Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study.

ABSTRACT: Brain age predicted differences (brain-PAD: predicted brain age minus chronological age) have been reported to be significantly larger for individuals with chronic pain compared with those without. However, a debate remains after one article showed no significant differences. Using Gaussian Process Regression, an article provides evidence that these negative results might owe to the use of mixed samples by reporting a differential effect of chronic pain on brain-PAD across pain types. However, some remaining methodological issues regarding training sample size and sex-specific effects should be tackled before settling this controversy. Here, we explored differences in brain-PAD between musculoskeletal pain types and controls using a novel convolutional neural network for predicting brain-PADs, ie, DeepBrainNet. Based on a very large, multi-institutional, and heterogeneous training sample and requiring less magnetic resonance imaging preprocessing than other methods for brain age prediction, DeepBrainNet offers robust and reproducible brain-PADs, possibly highly sensitive to neuropathology. Controlling for scanner-related variability, we used a large sample (n = 660) with different scanners, ages (19-83 years), and musculoskeletal pain types (chronic low back [CBP] and osteoarthritis [OA] pain). Irrespective of sex, brain-PAD of OA pain participants was ∼3 to 4.7 years higher than that of CBP and controls, whereas brain-PAD did not significantly differ among controls and CBP. Moreover, brain-PAD was significantly related to multiple variables underlying the multidimensional pain experience. This comprehensive work adds evidence of pain type-specific effects of chronic pain on brain age. This could help in the clarification of the debate around possible relationships between brain aging mechanisms and pain.

Association of phase angle with sarcopenia in chronic musculoskeletal pain patients: a retrospective study.

BACKGROUND: In chronic musculoskeletal pain patients, detection of sarcopenia is of significant clinical interest. Phase angle, which can be measured through bioelectrical impedance analysis (BIA), can detect sarcopenia; however, the evidence in chronic musculoskeletal pain patients is limited. This study aimed to assess the relationship between phase angle and sarcopenia in patients with chronic musculoskeletal pain. Our hypothesis was that phase angle would be a useful indicator to identify sarcopenia in patients with chronic musculoskeletal pain. METHODS: A total of 190 patients (51 men and 139 women) with chronic musculoskeletal pain were included in this retrospective cross-sectional study. Patient data of backgrounds, numeric rating scale score for pain, skeletal muscle index, and phase angle assessed using BIA were retrospectively reviewed. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria 2019. RESULTS: A total of 51 patients (26.7%), including 10 men (19.6%) and 41 women (29.5%), were diagnosed with sarcopenia. Phase angle, sarcopenia-related factors, age, and body mass index (BMI) differed significantly in patients with and without sarcopenia. On multiple logistic regression analysis, the prevalence of sarcopenia was significantly correlated with phase angle and BMI. The areas under the curve exhibited high accuracy in discriminating sarcopenia in men and moderate accuracy in both sexes and in women. CONCLUSIONS: Phase angle may be a valid discriminator of sarcopenia in patients with chronic musculoskeletal pain.

Chronic musculoskeletal pain prospectively predicts insomnia in older people, not moderated by age, gender or co-morbid illnesses.

The study evaluated if chronic musculoskeletal (MSK) pain predicts the severity of insomnia, and whether the effect is moderated by age, gender, and number of comorbid diseases in older people. An 18-month prospective study was performed within the framework of a community health program in Hong Kong. A total of 498 older people aged ≥ 60 with multimorbidity were recruited. The predictors included the presence of chronic MSK pain, pain measured by the Brief Pain Inventory (BPI), insomnia measured by baseline Insomnia Severity Index (ISI), and number of co-morbid diseases, age, and gender. The outcome was ISI repeated at 18 months. The moderators included age, gender, and number of comorbid diseases. Multivariate linear regression and moderation analysis were conducted. We found that the presence of chronic MSK pain (ß = 1.725; 95% CI, 0.607-2.842; P < 0.01) predicted the severity of ISI, after controlling for age, gender, BMI, and the number of comorbid diseases. Participants with chronic MSK pain throughout the period had worse trend of improvement in ISI compared to those who were "pain-free" (ß = 2.597; 95% CI, 1.311-3.882; P < 0.001). Age, gender, and number of comorbid diseases did not moderate the longitudinal relationship. We propose that pain management should prioritized in the prevention of insomnia.

Pain mapping and characteristics in breast cancer survivors during task-oriented training: analysis at 3, 6, and 9 months.

