I am a
Home I AM A Search Login

Papers: 24 Dec 2022 - 30 Dec 2022

Share this

Piezo2 channels expressed by colon-innervating TRPV1-lineage neurons mediate visceral mechanical hypersensitivity.

Inflammatory and functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and obstructive bowel disorder (OBD) underlie the most prevalent forms of visceral pain. Although visceral pain can be generally provoked by mechanical distension/stretch, the mechanisms that underlie visceral mechanosensitivity in colon-innervating visceral afferents remain elusive. Here, we show that virally mediated ablation of colon-innervating TRPV1-expressing nociceptors markedly reduces colorectal distention (CRD)-evoked visceromotor response (VMR) in mice. Selective ablation of the stretch-activated Piezo2 channels from TRPV1 lineage neurons substantially reduces mechanically evoked visceral afferent action potential firing and CRD-induced VMR under physiological conditions, as well as in mouse models of zymosan-induced IBS and partial colon obstruction (PCO). Collectively, our results demonstrate that mechanosensitive Piezo2 channels expressed by TRPV1-lineage nociceptors powerfully contribute to visceral mechanosensitivity and nociception under physiological conditions and visceral hypersensitivity under pathological conditions in mice, uncovering potential therapeutic targets for the treatment of visceral pain.

Learn More >

Expectations for improvement: a neglected but potentially important covariate or moderator for chronic pain clinical trials.

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants' expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and non-pharmacological pain treatments. We highlight the potential benefit of adjusting for participants' expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PERSPECTIVE: : This focus article provides an overview of the relationship between participants' baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity.

Learn More >

Computational design of peptides to target Na1.7 channel with high potency and selectivity for the treatment of pain.

The voltage-gated sodium Na1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human Na1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human Na1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with ICs of 7 nM and 4 nM for hNa1.7 and more than 1,000-fold selectivity over human Na1.1, Na1.3, Na1.4, Na1.5, Na1.8, and Na1.9 channels. PTx2-3127 inhibits Na1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally-designed peptide inhibitors of human Na1.7 channels have transformative potential to define a new class of biologics to treat pain.

Learn More >

‘My back is fit for movement’: A qualitative study alongside a randomised controlled trial for chronic low back pain.

A new wave of treatments has emerged to target the altered nervous system and maladaptive conceptualizations about pain for chronic low back pain. The acceptability of these treatments is still uncertain. We conducted a qualitative study alongside a randomized controlled trial to identify perceptions of facilitators/barriers to participation in a non-pharmacological intervention that resulted in clinically meaningful reductions across 12 months for disability compared to a sham intervention. We conducted semi-structured interviews with participants from the trial's active arm after they completed the 12-week program. We included a purposeful sample (baseline and clinical characteristics) (n=20). We used reflexive thematic analysis informed by the Theoretical Framework of Acceptability for health care interventions. We identified positive and negative emotional/cognitive responses associated with treatment acceptability and potential efficacy, including emotional support, cognitive empowerment, readiness for self-management, and acceptance of face-to-face and online components designed to target the brain. These findings suggest the importance of psychoeducation and behaviour change techniques to create a positive attitude towards movement and increase the perception of pain control; systematic approaches to monitor and target misconceptions about the interventions during treatment; and psychoeducation and behaviour change techniques to maintain the improvements after the cessation of formal care. Perspective: This article presents the experiences of people with chronic low back pain toward a new non-pharmacological brain-targeted treatment that includes face-to-face and self-directed approaches. The facilitators and barriers of the interventions could potentially inform adaptations and optimization of treatments designed to target the brain to treat chronic low back pain.

Learn More >

Chronic Pain and High Impact Chronic Pain in Children and Adolescents: A Cross-Sectional Study.

The aims of this study were to: (1) estimate the prevalence of chronic pain (CP) and high impact chronic pain (HICP) in a community sample of children and adolescents; and (2) compare groups (those without CP, those with CP but no HICP, and those with HICP) with respect to demographic variables, pain variables, and physical, psychological, and school-related function. One thousand one hundred and fifteen children and adolescents participated (56% girls; age: ߂= 11.67; SD = 2.47; range = 8 to 18 years). The prevalence of CP and HICP was 46% and 5%, respectively, and was higher in girls and increased with age. Participants with HICP reported greater pain intensity and higher pain frequency than those with CP but no HICP. In addition, participants with HICP reported lower mobility, greater fatigue, worst sleep quality, more anxiety and depression symptoms, worst cognitive function, missing more school days, and worse perceived school performance. HICP is a prevalent condition in children and adolescents and is associated with many negative consequences. Stakeholders must be aware of this and ensure that treatment programs are available to reduce the individual and societal impact of HICP in young individuals. PERSPECTIVE: : This article provides information on CP and HICP prevalence and impact in children and adolescents. By better understanding the nature and score of these conditions, we will be able to develop more effective early interventions to help this population and thereby reduce their long-term negative impact.

Learn More >

A transcriptome dataset for gonadectomy-induced changes in rat spinal cord.

