate logistic regression models focused on children who developed multisite pain 1 year later (n=331) and children who remained pain free (n=3335). RESULTS: Female sex (odds ratio [OR]=1.35; 95% CI, 1.07, 1.71; P =0.01), elevated nonpainful somatic symptoms (OR=1.17; 95% CI, 1.06, 1.29; P <0.01), total sleep problems (OR=1.20; 95% CI, 1.07, 1.34; P <0.01), and attentional issues (OR=1.22; 95% CI, 1.10, 1.35; P <0.001) at baseline were associated with new multisite pain 1 year later. Baseline negative affect was not associated with new multisite pain. DISCUSSION: Identifying symptom-based risk factors for multisite pain in children is critical for early prevention. Somatic awareness, sleep and attention problems represent actionable targets for early detection, treatment, and possible prevention of multisite pain in youth.

Psychosocial predictors of change in sexual activity and sexual function after hysterectomy in women with pelvic pain.

BACKGROUND: Potential impact on sexual function is an often-cited concern for many patients considering hysterectomy. The existing literature indicates that sexual function remains stable to slightly improved for most patients who undergo hysterectomy, but most studies demonstrate a small subset of patients in whom sexual function declines after surgery. Unfortunately, there is a lack of clarity as to surgical, clinical, and psychosocial factors that may influence the likelihood of sexual activity after surgery or the magnitude and direction of change in sexual function. Although psychosocial factors are strongly associated with overall female sexual function, there is minimal data exploring the potential impact of these factors on the change in sexual function after hysterectomy. OBJECTIVE: This study aimed to evaluate the relationship between baseline psychosocial factors and both sexual activity and sexual function at 6 months after hysterectomy. STUDY DESIGN: Patients undergoing hysterectomy for benign, non-obstetric indications were prospectively recruited as part of an observational cohort study evaluating presurgical predictors of posthysterectomy outcomes on pain, quality of life, and sexual function. The Female Sexual Function Index was administered before hysterectomy and 6 months after surgery. Presurgical psychosocial assessments included validated self-reported measures of depression, resilience, relationship satisfaction, emotional support, and social participation. RESULTS: Complete data was available for 193 patients, of whom 149 (77.2%) reported sexual activity at 6 months after hysterectomy. In the binary logistic regression model examining sexual activity at 6 months, older age was associated with a lower likelihood of sexual activity (odds ratio, 0.91; 95% confidence interval, 0.85-0.96; P=.002). Higher relationship satisfaction before surgery was associated with a greater likelihood of sexual activity at 6 months (odds ratio, 1.09; 95% confidence interval, 1.02-1.16; P=.008). As expected, preoperative sexual activity was associated with a greater likelihood of postoperative sexual activity (odds ratio, 9.78; 95% confidence interval, 3.95-24.19, P<.001). Analyses using Female Sexual Function Index scores were limited to patients who were sexually active at both time points (n=132 [68.4%]). The total Female Sexual Function Index score did not change significantly from baseline to 6 months, but there were statistically significant changes in several individual domains of sexual function. Patients reported significant improvement in desire (P=.012), arousal (P=.023), and pain (P<.001) domains. However, significant decreases were reported in orgasm (P<.001) and satisfaction (P<.001) domains. The proportion of patients who met the criteria for sexual dysfunction was quite high (>60%) at both time points, but there was not a statistically significant change in the proportion from baseline to 6 months. In the multivariate linear regression model, there was no relationship between change in sexual function score and any of the variables examined, including age, endometriosis history, pelvic pain severity, or psychosocial measures. CONCLUSION: In this cohort of patients with pelvic pain undergoing hysterectomy for benign indications, both sexual activity and sexual function remained fairly stable after hysterectomy. Higher relationship satisfaction, younger age, and preoperative sexual activity were associated with a greater probability of sexual activity at 6 months after surgery. Psychosocial factors, such as depression, relationship satisfaction, and emotional support, and history of endometriosis were not related to change in sexual function among patients who were sexually active both before hysterectomy and at 6 months after surgery.

Neurobiology and long-term impact of bladder-filling pain in humans: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network study.

ABSTRACT: 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.

Neurotrophins and Their Receptors, Novel Therapeutic Targets for Pelvic Pain in Endometriosis, Are Coordinately Regulated by IL-1ß via the JNK Signaling Pathway.

Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1ß, a prominent cytokine in endometriosis, was tested herein. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESCs) were subjected to dose-response and time-course experiments with IL-1ß and kinase inhibitors to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF, and their receptors tropomyosin receptor kinase (Trk) A, TrkB, and p75 neurotrophin receptor were all expressed in primary ESCs. IL-1ß stimulated higher TrkA/B expression in ESCs derived from endometriosis cases (2.8- ± 0.2-fold) than cells from controls (1.5- ± 0.3-fold, t-test, P < 0.01), effects that were mediated via the c-Jun N-terminal kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P = 0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1ß. We postulate that JNK inhibitors, such as SP600125, have the potential to reduce neuroinflammation in women with endometriosis.

Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis.

ABSTRACT: Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.

Early and recent exposure to adversity, TLR-4 stimulated inflammation, and diurnal cortisol in women with interstitial cystitis/bladder pain syndrome: A MAPP research network study.

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1ß, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS.

Association Between Nociplastic Pain and Pain Severity and Impact in Women With Chronic Pelvic Pain.

Exploring the relationship between nociplastic pain and the severity and impact of pelvic pain symptoms could lend insight into the heterogeneous symptom presentation and treatment response that complicates management of chronic pelvic pain. In this prospective cross-sectional study, we sought to evaluate relationships between degree of nociplastic pain, measured by the Fibromyalgia (FM) Survey Score, and multiple aspects of the chronic pelvic pain (CPP) experience, including severity, frequency, tenderness during pelvic myofascial exam, interference with daily life, and high-impact pain. The study included 303 women who presented to a tertiary referral clinic for chronic pelvic pain and endometriosis. Multiple measures of pelvic pain, including pain severity, frequency, interference, pelvic myofascial pain, and high-impact pain were examined in General Linear Models with FM Survey Score as the primary predictor of interest in models controlling for endometriosis, surgical history, use of opioids, body mass index, and patient age. Higher level of nociplastic pain was associated with greater pelvic pain severity, frequency, interference, and pelvic myofascial pain (all P < .05). For all models, degree of nociplastic pain was more strongly associated with pain outcomes than the presence of endometriosis, and use of opioids was the only stronger predictor of worse pain outcomes. The likelihood of high impact pain increased 7% for each additional point on the FM Survey Score. Degree of nociplastic pain was robustly associated with severity, frequency, and impact of pelvic pain, and was independent of the presence of endometriosis, history of surgical procedures for pelvic pain, age, and BMI. Trial registration: not applicable PERSPECTIVE: This article evaluates the impact of nociplastic pain on symptoms and functional status in chronic pelvic pain. These findings raise the possibility that a simple screening tool for nociplastic pain might provide clinically actionable information without the need for deep neurobiological phenotyping and may inform development of personalized management strategies.

The Biology of Pain: Through the Rheumatology Lens.

Chronic pain is a major socioeconomic burden globally. The most frequent origin of chronic pain is musculoskeletal. In inflammatory musculoskeletal diseases such as rheumatoid arthritis (RA), chronic pain is a primary determinant of deleterious quality of life. The pivotal role of peripheral inflammation in the initiation and perpetuation of nociceptive pain is well-established among patients with musculoskeletal diseases. However, the persistence of pain, even after the apparent resolution of peripheral inflammation, alludes to the coexistence of different pain states. Recent advances in neurobiology have highlighted the importance of nociplastic pain mechanisms. In this review we aimed to explore the biology of pain with a particular focus on nociplastic pain in RA.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Generalized sensory sensitivity is associated with comorbid pain symptoms: a replication study in women with dysmenorrhea.

ABSTRACT: 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 2 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 patients with dysmenorrhea 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 2-factor structure in this cohort (comparative fit index = 0.971 and root mean square error of approximation =0.055; 90% CI: 0.000-0.097). Generalized sensory sensitivity was associated with the severity of bladder, bowel, and overall pain in multivariable models including SPACE, patient age, and BMI (all ß > 0.32, all P < 0.05). Sleep, pain, affective disturbances, cognitive issues, and reduced energy were associated with menstrual pain during nonsteroidal anti-inflammatory drug use, whereas GSS was associated with the same in the absence of nonsteroidal anti-inflammatory drug use (both P < 0.05). This 2-factor model of symptoms seems 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.

Protocol for Biospecimen Collection and Analysis Within the BACPAC Research Program.

The Biospecimen Collection and Processing Working Group of the National Institutes of Health (NIH) HEAL Initiative BACPAC Research Program was charged with identifying molecular biomarkers of interest to chronic low back pain (cLBP). Having identified biomarkers of interest, the Working Group worked with the New York University Grossman School of Medicine, Center for Biospecimen Research and Development-funded by the Early Phase Pain Investigation Clinical Network Data Coordinating Center-to harmonize consortium-wide and site-specific efforts for biospecimen collection and analysis. Biospecimen collected are saliva, blood (whole, plasma, serum), urine, stool, and spine tissue (paraspinal muscle, ligamentum flavum, vertebral bone, facet cartilage, disc endplate, annulus fibrosus, or nucleus pulposus). The omics data acquisition and analyses derived from the biospecimen include genomics and epigenetics from DNA, proteomics from protein, transcriptomics from RNA, and microbiomics from 16S rRNA. These analyses contribute to the overarching goal of BACPAC to phenotype cLBP and will guide future efforts for precision medicine treatment.