Effects of Nature-Based Multisensory Stimulation on Pain Mechanisms in Women with Fibromyalgia Syndrome: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: The term "nature-based sensory stimuli" refers to the sensory information produced by biotic and abiotic agents from natural environments. The literature has reported the beneficial effects of these agents on various pain dimensions in non-clinical populations. AIMS: To evaluate the potential analgesic effects of nature-based multisensory stimulation in women with fibromyalgia syndrome. METHODS: A randomized, double-blind, placebo-controlled, parallel-group trial with a 1:1 allocation ratio was conducted. Forty-two women with fibromyalgia syndrome interacted with either different plant species with flowers, stones, and soil organic matter or their synthetic imitations for 30 minutes. Outcome measurements were performed before and after the intervention, including clinical pain intensity using the Numeric Rating Scale, cold pain thresholds using the Cold Pressor Test, mechanical hyperalgesia and wind-up using a monofilament, and pressure pain thresholds using a pressure algometer. RESULTS: Analyses revealed group × time interactions for clinical pain intensity (F = 7.915, p = .008), cold-water immersion time (F = 7.271, p = .010), mechanical hyperalgesia (F = 4.701, p = .036), and pressure pain threshold (p ≤ .017). Between-group differences were found in clinical pain intensity (p = .012), cold pain thresholds (p = .002), and pressure pain thresholds (p < .05). The experimental group exhibited reduced clinical pain intensity (p = .001) and increased pressure pain thresholds (p ≤ .034). CONCLUSIONS: Women with fibromyalgia syndrome may benefit from multisensory stimulation using biotic and abiotic agents from natural environments for 30 minutes. Interacting with flowering plants and soil components appears to induce analgesic effects.

How Treatment Motivation Predicts Favorable Outcomes in Interdisciplinary Multimodal Pain Treatment Among Patients with Chronic Primary Pain.

As motivation for psychological treatment at intake has been shown to predict favorable outcomes after an inpatient stay, this study aimed to further characterize the different components of psychological treatment motivation that predict favorable treatment outcomes. 294 inpatients with chronic primary pain participating in an interdisciplinary multimodal pain treatment in a tertiary psychosomatic university clinic completed a battery of psychological questionnaires at intake and discharge. Treatment motivation was assessed at intake using the scales of the FPTM-23 questionnaire, while pain intensity, pain interference, anxiety, and depression were assessed both at intake and discharge. After treatment, pain intensity, pain interference, anxiety, and depression were significantly reduced. While higher levels on the FPTM-23 scale of suffering predicted smaller decreases in anxiety after treatment, higher scores on the scale of hope, i.e., lower levels of hopelessness, predicted lower levels of pain interference, anxiety, and depression after treatment. None of the scales of treatment motivation predicted pain intensity levels after treatment. Above and beyond providing symptom relief, reducing hopelessness and fostering hope regarding the treatment process and outcome might help clinicians treat patients with chronic primary pain more effectively.

Functional neurological disorder is common in patients attending chronic pain clinics.

BACKGROUND AND PURPOSE: Chronic pain is a common comorbidity in those with functional neurological disorder (FND); however, the prevalence and characteristics of FND in those with chronic pain is unknown. METHODS: A retrospective electronic records review was made of consecutive new patients attending a chronic pain clinic of a regional service. Clinical features, medication for and outcome of chronic pain, any lifetime diagnoses of functional disorders, FND, and psychiatric disorders, and undiagnosed neurological symptoms were recorded. RESULTS: Of 190 patients attending the chronic pain clinic, 32 (17%) had a lifetime diagnosis of FND and an additional 11 (6%) had undiagnosed neurological symptoms. Pain patients with comorbid FND were more likely to have chronic primary pain (88% with FND, 44% without FND, p < 0.0001), widespread chronic primary pain (53%, 15%, p < 0.00001), and depression (84%, 52%, p < 0.005) and less likely to have a pain-precipitating event (19% vs. 56%, p < 0.001). However, there was no significant difference between these patients in opiate prescription, benzodiazepine prescription, or pain outcome. CONCLUSIONS: This first study of FND in a chronic pain patient population found a remarkably high prevalence of FND (17%) and is possibly an underestimation. The size of the overlap indicates that FND and chronic pain research fields are likely to have a lot to learn from each other.

The potent analgesia of intrathecal 2R, 6R-HNK via TRPA1 inhibition in LF-PENS-induced chronic primary pain model.

BACKGROUND: Chronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown. METHODS: Based on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro. RESULTS: Intrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol. CONCLUSIONS: In the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes.

Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT2C receptors but downregulated 5-HT3 receptors in the spinal dorsal horn. Subsequent spinal administration of RS102221 to inhibit 5-HT2C receptors or SR57227 to activate 5-HT3 receptors reversed the analgesic effect of SAHA under both conditions. These results indicate that SAHA attenuates the pro-nociceptive effects of stress combined with orofacial inflammation and the effects of stress alone. This likely occurs through epigenetic regulation of spinal 5-HT2C and 5-HT3 receptor expression, suggesting that SAHA has potential therapeutic value in FMS or comorbid FMS-TMD patients with somatic hyperalgesia.

Management of chronic primary pelvic pain syndromes.

Management of chronic pelvic pain (CPP) remains a huge challenge for care providers and a major burden for healthcare systems. Treating chronic pain that has no obvious cause warrants an understanding of the difficulties in managing these conditions. Chronic pain has recently been accepted as a disease in its own right by the World Health Organization, with chronic pain without obvious cause being classified as chronic primary pain. Despite innumerable treatments that have been proposed and tried to date for CPP, unimodal therapeutic options are mostly unsuccessful, especially in unselected individuals. In contrast, individualised multimodal management of CPP seems the most promising approach and may lead to an acceptable situation for a large proportion of patients. In the present review, the interdisciplinary and interprofessional European Association of Urology Chronic Pelvic Pain Guideline Group gives a contemporary overview of the most important concepts to successfully diagnose and treat this challenging disease.

Migraine in the context of chronic primary pain, chronic overlapping pain disorders, and functional somatic disorders: A narrative review.

OBJECTIVE: To contextualize migraine as the most common primary headache disorder in relation to other chronic primary pain and non-pain functional somatic and mental conditions. BACKGROUND: Migraine is increasingly understood as a sensory processing disorder within a broader spectrum of symptom disorders. This has implications for diagnosis and treatment. METHOD: Narrative review based on a search of the literature of the last 15 years on the overlap of migraine with other symptom disorders. RESULTS: Migraine as the prototypical primary headache disorder not only comprises many non-headache symptoms in itself, it also shows high comorbidity with other chronic pain and non-pain conditions (e.g., fibromyalgia syndrome, irritable bowel syndrome, functional non-epileptic seizures, depression, anxiety, and posttraumatic stress disorder). Such "symptom disorders" share several etiological factors (e.g., female preponderance, psychological vulnerability) and psychophysiological mechanisms (e.g., altered sensory processing, pain expectancy). These facts are acknowledged by several recent integrative conceptualizations such as chronic primary pain, chronic overlapping pain conditions, or functional somatic disorders. Accordingly, migraine management increasingly addresses the total symptom burden and individual contributors to symptom experience, and thus incorporates centrally acting pharmacological and non-pharmacological, that is, psychological and behavioral, treatment approaches. CONCLUSIONS: Migraine and also other primary headache disorders should be seen as particular phenotypes within a broader spectrum of symptom perception and processing disorders that require integrative diagnostics and treatment. A harmonization of classifications and better interdisciplinary collaboration are desirable.

Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies.

Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.

ICD-11 Classification of Pediatric Chronic Pain Referrals in Ireland, with Secondary Analysis of Primary vs Secondary Pain Conditions.

OBJECTIVE: To classify pediatric chronic pain referrals in Ireland according to the classification system of the 11th version of the International Classification of Diseases (ICD-11). In addition, differences between primary and secondary pain groups were assessed. METHODS: Retrospective review of complex pain assessment forms completed at the time of initial attendance at pediatric chronic pain clinics in Dublin, Ireland. Patients were classified as having a chronic primary (CPP) or chronic secondary (CSP) pain condition as per ICD-11 classification. Secondary analysis of between-group and within-group differences between primary and secondary pain conditions was undertaken. RESULTS: Of 285 patients coded, 123 patients were designated as having a CPP condition (77% of whom were assigned an adjunct parent code) and 162 patients as having a CSP condition (61% of whom were assigned an adjunct parent code). Between-group comparisons found that the lowest reported pain scores were higher in CPP than in CSP conditions. There were stronger correlations between parental pain catastrophizing and pain intensity, school attendance, and pain interference with social activities in the CSP group than in the CPP group. CONCLUSIONS: The majority of children with both CPP and CSP were assigned multiple parent codes. There appears to be a gradient in the differences in biopsychosocial profile between CPP and CSP conditions. Additional field testing of the ICD-11 classification in pediatric chronic pain will be required.

