Papers: 19 Nov 2022 - 25 Nov 2022

Given that adolescence is a significant period of brain plasticity and development, early life factors have the potential to alter long term outcomes. For instance, adversities such as consumption of a high-fat high-sugar (HFHS) diet and adverse childhood experiences (ACEs; e.g., neglect), and their resulting inflammation and microglial activation can influence pain outcomes by priming the neuroimmune system to overrespond to stressors. Chronic pain is highly prevalent amongst the adolescent population, with the prevalence and manifestation being sexually dimorphic. Although clinical studies show that females are twice as likely to report pain problems compared to males, the majority of pre-clinical work uses male rodents. Therefore, our aim was to examine the effects of sex, a HFHS diet, and an ACE on chronic pain outcomes following a stressor in adolescence. Rat dams were randomly assigned to a Standard or HFHS diet, with pups maintained on their respective diets then randomly allocated to a No Stress or ACE paradigm, and a Sham or Injury condition as a stressor. Results showed that early life adversities increased nociceptive sensitivity, inflammation, and microglial activation systemically and within the brain. Behaviourally, pain outcomes were more prominent in females, however the neuroimmune response was exacerbated in males. These results demonstrate the sexual dimorphism of chronic pain outcomes following early life adversities and provide insight into the mechanisms driving these changes, which will inform more targeted and effective treatment strategies for youth living with chronic pain.

Optical control of G protein-coupled receptor (GPCR) signaling is a highly valuable approach for comprehensive understanding of GPCR-based physiologies and controlling them precisely. However, optogenetics for GPCR signaling is still developing and requires effective and versatile tools with performance evaluation from their molecular properties. Here, we systematically investigated performance of two bistable opsins that activate Gi/Go-type G protein (mosquito Opn3 (MosOpn3) and lamprey parapinopsin (LamPP)) in optical control in vivo using . Transgenic worms expressing MosOpn3, which binds 13- retinal to form photopigments, in nociceptor neurons showed light-induced avoidance responses in the presence of all- retinal, a retinal isomer ubiquitously present in every tissue, like microbial rhodopsins and unlike canonical vertebrate opsins. Remarkably, transgenic worms expressing MosOpn3 were ~7,000 times more sensitive to light than transgenic worms expressing ChR2 in this light-induced behavior, demonstrating the advantage of MosOpn3 as a light switch. LamPP is a UV-sensitive bistable opsin having complete photoregenerative ability by green light. Accordingly, transgenic worms expressing LamPP in cholinergic motor neurons stopped moving upon violet light illumination and restored coordinate movement upon green light illumination, demonstrating color-dependent control of behavior using LamPP. Furthermore, we applied molecular engineering to produce MosOpn3-based tools enabling light-dependent upregulation of cAMP or Ca levels and LamPP-based tool enabling clamping cAMP levels color dependently and context independently, extending their usability. These findings define the capacity of two bistable opsins with similar retinal requirement as ChR2, providing numerous strategies for optical control of various GPCR-based physiologies as well as GPCR signaling itself.

The midbrain periaqueductal gray (PAG) plays a central role in pain modulation via descending pathways. Opioids and cannabinoids are thought to activate these descending pathways by relieving intrinsic GABAergic inhibition of PAG neurons which project to the rostroventromedial medulla (RVM), a process known as disinhibition. However, the PAG also receives descending extrinsic GABAergic inputs from the central nucleus of the amygdala (CeA) which are thought to inhibit PAG GABAergic interneurons. It remains unclear how opioids and cannabinoids act at these different synapses to control descending analgesic pathways. We used optogenetics, tract tracing and electrophysiology to identify the circuitry underlying opioid and cannabinoid actions within the PAG of male and female rats. It was observed that both RVM-projection and nonprojection PAG neurons received intrinsic-PAG and extrinsic-CeA synaptic inputs, which were predominantly GABAergic. Opioids acted via presynaptic µ-receptors to suppress both intrinsic and extrinsic GABAergic inputs onto all PAG neurons, although this inhibition was greater in RVM-projection neurons. By contrast, cannabinoids acted via presynaptic CB1 receptors to exclusively suppress the direct descending GABAergic input from the CeA onto RVM-projection PAG neurons. These findings indicate the CeA controls PAG output neurons which project to the RVM via parallel direct and indirect GABAergic pathways. While µ-opioids indiscriminately inhibit GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate the descending control of analgesia from the PAG. The disinhibition hypothesis of analgesia states that opioids activate the midbrain periaqueductal gray (PAG) descending pathway by relieving the tonic inhibition of projection neurons from GABAergic interneurons. However, the PAG also receives extrinsic GABAergic inputs and is the locus of action of cannabinoid analgesics. Here, we show the relative sensitivity of GABAergic synapses to opioids and cannabinoids within the PAG depends on both the origin of presynaptic inputs and their postsynaptic targets. While opioids indiscriminately inhibit all GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG descending projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate PAG descending outputs.

Reliable and objective biomarkers promise to improve the assessment and treatment of chronic pain. Resting-state electroencephalography (EEG) is broadly available, easy-to-use, cost-efficient and, therefore, appealing as a potential biomarker of chronic pain. However, results of EEG studies are heterogeneous. We therefore conducted a systematic review (PROSPERO CRD42021272622) of quantitative resting state EEG and magnetoencephalography (MEG) studies in adult patients suffering from different types of chronic pain. We excluded populations with severe psychiatric or neurologic comorbidity. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. Semi-quantitative data synthesis was conducted using modified albatross plots. We included 76 studies after searching MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and EMBASE. For cross-sectional studies which can serve to develop diagnostic biomarkers, we found higher theta and beta power in chronic pain patients than in healthy participants. For longitudinal studies, which can yield monitoring and/or predictive biomarkers, we found no clear associations of pain relief with M/EEG measures. Likewise, descriptive studies which can yield diagnostic or monitoring biomarkers showed no clear correlations of pain intensity with M/EEG measures. Risk of bias was high in many studies and domains. Together, the present systematic review synthesizes evidence how resting-state M/EEG might serve as a diagnostic biomarker of chronic pain. Beyond, the review might help to guide future M/EEG studies on the development of pain biomarkers.

Treatment of neuropathic pain remains inadequate despite the elucidation of multiple pathophysiological mechanisms and the development of promising therapeutic compounds. The lack of success in translating knowledge into clinical practice has discouraged pharmaceutical companies from investing in pain medicine; however, new patient stratification approaches could help bridge the translation gap and develop individualized therapeutic approaches. As we highlight in this article, subgrouping of patients according to sensory profiles and other baseline characteristics could aid the prediction of treatment success. Furthermore, novel outcome measures have been developed for patients with neuropathic pain. The extent to which sensory profiles and outcome measures can be employed in routine clinical practice and clinical trials and across distinct neuropathic pain aetiologies is yet to be determined. Improvements in animal models, drawing on our knowledge of human pain, and robust public-private partnerships will be needed to pave the way to innovative and effective pain medicine in the future.

Understanding when multiple sclerosis (MS) lesions become clinically symptomatic may provide insight into disease pathophysiology. Our objective was to temporally associate lesion formation and trigeminal neuralgia (TN) symptom onset in MS.

Patients with severe traumatic peripheral nerve injury (PNI) always suffer from incomplete recovery and poor functional outcome. Physical exercise-based rehabilitation, as a non-invasive interventional strategy, has been widely acknowledged to improve PNI recovery by promoting nerve regeneration and relieving pain. However, effects of exercise on chronic plastic changes following severe traumatic PNIs have been limitedly discussed. In this study, we created a long-gap sciatic nerve transection followed by autograft bridging in rats and tested the therapeutic functions of treadmill running with low intensity and late initiation. We demonstrated that treadmill running effectively facilitated nerve regeneration and prevented muscle atrophy and thus improved sensorimotor functions and walking performance. Furthermore, exercise could reduce inflammation at the injured nerve as well as prevent the overexpression of TRPV1, a pain sensor, in primary afferent sensory neurons. In the central nervous system, we found that PNI induced transcriptive changes at the ipsilateral lumber spinal dorsal horn, and exercise could reverse the differential expression for genes involved in the Notch signaling pathway. In addition, through neural imaging techniques, we found volumetric, microstructural, metabolite, and neuronal activity changes in supraspinal regions of interest (i.e., somatosensory cortex, motor cortex, hippocampus, etc.) after the PNI, some of which could be reversed through treadmill running. In summary, treadmill running with late initiation could promote recovery from long-gap nerve transection, and while it could reverse maladaptive plasticity after the PNI, exercise may also ameliorate comorbidities, such as chronic pain, mental depression, and anxiety in the long term.

The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine.

Over twenty years have passed since published "The Girl Who Cried Pain: A Bias Against Women in the Treatment of Pain." This article revisits the conclusions drawn in that piece and explores what we have learned in the last two decades regarding the experience of men and women who have chronic pain and whether women continue to be treated less aggressively for their pain than men.

Netherton syndrome (NS) is a rare disorder of cornification associated with high morbidity. It is caused by bi-allelic mutations in SPINK5 encoding the serine protease inhibitor LEKTI. Previous studies have shown Th17 skewing with IL-23 upregulation in NS, raising the possibility that targeting these inflammatory pathways may alleviate disease manifestations. We ascertained the therapeutic efficacy of six doses of ustekinumab administered to three patients with NS over a period of 13 months using the Ichthyosis Area and Severity Index (IASI), the Dermatology Life Quality Index (DLQI), a visual analogue scale (VAS) for itch and the peak-pruritus numeric rating scale (PP-NRS). Histopathology analysis including CD3, CD4, CD8 and interleukin 17 (IL-17) immunostaining, was performed at baseline and 4 weeks following the last ustekinumab dose. Total IASI scores were reduced by 28% in two patients at week 16 with sustained response by week 56. No consistent improvement in DLQI, VAS for itch and PP-NRS scores was observed. The inflammatory infiltrate and the degree of acanthosis were slightly reduced at week 56 as compared to baseline. No significant change in immunostaining of the various inflammatory markers was observed at week 56. In conclusion, this case series did not demonstrate a significant therapeutic effect of ustekinumab in NS.

The present study aimed to explore the relationship between the COVID-19 pandemic and headache-related disability among a sample of young adults with migraine.

Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland.

During prolonged standing, insufficient calf muscle pumping accompanies venous stasis and hypertension in the lower legs, resulting in valve dysfunction, venous wall problems, and sub-sequent inflammation. Compression therapy, which includes medical compression stockings (MCS) and mechanical intermittent pneumatic compression (IPC), is one of the most effective therapeutic interventions for treating chronic venous diseases. This study aimed to compare the therapeutic effect among resting, IPC and MCS alone, and IPC with MCS in long-standing workers (> 8 h daily).

To quantitatively summarize the specific changes in brain structure and function in migraine patients.

The migraine attack is classically divided into the prodromal, aura, headache and postdromal phase. Previous studies have highlighted non-headache symptoms associated with migraine occurring during the prodromal or postdromal phase. This study aimed to track the evolution of non-headache symptoms throughout all phases of the migraine attack. We also wished to delineate the phenotype of patients with more symptomatic migraine episodes and explore the association between non-painful symptoms and migraine disease activity and patients' disability.

Diabetes-associated cognitive dysfunction has become a major public health concern. However, the mechanisms driving this disease are elusive. Herein, we explored how electroacupuncture improves learning and memory function in diabetic rats.