Circulating sex steroid hormones are critical for neural function and development of neuroplasticity in many regions of the central nervous system. In the spinal cord, our knowledge of steroid hormone influence mostly derives from mechanistic studies of pain processing in dorsal spinal cord circuits; less is known regarding hormonal influence of ventral spinal motor function. Gonadectomy (surgical removal of the testes in males and ovaries in females) rapidly and persistently reduces circulating sex steroids in both females and males, providing a means to interrogate the role of hormones on neural function. Here we provide a next-generation RNA sequencing (RNA-seq) data set to evaluate the impact of gonadectomy on the transcriptome of ventral spinal cord tissue of adult female and male rats.

Learn More >

Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment.

Cannabinoids are often prescribed for neuropathic pain, but the evidence-based recommendation is "weak against."

Learn More >

Artificial Intelligence in osteoarthritis: repair by knee joint distraction shows association of pain, radiographic and immunologic outcomes.

Knee joint distraction (KJD) has been associated with clinical and structural improvement and synovial fluid (SF) marker changes. The current objective was to analyze radiographic changes after KJD using an automatic AI-based measurement method, and relate these to clinical outcome and SF markers.

Learn More >

Age and sex drive differential behavioral and neuroimmune phenotypes during postoperative pain.

Surgical procedures in the geriatric population are steadily increasing, driven by improved healthcare technologies and longer lifespans. However, effective postoperative pain treatments are lacking, and this diminishes quality of life and recovery. Here we present one of the first preclinical studies to pursue sex- and age-specific differences in postoperative neuroimmune phenotypes and pain. We found that aged males, but not females, had a delayed onset of mechanical hypersensitivity post-surgery and faster resolution than young counterparts. This sex-specific age effect was accompanied by decreased paw innervation and increased local inflammation. Additionally, we find evidence of an age-dependent decrease in hyperalgesic priming and perioperative changes in nociceptor populations and spinal microglia in the aged. These findings suggest that impaired neuronal function and maladaptive inflammatory mechanisms influence postoperative pain development in advanced age. Elucidation of these neuroimmune phenotypes across age and sex enables the development of novel therapies that can be tailored for improved pain relief.

Learn More >

Pain severity at emergency department discharge as a predictor for chronification of pain.

Inadequate pain management remains a problem in the emergency department (ED) and might increase the risk of chronic pain. Previous studies suggested that pain intensity is associated with pain chronification in specific patient groups. This study aims to study the association between pain intensity {[verbal] numeric rating scale ([V]NRS) ≥ 7} at discharge from the ED and pain chronification in the general population.

Learn More >

Glial regulators of ions and solutes required for specific chemosensory functions in C. elegans

Glia and accessory cells regulate the microenvironment around neurons and primary sensory cells. However, the impact of specific glial regulators of ions and solutes on functionally diverse primary cells is poorly understood. Here, we systemically investigate the requirement of ion channels and transporters enriched in Amsh glia for the function of chemosensory neurons. Although Amsh glia ablated worms show reduced function of ASH, AWC, AWA, and ASE neurons, we show that the loss of glial enriched ion channels and transporters impacts these neurons differently, with nociceptor ASH being the most affected. Furthermore, our analysis underscores the importance of K, Cl, and nucleoside homeostasis in the Amphid sensory organ and uncovers the contribution of glial genes implicated in neurological disorders. Our findings build a unique fingerprint of each glial enriched ion channel and transporter and may provide insights into the function of supporting cells of mammalian sensory organs.

Learn More >

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater.

Pain, usually caused by a strong or disruptive stimulus, is an unpleasant sensation that serves as a warning to organisms. To adapt to extreme environments, some terrestrial animals have evolved to be inherently insensitive to pain. Cetaceans are known as supposedly indifferent to pain from soft tissue injury representatives of marine mammals. However, the molecular mechanisms that explain how cetaceans are adapted to pain in response to seawater environment remain unclear. Here, we performed a molecular evolutionary analysis of pain-related genes in selected representatives of cetaceans. gene was identified to be pseudogenized in all odontocetes (toothed whales) except from (sperm whales), and relaxed selection of this gene was detected in toothed whales with pseudogenized . In addition, positive selection was detected in pain perception (i.e., , , , and ) and analgesia (i.e., , , , and ) genes among the examined cetaceans. In this study, potential convergent amino acid substitutions within predicted proteins were found among the examined cetaceans and other terrestrial mammals, inhabiting extreme environments (e.g., V441I of TRPV1 in cetaceans and naked mole rats). Moreover, specific amino acid substitutions within predicted sequences of several proteins were found in the studied representatives of cetaceans (e.g., F56L and D163A of ASIC3, E88G of GRK2, and F159L of OPRD1). Most of the substitutions were located within important functional domains of proteins, affecting their protein functions. The above evidence suggests that cetaceans might have undergone adaptive molecular evolution in pain-related genes through different evolutionary patterns to adapt to pain, resulting in greater sensitivity to pain and more effective analgesia. This study could have implications for diagnosis and treatment of human pain.

Learn More >

Efficacy and safety evaluation of dexmedetomidine for postoperative patient controlled intravenous analgesia: A systematic review and meta-analysis.

