Multiple Chronic Pain Research Articles

The association among multiple-site chronic pain, sedentary behavior, and major depressive disorders: a mendelian randomization study.

Observational studies have reported that major depressive disorder (MDD) is associated with sedentary behavior (SB) and multiple chronic pain (MCP), but their associations remain unclear. Mendelian randomization analysis was used to assess the association. Single nucleotide polymorphisms (SNPs) associated with MCP, SB [time spent watching television (Tel), using a computer (Com), or driving (Dri)], and MDD were collected from genome-wide association studies and screened as instrumental variants with a threshold of 1 × 10-5. Mendelian randomization was performed to examine their associations. Sensitivity analyses were conducted to evaluate robustness. MCP was associated with a higher risk of MDD [odds ratio (OR) inverse variance weighting (IVW) = 1.88; 95% confidence interval (CI), 1.64-2.15; P = 4.26 × 10-8), and causally related to SB (Tel: ORIVW = 1.23; 95% CI, 1.19-1.26; P = 6.02 × 10-38) (Dri: ORIVW = 1.05; 95% CI, 1.03-1.08; P = 3.92 × 10-5). Causality of SB on MCP was detected for Tel (ORIVW = 1.46; 95% CI, 1.39-1.53; P = 1.40 × 10-54) and Com (ORIVW = 0.88; 95% CI, 0.83-0.93; P = 2.50 × 10-6). No association was observed for SB on MDD. There is currently insufficient evidence to support that leisure activities are a mediating factor in MCP-induced MDD. There are complex relationships among MCP, SB, and MDD. More research and learning about potential relationships and mechanisms among these phenotypes should be supplied.

What has brain diffusion magnetic resonance imaging taught us about chronic primary pain: a narrative review.

Chronic pain is a pervasive and debilitating condition with increasing implications for public health, affecting millions of individuals worldwide. Despite its high prevalence, the underlying neural mechanisms and pathophysiology remain only partly understood. Since its introduction 35 years ago, brain diffusion magnetic resonance imaging (MRI) has emerged as a powerful tool to investigate changes in white matter microstructure and connectivity associated with chronic pain. This review synthesizes findings from 58 articles that constitute the current research landscape, covering methods and key discoveries. We discuss the evidence supporting the role of altered white matter microstructure and connectivity in chronic primary pain conditions, highlighting the importance of studying multiple chronic pain syndromes to identify common neurobiological pathways. We also explore the prospective clinical utility of diffusion MRI, such as its role in identifying diagnostic, prognostic, and therapeutic biomarkers. Furthermore, we address shortcomings and challenges associated with brain diffusion MRI in chronic primary pain studies, emphasizing the need for the harmonization of data acquisition and analysis methods. We conclude by highlighting emerging approaches and prospective avenues in the field that may provide new insights into the pathophysiology of chronic pain and potential new therapeutic targets. Because of the limited current body of research and unidentified targeted therapeutic strategies, we are forced to conclude that further research is required. However, we believe that brain diffusion MRI presents a promising opportunity for enhancing our understanding of chronic pain and improving clinical outcomes.

Structure-Guided Design of Partial Agonists at an Opioid Receptor.

The persistence of chronic pain and continuing overdose deaths from pain-relieving opioids targeting μ opioid receptor (μOR) have fueled the need for reliable long-term analgesics which use different targets and mechanisms. The δ opioid receptor (δOR) is a potential alternative target for non-addictive analgesics to alleviate chronic pain, made more attractive by its lack of respiratory depression associated with μOR agonists. However, early δOR full agonists were found to induce seizures, precluding clinical use. Partial δOR agonists may offer more controlled activation of the receptor compared to full agonists, but the development of such ligands has been hindered by uncertainty over the molecular mechanism mediating partial agonism. Using a structure-based approach, we explored the engagement of the sodium binding pocket in δOR and developed a bitopic ligand, C6-Quino, predicted to be a selective δOR partial agonist. Functional studies of C6-Quino revealed that it displayed δOR partial agonist activity at both G-protein and arrestin pathways. Its interaction with the sodium pocket was confirmed and analyzed using a single particle cryo-EM. Additionally, C6-Quino demonstrated favorable chemical and physiological properties like oral activity, and analgesic activity in multiple chronic pain models. Notably, μOR-related hyperlocomotion and respiratory depression, and δOR-related convulsions, were not observed at analgesic doses of C6-Quino. This fundamentally new approach to designing δOR ligands provides a blueprint for the development of partial agonists as safe analgesics and acts as a generic method to optimize signaling profiles of other Class A GPCRs.