[Chronic pain in children and adolescents: an economic perspective]. / Chronischer Schmerz bei Kindern und Jugendlichen: eine ökonomische Betrachtung.

BACKGROUND: Chronic pain is a frequent and disabling health problem in children and adolescents and is associated with high health care utilization and costs. OBJECTIVE: The aim of this study was to analyze the direct and indirect costs of chronic pain in children and adolescents in monetary terms before and after multimodal pain therapy from a societal perspective. MATERIALS AND METHODS: Health care costs 12 months before and after multimodal pain therapy include direct costs from statutory health insurances and parents as well as indirect costs due to working days lost. RESULTS: Direct median costs before multimodal treatment were 5619 € (min-max: 377-35,509 €) per year. In the year after pain therapy, costs decreased to a median of 3262 € (min-max: 142-42,910 €) (p = 0.001). In all, 55% of patients showed a significant cost reduction, while 18% had a cost increase. CONCLUSIONS: An effective multimodal pain therapy may reduce health care costs in children and adolescents. Further economic studies are needed to evaluate long-term effects of pain therapy for children and adolescents with chronic pain in a controlled design.

Emotional Awareness and Expression Therapy for Chronic Pain: Rationale, Principles and Techniques, Evidence, and Critical Review.

PURPOSE OF REVIEW: Patients with chronic pain, especially primary or centralized pain, have elevated rates of psychosocial trauma and intrapersonal or intrapsychic conflict. To address these risk factors and potentially reduce pain, the authors developed emotional awareness and expression therapy (EAET). This article presents the rationale for EAET, describes its principles and techniques, reviews its development and early testing as well as recent clinical trials, and critically analyzes the evidence base. RECENT FINDINGS: Four initial trials (between 2006 and 2011) demonstrated the efficacy of earlier versions of EAET. Four recent randomized, controlled trials of different EAET durations (1 to 8 sessions) and formats (individual or group) in patients with fibromyalgia, irritable bowel syndrome, pelvic pain, or medically unexplained symptoms support the earlier findings. EAET reliably reduces pain and interference, although improvements in anxiety and depression are less reliably achieved and may be delayed. The largest and best conducted trial found superiority of EAET over cognitive-behavioral therapy for fibromyalgia. Patient retention in EAET is high, and adverse events are rare. EAET merits inclusion as a treatment option for primary pain conditions, and it may be the preferred treatment for some patients. Research is needed on EAET with other pain conditions and samples, using better controls and comparison conditions, and on additional ways to motivate and help patients engage in successful emotional processing.

"What script am I meant to use?": a qualitative study in chronic primary pain.

BACKGROUND: Chronic primary pain (CPP) as a diagnosis has been introduced in the recent International Classification of Diseases, 11th Revision (ICD-11). CPP captures the experience of pain as the primary problem, without an underlying attributable cause. Dissemination of UK guidance regarding CPP represents the first time it has been recognised as a condition in its own right. Little is known regarding General Practitioner (GP) views concerning caring for patients with CPP and how related guidance is viewed and applied in practice. AIM: To explore GP perspectives in relation to caring for people with CPP, including challenges encountered and use of related guidelines in practice. DESIGN & SETTING: A UK-wide qualitative interview study in primary care. METHOD: Purposive and snowball sampling were used to recruit 15 GP participants from England, Northern Ireland, Wales and Scotland. Semi-structured interviews were undertaken and analysed using reflexive thematic analysis. RESULTS: Three main themes were generated: (1) "How to start? Problematic beginnings" referred to difficulties regarding diagnosis; (2) "Where to go? Mapping the management challenge" and (3) "How to get there? Navigating strategies and response", explored GP awareness and acceptability of UK guidelines for chronic pain. Areas identified for potential improvement included increased access to NPM and secondary care services, support with de-prescribing and an expanded multidisciplinary team input. CONCLUSION: CPP is complex to both diagnose and manage. Although guidelines provide a useful framework, they pose challenges when translating into day-to-day practice.

Application of a Clinical Approach to Diagnosing Primary Pain: Prevalence and Correlates of Primary Back and Neck Pain in a Community Physiatry Clinic.