To investigate the efficacy and safety of dexmedetomidine (DEX) for postoperative patient controlled intravenous analgesia (PCIA). Two investigators independently searched Pubmed, Embase, Scopus, Cochrane Library and CBM for randomized controlled trials of DEX for PCIA. Thirty-seven studies with a total of 5,409 patients were included in this meta-analysis. Compared with analgesics alone, DEX for PCIA reduced pain score at 24 h [mean difference (MD) = -0.70; 95% confidence interval (CI): -0.85, -0.54; < 0.00001, = 90%] and 48 h postoperatively (MD = -0.43; 95% CI: -0.52, -0.34; < 0.00001, = 96%). Moreover, DEX reduced analgesics consumption during the first 24 h [standardized mean difference (SMD) = -0.25; 95% CI: -0.34, -0.16; < 0.00001, = 91%] and the number of resuscitation analgesics administered [odds ratio (OR) = 0.54; 95% CI: 0.44, 0.66; < 0.00001, = 72%]. Furthermore, DEX improved patient satisfaction (OR = 3.55; 95% CI: 2.36, 5.35; < 0.00001, = 60%), and reduced incidence of side effects, such as postoperative nausea and vomiting (PONV) (OR = 0.47; 95% CI: 0.39, 0.57; < 0.00001, = 59%) and pruritus after surgery (OR = 0.45; 95% CI: 0.30, 0.68; = 0.0001, = 0%). Besides, DEX attenuates inflammatory cytokine levels, such as IL-6 (MD = -5.73; 95% CI: -8.34, -3.12; < 0.00001, = 91%) and TNF-α (MD = -0.63; 95% CI: -0.76, -0.50; < 0.00001, = 89%). Finally, DEX increased the risk of bradycardia (OR = 1.66; 95% CI: 1.12, 2.45; = 0.01, = 15%), but the complication of hypotension did not differ between the two groups (OR = 1.30; 95% CI: 0.84, 2.04; = 0.25, = 0%). DEX is used for postoperative PCIA analgesia, which can significantly improve the analgesic effect, effectively control postoperative inflammatory response, reduce the dosage and adverse reactions of analgesics, and improve postoperative patient satisfaction. Of course, the impact of the immunosuppressive effect of DEX on the prognosis of patients needs further study. CRD42022340933, https://www.crd.york.ac.uk/prospero/.

Learn More >

The impact of a postoperative multimodal analgesia pathway on opioid use and outcomes after cardiothoracic surgery.

The Enhanced Recovery after Surgery Cardiac Society recommends using multimodal analgesia (MMA) for postoperative pain however, evidence-based guidelines have yet to be established. This study examines the impact of a standardized postoperative MMA pathway in reducing opioid consumption and related complications after cardiothoracic surgery (CTS).

Learn More >

Imbalance in the spinal serotonergic pathway induces aggravation of mechanical allodynia and microglial activation in carrageenan inflammation.

This study investigated the effect of an excess and a deficit of spinal 5-hydroxytryptamine (5-HT) on the mechanical allodynia and neuroglia activation in a rodent pain model of carrageenan inflammation.

Learn More >

Conversion ratios for opioid switching: a pragmatic study.

The final conversion ratios among opioids used for successful switching are unknown. The aim of this study was to determine the initial and final conversion ratios used for a successful opioid switching in cancer patients, and eventual associated factors.

Learn More >

Preparation and Optimization of Liposome Containing Thermosensitive Nasal Hydrogel System for Brain Delivery of Sumatriptan Succinate.

in situ in situ in vivo in situ

Learn More >

Safety and efficacy of high-dose clobetasol propionate 0.05% in cutaneous lichen planus.

Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (>5 g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2 months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.

Learn More >

A Review of Chronic Pain and Device Interventions: Benefits and Future Directions.

Chronic pain is a debilitating condition with a growing prevalence both in the USA and globally. The complex nature of this condition necessitates a multimodal approach to pain management that extends beyond the established pharmaceutical interventions currently employed. A variety of devices comprising both invasive and noninvasive approaches are available to patients, serving as adjuvants to existing regimens. The benefits of these interventions are notable for their lack of addiction potential, potential for patient autonomy regarding self-administration, minimal to no drug interaction, and overall relative safety. However, there remains a need for further research and more robust clinical trials to assess the true efficacy of these interventions and elucidate if there is an underlying physiological mechanism to their benefit in treating chronic pain or if their effect is predominantly placebo in nature. Regardless, the field of device-based intervention and treatment remains an evolving field with much promise for the future chronic pain management.

Learn More >

A Correlation between Upper Extremity Compressive Neuropathy and Nerve Compression Headache.

Learn More >

How the COVID-19 emergency changed our modality to treat patients with migraine: a positive aspect of the pandemic.

Learn More >

Teaching Images: intrathecal pump catheter aneurysm.

Learn More >

An Interpretative Phenomenological Analysis of Living with Chronic Low Back Pain in Ethiopia.

People with chronic low back pain experience myriads of problems from living with their condition. This study aimed to explore the lived experience of people with chronic low back pain in Ethiopia.

Learn More >

An investigation of the relationship between cutaneous allodynia and kinesiophobia, gastrointestinal system symptom severity, physical activity and disability in individuals with migraine.

To investigate the relationship between cutaneous allodynia (CA) and kinesiophobia, gastrointestinal system (GIS) symptom severity, physical activity, and disability, and to determine whether CA, pain, and disability were influencing factors for kinesiophobia, GIS symptoms, and physical activity in individuals with migraine.