As a chronic disease that affects the whole world, there is no definite treatment for knee osteoarthritis (KOA). Wu Qin Xi (WQX) is still in preliminary exploration as a traditional Chinese exercise in the treatment of osteoarthritis of the knee. The purpose of this study was to conduct a meta-analysis of previous studies and to investigate the efficacy of the WQX exercises on pain and function in patients with KOA.

There is limited research on whether digital interventions can prevent acute or subacute pain from developing into chronic pain. This observational study's primary objective examined whether chronic pain was more likely to be prevented in digital acute MSK program participants than nonparticipants. An exploratory objective was time to pain relief for program participants versus nonparticipants.

The lack of a satisfactory strategy for postoperative pain management significantly impairs the quality of life for many patients. However, existing nanoplatforms cannot provide a longer duration of nerve blockage with intensity-adjustable characteristics under imaging guidance for clinical applications.

Appropriate prescribing practices are imperative to ensure adequate pain control, without excess opioid dispensing across colorectal patients.

The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials.

The purpose of this review is to summarize advances in behavioral treatments for pain and headache disorders, as well as recent innovations in telemedicine for behavioral treatments.

Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient's quality of life. Earlier studies have shown that the trigeminal ganglion (TG) comprises several receptors and signal molecules that are involved in the process of peripheral sensitization, which influences the development and persistence of neuropathic pain. Targeting TG can modulate this sensitization pathway and mediate the pain-relieving effect. So far,there are few studies in which modulation approaches to TG itself have been suggested so far. "Trigeminal ganglion modulation" and "trigeminal neuralgia" were used as search phrases in the Scopus Index and PubMed databases to discover articles that were pertinent to the topic. In this review, we address the role of the trigeminal ganglion in TN and underlying molecules and neuropeptides implicated in trigeminal pain pathways in processing pathological orofacial pain. We also reviewed different modulation approaches in TG for TN management. Furthermore, we discuss the prospect of targeting trigeminal ganglion to manage such intractable pain.

Most patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis.

In advanced cancer, pain is a poor prognostic factor, significantly impacting patients' quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that *10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (), rs1641025 () and rs1718125 () though significant have limited pharmacogenetic implications due to insufficient evidence. rs1799971, rs4680 and (rs1045642, rs1128503, and rs2032582) need to be further explored in future for relevance in Asian populations.

This study was performed to evaluate trends in and provide future direction for anesthesiology education, research, and clinical practice.

Neuropathic pain is a common chronic condition, which remains poorly understood. Many patients receiving treatment continue to experience severe pain, due to limited diagnostic/treatment management programmes. The development of objective clinical diagnostic/treatment strategies requires identification of robust biomarkers of neuropathic pain. To this end, we looked to identify biomarkers of chronic neuropathic pain by assessing gene expression profiles in an animal model of neuropathic pain, and differential gene expression in patients to determine the potential translatability. We demonstrated cross-species validation of several genes including those identified through bioinformatic analysis by assessing their expression in blood samples from neuropathic pain patients, according to conservative assessments of significance measured using Bonferroni-corrected p-values. These include CASP5 (p = 0.00226), CASP8 (p = 0.00587), CASP9 (p = 2.09 × 10), FPR2 (p = 0.00278), SH3BGRL3 (p = 0.00633), and TMEM88 (p = 0.00038). A ROC analysis revealed several combinations of genes to show high levels of discriminatory power in the comparison of neuropathic pain patients and control participants, of which the combination SH3BGRL3, TMEM88, and CASP9 achieved the highest level (AUROC = 0.923). The CASP9 gene was found to be common in five combinations of three genes revealing the highest levels of discriminatory power. In contrast, the gene combination PLAC8, ROMO1, and A3GALT2 showed the highest levels of discriminatory power in the comparison of neuropathic pain and nociceptive pain (AUROC = 0.919), when patients were grouped by S-LANSS scores. Molecules that demonstrate an active role in neuropathic pain have the potential to be developed into a biological measure for objective diagnostic tests, or as novel drug targets for improved pain management.

The aim of this review is to draw attention to neurosurgical approaches for treating chronic and opioid-resistant pain. In a first chapter, an up-to-date overview of the main pathophysiological mechanisms of pain has been carried out, with special emphasis on the details in which the surgical treatment is based. In a second part, the principal indications and results of different surgical approaches are reviewed. Cordotomy, Myelotomy, DREZ lesions, Trigeminal Nucleotomy, Mesencephalotomy, and Cingulotomy are revisited. Ablative procedures have a limited role in the management of chronic non-cancer pain, but they continues to help patients with refractory cancer-related pain. Another ablation lesion has been named and excluded, due to lack of current relevance. Peripheral Nerve, Spine Cord, and the principal possibilities of Deep Brain and Motor Cortex Stimulation are also revisited. Regarding electrical neuromodulation, patient selection remains a challenge.

This study aimed to investigate the relationship between the presence of hip osteoarthritis and the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, monocyte-lymphocyte ratio, and neutrophil-monocyte ratio.

Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache.

Pain can be present in up to 50% of people with post-COVID-19 condition. Understanding the complexity of post-COVID pain can help with better phenotyping of this post-COVID symptom. The aim of this study is to describe the complex associations between sensory-related, psychological, and cognitive variables in previously hospitalized COVID-19 survivors with post-COVID pain, recruited from three hospitals in Madrid (Spain) by using data-driven path analytic modeling. Demographic (i.e., age, height, and weight), sensory-related (intensity or duration of pain, central sensitization-associated symptoms, and neuropathic pain features), psychological (anxiety and depressive levels, and sleep quality), and cognitive (catastrophizing and kinesiophobia) variables were collected in a sample of 149 subjects with post-COVID pain. A Bayesian network was used for structural learning, and the structural model was fitted using structural equation modeling (SEM). The SEM model fit was excellent: RMSEA < 0.001, CFI = 1.000, SRMR = 0.063, and NNFI = 1.008. The only significant predictor of post-COVID pain was the level of depressive symptoms (β=0.241, = 0.001). Higher levels of anxiety were associated with greater central sensitization-associated symptoms by a magnitude of β=0.406 ( = 0.008). Males reported less severe neuropathic pain symptoms (-1.50 SD S-LANSS score, < 0.001) than females. A higher level of depressive symptoms was associated with worse sleep quality (β=0.406, < 0.001), and greater levels of catastrophizing (β=0.345, < 0.001). This study presents a model for post-COVID pain where psychological factors were related to central sensitization-associated symptoms and sleep quality. Further, maladaptive cognitions, such as catastrophizing, were also associated with depression. Finally, females reported more neuropathic pain features than males. Our data-driven model could be leveraged in clinical trials investigating treatment approaches in COVID-19 survivors with post-COVID pain and can represent a first step for the development of a theoretical/conceptual framework for post-COVID pain.

Migraine, a common neurological disease, is known to impact the quality of life of individuals with this condition. We performed a systematic review with meta-analysis to investigate the abnormalities associated with executive functions of migraineurs as compared with healthy controls. In addition, we investigated the differences between patients with and without aura. A total of 25 studies were included in the systematic review and 19 in the meta-analysis. Meta-analysis was conducted using random effects models, with the unit of analysis as the standardised mean difference (calculated as Hedges'g). Patients with migraine had worse performance in the trail making test A (g = 0.40; 95% confidence interval [CI] 0.05-0.74;  = 0.0271) and B (g = 0.40; 95% CI 0.16-0.64;  = 0.0026), and digit span backward test (g = -0.20; 95% CI – 0.31, – 0.09;  = 0.0105). Subgroup analysis revealed no difference between migraine with and without aura. These results suggest that migraine patients may present worse performance for specific executive functional domains, including attention, working memory, and mental flexibility.

To characterize the geographic distribution of United States (US) headache subspecialists in 2021 compared to 2012 and analyze trends in distribution of and growth by geography.

: The relationship between migraine and tension-type headache (TTH) with Parkinson's disease (PD) is controversial, while a common pathophysiological link remains obscure. The aim of this systematic review is to investigate the association between PD, migraine and TTH. : Following PRISMA, we searched MEDLINE, WebofScience, Scopus, CINAHL, Cochrane Library and ClinicalTrials.gov up to 1 July 2022 for observational studies examining the prevalence and/or associations of PD with migraine and TTH. We pooled proportions, standardized mean differences (SMD) and odds ratios (OR) with random effects models. The risk of bias was assessed with the Newcastle-Ottawa scale (PROSPERO CRD42021273238). : Out of 1031 screened studies, 12 were finally included in our review (median quality score 6/9). The prevalence of any headache among PD patients was estimated at 49.1% (760 PD patients; 95% CI 24.8-73.6), migraine prevalence at 17.2% (1242 PD patients; 95% CI 9.9-25.9), while 61.5% (316 PD patients; 95% CI 52.6-70.1) of PD patients with migraine reported headache improvement after PD onset. Overall, migraine was not associated with PD (302,165 individuals; OR = 1.11; 95% CI 0.72-1.72).However, cohort studies demonstrated a positive association of PD among lifetime migraineurs (143,583 individuals; OR = 1.54, 95% CI 1.28-1.84), while studies on 12-month migraine prevalence yielded an inverse association (5195 individuals; OR = 0.64, 95% CI 0.43-0.97). Similar findings were reported by 3 studies with data on the TTH-PD relationship (high prevalence, positive association when examined prospectively and an inverse relationship on 12-month prevalence). These data were not quantitatively synthesized due to methodological differences among the studies. Finally, PD patients suffering from any headache had a lower motor unified Parkinson's disease rating scale (UPDRS) score (503 PD patients; SMD -0.39; 95% CI -0.57 to -0.21) compared to PD patients not reporting headache. There is an unclear association of headaches in genetic PD cohorts. : Observational data suggest that migraine and TTH could be linked to PD, but the current literature is conflicting.

Physiotherapists trained to deliver biopsychosocial interventions for complex musculoskeletal pain problems often report difficulties in confidence and competency at the end of training. Cognitive Functional Therapy (CFT) is an individualized biopsychosocial intervention and understanding the facilitators and barriers to training in CFT will help inform future training programs. This study aimed to explore physiotherapists' and trainers' perceptions of the process of developing competency in CFT.

To review the current state of pharmaceutical treatment recommendations for the management of osteoarthritis.

The current study explored the antinociceptive activity of magnolol in post-incisional inflammatory nociceptive pain.

The current study evaluated the feasibility and preliminary clinical impact of robot-led distraction during needle procedures in children with chronic diseases on pain-related memories. Participants were 22 children (8-12 years old) diagnosed with a chronic disease (e.g., chronic immune deficiency) and undergoing a needle procedure as part of their routine treatment. Children were randomized to the experimental group (i.e., robot-led distraction) or control group (i.e., usual care). For feasibility, we evaluated study- and needle-procedure-related characteristics, intervention fidelity and acceptability, and nurse perceptions of the intervention. Primary clinical outcomes included children's memory bias for pain intensity and pain-related fear (1 week later). Results indicated that intervention components were >90% successful. Overall, the robot-led distraction intervention was perceived highly acceptable by the children, while nurse perceptions were mixed, indicating several challenges regarding the intervention. Preliminary between-group analyses indicated a medium effect size on memory bias for pain intensity (Hedges' g = 0.70), but only a very small effect size on memory bias for pain-related fear (Hedges' g = 0.09), in favor of the robot-led distraction intervention. To summarize, while feasible, certain challenges remain to clinically implement robot-led distraction during needle procedures. Further development of the intervention while accounting for individual child preferences is recommended.

A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein, we attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort.