PURPOSE: To evaluate the frequency and characteristics of trunk and upper limb pain in women diagnosed with breast cancer, in different movement planes, during task-oriented training (TOT) 3, 6, and 9 months after surgery. METHODS: A prospective cohort study with 20 women. The body pain diagram (BPD), VAS, and McGill questionnaire were used. The TOT consisted of 20 exercises based on the Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH) questionnaire. BPD overlay was performed in GIMP® image editor. The chi-square test was applied to the relationship between population characteristics and pain. Freedman's ANOVA and the Cochran's Q test were used in the comparison of pain site frequencies and intensity over time. RESULTS: In total, 297 BPDs were generated, which identified the affected upper limb as the body area with the highest frequency of pain at the three moments. However, at 9 months, the unaffected upper limb presented the same frequency as the affected limb. Radiotherapy presented a statistically significant relationship (p < 0.05) with pain at 9 months. The pain was characterized as moderate at the three moments, affective at 3 and 6 months, and sensory at 9 months. CONCLUSION: The most frequent area of pain at 3 and 6 months was the affected upper limb however, at 9 months, the unaffected upper limb presented the same frequency of pain as the affected upper limb. Pain was characterized as moderate at the three evaluation moments.

Does moxonidine reduce Achilles tendon or musculoskeletal pain in women with polycystic ovarian syndrome? A secondary analysis of a randomised controlled trial.

BACKGROUND: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. METHODS: A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. RESULTS: There was no difference in mean change in musculoskeletal symptoms (- 0.6 ± 1.7 vs - 0.4 ± 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 ± 8.8 vs placebo + 4.2 ± 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. CONCLUSIONS: This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01504321 . Registered 5 January 2012.

Foot exercise plus education versus wait and see for the treatment of plantar heel pain (FEET trial): a protocol for a feasibility study.

BACKGROUND: Plantar heel pain (PHP) is present in a wide range of individuals and creates significant burden to quality of life and participation in physical activity. The high recurrence rates and persistence of PHP suggests current management options may not address all potentially modifiable factors associated with the condition. Reports of intrinsic foot muscle (IFM) atrophy in individuals with PHP, together with biomechanical evidence of their important contribution to optimal foot function, suggests that an intervention focused on IFM training may be beneficial in managing PHP. We will test the feasibility of a prospective, assessor-blinded, parallel-group, randomised clinical trial that compares foot exercise plus education to brief advice in individuals with PHP. METHODS: Twenty participants with PHP will be randomly allocated to one of two groups for a 12-week intervention period: (i) foot exercise plus education, or (ii) brief advice. The foot exercise plus education group will attend eight sessions with a physiotherapist and receive detailed education on self-management strategies as well as a progressive exercise program for the IFMs. The brief advice group will attend one session with a physiotherapist and receive brief information about self-management strategies and reassurance. Outcome measures will be obtained at baseline and the primary end-point of 12 weeks. Primary outcomes will be the feasibility of conducting a full-scale randomised clinical trial (RCT), and the credibility and acceptability of the foot exercise plus education intervention. Secondary outcomes will explore treatment effects, which will consist of pain, physical function, physical activity level, pain self-efficacy, perceived treatment effect, magnetic resonance and ultrasound image measurement of IFM morphology, ultrasound imaging measurement of plantar fascia thickness, IFM motor performance, foot posture, foot mobility, ankle dorsiflexion range of motion, toe flexor and plantar flexor strength/endurance. DISCUSSION: To reduce the burden of PHP on individuals and society, there is a need to establish effective treatments that are feasible and accepted by patients and health professionals. This trial will be the first to evaluate the feasibility of conducting a full-scale RCT, as well as the credibility, acceptability, and treatment effects, of education and foot exercise for PHP. The findings of this study will inform the development of a full-scale RCT. TRIAL REGISTRATION: The trial protocol was prospectively registered with the Australia and New Zealand Clinical Trial Registry (ACTRN12619000987167) on 11th July 2019.

Shoulder pain has most impact on poor quality of life among various types of musculoskeletal pain in middle-aged and elderly people: Yakumo study.