Learn More >

Primary somatosensory cortex and periaqueductal gray functional connectivity as a marker of the dysfunction of the descending pain modulatory system in fibromyalgia.

Resting-state functional connectivity (rs-FC) may aid in understanding the link between pain-modulating brain regions and the descending pain modulatory system (DPMS) in fibromyalgia (FM). This study investigated whether the differences in rs-FC of the primary somatosensory cortex in responders and non-responders to the conditioned pain modulation test (CPM-test) are related to pain, sleep quality, central sensitization, and the impact of FM on quality of life.

Learn More >

High-impact chronic pain: evaluation of risk factors and predictors.

The concept of high-impact chronic pain (HICP) has been proposed for patients with chronic pain who have significant limitations in work, social life, and personal care. Recognition of HICP and being able to distinguish patients with HICP from other chronic pain patients who do not have life interference allows the necessary measures to be taken in order to restore the physical and emotional functioning of the affected persons. The aim was to reveal the risk factors and predictors associated with HICP.

Learn More >

Re: Strand N et al. Evidence-Based Clinical Guidelines from the American Society of Pain and Neuroscience for the Use of Implantable Peripheral Nerve Stimulation in the Treatment of Chronic Pain. J Pain Res. 2022 Aug 23;15:2483-2504 [Letter].

Learn More >

Response to “Letter to the Editor: Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis.”.

Learn More >

Preserved distraction analgesia but greater impact of pain on task performance in old compared with young subjects.

In this study, we compared two working memory conditions to study the analgesic effect of a distraction in elderly versus young people and the effect of pain on performance on the distracting task.

Learn More >

Benefits of physical therapy in improving quality of life and pain associated with endometriosis: Systematic Review and Meta-analysis.

To assess whether non-pharmacological conservative therapies interventions are beneficial in improving pain intensity and quality of life in women with endometriosis compared to placebo.

Learn More >

No more tears from surgical site infections in interventional pain management.

As the field of interventional pain management (IPM) grows, the risk of surgical site infections (SSIs) is increasing. SSI is defined as an infection of the incision or organ/space that occurs within one month after operation or three months after implantation. It is also common to find patients with suspected infection in an outpatient clinic. The most frequent IPM procedures are performed in the spine. Even though primary pyogenic spondylodiscitis hematogenous spread is the most common type among spinal infections, secondary spinal infections from direct inoculation should be monitored after IPM procedures. Various preventive guidelines for SSI have been published. Cefazolin, followed by vancomycin, is the most commonly used surgical antibiotic prophylaxis in IPM. Diagnosis of SSI is confirmed by purulent discharge, isolation of causative organisms, pain/tenderness, swelling, redness, or heat, or diagnosis by a surgeon or attending physician. Inflammatory markers include traditional (C-reactive protein, erythrocyte sedimentation rate, and white blood cell count) and novel (procalcitonin, serum amyloid A, and presepsin) markers. Empirical antibiotic therapy is defined as the initial administration of antibiotics within at least 24 hours prior to the results of blood culture and antibiotic susceptibility testing. Definitive antibiotic therapy is initiated based on the above culture and testing. Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria infections appears to be superior to monotherapy in mortality with the risk of increasing antibiotic resistance rates. The never-ending war between bacterial resistance and new antibiotics is continuing. This article reviews prevention, diagnosis, and treatment of infection in pain medicine.

Learn More >

Understanding how patients’ pain beliefs influence chronic low back pain management in Ghana: a grounded theory approach.

Chronic low back pain (CLBP) is associated with negative consequences in high and low/middle-income countries. Pain beliefs are important psychosocial factors that affect the occurrence and progression of CLBP and may be influenced by the sociocultural context and interactions with healthcare professionals (HCPs). The pain beliefs of Ghanaian patients with CLBP are unknown and the factors influencing pain beliefs in African contexts are unclear.

Learn More >

Nociceptors are needed to guide tooth development, function, repair, and regeneration.

Learn More >

From dolphins to dogs: new opportunities to understand the role of P2X4 receptors in spinal cord injury and neuropathic pain.

Learn More >

Editorial: Biomarkers in migraine beyond diagnosis.

Learn More >

BIOMARKERS OF MIGRAINE AND CLUSTER HEADACHE: DIFFERENCES AND SIMILARITIES.

To identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared.

Learn More >

Plasma Brain-Derived Neurotrophic Factor and Opioid Therapy: Results of Pilot Cross-Sectional Study.

The neurotoxic effect of opioid has not been thoroughly described. No studies have been conducted to explain the effect of opioids in chronic non-cancer pain therapy on the neurotrophic factors level. Due to the ability to cross the blood-brain barrier, it seems the determination of serum Brain-derived neurotrophic factor (BDNF) concentration is a reliable presentation of the concentration in the central nervous system. The aim of the study was to explore the changes of plasma BDNF concentration during long-term opioid therapy. The study group included 28 patients with chronic low back pain treated with opioid therapy buprenorphine (n=10), tramadol (n=8), oxycodone (n=6), morphine (n=3), fentanyl (n=1). The control group included 11 patients. Measurements of plasma BDNF concentrations were performed, and information about opioid therapy were recorded (age, sex, opioid substance type, daily dose and the duration of opioid therapy). Data were analyzed using nonparametric tests. The median BDNF level in the study group was significantly lower (2.73 ng/mL) than that in the control group (5.04 ng/mL, <0.05). BDNF levels did not differ among groups based on the type of opioid substance used, but the lowest median value was observed for tramadol (2.62 ng/mL), and the highest median value was observed for buprenorphine (2.73 ng/mL). The widest minimum-maximum ranges of BDNF for oxycodone were noted, minimum 1.23 ng/mL and maximum 4.57 ng/mL, respectively. BDNF concentrations were correlated with age in the tramadol group and with the duration of opioid therapy in the buprenorphine group. Chronic opioid therapy for noncancer pain induces specific changes in the BDNF concentration. Tramadol and buprenorphine exerted an important effect on BDNF levels in the examined patients. The BDNF level depends on duration of opioid therapy with buprenorphine, and age in tramadol therapy.