Bone metastases frequently occur in patients with cancer. Skeletal-related events (SREs), including pain, impaired mobility, hypercalcemia, pathological fracture, spinal cord and nerve root compression, and bone marrow infiltration, can decrease the quality of life of the patients and increase the risk of morbidity. The mechanism of pain due to bone metastasis is complicated and involves various interactions among tumor cells, bone cells, activated inflammatory cells, and bone-innervating neurons. Cancer pain due to bone metastasis can be crippling and a chronic state that causes sarcopenia. For pain management, it is important to diagnose whether the pain is based on background pain or breakthrough pain due to bone metastasis. In addition, the management goal of cancer pain due to bone metastasis is not only to achieve pain relief but also to prevent pain progression and SREs. Pain mechanisms should be applied to achieve optimal management. This review aims to discuss the mechanisms of cancer pain due to bone metastasis and review the recommended drug therapies.

The study aimed to identify the effects of transcutaneous electrical nerve stimulation (TENS) in women with chronic pelvic pain (CPP) by conducting a systematic review and meta-analysis of randomized controlled trials.

The purpose of this study was to determine whether the timing of tread-mill exercise application can control expression levels of neuropathic pain- and regeneration-related proteins in the ipsilateral lumbar 4 (L4) to 6 (L6) dorsal root ganglion cells (DRG) after sciatic nerve injury (SNI). The experimental rats were randomly divided into five groups: the normal control, SNI+sedentary (IS), exercise+SNI (EI), SNI+exercise (IE), exercise+SNI+exercise (EIE) groups. The rats in exercise groups per-formed treadmill exercise at a speed of 8 m/min for 30 min once a day during 14 days before and/or after SNI. For investigating the expression of specific neuropathic pain and regeneration-related proteins in DRG, we prepared L4 to L6 DRG in the ipsilateral side. In the quantitative analysis, growth associated protein 43 (GAP-43) and brain-derived neurotrophic factor levels were further increased in the ipsilateral DRG at all treadmill exercise groups than those in IS group. In the histological findings, GAP-43 was qualitatively increased IE and EIE groups than IS group at DRG. Wnt3a and β-catenin were dramatically downregulated in EIE and IE groups than IS groups. In addition, nuclear factor kappa-light-chain-enhancer of activated B cells and tumor necrosis factor-α were significantly decreased in IE and EIE groups than IS group in the ipsilateral DRG. Our findings suggested novel information that regular low-intensity exercise before and/or after SNI might be a therapeutic and preventive approaches for relieving neuropathic pain and improving axonal elongation after peripheral nerve injury.

Numerous medications are used for the preventive treatment of chronic migraine (CM), including oral treatments, onabotulinumtoxinA (onabotA; BOTOX), and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Despite substantial clinical trial evidence, less is published about the real-world experience of these treatments based on data routinely collected from a variety of sources. This systematic review assessed real-world evidence on the effectiveness and safety of preventive treatments for CM in adults.

Systematic Review.

To assess the prevalence and burden of autonomic symptoms in migraine, and determine the relationship with migraine frequency.

Minimizing acute postsurgical pain (APSP) remains a challenge, despite extensive research about it. This study comprehensively analyzed the literature on APSP to assess how the field has developed and where it may go in the future.

To analyze the association between adherence to a home exercise program and central sensitization, pain intensity, and functionality in individuals with knee osteoarthritis (KOA).

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 – ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2'-3'-dideoxycitidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance. AM1710 and LY2828360 alleviated ddC-induced neuropathic nociception in mice of both sexes. These benefits were absent in global CB2 knockout mice, which exhibited robust morphine antinociception. Like morphine, AM1710 blunted ddC-induced increases in proinflammatory cytokine (IL-1β, TNF-α) and chemokine (CCL2) mRNA expression levels. We generated advillin;CB2 conditional knockout mice to ascertain the role of CB2 localized to primary sensory neurons in CB2-mediated therapeutic effects. Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillin;CB2 mice, which exhibited robust ddC-induced neuropathy. In ddC-treated CB2 mice, LY2828360 suppressed development of morphine tolerance and reversed established morphine tolerance, albeit with greater efficacy in male compared to female mice. LY2828360 failed to block or reverse morphine tolerance in advillin;CB2 mice. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

The objectives of this study were to (1) report long-term health-related quality of life (HRQoL) outcomes among patients using rimegepant preventatively in BHV3000-305 (NCT03732638) open-label extension (OLE) and (2) map Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2) to EQ-5D-3L utility values over the double-blind treatment (DBT; 0-12 weeks) and the OLE (13-64 weeks) to assess the influence of treatment on these values.

Sural nerve neuroma is often caused by an injury during prior surgery, for example, osteosynthesis or ligament refixations at ankle level. Different surgical techniques to treat neuroma have been described. Neurectomy of an injured symptomatic sural nerve has been described as a treatment option for neuropathic pain. The aim of this study was to evaluate the outcomes of this technique to operatively treat sural nerve neuroma in our department.

Non-surgical refractory back pain (NSRBP) is persistent, severe back pain that is not considered surgically correctable. Published studies have demonstrated clinically important long-term improvement in pain and functional capacity when 10kHz spinal cord stimulation (SCS) is used to treat NSRBP. This study examines if real-world patients in interventional pain practice obtain the same outcomes, and have any reduction in health care utilization (HCU) following 10kHz SCS implant.

Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an "older" appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain's impact.

Spinal cord stimulation (SCS) is an important option for patients with chronic neuropathic pain. In the United States, a successful SCS trial determines eligibility for SCS implant. Metrics to determine success are often self-reported and subjective, which may limit achievement of patient goals. This study aimed to assess whether patients undergoing SCS implant after successful trial felt that use of external accelerometry prior to implant was a useful educational tool to objectively appraise function and achievement of treatment goals.

Diabetic somatic neuropathy is one of the most prevalent complications in type 1 diabetes mellitus (T1D). Many treatments were investigated to alleviate the pain associated with this condition. Capsaicin is a naturally occurring lipophilic alkaloid that proved to be an effective and safe treatment of chronic painful disorders. Despite the known therapeutic benefits of capsaicin, the conventional topical formulations have limited bioavailability. Therefore, the current study aims to develop capsaicin nanoemulgel to increase skin permeation and enhance its activity against neuropathic pain. Low-energy emulsification method was used to prepare nanoemulsions, using eucalyptus oil as the oily phase, Tween 80 as a surfactant, propylene glycol, ethanol and isopropyl alcohol as co-surfactants. Pseudo-ternary phase diagrams were constructed to investigate and optimize the formulation. Subsequently, the optimum formulation was formulated as a nanoemulgel and investigated for, skin permeation using Franz diffusion cell, and diabetic neuropathy (DN) management using alloxan-induced diabetic mice. The selected nanoemulsion containing 0.05% capsaicin is composed of 8 % oil, 24 % S (Tween 80: isopropyl alcohol 2:1 w/w) and 68 % water. It is characterized by nanosized globules (28.15 ± 0.24 nm) with a relatively low polydispersity index (0.27 ± 0.05). The nanoemulgel revealed 4-fold increase in capsaicin cumulative permeation when compared to the conventional gel, and an improvement in its antinociceptive properties was observed in the treated diabetic mice ( < 0.05). The selected capsaicin nanoemulgel would be a promising transdermal formulation that may alleviate diabetic neuropathy in T1D patients.

Neurological disorders such as Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, migraine etc. are affecting more and more elderly people's day by day. Conventional route of administration to treat these diseases has to face a major hindrance that is blood brain and blood- (CSF) barrier to achieve desired concentration of drug at the site of action for therapeutic effect. Hence, intranasal route of delivery is considered as promising and alternative route to achieve desired goals. In last four decades, brain targeting strategies are widely studied and considered having great potential by researchers; especially intranasal delivery owing to its benefits. Various nano formulations such as nanoemulsions, nanosuspensions, hydrogels, in situ gels, dendrimers and lipidic formulations are studied widely. Lipid nano formulations especially second generation nanostructured lipid carriers offer greater advantages in terms of stability, fabrication techniques, scalability, drug loading and drug targeting. Nanostructured lipid carrier (NLCs) constitute of two major components viz solid lipid and liquid lipid in a specific ratio. In this review, authors have discussed about the possible synergistic actions of oils/liquid lipids with synthetic drugs resulting into great therapeutic benefits.

Endometriosis is an estrogen-dependent chronic progressive gynecological disease that affects around 10% of women of reproductive age. A recent study shows that brain-derived neurotrophic factor (BDNF) has the potential as a clinical marker in the diagnosis of endometriosis. We aimed to determine whether BDNF levels are correlated with pain scores associated with endometriosis.

Hypoechogenicity of the raphe nuclei (hR) has been related to major depression. Comorbidity between migraine and depression is bidirectional postulating a common mechanism of serotonergic dysfunction. We aimed to investigate the association between migraine and hR and its role as biomarker of migraine-associated depression and disease severity.

Chronic low back pain, defined as low back pain lasting more than 3 months, is a globally prevalent health problem with significantly high medical and economic burden on individuals and the society. This study aimed to estimate the prevalence of chronic low back pain and examine its association with health outcomes including physical function, mental health, and quality of life among adult population in Singapore. Cross-sectional secondary data analysis was performed using baseline data of the 1941 adults (mean age: 52.6 years, range: 21-97 years) from a representative population health survey conducted in the Central region of Singapore. Those with self-reported chronic low back pain in past six months were identified. The Late-Life Function and Disability Instrument, Patient Health Questionnaire-9, and EQ-5D-5L were used to measure physical function and limitation, mental health, and health-related quality of life, respectively. Generalized Linear Regressions were used to examine the association of chronic low back pain with physical function, limitation, depressive symptoms, and health-related quality of life. There were 8.1% (n = 180) participants reporting having chronic low back pain in past six months, among whom 80.5% sought treatments at either primary care, specialist outpatient, or Traditional Chinese Medicine clinics. Individuals with chronic low back pain reported poorer physical function, more limitations in performing major life tasks and social activities, more depressive symptoms, and lower health-related quality of life (all p < 0.01), even after adjusting for socio-demographics, lifestyle factors, and number of morbidities. The prevalence of chronic low back pain was 8.1% among the study population. Chronic low back pain was associated with poorer physical function, more limitations and depressive symptoms, and lower health-related quality of life. The findings highlight the significant impact of chronic low back pain on physical function and limitation, mental health, and health-related quality of life in a general population. Increased awareness on prevention, early and proper management of low back pain, and rehabilitation policies are required to better tackle the burden of low back pain at the population level.

The recent integration of regional anesthesia techniques into the cardiac surgical patient population has become a component of enhanced recovery after cardiac surgery pathways. Fascial planes of the chest wall enable single-injection or catheter-based infusions to spread local anesthetic over multiple levels of innervation. Although median sternotomy remains a common approach to cardiac surgery, minimally invasive techniques have integrated additional methods of performing cardiac surgery. Understanding the surgical approach and chest wall innervation is crucial to success in choosing the appropriate chest wall block. Parasternal intercostal plane techniques (previously termed "pectointercostal fascial plane" and "transversus thoracic muscle plane") provide anterior chest and ipsilateral sternal coverage. Anterolateral chest wall coverage is feasible with the interpectoral plane and pectoserratus plane blocks (previously termed "pectoralis") and superficial and deep serratus anterior plane blocks. The erector spinae plane block provides extensive coverage of the ipsilateral chest wall. Any of these techniques has the potential to provide bilateral chest wall analgesia. The relative novelty of these techniques requires ongoing research to be strategic, thoughtful, and focused on clinically meaningful outcomes to enable widespread evidence-based implementation. This review article discusses the key perspectives for performing and assessing chest wall blocks in a cardiac surgical population.