The Effect of Corrective Exercises on Strength, Power, and Endurance of Gluteal Muscles in Women With Weakness and Inhibition of Gluteal Muscles

Background and Aims Most women experience weakness and inhibition of the gluteal muscles, which negatively affects athletic performance and is known to cause multiple injuries and chronic pain. This study aimed to determine the effect of corrective exercises on gluteal muscles strength, endurance, and power in women with gluteal muscles weakness and inhibition. Methods We purposively identified 28 non-athletic women aged 25 to 45 years who were referred to Babolsar Rehabilitation Clinic (Babolsar City, Iran) for physiotherapy due to reasons such as fracture, strain, sprain, and dislocation of the upper extremity joints. They experienced inhibition and weakness of the gluteal muscles. After completing the physiotherapy course and returning to normal life, they entered the present study and were randomly divided into the control (n=15) and exercise (n=13) groups. The exercise group performed a corrective exercises program including inhibitory, lengthening, activating, and strengthening exercises with theraband for 8 weeks (3 sessions per week and 30 to 45 minutes per session). The power of extensors, abductors, and external rotators of gluteal muscles was measured using the Diako cable machine and based on the formula of one-repetition maximum. The power and endurance of gluteal muscles were measured by the single-leg glute bridge test and the vertical jump test in two groups. The data were analyzed by covariance analyses. Results The results showed a significant improvement in the strength of the gluteal muscles in the movements of extension, abduction, and external rotation of the thigh, also in the endurance and power of the gluteal muscles in the exercise group compared to the control group in the posttest (P<0.05). Conclusion This study showed that corrective exercises, including inhibitory techniques, lengthening, activating, and strengthening exercises, have the necessary components to improve the strength, endurance, and power of gluteal muscles. Therefore, this exercise program is recommended for people with weakness and inhibition of the gluteal muscles.

Prognostic factors for wellbeing in patients with hyaline fibromatosis syndrome.

Hyaline fibromatosis syndrome (HFS) is a congenital disorder characterized by subcutaneous skin nodules, congenital multiple arthrogryposis, gingival hyperplasia, and chronic pain. The intellectual ability of patients with HFS is generally normal. This syndrome arises from variants of ANTXR2. Thus far, about 100 cases have been reported but few of these were reported from Japan. This study reports five additional Japanese patients with genetically confirmed HFS, from unrelatd families, and discusses the clinical course and quality of life of these patients. At our last visit the ages of the patients were 3-19 years (the median age was 5 years). All the patients had arthrogryposis, skin nodules, and gingival hyperplasia, and four patients had chronic pain, all of which are distinctive, clinical characteristics of HFS. Four of the patients (80%) had pruritic skin nodules, and three experienced sleep disruptions due to pruritis. The visceral complications are an index of HFS severity. One patient in the present cohort had a mucosal abnormality without any gastrointestinal symptoms. Preventive and routine management of pruritis caused by skin nodules should be shared with the patient's family. Even asymptomatic patients might have endoscopic finding, which would be a soft marker that could predict the development of protein losing enteropathy.