Learn More >

Pathogenesis of acquired heterotopic ossification: Risk factors, cellular mechanisms, and therapeutic implications.

Heterotopic ossification (HO), including hereditary and acquired HO, is the formation of extraskeletal bone in skeletal muscle and surrounding soft tissues. Acquired HO is often caused by range of motion, explosion injury, nerve injury or burns. Severe HO can lead to pain and limited joint activity, affecting functional rehabilitation and quality of life. Increasing evidence shows that inflammatory processes and mesenchymal stem cells (MSCs) can drive HO. However, explicit knowledge about the specific mechanisms that result in HO and related cell precursors is still limited. Moreover, there are no effective methods to prevent or reduce HO formation. In this review, we provide an update of known risk factors and relevant cellular origins for HO. In particular, we focus on the underlying mechanisms of MSCs in acquired HO, which follow the osteogenic program. We also discuss the latest therapeutic value and implications for acquired HO. Our review highlights the current gaps in knowledge regarding the pathogenesis of acquired HO and identifies potential targets for the prevention and treatment of HO.

Learn More >

Pilot Investigation of Somatosensory Functioning and Pain Catastrophizing in Pediatric Spinal Fusion Surgery.

Chronic post-surgical pain (CPSP) is a significant concern and contributes to the opioid epidemic; however, little is known about CPSP in young people.

Learn More >

Antibodies against the gastrin-releasing peptide precursor pro-GRP reveal its expression in the mouse spinal dorsal horn.

Gastrin-releasing peptide (GRP) in the spinal dorsal horn acts on the GRP receptor, and this signalling mechanism has been strongly implicated in itch. However, the source of GRP in the dorsal horn is not fully understood. For example, the BAC transgenic mouse line GRP::GFP only captures around 25% of GRP-expressing cells, and Grp mRNA is found in several types of excitatory interneuron. A major limitation in attempts to identify GRP-expressing neurons has been that antibodies against GRP cross-react with other neuropeptides, including some that are expressed by primary afferents. Here we have developed two antibodies raised against different parts of the precursor protein, pro-GRP. We show that labelling is specific, and that the antibodies do not cross-react with neuropeptides in primary afferents. Immunoreactivity was strongest in the superficial laminae, and the two antibodies labelled identical structures, including glutamatergic axons and cell bodies. The pattern of pro-GRP-immunoreactivity varied among different neurochemical classes of excitatory interneuron. Cell bodies and axons of all GRP-GFP cells were labelled, confirming reliability of the antibodies. Among the other populations, we found the highest degree of co-expression (>50%) in axons of NPFF-expressing cells, while this was somewhat lower (10-20%) in cells that expressed substance P and NKB, and much lower (<10%) in other classes. Our findings show that these antibodies reliably detect GRP-expressing neurons and axons, and that in addition to the GRP-GFP cells, excitatory interneurons expressing NPFF or substance P are likely to be the main source of GRP in the spinal dorsal horn.

Learn More >

Chronic inflammatory demyelinating polyneurophaty: assessment of the cognitive function and quality of life.

 Studies were carried out with the objective of evaluating the quality of life (QoL) of patients affected by chronic inflammatory demyelinating polyradiculopathy (CIDP). However, the cognitive issue is still little addressed.

Learn More >

How Much Do Parents Know About Pain in Their Children?

Adequate pain control is essential to the comprehensive management of pediatric patients within the emergency department.The aim of this study is to evaluate parents' knowledge about pain in the pediatric population patient and secondarily describe erroneous concepts that can affect a correct children's pain management.

Learn More >

Pediatric Migraine: Diagnosis and Management.

The WHO recognizes migraine as one of the most disabling diseases […].

Learn More >

Prescription Opioid Use among Patients with Chronic Noncancer Pain before and after the COVID-19 Outbreak in Taiwan: A Multicenter Prospective Observational Study.

The COVID-19 outbreak disrupted medical access for patients receiving chronic opioid therapy. This study investigated their prescription opioid dosages before and after the 2020 outbreak in Taiwan.

Learn More >

High Fiber Plant-based Diet for Chronic Pain and Posttraumatic Stress Disorder: A Feasibility Study.

Learn More >

Investigating the potential of GalR2 as a drug target for neuropathic pain.