Chronic pain is highly prevalent in older adults and can cause functional limitations, negatively affecting health and quality of life. Physical activity is a non-pharmacological approach used to prevent chronic pain as it promotes the release of endogenous opioids that block pain sensitivity. Therefore, we developed a systematic review protocol to analyse the relationship between physical activity and the occurrence and intensity of chronic pain in older adults.

Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care.

Migraine and tension-type headache (TTH) are important health problems because cause loss of workforce, affect quality of life and are frequently associated with anxiety and depression. Illness perception is defined as a cognitive aspect of illness. The aim of this study is to determinethe relationship of migraine and TTH with quality of life, illness perception, anxiety and depression.

Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys (Y918C)). E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but does in the Y918C model. Based on these results, the E365del mutant mouse, as well as the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.

In some patients with rheumatoid arthritis (RA), joint pain is more severe than expected based on the amount of joint swelling (referred to as disproportionate articular pain [DP]). We assessed DP prevalence and effects of sarilumab, an interleukin-6 inhibitor, on DP.

Young adults with chronic pain and symptoms experience disruptions to their social, emotional, physical, and vocational functioning. Interdisciplinary pain rehabilitation programs for pediatric and adult populations are not designed specifically to address the developmental needs of young adults. This paper describes the development of a novel intensive interdisciplinary outpatient rehabilitation program tailored to the unique needs of young adults with chronic pain and symptoms. Tailored content included vocational assessment and consultation, financial literacy education, and sexual health education. Outcome data demonstrate treatment gains with reductions in pain interference, pain severity, pain catastrophizing and depressive symptoms, and improvements in mental and physical quality of life, perceived performance, perceived satisfaction with performance, and objective measures of physical functioning. The paper concludes with clinical recommendations for the management of chronic pain and symptoms in young adults, applicable across multiple treatment settings.

Neurocytokines may upregulate or downregulate neuropathic pain. We hypothesized that dextrose (D-glucose) injections for therapeutic purposes (dextrose prolotherapy: DPT) in painful knee osteoarthritis (KOA) would favorably affect synovial-fluid neurocytokine concentrations.

Chronic pain involves both central and peripheral neuronal plasticity that encompasses changes in the brain, spinal cord, and peripheral nociceptors. Within the forebrain, mesocorticolimbic regions associated with emotional regulation have recently been shown to exhibit lasting gene expression changes in models of chronic pain. To better understand how such enduring transcriptional changes might be regulated within brain structures associated with processing of pain or affect, we examined epigenetic modifications involved with active or permissive transcriptional states (histone H3 lysine 4 mono and trimethylation, and histone H3 lysine 27 acetylation) in periaqueductal gray (PAG), lateral hypothalamus (LH), nucleus accumbens (NAc), and ventral tegmental area (VTA) 5 weeks after sciatic nerve injury in mice to model chronic pain. For both male and female mice in chronic pain, we observed an overall trend for a reduction of these epigenetic markers in periaqueductal gray, LH, and NAc, but not VTA. Moreover, we discovered that some epigenetic modifications exhibited changes associated with pain history, while others were associated with individual differences in pain sensitivity. When taken together, these results suggest that nerve injury leads to chronic chromatin-mediated suppression of transcription in key limbic brain structures and circuits, which may underlie enduring changes in pain processing and sensitivity within these systems.

Animal modelling of arthritis is often associated with pain and suffering. Severity may be reduced with the use of analgesia which is, however, often withheld due to concerns of introducing a confounding variable. It is therefore important to design and validate pain relief protocols that reduce pain without compromising the scientific objectives. The present study evaluated the effect of buprenorphine analgesia in the immediate post-induction period of an adjuvant-induced monoarthritic rat model. The aim of this study was to extend previous work on refinement of the model by alleviating unnecessary pain.

This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency of breathing, expiratory time, tidal volume, minute ventilation, or expiratory drive but pronounced changes in inspiratory time, end-inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF, relaxation time, apneic pause, inspiratory drive and non-eupneic breathing index, (b) minimal changes in arterial blood-gas (ABG) chemistry (pH, pCO, pO, SO) and Alveolar-arterial (A-a) gradient (index of alveolar gas exchange), and (c) minimal changes in antinociception (tail-flick latency). Subsequent injection of morphine (10 mg/kg, IV) elicited markedly smaller effects on the above parameters, ABG chemistry, and A-a gradient in rats receiving L-CYSee, whereas morphine antinociception was not impaired. Infusions of L-cysteine or L-serine ethyl ester (oxygen rather than sulfur moiety), did not affect morphine actions on ABG chemistry or A-a gradient. L-CYSee (250 μmol/kg, IV) injection elicited dramatic changes in ventilatory parameters given 15 min after injection of morphine in rats receiving L-CYSee. Our findings suggest that (a) L-CYSee acts in neurons that drive ventilation, (b) L-CYSee reversal of the adverse actions of morphine on ventilation, ABG chemistry and A-a gradient may be via modulation of intracellular signaling pathways activated by morphine rather than by direct antagonism of opioid receptors since morphine antinociception was not diminished by L-CYSee, and (c) the thiol moiety of L-CYSee is vital to efficacy, (d) intracellular conversion of L-CYSee to an S-nitrosylated form may be part of its mechanism of action.

DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in neurons in mammals. However, effects of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression and hydroxymethylation status on neuron injury remain unclear. This study was designed to explore the effects of TET1 and TET2 expression in the inflammatory pain of rats induced by complete Freund's adjuvant (CFA). Mechanical paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) were detected to assess pain behavior. The expression of TET1 and TET2 were measured in the dorsal root ganglion (DRG) with western blotting analysis. Immunofluorescence staining is employed to detect the expression and co-location of TRPV1 with TET1. Intrathecal administration of Bobcat339 was used to inhibit TET1 function in DRG. The PWT and TWL of rats were significantly reduced after CFA Injection. Western blot results showed that the expression of TET1 was significantly increased at 3 d after CFA injection, but TET2 had no statistical difference. Immunofluorescence results showed that TET1 was co-localized with TRPV1. Intrathecal administration of Bobcat339 improved mechanical and thermal pain threshold in CFA rats. Our findings highlight the role of TET1 in chronic inflammatory pain model. The expression of TET1 was increased in CFA rats, and suppression of TET1 will ameliorate inflammatory pain.

The Greek Society of Migraine and Headache Patients (GSMHP), maintaining a strong commitment to research and information, conducted its second web-based online survey named "Migraine in Greece-2020", following its first one conducted in 2018. The 2020 study included 2,105 migraine patients who were called to answer 151 questions. The purposes of the current research were to record the demographic and clinical characteristics of migraine patients in Greece, including the severity and effects of migraine on respondents' quality of life, as well as to survey the effects of the coronavirus pandemic on the course of migraine. Our population, internet-based study provides data that will hopefully contribute to better comprehend the clinical phenotype and course of migraine during the COVID-19 pandemic.

Nociception is the most prevalent pain mechanism in Parkinson disease (PD). It negatively affects quality of life, and there is currently no evidence-based treatment for its control. Burst spinal cord stimulation has been used to control neuropathic pain and recently has been shown to relieve pain of nociceptive origin. In this study, we hypothesize that burst transspinal magnetic stimulation (bTsMS) reduces nociceptive pain in PD.

Traditional spinal cord stimulation (t-SCS) has been used to treat chronic pain for over 50 years. However, up to 30% of patients undergo explant, with the main indication being loss of efficacy (LoE), and few alternative treatment options exist for these patients. Strategies to mitigate LoE commonly include conversion to another type of SCS (termed 'salvage' or 'rescue'). This review summarizes the existing literature concerning the efficacy and safety of 10 kHz SCS as a salvage therapy.

Complex regional pain syndrome (CRPS) is associated with a range of sensory disturbances on the symptomatic side of the body but whether this includes olfaction is uncertain. To clarify this, the aims of this study were to compare ratings of intensity and hedonic appeal of household odorants in CRPS patients and controls, and to determine whether ratings differed between the symptomatic and contralateral sides within the sample of patients.

Central post-stroke pain (CPSP) refers to neuropathic pain in areas of the body corresponding to stroke lesions. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is safe and effective against neuropathic pain. In this randomized double-blind placebo-controlled study, we studied the effect of duloxetine in CPSP patients.

Migraine is a highly prevalent neurological disease of varying attack frequency. Headache attacks that are accompanied by a combination of impact on daily activities, photophobia and/or nausea are most commonly migraine. The headache phase of a migraine attack has attracted more research, assessment tools and treatment goals than any other feature, characteristic, or phase of migraine. However, the migraine attack may encompass up to 4 phases: the prodrome, aura, headache phase and postdrome. There is growing recognition that the burden of migraine, including symptoms associated with the headache phase of the attack, may persist between migraine attacks, sometimes referred to as the "interictal phase." These include allodynia, hypersensitivity, photophobia, phonophobia, osmophobia, visual/vestibular disturbances and motion sickness. Subtle interictal clinical manifestations and a patient's trepidation to make plans or commitments due to the unpredictability of migraine attacks may contribute to poorer quality of life. However, there are only a few tools available to assess the interictal burden. Herein, we examine the recent advances in the recognition, description, and assessment of the interictal burden of migraine. We also highlight the value in patients feeling comfortable discussing the symptoms and overall burden of migraine when discussing migraine treatment needs with their provider.

Transforaminal epidural steroid injection (TFESI) or dorsal root ganglion pulsed radiofrequency (PRF) are alternative treatments for lumbosacral radicular pain (LSRP). This study aimed to investigate the clinical efficacy of TFESI combined with dorsal root ganglion PRF using bipolar technology to treat LSRP in patients with pain duration ≥ 2 years.

Intervertebral disc degeneration (IDD) is the main cause of low back pain. An increasing number of studies have suggested that inflammatory response or the senescence of nucleus pulposus (NP) cells is strongly associated with the progress of IDD. Eupatilin, the main flavonoid extracted from , was reported to be associated with the inhibition of the intracellular inflammatory response and the senescence of cells. However, the relationship between eupatilin and IDD is still unknown. In this study, we explored the role of eupatilin in tumor necrosis factor-α (TNF-α)-induced activation of inflammatory signaling pathways and NP cell senescence, in the anabolism and catabolism of NP cell extracellular matrix (ECM) and in the effect of the puncture-induced model of caudal IDD in the rat. , eupatilin significantly inhibited TNF-α-induced ECM degradation, downregulated the expression of related markers of NP cells (MMP3, MMP9, and MMP13), and upregulated the expression of and . Furthermore, eupatilin reduced TNF-α-induced cell senescence by inhibiting the expression of the senescence of NP cell-related markers (p21 and p53). Mechanistically, ECM degradation and cell senescence were reduced by eupatilin, which inhibited the activation of MAPK/NF-κB signaling pathways. Consistent with the data, eupatilin administration ameliorated the puncture-induced model of caudal IDD in the rat. In conclusion, eupatilin can inhibit the inflammatory response and the senescence of NP cells, which may be a novel treatment strategy for IDD.

Theory of planned of behavior (TPB) constructs have been linked to health behavior intentions. Intentions to try mindfulness-based stress reduction (MBSR), a first-line therapy for chronic low back pain (cLBP), have been less studied. This study aimed to identify which TPB constructs could inform strategies to improve adoption of MBSR.

Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer. Here, a novel TRPA1 inhibitor is described and tested together with two other known TRPA1 antagonists. The novel lipoyl derivative has been successfully assessed for its ability to reduce human osteosarcoma MG-63 cell viability, motility, and gene expression of the CIBP pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). A putative three-dimensional (3D) model of the inhibitor covalently bound to TRPA1 is also proposed. The in vitro data suggest that the novel inhibitor described here may be highly interesting and stimulating for new strategies to treat osteosarcomas.

Chronic pain (CP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage lasting longer than 3 months. CP is the main reason why people seek medical care and exerts an enormous economic burden. Genome-wide expression analysis has revealed that diverse essential genetic elements are altered in CP patients. Although many possible mechanisms of CP have been revealed, we are still unable to meet all the analgesic needs of patients. In recent years, non-coding RNAs (ncRNAs) have been shown to play essential roles in peripheral neuropathy and axon regeneration, which is associated with CP occurrence and development. Multiple key ncRNAs have been identified in animal models of CP, such as microRNA-30c-5p, ciRS-7, and lncRNA MRAK009713. This review highlights different kinds of ncRNAs in the regulation of CP, which provides a more comprehensive understanding of the pathogenesis of the disease. It mainly focuses on the contributions of miRNAs, circRNAs, and lncRNAs to CP, specifically peripheral neuropathic pain (NP), diabetic NP, central NP associated with spinal cord injury, complex regional pain syndrome, inflammatory pain, and cancer-induced pain. In addition, we summarize some potential ncRNAs as novel biomarkers for CP and its complications. With an in-depth understanding of the mechanism of CP, ncRNAs may provide novel insight into CP and could become new therapeutic targets in the future.

Non-specific low back pain affects people of all ages and is a leading contributor to disease burden worldwide. Chronic low back pain (LBP) reduces working hours, increases comorbidities, and increases rehabilitation needs. The aim of this study was to evaluate whether there were differences in pain, dysfunction, and psychological factors between two groups. The supplementary demonstrated the relationship between these influencing factors and anxiety. A cross-sectional study was designed to analyze the differences in pain, disability, and psychological function in non-specific LBP patients with and without anxiety. In total, 60 subjects were divided into two groups based on self-rated anxiety scores: 30 patients with SAS score ≥50 were in the low back pain with anxiety group, and 30 for the LBP without anxiety group with SAS score <50. The pain intensity was assessed using the Visual Analog Scale; psychological function, using the Pain Anxiety Symptoms Scale, the Tampa Scale for Kinesiophobia, and the Fear Avoidance Beliefs Questionnaire; functional disability, using the Oswestry Disability Index and the Roland-Morris Disability Questionnaire; quality of life using 36-Item Short-Form Health Survey questionnaire; and the quality of sleep using Pittsburgh Sleep Quality Index, and the relationships between variables and anxiety scores were estimated using Spearman correlation analysis. A total of 60 participants were enrolled after self-rated anxiety was assessed and the full investigation was finished. The analyses showed significant differences of pain intensity ( = 0.034, disability (ODI, = 0.007; RMDQ, = 0.012) and psychological function (TSK, = 0.000; PASS, = 0.009; FABQ, = 0.000; SF-36, = 0.000; and PSQI, = 0.000) between the two groups. Spearman correlation analysis showed that the anxiety score had significant positive correlations with functional disability (ODI, = 0.004 and 95% CI = 0.112-0.573; RMDQ, = 0.003, 95% CI = 0.135-0.586) and psychological function (TSK, = 0.001, 95% CI = 0.174-0.612), excellent positive correlation with quality of sleep (PASS, = 0.025, 95% CI = 0.031-0.512), and strongly negative correlations with the quality of life (SF-36, = 0.000, 95% CI = 0.761-0.433). We recognized that anxiety in low back pain patients was mainly due to interaction with the intensity of pain, disability level, and a mass of psychological function. The future research direction could be to alleviate the anxiety on the comprehensive efficacy of patients with low back pain.

Chronic pain has a large individual and societal burden. Previous reviews have shown that internet-based cognitive-behavioral therapy (iCBT) can support patients' pain coping. However, factors related to participant experience of iCBT and effective and safe iCBT delivery for chronic pain have not recently been summarized.

Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123).

Pain is a silent global epidemic impacting approximately a third of the population. Pharmacological and surgical interventions are primary modes of treatment. Cognitive/behavioural management approaches and interventional pain management strategies are approaches that have been used to assist with the management of chronic pain. Accurate data collection and reporting treatment outcomes are vital to addressing the challenges faced. In light of this, we conducted a systematic evaluation of the current digital application landscape within chronic pain medicine.

Mental stress and imbalance of its two neural stress systems, the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis, are associated with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED). However, the comprehensive analyses of psychological stress and stress systems are under-investigated, particularly in CP/CPPS patients complicated by lower urinary tract symptoms (LUTS) and ED.

Preemptive analgesia may improve postoperative pain management, but the optimal regimen is unclear. This study aimed to compare the effects and adverse events of preemptive analgesia on postoperative pain and opioid consumption.

Chronic pain is a debilitating condition that affects many older adults who often have limited access to non-pharmacological pain management strategies. One potentially effective and novel lifestyle medicine for chronic pain involves increasing physical activity through frequent movement across the day, thereby also decreasing the presence of extended sedentary bouts. The MORPH-II pilot randomized controlled refinement trial iterated on the MORPH trial, which was a first-of-its-kind group-mediated daylong physical activity (DPA) intervention for older adults with chronic pain rooted in social cognitive and self-determination theories and supported by an mHealth toolset designed to foster social connection and awareness of physical activity patterns. MORPH-II was delivered fully remotely videoconference software and supported by a technology kit comprising an iPad, activity monitor, and wireless weight scale. It was also implemented a refined coaching model designed to help participants better understand their own patterns of activity. A total of 44 participants were randomized to receive the 12-week group-mediated DPA intervention or to a low-contact control. Qualitative interviews suggest the program was well-received by participants and that participants developed an understanding of how patterns of physical activity related to their pain symptoms. Participants also highlighted several additional areas for refinement related to the coaching model and feedback provided within the mHealth app. Analyses of covariance, controlling for baseline values, revealed a small effect (  = 0.01) on pain intensity favoring the intervention condition, though both groups improved during the study period. There was a large effect favoring the intervention condition on ActivPAL-assessed average daily steps (  = 0.23) and postural shifts (  = 0.24). Control participants spent less time in short sedentary bouts (  = 0.09), and there was a small effect (  = 0.02) indicating intervention participants spent less time in extended sedentary bouts. Finally, relative to control, intervention participants demonstrated a moderate improvement in autonomy satisfaction (  = 0.05), relatedness frustration (  = 0.05), and competence frustration (  = 0.06), and a large magnitude improvement in competence satisfaction (  = 0.22). These findings indicate that the MORPH-II intervention was feasible and acceptable, and may positively impact steps, postural breaks, and several key domains of basic psychological needs detailed in self-determination theory.

Central sensitization refers to the increased responsiveness of nociceptive neurons in the central nervous system after repeated or sustained peripheral nociceptor activation. It is hypothesized to play a key role in the development of chronic pain. A hallmark of central sensitization is an increased sensitivity to noxious mechanical stimuli extending beyond the injured location, known as secondary hyperalgesia. For its ability to modulate the transmission and the processing of nociceptive inputs, attention could constitute a promising target to prevent central sensitization and the development of chronic pain. It was recently shown that the experimental induction of central sensitization at both forearms of healthy volunteers using bilateral high-frequency electrocutaneous stimulation (HFS), can be modulated by encouraging participants to selectively focus their attention to one arm, to the detriment of the other arm, resulting in a greater secondary hyperalgesia on the attended arm as compared to the unattended one. Given the potential value of the question being addressed, we conducted a preregistered replication study in a well-powered independent sample to assess the robustness of the effect, i.e., the modulatory role of spatial attention on the induction of central sensitization. This hypothesis was tested using a double-blind, within-subject design. Sixty-seven healthy volunteers performed a task that required focusing attention toward one forearm to discriminate innocuous vibrotactile stimuli while HFS was applied on both forearms simultaneously. Our results showed a significant increase in mechanical sensitivity directly and 20 min after HFS. However, in contrast to the previous study, we did not find a significant difference in the development of secondary hyperalgesia between the attended vs. unattended arms. Our results question whether spatial selective attention affects the development of secondary hyperalgesia. Alternatively, the non-replication could be because the bottom-up capture of attention caused by the HFS-mediated sensation was too strong in comparison to the top-down modulation exerted by the attentional task. In other words, the task was not engaging enough and the HFS pulses, including those on the unattended arm, were too salient to allow a selective focus on one arm and modulate nociceptive processing.

Temporomandibular joint osteoarthritis (TMJ OA) is a disease with a multifactorial etiology, involving many pathophysiological processes, and requiring comprehensive assessments to characterize progressive cartilage degradation, subchondral bone remodeling, and chronic pain. This study aimed to integrate quantitative biomarkers of bone texture and morphometry of the articular fossa and joint space to advance the role of imaging phenotypes for diagnosis of Temporomandibular Joint Osteoarthritis (TMJ OA) in early to moderate stages by improving the performance of machine-learning algorithms to detect TMJ OA status. Ninety-two patients were prospectively enrolled (184 h-CBCT scans of the right and left mandibular condyles), divided into two groups: 46 control and 46 TMJ OA subjects. No significant difference in the articular fossa radiomic biomarkers was found between TMJ OA and control patients. The superior condyle-to-fossa distance ( < 0.05) was significantly smaller in diseased patients. The interaction effects of the articular fossa radiomic biomarkers enhanced the performance of machine-learning algorithms to detect TMJ OA status. The LightGBM model achieved an AUC 0.842 to diagnose the TMJ OA status with Headaches and Range of Mouth Opening Without Pain ranked as top features, and top interactions of VE-cadherin in Serum and Angiogenin in Saliva, TGF-1 in Saliva and Headaches, Gender and Muscle Soreness, PA1 in Saliva and Range of Mouth Opening Without Pain, Lateral Condyle Grey Level Non-Uniformity and Lateral Fossa Short Run Emphasis, TGF-1 in Serum and Lateral Fossa Trabeculae number, MMP3 in Serum and VEGF in Serum, Headaches and Lateral Fossa Trabecular spacing, Headaches and PA1 in Saliva, and Headaches and BDNF in Saliva. Our preliminary results indicate that condyle imaging features may be more important in regards to main effects, but the fossa imaging features may have a larger contribution in terms of interaction effects. More studies are needed to optimize and further enhance machine-learning algorithms to detect early markers of disease, improve prediction of disease progression and severity to ultimately better serve clinical decision support systems in the treatment of patients with TMJ OA.

BACKGROUND: DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study.

Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan.

The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort.

Trigeminal neuralgia (TN) is a rare neuropathic pain disorder characterized by recurrent, paroxysmal episodes of short-lasting severe electric shock-like pain along the sensory distribution of the trigeminal nerve. Recent classification systems group TN into 3 main categories depending on the underlying pathophysiology. This article will present a case history and review the epidemiology, diagnostic criteria, classification, clinical features, diagnostic investigations, pathophysiology, and management of TN.