Treatment of sickle cell anemia using CRISPR and prime editing

Sickle cell disease is a hereditary blood disease caused by an invisible genetic mutation on the autosome, caused by a transversion mutation in which the 6th amino acid of the -peptide chain, glutamate, is replaced by valine, resulting in the formation of sickle hemoglobin, instead of normal hemoglobin. Due to genetic mutations leading to structural abnormalities in hemoglobin and morphological changes in red blood cells, red blood cells lose their deformability in hypoxic environments, leading to vascular blockage, causing severe pain and partial tissue ischemia in patients. Oxygen needs to be transported to various parts of the body through red blood cells, thereby affecting the transportation of oxygen in the body. In general, red blood cells are circular and elastic, making them easy to move in blood vessels. However, in sickle cells, these red blood cells are compressed and deformed, causing the transportation of oxygen in the blood to become stiff and viscous, potentially slowing or blocking blood flow. The most common complication of SCA is blockage of blood vessels, which leads to pain. Although this is a complex phenomenon, HbS aggregation is a fundamental pathological physiological phenomenon in SCA. HbS aggregation can lead to malignant changes in the shape and physical properties of red blood cells, leading to hemolytic anemia and preventing blood flow, especially in small blood vessels, which may damage some organs. Clinical manifestations include anemia, immunodeficiency, multiple organ damage, severe acute and chronic pain, and premature death. The quality of life of the patients was seriously affected.

Targeting the JAK2/STAT3 signaling pathway for chronic pain.

Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and minimal side effects remain unidentified. Substantial evidence indicates that the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a distinct and critical role in different stages of chronic pain. Aberrant activation of the JAK2/STAT3 signaling pathway is evident in multiple chronic pain models. Moreover, an increasing number of studies have demonstrated that the downregulation of JAK2/STAT3 can attenuate chronic pain in different animal models. In this review, we investigated the mechanism and role of the JAK2/STAT3 signaling pathway in modulating chronic pain. The aberrant activation of JAK2/STAT3 can trigger chronic pain by interacting with microglia and astrocytes, releasing proinflammatory cytokines, inhibiting anti-inflammatory cytokines, and regulating synaptic plasticity. We also retrospectively reviewed current reports on JAK2/STAT3 pharmacological inhibitors that demonstrated their significant therapeutic potential in different types of chronic pain. In summary, our results provide strong evidence that the JAK2/STAT3 signaling pathway is a promising therapeutic target for chronic pain.

Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain

ABSTRACT Background Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. Methods Male Kunming mice (8–10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). Results Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. Conclusions The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.

Are We Any Closer to Understanding How Chronic Pain Develops? A Systematic Search and Critical Narrative Review of Existing Chronic Pain Vulnerability Models.

Identifying biopsychosocial factors underlying chronic pain vulnerability is essential for the design of preventative efforts. Multiple chronic pain vulnerability models exist, however, there is a lack of comprehensive evaluation of these models in the literature, potentially due to the lack of guidelines that specify the criteria by which these types of work should be assessed. In this work, we created evaluation criteria (based on the general goals of conceptual models), and we then used them to critically review the chronic pain vulnerability models available in the current peer-reviewed literature (identified through a systematic search). Particularly, we evaluated the models on the basis of conceptual clarity/specificity of measures, depth of description of aetiological and mechanistic factors, use of a whole system approach, and quality of the evidence associated with the models. We found nine conceptual models that have been explored in detail (eg, fear avoidance model, diathesis-stress model). These models excel at clarity and are supported mostly by self-report evidence of a psychological nature (anxiety sensitivity, pain catastrophizing, etc.), but provide little explanation of mechanistic and aetiological factors. In the future, models could be improved by complementing them with proposals from other models and exploring potential causal factors and mechanisms maintaining the condition. This task could be carried out through prospective cohort studies, and computational approaches, amongst others.

ID: 204351 Applying Differing Neuromodulation Strategies to Treat Chronic Pain in a Patient With Traumatic Brain Injury

More than half of patients with Traumatic Brain Injury (TBI) experience chronic pain [1]. The application of neuromodulation for chronic pain in patients with TBI is not well studied and evidence-based guidelines regarding the management of TBI-related pain is lacking [1]. We report a case highlighting the use of neuromodulation strategies to alleviate multiple chronic pain complaints in a patient with TBI.