Objectives: To investigate the severity and effect on quality of life (QOL) of various types of pain in healthy volunteers.Methods: A total of 384 subjects (male: 158, female: 226, average age: 63 years) were included in a prospective cohort study (Yakumo study). Shoulder pain, low back pain (LBP), sciatica, knee pain, and the American Shoulder and Elbow Surgeons (ASES) shoulder score were evaluated with SF-36.Results: The prevalence of shoulder pain, LBP, sciatica, and knee pain was 42%, 44%, 16%, and 48%, respectively, with similar severities of pain. Shoulder pain visual analogue scale (VAS) and ASES shoulder scores were significantly correlated with SF-36 domains. Subjects with poor physical QOL had significantly higher VAS scores for all pain types and a lower ASES shoulder score. Shoulder pain VAS was also significantly related to poor mental QOL. Multivariate regression analysis adjusted for age and gender showed that shoulder pain VAS (OR: 1.25, p < .05) and 10-m gait speed (OR: 1.82, p < .05) were significant independent risk factors for poor physical QOL.Conclusion: Only shoulder pain of similar severity to other pain and shoulder complaints impacted on both physical and mental QOL. The severity of shoulder pain was an independent risk factor for poor physical QOL.

Bone Pain in Cancer Patients: Mechanisms and Current Treatment.

The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be multimodal (pharmacological and non-pharmacological), including causal anticancer and symptomatic analgesic treatment to improve quality of life (QoL). The aim of this paper is to discuss the mechanisms involved in the occurrence and persistence of cancer-associated bone pain and to review the treatment methods recommended by experts in clinical practice. The final part of the paper reviews experimental therapeutic methods that are currently being studied and that may improve the efficacy of bone pain treatment in cancer patients in the future.

Subtle changes of gray matter volume in fibromyalgia reflect chronic musculoskeletal pain rather than disease-specific effects.

Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Neuroimaging studies provided evidence of altered gray matter volume (GMV) in FMS but, similarly, in chronic pain of other origin as well. Therefore, the purpose of this study was to evaluate the disease specificity of GMV alterations in FMS by direct comparison. Structural MRI data of the brain were acquired in 25 females with FMS and two different control groups: 21 healthy subjects and 23 patients with osteoarthritis. Regional GMVs were compared by voxel-based morphometry and additional ROI-analyses. In conclusion, we did not identify significant GMV alterations in either FMS or OA patients compared to healthy controls when adopting a conservative statistical approach with multiple comparison correction. However, even under a more liberal approach no FMS-specific GMV changes were found because both pain groups presented increased gray matter volumes in the precentral gyrus and decreased GMV in the angular gyrus/middle occipital gyrus and middle temporal gyrus in comparison with healthy controls. Since no differences between both pain groups could be detected cortical GMV changes in FMS should not be interpreted as FMS-specific but might rather reflect changes in chronic pain in general. This previously held notion is confirmed in this study by direct comparison with a control group consisting of another pain disorder.

The impact of multimorbidity on foot health outcomes in podiatry patients with musculoskeletal foot pain: a prospective observational study.

BACKGROUND: Multimorbidity is prevalent and adversely affects health outcomes. Foot pain is common and one of the primary reasons for utilisation of podiatry services. At present, little is known about the impact of multimorbidity on foot health and related outcomes following podiatric intervention. The aims of this study were to evaluate whether there is a difference in foot health outcomes following exposure to podiatric foot care for people with and without multimorbidity; and ii) to evaluate whether the presence or absence of multimorbidity affects patients' perceptions of change in foot pain. METHODS: The PROMFoot study is a prospective cohort study of adults with a new episode of foot pain attending the podiatry service within the NHS Greater Glasgow and Clyde health board. Baseline medical comorbidity status (no condition, single condition, multiple conditions), longitudinal data on foot health measured using the Foot Health Status Questionnaire (FHSQ), and patient rating of change scores for foot pain were obtained from the PROMFoot study at baseline, and 3 and 6 months after podiatric intervention. Foot health scores (pain, function, footwear and general foot health) and perceptions of change for foot pain were compared between comorbidity groups. RESULTS: A total of 115 participants (59% female) with a mean age of 55 years were included. Multimorbidity was common, affecting 61 participants (53%); while 28 (24.3%) and 26 (22.6%) reported single or no medical comorbidities respectively. Significantly worse foot health scores for all FHSQ domains were observed for the multimorbidity group at baseline, 3 and 6 months. Change scores for foot pain were similar between groups and demonstrate modest improvements, however multimorbidity group membership was strongly associated with a perceptions of change in foot pain. Multimorbidity was independently associated with poorer foot function outcomes at 3 months, and poorer foot pain and foot function outcomes at 6 months. CONCLUSIONS: Multimorbidity was associated with poor foot health outcomes and lower rates of self-perceived improvement in foot pain over 6 months following podiatric intervention in a sample of patients attending podiatric biomechanics clinics for a new episode of foot pain.

Shifting brain circuits in pain chronicity.