Neuropathic pain is a chronic and debilitating condition characterised by episodes of hyperalgesia and allodynia. It occurs following nerve damage from disease, inflammation or injury and currently impacts up to 17% of the UK population. Existing therapies lack efficacy and have deleterious side effects that can be severely limiting. Galanin receptor 2 (GalR2) is a G-protein coupled receptor (GPCR) implicated in the control and processing of painful stimuli. Within the nervous system it is expressed in key tissues involved in these actions such as dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. Stimulation of GalR2 is widely reported to have a role in the attenuation of inflammatory and neuropathic pain. Several studies have indicated GalR2 as a possible drug target, highlighting the potential of specific GalR2 agonists to both provide efficacy and to address the side-effect profiles of current pain therapies in clinical use. A strong biological target for drug discovery will be well validated with regards to its role in the relevant disease pathology. Ideally there will be good translational models, sensitive probes, selective and appropriate molecular tools, translational biomarkers, a clearly defined patient population and strong opportunities for commercialisation. Before GalR2 can be considered as a drug target suitable for investment, key questions need to be asked regarding its expression profile, receptor signalling and ligand interactions. This article aims to critically review the available literature and determine the current strength of hypothesis of GalR2 as a target for the treatment of neuropathic pain.

Learn More >

A Qualitative Study of Psychosocial Factors in Patients With Knee Osteoarthritis: Insights Learned From an Asian Population.

A patient's experience with knee osteoarthritis (OA) is influenced by many psychosocial contributors that can influence the impact of pain. Such factors are known to explain some of the discordance between objective clinical parameters and patient-reported levels of disability and treatment effectiveness. However, few data are available to help clinicians understand the psychosocial factors that apply to the world's many Asian populations. Insights gained from a qualitative study in such a population may support targeted interventions.

Learn More >

Accumulation of health complaints is associated with persistent musculoskeletal pain two years later in adolescents: The Fit Futures study.

There is limited knowledge on the association between different health complaints and the development of persistent musculoskeletal pain in adolescents. The aims of this study were to assess whether specific health complaints, and an accumulation of health complaints, in the first year of upper-secondary school, were associated with persistent musculoskeletal pain 2 years later. We used data from a population-based cohort study (the Fit Futures Study in Norway), including 551 adolescents without persistent musculoskeletal pain at baseline. The outcome was persistent musculoskeletal pain (≥3 months) 2 years after inclusion. The following self-reported health complaints were investigated as individual exposures at baseline: asthma, allergic rhinitis, atopic eczema, headache, abdominal pain and psychological distress. We also investigated the association between the accumulated number of self-reported health complaints and persistent musculoskeletal pain 2 years later. Logistic regression analyses estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs). At the 2-year follow-up, 13.8% (95% CI [11.2-16.9]) reported persistent musculoskeletal pain. Baseline abdominal pain was associated with persistent musculoskeletal pain 2 years later (OR 2.33, 95% CI [1.29-4.19], p = 0.01). Our analyses showed no statistically significant associations between asthma, allergic rhinitis, atopic eczema, headache or psychological distress and persistent musculoskeletal pain at the 2-year follow-up. For the accumulated number of health complaints, a higher odds of persistent musculoskeletal pain at the 2-year follow-up was observed for each additional health complaint at baseline (OR 1.33, 95% CI [1.07-1.66], p = 0.01). Health care providers might need to take preventive actions in adolescents with abdominal pain and in adolescents with an accumulation of health complaints to prevent development of persistent musculoskeletal pain. The potential multimorbidity perspective of adolescent musculoskeletal pain is an important topic for future research to understand the underlying patterns of persistent pain conditions in adolescents.

Learn More >

Acute Postoperative Pain Impact Trajectories and Factors Contributing to Trajectory Membership.

Ongoing postoperative pain assessments are vital to optimizing pain management and attenuating the development of poor health outcomes after surgery. This study aimed to characterize acute multidimensional trajectories of pain impact on physical function, sleep, mood and stress and examine clinical characteristics and demographics associated with trajectory membership. Additionally, this study compared levels of pain intensity and prescription opioid use at two-weeks and one month postoperatively, across acute symptom trajectories.

Learn More >

The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function.

Chronic pain has a debilitating consequences on health and lifestyle. The currently available analgesics are often ineffective and accompanied by undesirable adverse effects. Although adenosine receptors (AR) activation can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A, A, A and A ARs) are not fully understood. The aim of this study was to investigate the role of different AR ligands on inflammatory pain. The von Frey filament test was used to assess the anti-nociceptive effects of adenosine ligands on Complete Freund's Adjuvant (CFA)-induced mechanical allodynia in (180-220 g) adult male Sprague Dawley rats (expressed as paw withdrawal threshold, PWT). Neither the AAR selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the AAR selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, the AAR selective agonist ( ±)-5'-Chloro-5'-deoxy-ENBA, the AAR selective agonist 2-Cl-IB-MECA, the AAR selective antagonist ZM 241385 and the AAR selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. Co-administration of the selective antagonists of AAR and AAR PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reversed the anti-nociceptive effects of their corresponding agonists. Furthermore, calcium imaging studies reveled that the effective AR ligands in the behavioral assay also significantly inhibit capsaicin-evoked calcium responses in cultured rat dorsal root ganglia (DRG) neurons. In conclusion, modulating the activity of the transient receptor potential vanilloid 1 (TRPV1) receptor by ARs ligands could explain their anti-nociceptive effects observed in vivo. Therefore, the cross talk between ARs and TRPV1 receptor may represent a promising targets for the treatment of inflammatory pain conditions.