Comparison of clinical outcomes associated with spinal cord stimulation (SCS) or conventional medical management (CMM) for chronic pain: a systematic review and meta-analysis.

This study aims to evaluate the efficacy and safety of spinal cord stimulation (SCS) compared to conventional medical management (CMM) for patients diagnosed with chronic pain. Furthermore, the study seeks to compare the utilization of analgesics, as well as the long-term outcomes in terms of quality of life and functional capacity. We systematically searched Cochrane Library, Web of Science, PubMed, and EMBASE for randomized controlled trials from inception up to February 2022. Inclusion and exclusion criteria were set according to the PICOS criteria. We searched for studies in which SCS was compared with CMM alone for chronic pain. Two reviewers independently identified eligible studies and extracted data. Risk of bias assessments were performed according to Cochrane review criteria and Interventional Pain Management Techniques-quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) criteria. The present meta-analysis comprised eight studies and included a total of 893 patients. Our findings demonstrate that spinal cord stimulation (SCS) in combination with conventional medical management (CMM) is associated with a significant reduction in visual analogue scale (VAS) pain intensity (P = 0.0005) and decreased scores on the McGill Pain Questionnaire (MPQ) (P < 0.0001). Moreover, SCS plus CMM was found to improve patients' quality of life, as evidenced by improvements in SF-36 scores (P < 0.00001), EQ-5D utility index (P = 0.008), and Oswestry Disability Index (ODI) (P < 0.00001). Based on the results of four high-quality randomized controlled trials (RCTs), the level of evidence supporting the efficacy of SCS for the treatment of painful neuropathy is graded as level I to II. In contrast, there is currently only low-level evidence to support the use of high-frequency stimulation and other chronic pain conditions, which can be attributed to a lack of sufficient randomized controlled trials. The principal limitation of our study is the significant heterogeneity observed among the cohorts investigated. The primary source of this heterogeneity is the fact that spinal cord stimulation is indicated for the treatment of multiple chronic pain conditions. Moreover, variations in the stimulation parameters, differences among manufacturers, and the specific surgical implantation settings contribute to the increased heterogeneity observed in our analyses. To address this issue, we conducted a subgroup analysis based on specific situations and performed evidence synthesis to mitigate the potential impact of heterogeneity. These approaches allow for a more precise interpretation of the results and a more accurate evaluation of the quality of the included studies. SCS is an effective treatment to relieve the pain level of chronic pain, decrease analgesic usage, and increase long-term quality of life and functional capacity.

Effect of Music Therapy On Pain Perception, Fatigue Level, And Physiological Variables in Patients Undergoing Hemodialysis- A Prospective Randomized Interventional Trial

Chronic renal failure (CRF) is a severe and chronic illness that can significantly impact a person's quality of life. It is caused by various pathologies and can lead to multiple complications, including fatigue and chronic pain. Hemodialysis is a standard and lifesaving treatment for patients with CRF, but the prolonged immobilization required during this procedure can exacerbate fatigue and pain. Music therapy is a non-invasive treatment that has positively impacted patients undergoing hemodialysis. In the study we have done, the therapy consisted of passive listening and active participation in the form of deep breathing for eight weeks. To provide music therapy based on client preference to patients undergoing hemodialysis for chronic renal failure. To observe the fatigue and subjective pain perception level after eight weeks of musical intervention.The sessions began with a warm-up session of OM chanting, which was used to set the atmosphere and bring attention to the subject. Then, devotional songs were played for 10 minutes based on the patient's preferences, followed by 20 minutes of Indian classical Veena music. The therapy sessions were administered every third day, twice a week when the patients underwent hemodialysis. Each session lasted around 3 hours. Subjective parameters of fatigue and pain perception were assessed before the intervention, after four weeks, and after eight weeks of musical intervention. The results indicated that music therapy lowered these patients' fatigue and pain perception. The fatigue level, estimated by the CIS (Checklist Individual Strength) score, was reduced by 30%, and the pain perception score dropped from 8 to 6.5. The findings of this study suggest that music therapy can be an effective complementary treatment for patients undergoing hemodialysis, as it can help to reduce fatigue and pain perception. It is essential because these symptoms can significantly impact patients' quality of life and may impact adherence to treatment regimens. However, it's also worth noting that this study only assesses the effect in a small sample size. For a short period, more research is needed in a larger population with a longer duration. Exploring different music or other therapeutic techniques is also beneficial to find the most effective approach for individual patients.