Chronic back or neck pain (CBNP) can be primary (nociplastic or neuroplastic; without clear peripheral etiology) or secondary (to nociceptive or neuropathic causes). Expanding on available models of nociplastic pain, we developed a clinic-ready approach to diagnose primary/nociplastic pain: first, a standard physical exam and review of imaging to rule out secondary pain; and second, a detailed history of symptom presentation to rule in primary pain. We trained a physician who evaluated 222 patients (73.9% female, age M = 59.6) with CBNP; patients separately completed pain and psychosocial questionnaires. We estimated the prevalence of primary CBNP and explored biomedical, imaging, and psychological correlates of primary CBNP. Although almost all patients (97.7%) had at least 1 spinal anomaly on imaging, the diagnostic approach estimated that 88.3% of patients had primary pain, 5.0% had secondary pain, and 6.8% had mixed pain. Patients with primary pain were more likely than the other 2 groups of patients (combined as "non-primary pain") to report certain functional conditions, central sensitization, and features such as sensitivity to light touch, spreading pain, and pain worsening with stress; however, no difference was detected in depression, anxiety, and pain catastrophizing between those with primary and nonprimary pain. These findings are consistent with prior estimates that 85 to 90% of CBNP is "nonspecific." Further research is needed to validate and perhaps refine this diagnostic approach, which holds the potential for better outcomes if patients are offered treatments targeted to primary pain, such as pain neuroscience education and several emerging psychological therapies. PERSPECTIVE: We developed an approach to diagnose chronic primary pain, which was applied in a physiatry clinic to 222 patients with CBNP. Most patients (88.3%) had primary pain, despite almost universal anomalies on spinal imaging. This diagnostic approach can guide educational and psychological treatments tailored for primary pain.

Chronic stress induces wide-spread hyperalgesia: The involvement of spinal CCK1 receptors.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.

Social cognition abilities in patients with primary and secondary chronic pain.

Previous evidence suggested that chronic pain is characterized by cognitive deficits, particularly in the social cognition domain. Recently, a new chronic pain classification has been proposed distinguishing chronic primary pain (CPP), in which pain is the primary cause of patients' disease, and chronic secondary pain (CSP), in which pain is secondary to an underlying illness. The present study aimed at investigating social cognition profiles in the two disorders. We included 38 CPP, 43 CSP patients, and 41 healthy controls (HC). Social cognition was assessed with the Ekman-60 faces test (Ekman-60F) and the Story-Based Empathy Task (SET), whereas global cognitive functioning was measured with the Montreal Cognitive Assessment (MoCA). Pain and mood symptoms, coping strategies, and alexithymia were also evaluated. Correlations among clinical pain-related measures, cognitive performance, and psychopathological features were investigated. Results suggested that CSP patients were impaired compared to CPP and HC in social cognition abilities, while CPP and HC performance was not statistically different. Pain intensity and illness duration did not correlate with cognitive performance or psychopathological measures. These findings confirmed the presence of social cognition deficits in chronic pain patients, suggesting for the first time that such impairment mainly affects CSP patients, but not CPP. We also highlighted the importance of measuring global cognitive functioning when targeting chronic pain disorders. Future research should further investigate the cognitive and psychopathological profile of CPP and CSP patients to clarify whether present findings can be generalized as disorder characteristics.

Interstitial cystitis-an imbalance of risk and protective factors?

Interstitial cystitis (IC) presents as a chronic pain condition with variable combinations of symptoms depending on the species and individual patient. It is diagnosed by the presence of lower urinary tract signs and symptoms in combination with a variety of comorbid health problems, a history of life adversities, and the absence of other conditions that could cause the lower urinary tract signs. IC occurs naturally in humans and cats as a dimensional condition, with patients presenting with mild, moderate, and severe symptoms. Most patients appear to recover without specific treatment. A number of rodent models of IC have been used to study its causes and treatments. Unfortunately, current therapies generally fail to ameliorate IC symptoms long-term. The recent classification of IC as a chronic primary pain disorder calls for a rethinking of current clinical and research approaches to it. Beginning when a patient encounters a clinician, precipitating, perpetuating, and palliating risk factors can be addressed until a cause or reliably effective therapy is identified, and identifying predisposing and preventive factors can inform epidemiological studies and health promotion interventions. Predisposing, precipitating, and perpetuating risk factors, including environmental, psychological, and biological, increase the activity of the central threat response system (CTRS), which plays a clinically important role in IC symptoms. Studies in cats and rodent models have revealed that environmental enrichment (EE), in the absence of bladder-directed therapies, leads to amelioration of IC symptoms, implying a central role for the CTRS in symptom precipitation and perpetuation. Conceptually moving the source of IC pain to the brain as a motivational state rather than one resulting from peripheral nociceptive input offers both clinicians and researchers novel opportunities to improve care for patients with IC and for researchers to use more ecologically valid rodent models. It may even be that IC results from an excess of risk to protective factors, making this imbalance a targetable cause rather than a consequence of IC.