Learn More >

LQM10, a guanylhydrazone derivative, reduces nociceptive and inflammatory responses in mice.

In the present study, we examined the antinociceptive and anti-inflammatory activities of a guanylhydrazone derivative, (E)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-guanylhydrazone hydrochloride (LQM10), in mice. The antinociceptive effect was determined by assessing behavioural responses in different pain models, while anti-inflammatory activity was examined in carrageenan-induced pleurisy. Intraperitoneal LQM10 administration reduced the acetic acid-induced nociceptive behaviour, a phenomenon which was unaltered by pretreatment with yohimbine, atropine, naloxone, or glibenclamide. In the formalin assay, LQM10 reduced nociceptive behaviour only in the second phase, indicating an inhibitory effect on inflammatory pain. LQM10 did not alter the pain latency in the hot plate assay and did not impact the locomotor activity of mice in the rotarod assay. In the carrageenan-induced pleurisy assay, LQM10 treatment inhibited critical events involved in inflammatory responses, namely, leucocyte recruitment, plasma leakage, and increased inflammatory mediators (tumour necrosis factor [TNF]-α and interleukin [IL]-1β) in the pleural exudate. Overall, these results indicate that LQM10 exhibits antinociceptive effects associated with peripheral mechanisms and anti-inflammatory activity mediated via a reduction in leucocyte migration and proinflammatory mediators, rendering this compound a promising candidate for treating pain and inflammatory process.

Learn More >

Assessing pain catastrophizing and functional disability in pediatric epidermolysis bullosa patients.

The primary objective was to assess pain catastrophizing and functional disability in pediatric patients with epidermolysis bullosa (EB) and their parents/guardians. Secondary objectives included examining relationships between pain catastrophizing, functional disability, and correlations with other factors (e.g., age, disease severity, and percent of body surface area (BSA) involved).

Learn More >

Epidemiological trends of hand osteoarthritis from 1990 to 2019: Estimates from the 2019 Global Burden of Disease study.

Hand osteoarthritis (OA) is a chronic progressive disease characterized by disabling pain in the hand, with a high clinical burden. This study is designed to assess the epidemiological patterns of hand OA from 1990 to 2019 and analyze its secular trends based on sex, age, and socio-demographic index (SDI) at global, regional, and national levels.

Learn More >

Low Back Pain, Disability, and Quality of Life One Year following Intradiscal Injection of Autologous Bone Marrow Aspirate Concentrate.

Degenerative disc disease is a common cause of chronic low back pain. Surgical intervention is an invasive treatment associated with high costs. There is growing interest in regenerative medicine as a less invasive but direct disc treatment for chronic discogenic low back pain.

Learn More >

Efficacy of Dural Sinus Quantitative Measurements in Idiopathic Intracranial Hypertension : A Practical Diagnostic Feature.

This study aimed to investigate the potential contribution of quantitative measurements of dural venous sinuses to the diagnosis of idiopathic intracranial hypertension (IIH) and the relationship between IIH and dural venous sinus dimensions on 3D post-gadolinium T1-weighted magnetic resonance (MR) images.

Learn More >

Different MRI-based methods for the diagnosis of neurovascular compression in trigeminal neuralgia or hemifacial spasm: A network meta-analysis.

Accurate preoperative diagnosis of neurovascular compression (NVC) is crucial in the treatment of trigeminal neuralgia (TN) or hemifacial spasm (HFS). At present, there are many magnetic resonance imaging (MRI)-based methods for diagnosing NVC in clinical practice. This network meta-analysis (NMA) aimed to evaluate the diagnostic performance of different MRI-based imaging methods for NVC in patients with TN and HFS.

Learn More >

Tetramethylpyrazine and Astragaloside IV have synergistic effects against spinal cord injury-induced neuropathic pain via the OIP5-AS1/miR-34a/Sirt1/NF-κB axis.

Both Tetramethylpyrazine (TMPZ) and Astragaloside IV (AGS-IV) can ameliorate neuronal apoptosis and neuroinflammation in CNS diseases. This study revolves around the underlying mechanism of TMPZ and AGS-IV in spinal cord injury (SCI)-associated neuropathic pain (NP).

Learn More >

Altered functional activity in the right superior temporal gyrus in patients with definite vestibular migraine.

Vestibular migraine (VM) is one of the most common causes of episodic central vestibular disorders; it is worth investigating whether VM belongs to the migraine subtype or is a separate disorder. The study is aimed at investigating resting-state functional brain activity alterations in patients with definite VM (dVM).

Learn More >

pH-Switched Near-Infrared Fluorescent Strategy for Ratiometric Detection of ONOO in Lysosomes and Precise Imaging of Oxidative Stress in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is well-known as a kind of autoimmune disease, which brings unbearable pain to the patients by multiple organ complications besides arthritis. To date, RA can be hardly cured, but early diagnosis and standard treatment can relieve symptoms and pain. Therefore, an effective tool to assist the early diagnosis of RA deserves considerable attention. On account of the overexpressed ONOO during the early stage of RA, a near-infrared (NIR) receptor, Lyso-Cy, is proposed in this work by linker chemistry to expand the conjugated rhodamine framework by cyanine groups. Contributed by the pH-sensitive spiral ring in rhodamine, receptor Lyso-Cy has been found to be workable in lysosomes specifically, which was confirmed by the pH-dependent spectra with a narrow responding region and a well-calculated p value of 5.81. We presented an excellent ratiometric sensing protocol for ONOO in an acidic environment, which was also available for targeting ONOO in lysosomes selectively. This innovative dual-targeting responsive design is expected to be promising for assisting RA diagnosis at an early stage with respect to the joint inflammatory model established in this work at the organism level.