Protocol for a pragmatic feasibility randomised controlled trial of peer coaching for adults with long-term conditions: PEER CONNECT

IntroductionPatients with low levels of knowledge, skills and confidence to manage their health and well-being (activation) are more likely to have unmet health needs, delay seeking healthcare and need emergency...

Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial.

Translation of promising preclinical efficacy data for investigational analgesics to positive clinical trial outcomes is limited, despite the large collective effort to date. However, one target with positive proof-of-concept clinical trial data is the angiotensin II type 2 (AT2) receptor. This review addresses the obstacles impeding successful preclinical to clinical research translation in the novel analgesics field, and it also provides an overview of the discovery and development of EMA401, a peripherally restricted, highly selective, orally active, small-molecule AT2 receptor antagonist for relief of neuropathic pain. Multiple AT2 receptor antagonists evoked dose-dependent antiallodynia in the chronic constriction injury of the sciatic nerve rat model of neuropathic pain. In AT2 receptor knockout chronic constriction injury mice, antiallodynia was abolished, affirming the AT2 receptor as the target. Subsequently, AT2 receptor antagonists were shown to evoke pain relief in multiple rodent chronic pain models. EMA401 (sodium salt) was selected as the drug candidate based on its >10,000-fold binding selectivity c.f. the angiotensin II type 1 receptor, good potency, and favourable pharmacokinetics. Animal toxicology and safety testing along with phase 1 clinical trials in healthy volunteers showed that oral EMA401 was safe and well-tolerated. Based on these data, a proof-of-concept clinical trial of oral EMA401 was undertaken in patients with postherpetic neuralgia. This 4-week trial showed that EMA401 evoked superior relief of postherpetic neuralgia relative to placebo and there were no serious adverse events in the EMA401 group.

Cannabis-based medicinal products: a clinical guide

Cannabis sativa L has a long history as a medicinal plant, dating back more than two millennia. Preclinical studies using both pharmacological and genetic approaches have increased the understanding of this plant and its importance in providing therapeutic strategies for a variety of conditions. The cannabis plant comprises hundreds of different active compounds with potential therapeutic properties, with cannabinoids being the main class of active compounds. Recent drug development has produced cannabinoid-rich cannabis-based medicinal products, which were legalised in November 2018 in the UK. They are increasingly prescribed for conditions, including multiple sclerosis, epilepsy and chronic pain. This article aims to review the current literature on the therapeutic effects and applications of the two main cannabinoids found in cannabis-based medicinal products.

The Prevalence of Elevated Impedances and Magnetic Resonance Imaging Ineligibility Following Implantation of 10 kHz Spinal Cord Stimulation Devices: A Retrospective Review

ObjectivesSpinal cord stimulation (SCS) is increasingly utilized in the treatment of multiple chronic pain conditions. However, patients will continue to experience other medical issues and the potential for future magnetic resonance imaging (MRI) needs must not be overlooked. SCS devices have device-specific MRI conditional labeling and if impedances are elevated the patient may not be able to obtain an MRI. With 10 kHz SCS devices specifically, an impedance value above 10,000 ohms (Ω) is MRI ineligible. The primary objective of this article was to report the incidence of elevated impedances with a multilumen lead design per electrode, per lead, and to describe the total number of MRI ineligible patients due to elevated impedances using 10 kHz SCS cutoff values. The secondary objective was to determine whether certain patient demographics or surgery characteristics put patients at increased risk of elevated impedances. Materials and MethodsWe performed a retrospective review of 327 patients who were implanted with a 10 kHz SCS device between January 2015 and November 2020. Regression models were fitted to determine associations between MRI ineligibility status with clinical characteristics including age, sex, BMI, lead location, implantable pulse generator (IPG) location, and time since implant. ResultsWe found elevated impedances with subsequent MRI ineligibility in 13 patients (4.0%). Regression analysis did not identify any associations with MRI ineligibility and patient risk factors including age, sex, body mass index, lead location, IPG location, and follow-up time since implant. ConclusionWe found the prevalence of elevated impedances above 10,000 Ω to be 4% of implanted patients. This information is important for patients and physicians alike and should be considered when device selection is occurring in the pre-operative visits.