Posttraumatic trigeminal neuropathy in association with dental implant surgery is preventable, and this should be the emphasis for all clinicians considering this treatment for a patient. Once the nerve injury and posttraumatic neuropathy with or without pain ensues, there is very little the clinician can do to reverse it and the high pain and permanency of the neuropathy will have a significant functional and psychological impact on the patient. Immediate implant removal is required, and home check should be routine for all cases. International diagnostic criteria are available and should be implemented in everyday practice.

This article presents the case of a patient with persistent right-sided jaw pain with a history of multiple temporomandibular joint surgeries in the setting of persistent widespread body pain, the causes of which were fibromyalgia and osteoarthritis with multiple joint replacements, as well as psychological diagnoses of PTSD and depression. Despite extensive treatment from her orofacial pain team in combination with neurology and neurosurgery, her severe pain persisted, likely due to the consequences of untreated PTSD and depression, which led to avoidance of activities that would exacerbate her pain and thus to further disability and emotional deterioration.

Pain is a common and most debilitating symptom of head and neck cancers (HNC). The prevalence of pain in HNC is nearly 70%. There are no universally accepted classification or diagnostic criteria for HNC-related pain, and currently, HNC-related pain is classified based on the underlying pathophysiological mechanism, the location of the tumor, and the protagonist of pain. The clinical presentation of HNC-related pain varies and can be similar to primary pain disorders. The management of HNC-related pain primarily consists of pharmacotherapy. However, in some cases, interventions may be needed. This article will present a case study and review the epidemiology, diagnostic criteria and classification, clinical features, pathophysiology, and HNC-related pain management.

The aim of this study was to explore differential psychological profiles among patients with chronic pain with and without fibromyalgia, and to determine the results of the cognitive behavioral therapy (CBT) for pain. Thirty patients with chronic pain and 60 patients with fibromyalgia were referred to 10 weekly sessions of CBT in a general hospital and were evaluated in pain-related variables, psychopathological symptoms, coping strategies, resilience, and quality of life. The program was implemented in specific groups for patients with fibromyalgia and nonfibromyalgia chronic pain. After the intervention, patients with fibromyalgia showed higher levels of psychopathology, rated their health status as poorer, and presented larger amplification of symptoms, higher levels of somatization, a more ruminating style of thinking and greater distress. Patients without fibromyalgia achieved better therapeutic results in both pain intensity (d = 0.39 vs. d = 0.12) and psychopathological distress (d = 0.77 vs. d = 0.11) compared to patients with fibromyalgia. Therefore, differential profiles and limited therapeutic results in fibromyalgia patients suggest the need to outline differentiated treatments and include other therapeutic strategies.

Interleukin (IL)-31 is a type 2 cytokine involved in the itch sensation in atopic dermatitis (AD). The cellular origins of IL-31 are generally considered to be Th2 cells. Macrophages are also a candidate as cellular sources of IL-31.

Chronic pain is a common disease that severely disrupts the quality of life. Persistent neuroinflammation and central sensitization play important roles in its pathogenesis. Caspase-11 is a critical modulator of inflammation of central nervous system. However, its role in chronic pain remains elusive. In this study, chronic pain and acute pain were induced via injecting complete Freund's adjuvant (CFA) and 5% formalin into the plantar of the right hind paw of wild-type (WT) and Caspase-11 deficient (Caspase-11) mice, respectively. In WT mice, CFA injection significantly decreased the hind paw mechanical pain threshold in Von Frey test on 1-7 days after injection and increased the caspase-11 level of ipsilateral dorsal horn of spinal cord on day 2 and day 5 after injection. Compared to the WT mice, Caspase-11 mice showed significantly higher mechanical pain threshold in the later phase of CFA-induced pain, but not in the early phase, and had no significant difference in 5% formalin induced licking and flinching behavior. In addition, the microglial activation, and the mRNA levels of caspase-1 and IL-18 in the spinal cord of Caspase-11 mice restored to baseline on the day 5 after CFA injection, but not in WT mice. Our data indicated that Caspase-11 contributed to persistent inflammation in ipsilateral dorsal horn of spinal cord, and consequently pain hypersensitivity in the later phase of CFA-induced pain.

Acid-sensing ion channels (ASICs) are blocked by many cationic compounds. Mechanisms of action, which may include pore block, modulation of activation and desensitization, need systematic analysis to allow predictable design of new potent and selective drugs. In this work, we studied the action of the serine protease inhibitors nafamostat, sepimostat, gabexate and camostat, on native ASICs in rat giant striatal interneurons and recombinant ASIC1a and ASIC2a channels, and compared it to that of well-known small molecule ASIC blocker diminazene. All these compounds have positively charged amidine and/or guanidine groups in their structure. Nafamostat, sepimostat and diminazene inhibited pH 6.5-induced currents in rat striatal interneurons at -80 mV holding voltage with IC values of 0.78 ± 0.12 μM, 2.4 ± 0.3 μM and 0.40 ± 0.09 μM, respectively, whereas camostat and gabexate were practically ineffective. The inhibition by nafamostat, sepimostat and diminazene was voltage-dependent evidencing binding in the channel pore. They were not trapped in the closed channels, suggesting "foot-in-the-door" mechanism of action. The inhibitory activity of nafamostat, sepimostat and diminazene was similar in experiments on native ASICs and recombinant ASIC1a channels, while all of them were drastically less active against ASIC2a channels. According to our molecular modeling, three active compounds bind in the channel pore between Glu 433 and Ala 444 in a similar way. In view of the relative safety of nafamostat for clinical use in humans, it can be considered as a potential candidate for the treatment of pathophysiological conditions linked to ASICs disfunction, including inflammatory pain and ischemic stroke.

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and anti-pruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in psoriatic mouse model, while CB1R antagonist aggravated these symptoms. As the expression of CB1R was abundant in dorsal root ganglia (DRG), we constructed mice with conditional CB1R knockout (CB1R-cKO) in primary sensory neurons and found that imiquimod (IMQ) induced psoriasiform inflammation and itch were both worsened in CB1R-cKO mice. Next, we observed that the CB1R mostly located in peptidergic neurons and deletion of CB1R in primary sensory neurons promoted the production and release of substance P (SP) to the skin tissue. Furthermore, the elevated SP in the skin affected the activation of ERK in keratinocytes and induced the accumulation of mast cells in the dermis. Last, we demonstrated that blocking the SP signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by IMQ in CB1R-cKO mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus via regulating SP expression.

Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3β mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.

Pain interference, fatigue, and impaired physical function are common features of idiopathic inflammatory myopathies (IIM). The objective of this study was to evaluate the construct validity and test-retest reliability of the Patient Reported Outcome Information System (PROMIS) Pain Interference 6av1.0, Fatigue 7av1.0, and Physical Function 8bv2.0 instruments.

The chimeric peptide EN-9 was reported as a κ-opioid/neuropeptide FF receptors bifunctional agonist that modulated chronic pain with no tolerance. Many lines of evidence have shown that the effect of the κ-opioid receptor is mediated by not only its specific activation but also downstream events participation, especially interaction with the μ-opioid receptor pathway in antinociception and tolerance on most occasions. The present study investigated the acute and chronic cross-tolerance of EN-9 with μ-opioid receptor agonist EM-2, DAMGO, and morphine after intracerebroventricularly (i.c.v) injection in the mouse tail-flick test. In the acute tolerance test, EN-9 showed symmetrical acute cross-tolerance to DAMGO but no cross-tolerance to EM2. In the chronic tolerance test, EN-9 had no tolerance after eight days of repeated administration. However, EN-9 illustrated complete cross-tolerance to morphine and symmetrical cross-tolerance to EM2. In addition, inhibition of NPFF receptor could induce the tolerance development of EN-9. These findings indicated that supraspinal EN-9-induced antinociception contains additional components, which are mediated by the downstream μ-opioid receptor pathway both in acute and chronic treatment, whereas the subtypes of μ-opioid receptor or NPFF system pathway involved in antinociceptive effects induced by EN-9 are complex. Identifying the receptor mechanism could help design preferable bifunctional opioid compounds.

Considering that insomnia and chronic pain are often comorbid, we aimed to compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), cognitive behavioral therapy for pain (CBT-P), and cognitive behavioral therapy for insomnia and pain (CBT-IP) in individuals with comorbid insomnia and chronic pain. We used PubMed, PsycINFO, CENTRAL, and Web of Science for our literature search. The outcomes included sleep, pain, disability, and depression at post-treatment and follow-up (3-12 months). Sixteen randomized controlled trials with 1094 participants were included. In the Bayesian network meta-analysis, CBT-I [standard mean difference (SMD) = -0.99, 95% credible interval (CrI) = -1.50 to -0.54] and CBT-IP (SMD = -0.70, 95% CrI = -1.60 to -0.08) were significantly more effective than the control for sleep at post-treatment. Additionally, CBT-I was significantly more effective than the control for pain, disability, and depression at post-treatment and sleep at follow-up. However, there were no significant differences in effectiveness between CBT-P and the control for any outcomes. Thus, CBT-I might be the most effective treatment option for individuals with comorbid insomnia and chronic pain. However, given the small sample sizes and high risk of bias of the included studies, these results must be interpreted with caution.

Relatively little work has evaluated both the disease of osteoarthritis (OA) and clinically-relevant pain outcome measures across different OA models in rats. The objective of this study was to compare sensitivity, pain, and histological disease severity across chemical and surgical models of OA in the rat. Stifle OA was induced in Sprague-Dawley rats via intraarticular injection of monoiodoacetate (MIA) or surgical transection of anterior cruciate ligament and/or destabilization of medial meniscus (ACL+DMM or DMM alone). Reflexive (e.g., mechanical and thermal stimuli) measures of sensitivity and non-reflexive assays (e.g., lameness, static hindlimb weight-bearing asymmetry, dynamic gait analysis) of pain were measured over time. Joint degeneration was assessed histologically. Six-weeks post OA-induction, the ACL+DMM animals had significantly greater visually observed lameness than MIA animals; however, both ACL+DMM and MIA animals showed equal pain as measured by limb use during ambulation and standing. The MIA animals showed increased thermal, but not mechanical, sensitivity compared to ACL+DMM animals. Joint degeneration was significantly more severe in the MIA model at 6 weeks. Our pilot data suggest both the ACL+DMM and MIA models are equal in terms of clinically relevant pain behaviors, but the MIA model is associated with more severe histological changes over time potentially making it more suitable for screening disease modifying agents. Future work should further characterize each model in terms of complex pain behaviors and biochemical, molecular, and imaging analysis of the sensory system and joint tissues, which will allow for more informed decisions associated with model selection and investigative outcomes.

Understanding of the role social factors play in chronic pain is growing, with more adaptive and satisfying social relationships helping pain management. During the COVID-19 pandemic, social distancing measures facilitated a naturalistic study of how changes to social interaction affected chronic pain intensity.

In this op-ed, we discuss the advantages of leveraging natural language processing (NLP) in the assessment of clinical reasoning. Clinical reasoning is a complex competency that cannot be easily assessed using multiple-choice questions. Constructed-response assessments can more directly measure important aspects of a learner's clinical reasoning ability, but substantial resources are necessary for their use. We provide an overview of INCITE, the Intelligent Clinical Text Evaluator, a scalable NLP-based computer-assisted scoring system that was developed to measure clinical reasoning ability as assessed in the written documentation portion of the now-discontinued USMLE Step 2 Clinical Skills examination. We provide the rationale for building a computer-assisted scoring system that is aligned with the intended use of an assessment. We show how INCITE's NLP pipeline was designed with transparency and interpretability in mind, so that every score produced by the computer-assisted system could be traced back to the text segment it evaluated. We next suggest that, as a consequence of INCITE's transparency and interpretability features, the system may easily be repurposed for formative assessment of clinical reasoning. Finally, we provide the reader with the resources to consider in building their own NLP-based assessment tools.