Transforming Growth Factor-ß-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain.

The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small-molecule inhibitor, takinib, to attenuate pain and inflammation in preclinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the catechol-O-methyltransferase (COMT) inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the DRG of Gcamp3 mice. In all 3 models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of proinflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid-based pain treatments.

Back Pain without Disease or Substantial Injury in Children and Adolescents: A Twin Family Study Investigating Genetic Influence and Associations.

This twin family study first aimed to investigate the evidence for genetic factors predicting the risk of lifetime prevalence of non-specific low back pain of at least three months duration (LBP (life)) and one-month current prevalence of thoracolumbar back pain (TLBP (current)) using a study of children, adolescents, and their first-degree relatives. Secondly, the study aimed to identify associations between pain in the back with pain in other regions and also with other conditions of interest. Randomly selected families (n = 2479) with child or adolescent twin pairs and their biological parents and first siblings were approached by Twins Research Australia. There were 651 complete twin pairs aged 6-20 years (response 26%). Casewise concordance, correlation, and odds ratios were compared for monozygous (MZ) and dizygous (DZ) pairs to enable inference about the potential existence of genetic vulnerability. Multivariable random effects logistic regression was used to estimate associations between LBP (life) or TLBP (current) as an outcome with the potentially relevant condition as predictors. The MZ pairs were more similar than the DZ pairs for each of the back pain conditions (all p values < 0.02). Both back pain conditions were associated with pain in multiple sites and with primary pain and other conditions using the combined twin and sibling sample (n = 1382). Data were consistent with the existence of genetic influences on the pain measures under the equal environments assumption of the classic twin model and associations with both categories of back pain were consistent with primary pain conditions and syndromes of childhood and adolescence which has research and clinical implications.

War experiences and relationship problems predict pain sensitivity cross-sectionally among patients with chronic primary pain.

BACKGROUND: Most patients suffering from chronic pain are more susceptible to pain and pressure due to higher pain sensitivity. Since psychosocial factors play a central role in developing and maintaining chronic pain, investigating associations between pain sensitivity and psychosocial stressors promises to advance the biopsychosocial understanding of chronic pain. OBJECTIVES: We aimed to replicate Studer et al.'s (2016) findings about associations of psychosocial stressors with pain sensitivity in a new sample of patients with chronic primary pain (ICD-11, MG30.0). METHODS: A pain provocation test was used on both middle fingers and earlobes to assess pain sensitivity among 460 inpatients with chronic primary pain. Potentially life-threatening accidents, war experiences, relationship problems, certified inability to work, and adverse childhood experiences were assessed as potential psychosocial stressors. Structural equation modeling was used to investigate associations between psychosocial stressors and pain sensitivity. RESULTS: We partially replicated Studer et al.'s findings. Similar to the original study, patients with chronic primary pain showed enhanced pain sensitivity values. Within the investigated group, war experiences (ß = 0.160, p < .001) and relationship problems (ß = 0.096, p = .014) were associated with higher pain sensitivity. In addition, the control variables of age, sex, and pain intensity also showed a predictive value for higher pain sensitivity. Unlike Studer et al., we could not identify a certified inability to work as a predictor of higher pain sensitivity. CONCLUSIONS: This study showed that beyond age, sex, and pain intensity, the psychosocial stressors of war experiences and relationship problems were associated with higher pain sensitivity.

EEG assessment of brain dysfunction for patients with chronic primary pain and depression under auditory oddball task.

In 2019, the International Classification of Diseases 11th Revision International Classification of Diseases (ICD-11) put forward a new concept of "chronic primary pain" (CPP), a kind of chronic pain characterized by severe functional disability and emotional distress, which is a medical problem that deserves great attention. Although CPP is closely related to depressive disorder, its potential neural characteristics are still unclear. This paper collected EEG data from 67 subjects (23 healthy subjects, 22 patients with depression, and 22 patients with CPP) under the auditory oddball paradigm, systematically analyzed the brain network connection matrix and graph theory characteristic indicators, and classified the EEG and PLI matrices of three groups of people by frequency band based on deep learning. The results showed significant differences in brain network connectivity between CPP patients and depressive patients. Specifically, the connectivity within the frontoparietal network of the Theta band in CPP patients is significantly enhanced. The CNN classification model of EEG is better than that of PLI, with the highest accuracy of 85.01% in Gamma band in former and 79.64% in Theta band in later. We propose hyperexcitability in attentional control in CPP patients and provide a novel method for objective assessment of chronic primary pain.