Multisensory sensitivity differentiates between multiple chronic pain conditions and pain-free individuals.

Multisensory sensitivity (MSS) to nonpainful stimuli has been identified as a risk factor for the presence of coexisting chronic pain conditions. However, it remains unclear whether MSS can differentiate pain phenotypes involving different levels of central sensitivity. Both pain-free and those with chronic pain, particularly fibromyalgia (FM), migraine, or low back pain (LBP) were recruited, with pain comorbidities assessed. MSS was highest in FM, followed by migraine, then LBP, and lowest in pain-free individuals (adjusted between condition Cohen d = 0.32-1.2, P ≤ 0.0007). However, when secondly grouping patients by the total number of pain comorbidities reported, those with a single pain condition (but not FM) did not have significantly elevated MSS vs pain-free individuals (adj d= 0.17, P = 0.18). Elevated MSS scores produced increased odds of having 2 or more pain comorbidities; OR [95% CI] =2.0 [1.15, 3.42], without, and 5.6 [2.74, 11.28], with FM ( P ≤ 0.0001). Furthermore, those with low MSS levels were 55% to 87% less likely to have ≥ 2 pain comorbidities with or without FM (OR 0.45 [0.22, 0.88]-0.13 [0.05, 0.39]; P ≤ 0.0001). Our findings support that MSS can differentiate between pain phenotypes with different degrees of expected central mechanism involvement and also serve as a risk and resilience marker for total coexisting chronic pain conditions. This supports the use of MSS as a marker of heightened central nervous system processing and thus may serve as a clinically feasible assessment to better profile pain phenotypes with the goal of improving personalized treatment.

Coupling cognitive and brainstem dysfunction in multiple sclerosis-related chronic neuropathic limb pain.

Chronic pain in multiple sclerosis is common and difficult to treat. Its mechanisms remain incompletely understood. Dysfunction of the descending pain modulatory system is known to contribute to human chronic pain conditions. However, it is not clear how alterations in executive function influence this network, despite healthy volunteer studies linking function of the descending pain modulatory system, to cognition. In adults with multiple sclerosis-associated chronic neuropathic limb pain, compared to those without pain, we hypothesized altered functional connectivity of the descending pain modulatory system, coupled to executive dysfunction. Specifically we hypothesized reduced mental flexibility, because of potential importance in stimulus reappraisal. To investigate these hypotheses, we conducted a case-control cross-sectional study of 47 adults with relapsing remitting multiple sclerosis (31 with chronic neuropathic limb pain, 16 without pain), employing clinical, neuropsychological, structural, and functional MRI measures. We measured brain lesions and atrophy affecting descending pain modulatory system structures. Both cognitive and affective dysfunctions were confirmed in the chronic neuropathic limb pain group, including reduced mental flexibility (Delis Kaplan Executive Function System card sorting tests P < 0.001). Functional connectivity of rostral anterior cingulate and ventrolateral periaqueductal gray, key structures of the descending pain modulatory system, was significantly lower in the group experiencing chronic neuropathic pain. There was no significant between-group difference in whole-brain grey matter or lesion volumes, nor lesion volume affecting white matter tracts between rostral anterior cingulate and periaqueductal gray. Brainstem-specific lesion volume was higher in the chronic neuropathic limb pain group (P = 0.0017). Differential functional connectivity remained after correction for brainstem-specific lesion volume. Gabapentinoid medications were more frequently used in the chronic pain group. We describe executive dysfunction in people with multiple sclerosis affected by chronic neuropathic pain, along with functional and structural MRI evidence compatible with dysfunction of the descending pain modulatory system. These findings extend understanding of close inter-relationships between cognition, function of the descending pain modulatory system, and chronic pain, both in multiple sclerosis and more generally in human chronic pain conditions. These findings could support application of pharmacological and cognitive interventions in chronic neuropathic pain associated with multiple sclerosis.