The evaluation of brain changes to a specific pain condition in pediatric and adult patients allows for insights into potential mechanisms of pain chronicity and possibly long-term brain changes. Here we focused on the primary somatosensory system (SS) involved in pain processing, namely the ventroposterolateral thalamus (VPL) and the primary somatosensory cortex (SI). We evaluated, using MRI, three specific processes: (a) somatotopy of changes in the SS for different pain origins (viz., foot vs. arm); (b) differences in acute (ankle sprain versus complex regional pain syndrome-CRPS); and (c) differences of the effects of CRPS on SS in pediatric versus adult patients. In all cases, age- and sex-matched individuals were used as controls. Our results suggest a shift in concurrent gray matter density (GMD) and resting functional connectivity strengths (rFC) across pediatric and adult CRPS with (a) differential patterns of GMD (VPL) and rFC (SI) on SS in pediatric vs. adult patterns that are consistent with upper and lower limb somatotopical organization; and (b) widespread GMD alterations in pediatric CRPS from sensory, emotional and descending modulatory processes to more confined sensory-emotional changes in adult CRPS and rFC patterns from sensory-sensory alterations in pediatric populations to a sensory-emotional change in adult populations. These results support the idea that pediatric and adult CRPS are differentially represented and may reflect underlying differences in pain chronification across age groups that may contribute to the well-known differences between child and adult pain vulnerability and resilience.

Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Tyrosine Kinase Inhibitor Therapy Cessation.

Clinical trials have shown that for some patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase inhibitors (TKIs), treatment-free remission (TFR) is achievable and safe. TFR is now a treatment goal for select patients who have experienced a sustained deep molecular response. An expected result of TFR would be a decrease in the frequency or intensity of adverse events (AEs) associated with TKI therapy. Unexpectedly, however, some clinical trials have reported new or worsening AEs, typically described as musculoskeletal pain, in patients attempting TFR. These AEs are hypothesized to be a TKI withdrawal syndrome, although the underlying mechanism is not known. Overall, musculoskeletal pain has been reported in approximately 20% to 30% of patients attempting TFR and is typically transient and easily managed. TKI cessation would be expected to improve patients' quality of life (QOL); however, in studies assessing QOL, patients have reported little change after ceasing TKI therapy, perhaps because they must tolerate long-term TKI therapy before they can attempt TFR. Here we review reports of musculoskeletal pain during TFR and changes in QOL after TKI cessation in clinical trials. As more patients attempt TFR in routine practice, the health care community will play an important role in helping these patients understand the benefits and risks of TFR, the effect it may have on their QOL, and the potential for musculoskeletal pain.

The interplay between sleeplessness and high-sensitivity C-reactive protein on risk of chronic musculoskeletal pain: longitudinal data from the Tromsø Study.

STUDY OBJECTIVES: To examine independent associations of sleeplessness and high-sensitivity C-reactive protein (hsCRP) with risk of chronic musculoskeletal pain, and to explore the joint effect of sleeplessness and hsCRP on risk of chronic musculoskeletal pain. METHODS: A population-based prospective study of 3214 women and 3142 men (mean age: 55.4, range: 32-87) without severe chronic musculoskeletal pain and with hsCRP ≤ 10 mg/L at baseline in 2007-2008. Modified Poisson regression was used to calculate adjusted risk ratios (RRs) with 95% confidence intervals (CIs) for any chronic musculoskeletal pain and chronic widespread pain (CWP) at follow-up in 2015-2016 associated with self-reported sleeplessness and hsCRP at baseline. RESULTS: Compared with persons without sleeplessness, women and men reporting often/or always sleeplessness had RRs of CWP of 2.53 (95% CI: 1.94-3.29) and 2.48 (95% CI: 1.63-3.77), respectively. There was no clear association between hsCRP and risk of any chronic musculoskeletal pain or CWP. Joint effect analyses using persons without sleeplessness and with a hsCRP < 1.00 mg/L as the reference gave RRs for chronic musculoskeletal pain of 1.73 (95% CI: 1.26-2.37) for those with often/always sleeplessness and hsCRP < 1.00 mg/L; 1.01 (95% CI: 0.78-1.32) for those without sleeplessness and hsCRP ≥3.00 mg/L; and 2.47 (95% CI: 1.79-3.40) if they had both often/always sleeplessness and hsCRP ≥ 3.00 mg/L. The corresponding RRs for CWP were 1.89 (95% CI: 1.27-2.83), 0.96 (95% CI: 0.68-1.37), and 2.83 (95% CI: 1.91-4.20), respectively. CONCLUSIONS: These results suggest that there is an interplay between sleeplessness and hsCRP on risk of any chronic musculoskeletal pain and CWP.