Chronic pain is primarily treated with pharmaceuticals, but the effects remain unsatisfactory. A promising alternative therapy is peripheral nerve stimulation (PNS), but it has been associated with suboptimal efficacy because its modulation mechanisms are not clear and the current therapies are primarily open loop (ie, manually adjusting the stimulation parameters). In this study, we developed a proof-of-concept computational modeling as the first step toward implementing closed-loop PNS in future biological studies. When developing new pain therapies, a useful pain biomarker is the wide-dynamic-range (WDR) neuron activity in the dorsal horn. In healthy animals, the WDR neuron activity occurs in a stereotyped manner; however, this response profile can vary widely after nerve injury to create a chronic pain condition. We hypothesized that if injury-induced changes of neuronal response can be normalized to resemble those of a healthy condition, the pathological aspects of pain may be treated while maintaining protective physiological nociception.

Seventy years ago, Hodgkin and Huxley published the first mathematical model that described action potential generation, laying the foundation for modern computational neuroscience. Since then, the field has evolved enormously with studies spanning from basic neuroscience to clinical neuromodulation applications. Computer models for neuromodulation have evolved in complexity and personalization, advancing clinical practice and novel neurostimulation therapies, such as spinal cord stimulation (SCS). SCS is a widely used therapy to treat chronic pain with rapidly expanding indications, such as restoring motor function. In general, simulations dramatically contributed to improved lead designs, stimulation configurations, waveform parameters, and programming procedures, as well as provided insight into potential mechanisms of action of electrical stimulation. However, while practical applications of neural models are relentlessly increasing in number and complexity, it is reasonable to ask whether this observed increase in complexity is necessary for improved accuracy and ultimately clinical efficacy. To this aim, we performed a systematic literature review with a qualitative meta-synthesis of the evolution of computational models, with a focus on complexity, personalization, and the use of medical imaging to capture realistic anatomy. Our review showed that increased model complexity improved both mechanistic as well as translational studies. More specifically, it enabled the development of patient-specific models that can help transform clinical practice in SCS. Finally, we combined our results to provide clear guidelines for standardization and expansion of computational models for SCS. Abstract figure legend Evolution of computational models of spinal cord stimulation. The use of computational models of spinal cord stimulation is rapidly expanding in the field of neuromodulation. Here, we evaluated the evolution of such models from the 1980s to 2022. Thanks to the advancement of medical images and computational tools, models evolved from 2D models (left) to 3D models with limited realism and tissue compartments (middle), then, to MRI-based patient specific models with high realism and complex tissue compartments (right). Model figures from left to right were adapted from Coburn 13, Capogrosso et al. 9, and Rowald et al. 62, respectively, with permission. Abbreviation key: gm-gray matter, wm-white matter, csf-cerebrospinal fluid, edf-epidural fat, root-roots and rootlets. This article is protected by copyright. All rights reserved.

Current clinical staging/grading schemes of endometriosis show poor correlation with clinical symptoms and histopathological confirmation is only in half of the clinically suspected endometriosis. In this study, done over an 8-year period, several histological features were analysed including an attempt to grade the severity of endometriosis histologically based on the number of per low power field. The components in each focus, the phasing of the glands and , the type of glands (endometrial type or undifferentiated type), and features were all analysed. This study attempts to histologically grade endometriosis while relating it to the clinical manifestations and anatomical location. Eighty cases of endometriosis were included. Most common clinical presentation was cyclical pain ( = 62) and the most common anatomical location was ( = 50). Histologically, severe endometriosis (>3 ) was seen in 37 cases. The components were mixed in 68 cases. Well-differentiated glandular pattern was typical ( = 54), while 6 cases had undifferentiated. Proliferative phase was seen in 38 cases. Fibrosis and inflammation were present in 29 and 42 cases, respectively. Significant vascular proliferation and plasma cell infiltrate was noted ( = 35). The severe grade was significantly associated with fibrosis ( = 0.03) and inflammation ( = 0.014). Endometriotic foci, unlike eutopic endometrium, shows significant plasma cell infiltrate and vascular proliferation.IMPACT STATEMENT Endometriosis, a chronic inflammatory condition in reproductive age group women. The currently used clinical staging and grading systems show poor correlation with patient symptoms and treatment outcomes. Endometriosis with classical histopathological features pose no diagnostic difficulty, however, there is poor concordance with histopathology. Atypical endometriosis is proposed as potential precursor for endometriosis related neoplasms, however, it remains as a controversial entity. The study identifies the uncommon histological patterns which may be encountered in biopsy samples from clinically identified endometriotic lesions. The recognition of these patterns will reduce clinico-pathological discrepancies. In keeping with the other grading systems, attempts at histological grading did not show any correlation with location or patient symptoms. Atypical features were seen only in two cases and was likely to be reactive in nature. Undifferentiated glandular pattern is often a under-recognized histological pattern. Histological grading of severity was a novel attempt to correlate with clinical parameters. Significant plasma cell infiltrate and vascular proliferation in endometriotic foci, underscores the quest for novel therapeutic targets. This study suggests that the use of non-invasive diagnostic methods like fibroscan/inflammatory markers to clinically identify severe disease should be investigated further.

The purpose of this study was to evaluate analgesic and safety considerations for high thoracic and cervical dorsal root ganglion (DRG) neuromodulation for complex regional pain syndrome (CRPS). We hypothesized that DRG neuromodulation would provide sustained analgesia with complications like that of low thoracic or lumbar electrode implantation.

The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each 'omic level was analyzed separately at both single-feature and systems-level (principal component [PCA] and partial least squares [PLS] regression analysis) and all 'omic levels were combined using an integrative multi-omics approach, all using the paired-sample design.

In Woldeamanuel and Oliveira (2022)'s article about the efficacy of exercise in the treatment of migraine, the ranking of the efficacy of strength training (mean difference, - 3.55), aerobic exercise (mean difference, - 2.18 to - 3.13), topiramate (mean difference, - 0.98), and amitriptyline (mean difference, 3.82) using network meta-analysis can mislead readers. First, the inclusion criteria were reported at a monthly frequency of migraine and the end of the intervention, but some article did not meet the inclusion criteria or had data inconsistency. Second, there was an inconsistency in the placebos used in the included studies, which can be problematic in network meta-analysis. Third, all three articles on strength training were rated as high-risk or exhibited some risk of bias. Finally, the effectiveness of this statistical method is questionable for assessing physical activities because strength training, aerobic exercise, and preventive medications can be simultaneously recommended for possible synergistic effects in the prevention of migraine.

Deficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case-control study investigated endogenous pain modulation in women with BMS.

Neuropathic pain following spinal cord injury (SCI) remains a difficult problem that affects more than 80% of SCI patients. Growing evidence indicates that neuroinflammatory responses play a key role in neuropathic pain after SCI. Short hairpin RNA (shRNA) interference is an efficient tool for the knockdown of disease-related specific gene expression after SCI, yet insufficient data is available to establish guidelines. In this study, we have constructed the transient receptor potential ankyrin 1 (TRPA1) shRNA encoded-lentiviral vector (LV-shTRPA1) and P38 MAPK shRNA encoded-lentiviral vector (LV-shP38) to investigate the silencing effects of shRNAs and their ability to reprogram the neuroinflammatory responses, thereby enhancing somatosensory recovery after SCI. Our in vitro data employing HEK293-FT and activated macrophages demonstrated that delivered LV-shRNAs showed high transduction efficacy with no cytotoxicity. Furthermore, a combination of LV-shP38 and LV-shTRPA1 was found to be most effective at suppressing target genes, cutting the expression of pro-inflammatory and pro-nociceptive factors in the dorsal horn of the spinal cord and dorsal root ganglia, thus contributing to the alleviation of neuronal hypersensitivities after SCI. Overall, our data demonstrated that the combination LV-shP38/shTRPA1 produced a synergistic effect for immunomodulation and reduced neuropathic pain with a favorable risk-to-benefit ratio. Collectively, our LV-mediated shRNA delivery will provide an efficient tool for gene silencing therapeutic approaches to treat various incurable disorders.

Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (- 5 to - 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (- 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (- 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective.

Cancer pain is the most prevalent symptom experienced by cancer patients. It substantially impacts a patient's long-term physical and emotional health, making it a pressing issue that must be addressed. Purinergic receptor P2X7 (P2X7R) is a widely distributed and potent non-selective ATP-gated ion channel that regulates tumor proliferation, chronic pain, and the formation of inflammatory lesions in the central nervous system. P2X7R plays an essential role in cancer pain and complications related to cancer pain including depression and opioid tolerance. This review focuses on the structure and distribution of P2X7R, its role in diverse tissues in cancer pain, and the application of P2X7R antagonists in the treatment of cancer pain to propose new ideas for cancer pain management.

This article provides an overview of the current understanding of evidence-based clinical analgesic use in birds. The field of avian analgesia has dramatically expanded during the last 20 years, affording more options for alleviating both acute and chronic pain. These options include opioids, nonsteroidal anti-inflammatory drugs, local anesthetics, and/or other drugs like gabapentin, amantadine, and cannabinoids, acting at different points in the nociceptive system thereby helping to provide greater pain relief while reducing the risk of adverse effects when combined.

The recognition and assessment of pain in avian species are crucial tools in providing adequate supportive care in clinical, laboratory, zoologic, rehabilitation, and companion animal settings. With birds being a highly diverse class of species, there is still much to be determined regarding how to create specific criteria to recognize and assess pain in these animals. This article provides a clinical review on the physiology of pain in birds, observed behavioral and physiologic alterations with pain, how different sources and degrees of pain can alter behaviors observed, and how this information can be applied in a clinical setting.

This chapter provides an overview of our current understanding of clinical analgesic use in reptiles. Currently, μ-opioid agonist drugs are the standard of care for analgesia in reptiles. Reptile pain is no longer considered a necessary part of recovery to keep the reptile from becoming active too early. Rather, treating pain allows for the reptile to begin normalizing their behavior. This recognition of pain and analgesia certainly benefits our reptile patients and greatly improves reptile welfare, but it also benefits our students and house officers, who will carry the torch and continue to demand excellence in reptile medicine.

Advances in reptile cognitive research would help to (1) better qualify behavioral responses to pain experiences, (2) monitor welfare impacts, and (3) model analgesic studies with ecologically relevant insight to better qualify interventional responses. The focus of future analgesic studies in reptiles require the continued elucidation of the opiate systems and the given variations across taxa in efficacy in nociceptive tests.

Ferrets often require pain management as part of comprehensive veterinary care. Recognition and objective quantification of pain, such as the ferret grimace scale, are the first steps of an analgesic plan. As in other species, a multimodal approach to pain management is preferred, which includes combining analgesic drugs of multiple classes and/or techniques to affect different areas of the pain pathway. This article reviews the current published literature on analgesic medications in domestic ferrets, including specific drugs, doses, dosing intervals, and routes of administration.

Rabbits occupy facets of veterinary medicine spanning from companion mammals, wildlife medicine, zoologic species, and research models. Therefore, analgesia is required for a variety of conditions in rabbits and is a critical component of patient care. Considerations when selecting an analgesic protocol in rabbits include timing of administration, route of administration, degree or anticipated pain, ability to access or use controlled drugs, systemic health, and any potential side effects. This review focuses on pharmacologic and locoregional management of pain in rabbits and emphasizes the need for further studies on pain management in this species.