Migraine Is Associated With High Risk of Erectile Dysfunction: A Systematic Review and Cumulative Analysis

Migraine, a common chronic primary headache, has been found to be associated with a high risk of erectile dysfunction (ED). The present study aims to summarize all the evidence related to this topic and demonstrate a quantified result on the association between migraine and ED, which has not been reported in the literature. MEDLINE, Excerpta Medica Database, and Cochrane Library were systematically searched for identifying the eligible studies (2000-2021). This study was registered in the PROSPERO (ID: CRD42021248013). The combined effects were synthesized with the relative risks (RR) or standard mean differences (SMD) with 95% confidence intervals (CI). 6 trials with a total of 51,657 participants were included, of which 6,175 were men with migraine. The pooled analysis indicated that migraine was associated with a significantly higher risk of ED as compared to the non-migraine general population (RR=1.63, 95%CI: 1.34 to 2.0, P < .001). Consistently, men with migraine have a significantly lower IIEF-5 score than healthy controls (SMD=-3.64, 95%CI: -6.4 to -0.89, P=.01). Stratification analysis on the mean age indicated that the association between migraine and ED was much stronger in the migraine patients with age < 40 years (RR=32.29, 95% CI: 6.41-162.64, P < .001; I2=0.0 %, P=.837) than in those with age > 40 years (RR=1.75, 95% CI: 1.11-2.78, P=.017; I2=89.2%, P=.002). Sensitivity analysis indicated that no single study had dominated the combined RR and the heterogeneity. ED is a common disease among migraine men, especially those patients whose age is under 40 years old. It shows a 32-fold increased risk of ED compared to the healthy controls. Migraine-induced ED may be correlated with multiple factors, that is, chronic illnesses, chronic pain, and psychosocial causes (like anxiety and depression). Since phosphodiesterase-5 inhibitors (ie, sildenafil) might induce or exacerbate migraine, thus it is not recommended to prescribe these drugs for patients with migraine-mediated ED. The present study provides evidence that migraine is associated with a significantly high risk of ED, especially in those aged < 40 years. The pathophysiological mechanisms of this action deserve further study. He W, Yang Y, Liang H, et al. Migraine Is Associated With High Risk of Erectile Dysfunction: A Systematic Review and Cumulative Analysis. J Sex Med 2022;19:430-440.

Components of the Endocannabinoid System and Effects of Cannabinoids Against Bone Diseases: A Mini-Review.

Background: The endocannabinoid system (ECS) is involved in multiple physiological processes, including appetite regulation, pain perception, motor function development, and immune response regulation. Cannabinoids have been approved for the clinical treatment of nausea and vomiting caused by cytostatic therapy or cancer chemotherapy, loss of appetite in HIV/AIDS-associated cachexia, refractory spasms induced by multiple sclerosis, chronic pain, and urinary incontinence. Methods: Check out the research on ECS and bone diseases in the past 20 years. Results: Many studies have demonstrated that endocannabinoids (eCBs) and cannabinoid receptors (CBRs) are expressed in bone and synovial tissues, playing important roles in bone metabolism. Preclinical studies using cannabis-based therapies in animal models have shown that cannabinoids (CBs) can alleviate the development of osteoarthritis (OA), prevent osteoporosis (OP), reduce cancer-induced osteolytic destruction, and improve fracture healing, highlighting the therapeutic potential of CBs for human bone diseases. Conclusions: The present review summarizes various components of the ECS in bone diseases and their potential as a therapeutic target.