Effects of a brief workplace-centered consultation for employees with musculoskeletal pain on health outcomes: a prospective cohort study.

Musculoskeletal (MSK) diseases affect a substantial proportion of the population. Specialist consultations were offered at the workplace for people with musculoskeletal (MSK)-complaints. We analyzed data on pain and well-being as well as health economic data at baseline. Lasting effects of the consultation were analyzed at a follow-up-interview after 12 months. Baseline data of 344 individuals were available. Occupations were divided into physically highly demanding (HD) or less demanding. Women reported significantly higher pain levels and less QoL than men. Sick leave days were significantly more in HD-workers. Independent of workload, significantly higher percentages of women had cervical- and upper limb-pain than men, with significantly higher pain in upper limbs in HD-workers. 235 participants were available for telephone-follow-up. QoL and MSK-pain improved significantly. Yearly out-of-pocket spendings for treatments significantly increased. NSAID use significantly decreased, whereas use of non-drug musculoskeletal-medical-services was significantly higher after one year. Regarding MSK-symptoms in gainfully employed individuals, the study showed significantly different workload-dependent differences in QoL. Significant effects of a consultation by a MSK-specialist were shown in terms of improved MSK-pain and overall well-being. This workplace-centered consultation had significant effects on beneficial health-behavior such as decreased use of NSAID and increased engagement in gymnastics and physiotherapy.

The impact of anxiety on chronic musculoskeletal pain and the role of astrocyte activation.

Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

Clinical features of pain in amyotrophic lateral sclerosis: A clinical challenge.

Pain in amyotrophic lateral sclerosis (ALS) is paradoxical in this disease of the upper and lower motor neurons. As such, it remains an underestimated and neglected clinical problem because it is poorly identified by physicians, its mechanisms are numerous and its treatments are generally not effective. Pain may be primary in the form of cramps, spasticity and neuropathy, or secondary as nociceptive pain, and may arise before the first motor symptoms. It may also lead to depression and, in all cases, affect patients' daily activities and quality of life. Given the high frequency of pain in ALS, the use of analgesic or sedative drugs is necessary and should reduce the course of the disease. Nevertheless, it is important to understand the pathophysiological mechanisms of pain in ALS, and to train physicians how to detect ALS pain early on and provide dedicated treatments. In France, the implementation of ALS centers is a positive response to the public-health problem resulting from this disorder.

Sequestration of artemin reduces inflammation-induced activation and sensitization of bone marrow nociceptors in a rodent model of carrageenan-induced inflammatory bone pain.

BACKGROUND: Pathologies that affect the bone marrow have a significant inflammatory component; however, it is not clear how inflammatory mediators affect nociceptive nerve terminals within the marrow cavity. METHODS: In this study, an in vivo bone-nerve preparation was used to directly record the physiological response properties of bone marrow nociceptors innervating the tibial marrow cavity of rats, before and after application of the inflammatory agent carrageenan. In addition, endogenous artemin was sequestered by application of an artemin neutralizing antibody to determine if this could prevent the inflammation-induced physiological changes observed. RESULTS: A single injection of carrageenan administered into the tibial marrow cavity produced rapid changes in weight bearing (pain-like behaviour) in conscious animals. Carrageenan, but not saline, activated bone marrow nociceptors in whole-nerve recordings and sensitized a subtype of Aδ-bone marrow nociceptors to mechanical stimulation. The activation and sensitization had a rapid time course that matched that of pain-like behaviours. Sequestration of endogenous artemin significantly reduced carrageenan-induced increases in ongoing activity and completely abolished sensitization of bone marrow nociceptors to mechanical stimulation. CONCLUSIONS: These observations indicate that inflammation affects the activity and sensitivity of bone marrow nociceptors; that artemin plays a role in these changes; and that artemin might be a promising target for pharmacological manipulations in the treatment of inflammatory bone pain. SIGNIFICANCE: Most pathologies that affect the bone marrow have an inflammatory component. We have used a model of carrageenan-induced inflammation to show that sequestration of artemin reduces inflammation-induced activation and sensitization of bone marrow nociceptors. Our findings suggest that artemin signalling is a target for the treatment of inflammatory bone pain.

A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: results of a pilot study.

PURPOSE: Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies. EXPERIMENTAL DESIGN: This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy. RESULTS: CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events. CONCLUSIONS: The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.

Familial episodic limb pain in kindreds with novel Nav1.9 mutations.

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as"". In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6-8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input-current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.