Recent myomorph and scuiromorph rodent analgesia studies are reviewed and evaluated for potential clinical application. Differences between laboratory animal studies and clinical use in diseased animals are discussed. Analgesia classes reviewed include local anesthetics, nonsteroidal anti-inflammatories, acetaminophen, opioids, and adjuvants such as anticonvulsants. Routes of administration including sustained-release mechanisms are discussed, as are reversal agents. Drug interactions are reviewed in the context of beneficial multimodal analgesia as well as potential adverse effects. Dosage recommendations for clinical patients are explored.

Available methods for recognizing and assessing pain in rodents have increased over the last 10 years, including the development of validated pain assessment scales. Much of this work has been driven by the needs of biomedical research, and there are specific challenges to applying these scales in the clinical environment. This article provides an introduction to pain assessment scale validation, reviews current methods of pain assessment, highlighting their strengths and weaknesses, and makes recommendations for assessing pain in a clinical environment.

This chapter provides an overview of our current understanding of clinical analgesic use in fish. Recently, the efficacy and pharmacokinetics of several analgesic drugs for use in fish have been investigated, and the most important data indicates that μ-opioid agonist drugs (e.g, morphine) are consistently effective as analgesics across fish species. In addition, bath application of some analgesic drugs may be useful, which affords multiple methods for delivering analgesics to fish. Although few published studies of non-steroidal anti-inflammatory drugs administered to fish show promise, we have much to learn about the analgesic efficacy of most drugs in this class.

Trigeminal neuropathic pain (TNP) is an intense pain condition characterized by hyperalgesia and allodynia; however, its neural mechanisms are not completely understood. Its management is complex, and studies that investigate its biochemical mechanisms are important for improving clinical approaches. This study aimed to evaluate the involvement of GABAergic, glutamatergic, and opioidergic systems and brain-derived neurotrophic factor (BDNF) levels in the TNP process in rats. TNP is induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Nociceptive responses were evaluated using the facial von Frey test before and after the administration of GABAergic and opioidergic agonists and glutamatergic antagonists. The rats were divided into vehicle-treated control (C), sham-surgery (SS), and CCI-ION groups, and then subdivided into the vehicle (V)-treated SS-V and CCI-ION-V groups, SS-MK801 and CCI-ION-MK801, treated with the N-methyl-D-aspartate receptor selective antagonist MK801; SS-PB and CCI-ION-PB, treated with phenobarbital; SS-BZD and CCI-ION-BZD, treated with diazepam; SS-MOR and CCI-ION-MOR, treated with morphine. BDNF levels were evaluated in the cerebral cortex, brainstem, trigeminal ganglion, infraorbital branch of the trigeminal nerve, and serum. CCI-ION induced facial mechanical hyperalgesia. Phenobarbital and morphine reversed the hyperalgesia induced by CCI-ION, and the CCI-BZD group had an increased nociceptive threshold until 60 min. CCI-ION-GLU increased the nociceptive threshold at 60 min. Cerebral cortex and brainstem BDNF levels increased in the CCI-ION and SS groups. Only the CCI group presented high levels of BDNF in the trigeminal ganglion. Our data suggest the involvement of GABAergic, glutamatergic, and opioidergic systems and peripheral BDNF in the TNP process.

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease.

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D and D receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D and D receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D/D receptors in reserpine-induced hypersensitivity in rats.

Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity.

Our previous study has illuminated that PGC-1α downregulation promoted chronification of pain after burn injury. RNA-seq analysis predicted association between Sp1 and chronic constriction injury (CCI)-provoked neuropathic pain. Further ChIP-Atlas data investigation suggested the binding to Sp1 to PGC-1α. Thereby, we performed this study to illustrate the functional relevance of the Sp1/PGC-1α axis in neuropathic pain.

Chronic noncancer pain is a global public health challenge. It is imperative to identify biological markers ("biomarkers") to understand the mechanisms underlying chronic pain and to monitor pain over time and after interventions. Transcranial magnetic stimulation (TMS) is a promising method for this purpose.

The chronic pain and functional limitations in osteoarthritis (OA) patients can increase risk of psychiatric disorders, e.g., major depression disorder (MDD), which may further aggravate the clinical symptoms of OA. Early detection of MDD is essential in the clinical practice of OA.

Osteoarthritis (OA) is driven by chronic low-grade inflammation and subsequent cartilage degradation. OA is the most prevalent degenerative joint disease worldwide, and its treatment remains a challenge. The aim of this study was to explore the potential effects and mechanism underlying the anti-OA properties of ginkgolide C (GC). Protective effects of GC on hydrogen peroxide (HO)-treated rat chondrocytes were evaluated using ELISA, qPCR, western blot analysis, flow cytometry, ROS detection and immunofluorescence . Ameliorating effects of GC on cartilage degeneration in rats were evaluated through behavioral assays, microcomputed tomography, histopathological analysis, western blot analysis and ELISA . , GC treatment inhibited the release of pro-apoptotic factors induced by HO and promoted the release of the anti-apoptotic proteins. In addition, GC decreased the expression of matrix metalloproteinase (MMP3 and MMP13), thrombospondin motifs 4 (ADAMTS4), and inflammatory mediators inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and SOX9 thereby inhibiting extracellular matrix (ECM) degradation. Mechanistically, GC exerts its anti-apoptotic and anti-inflammatory effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, In a rat model with post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT), GC inhibited joint pain, cartilage destruction, and abnormal bone remodeling of subchondral bone. GC inhibited HO-induced chondrocyte apoptosis through Nrf2/HO-1 and NF-κB axis, exerted anti-inflammatory effects, and inhibited cartilage degeneration in rat OA. Our findings advanced the concept that GC may contribute to cartilage metabolism through anti-inflammatory and anti-apoptotic effects, and the identified GC is a potential therapeutic agent for the treatment of OA.

Chronic pain can be difficult to predict and a challenge to treat. Biomarkers for chronic pain signal an opportunity for advancements in both management and prevention, and through their research and development offer new insights into the complex processes at play. This review considers the latest research in chronic pain biomarker development and considers how close we are to bringing these from bench to bedside. While some headway has been made that offers efficiencies in patient selection, it is unlikely that a single test will encompass the variety of chronic pain phenotypes. We offer some insights for the near future in biomarker development and areas of continued unmet need.

Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Ca3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Ca3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Ca3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Ca3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Ca3.2 channels.

Labour pain has been identified as an important reason for women to prefer caesarean section (CS). Fentanyl is one of the short acting opioids recommended by World Health Organization for pain relief during labour. This study aimed to identify and describe the available evidence on the use of fentanyl (monotherapy) for labour pain management by any routes of administration or regime.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition impacting 30% of cancer survivors. This study is the first to explore whether a brain-based vulnerability to chronic sensory CIPN exists.

Fabry disease is a rare X-linked lysosomal storage disorder. It is associated with physical distress and social challenges that may affect adults differently compared to pediatric patients. However, there is no disease-specific quality of life (QOL) scale that can provide a detailed assessment of QOL for adults with Fabry disease. Therefore, we aimed to determine the factor structure and assess the validity of a scale that was created to assess the QOL of adult patients with Fabry disease. This study was conducted in two phases. First, scale feasibility was confirmed through a questionnaire survey of nine patients. Second, a cross-sectional questionnaire survey of patients (aged ≥ 18 years) diagnosed with Fabry disease was conducted. Item development and refinement were conducted based on guidelines for scale development. Exploratory factor analysis was used to clarify the factor structure and confirm internal consistency. As a measure of QOL, construct validity was of the scale was verified based on its correlations with the Short Form-8 (SF-8) scale.

To evaluate the efficacy of different non-pharmacologic therapies (NPTs) on relieving depressive symptoms and pain intensity in individuals living with chronic low back pain (LBP) and associated depression.

The present study aimed to investigate the status of vestibular function in children with vestibular migraine of childhood (VMC) reflected by vestibular function test battery and explore the pathophysiological implication of these instrument-based findings.

Chronic pain is a distinct complication that profoundly affects the lives of individuals with sickle cell disease (SCD). Chronic SCD pain emerges with increasing age and is very prevalent in adults. The pathophysiology of chronic SCD pain is likely distinct from acute SCD pain and therefore needs a different treatment approach. Clinical trials evaluating the treatment of chronic SCD pain are lacking and treatment currently relies on evidence from other chronic pain conditions. Continued investigations into the underlying causes of chronic SCD pain are needed, and clinical trials focused on chronic pain therapy are imperative.

Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented.

Non-specific low back pain is a common, potentially disabling condition usually treated with self-care and non-prescription medication. For chronic low back pain, current guidelines recommend exercise therapy. Yoga is a mind-body exercise sometimes used for non-specific low back pain.

The use of perinatal-derived tissues and mesenchymal stromal cells (MSCs) as alternative treatment options to corticosteroid and hyaluronic acid injections has been gaining popularity. However, their ability to attenuate osteoarthritic (OA) symptoms while also slowing the progression of the disease remains controversial. Thus, the objective of this article is to summarize the results from both preclinical and clinical studies evaluating the efficacy of perinatal-derived tissue allografts and MSCs for the treatment of OA.

This study aims to explore how people with chronic pain explain their use or non-use of pain-related healthcare services and their expectations of the healthcare provider, and explore how explanations and expectations vary between different levels of pain-related healthcare use.

To examine associations of metabolic parameters (mean 30 years' time-weighted HbA and low-density lipoprotein-cholesterol (LDL-c), current methionine sulfoxide (MetSO), Advanced Glycation Endproducts (AGEs), inflammatory markers, and hypoglycaemia) with pain, fatigue, depression and quality of life (QoL) in people with long-term type 1 diabetes.

Unlike conventional dorsal spinal cord stimulation (SCS)-which uses single pulses at a fixed rate-burst SCS uses a fixed-rate, five-pulse stimuli cluster as a treatment for chronic pain; mechanistic explanations suggest burst SCS differentially modulate the medial and lateral pain pathways vs conventional SCS. Neural activation differences between burst and conventional SCS are quantifiable with the spinal-evoked compound action potential (ECAP), an electrical measure of synchronous neural activation.

The ability of clinical trials to inform the care of chronic pain may be limited if only an unrepresentative subset of patients are allowed to enroll. We summarize and report new insights on published studies that report on how trial exclusions affect the generalizability of their results. We conducted a PubMed search on the following terms: (("eligibility criteria" AND generalizability) OR ("exclusion criteria" AND generalizability) OR "exclusion criteria"[ti] OR "eligibility criteria"[ti]) AND pain. We only considered studies relevant if they analyzed data on (1) the prevalence and nature of exclusion criteria or (2) the impact of exclusion criteria on sample representativeness or study results. The 4 articles that were identified reported differences in patients who were included and excluded in different clinical trials: excluded patients were older, less likely to have a paid job, had more functional limitations at baseline, and used strong opioids more often. The clinical significance of these differences remains unclear. The pain medicine literature has very few published studies on the prevalence and impact of exclusion criteria, and the outcomes of excluded patients are rarely tracked. The frequent use of psychosocial exclusions is especially compromising to generalizability because chronic pain commonly co-occurs with psychiatric comorbidities. Inclusion of more representative patients in research samples can reduce recruitment barriers and broaden the generalizability of findings in patients with chronic pain. We also call for more studies that examine the use of exclusion criteria in chronic pain trials to better understand their implications.