Learn More >

Pain reduction method in recording F-waves from the vastus lateralis muscle.

Conventional recording of F-waves from the vastus lateralis muscle causes severe pain in some subjects. Thus, we aimed to investigate the effects of the stimulation frequency on pain and F-wave parameters when recording F-waves from this muscle and to develop a method for recording F-waves from the vastus lateralis muscle that causes minimal pain.

Learn More >

SKF96365 impedes spinal glutamatergic transmission-mediated neuropathic allodynia.

Spinal nerve injury causes mechanical allodynia and structural imbalance of neurotransmission, which were typically associated with calcium overload. Store-operated calcium entry (SOCE) is considered crucial elements-mediating intracellular calcium homeostasis, ion channel activity, and synaptic plasticity. However, the underlying mechanism of SOCE in mediating neuronal transmitter release and synaptic transmission remains ambiguous in neuropathic pain. Neuropathic rats were operated by spinal nerve ligations. Neurotransmissions were assessed by whole-cell recording in substantia gelatinosa. Immunofluorescence staining of STIM1 with neuronal and glial biomarkers in the spinal dorsal horn. The endoplasmic reticulum stress level was estimated from qRT-PCR. Intrathecal injection of SOCE antagonist SKF96365 dose-dependently alleviated mechanical allodynia in ipsilateral hind paws of neuropathic rats with ED of 18 μg. Immunofluorescence staining demonstrated that STIM1 was specifically and significantly expressed in neurons but not astrocytes and microglia in the spinal dorsal horn. Bath application of SKF96365 inhibited enhanced miniature excitatory postsynaptic currents in a dosage-dependent manner without affecting miniature inhibitory postsynaptic currents. Mal-adaption of SOCE was commonly related to endoplasmic reticulum (ER) stress in the central nervous system. SKF96365 markedly suppressed ER stress levels by alleviating mRNA expression of C/EBP homologous protein and heat shock protein 70 in neuropathic rats. Our findings suggested that nerve injury might promote SOCE-mediated calcium levels, resulting in long-term imbalance of spinal synaptic transmission and behavioral sensitization, SKF96365 produces antinociception by alleviating glutamatergic transmission and ER stress. This work demonstrated the involvement of SOCE in neuropathic pain, implying that SOCE might be a potential target for pain management.

Learn More >

Identification of the Involvement of Potassium Channels in Fibromyalgia.

Fibromyalgia is a central sensitivity syndrome that presents with chronic pain, fatigue, cognitive dysfunction, and disordered sleep. The pathophysiology which due to multisensory hypersensitivity of the central nervous system involves neuronal excitability leading to central sensitization. Treatments of the challenges associated with the complexities of fibromyalgia involve combinations of pharmacological and non-pharmacological therapeutic approaches which often offer limited benefit. Potassium (K+) channels play a fundamental role in establishing and maintaining stability of neuronal activity. The large molecular diversity and distribution of K+ channels support involvement in a broad range of physiological functions. In nociceptive pathways, neuronal hyperexcitability leading to pain sensation has been associated with reduced function of K+ channels and loss of cellular control. This article reviews the evidence of involvement of K+ channels in fibromyalgia. A potential role both in the pathophysiological processes responsible for the symptoms of fibromyalgia and as therapeutic targets for the management of the condition is considered.

Learn More >

Chronic low back pain and cognitive function.

Chronic low back pain can impact cognitive function. Patient can have decreased problem-solving abilities, decreased speed of information processing, delayed memory in addition to the development of different psychological conditions. Treating chronic pain effectively can potentially reduce those negative effects and potentially improve patients' cognitive function.

Learn More >

Benefits on pain and mental health of manual therapy for idiopathic scoliosis: A meta-analysis.

Idiopathic scoliosis (IS) is a common spinal disorder. Although several studies have reported the benefits of manual therapy for patients with IS in improving pain, anxiety, depression, and spinal disorders, the efficacy of manual therapy in the management of IS remain controversial. Therefore, this review was conducted to assess effects of manual therapy in the management of IS, primarily on pain and mental health of the patients and secondarily on their spinal disorders.

Learn More >

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Cilofexor, a Novel Nonsteroidal Farnesoid X Receptor Agonist, in Healthy Volunteers.

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n=15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least 1 dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose- proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor AUC by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses > 30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in Phase 2 studies in patients with NASH and PSC.

Learn More >

Establishing Minimal Clinically Important Difference in Sleep Outcomes after Spinal Cord Stimulation in Patients with Chronic Pain Disorders.

As one of the most common medical conditions for which patients seek medical care, chronic pain can be debilitating. The relationship between chronic pain and sleep is thought to be bidirectional, suggesting that treatment of one can be beneficial to the other. There is mounting evidence that spinal cord stimulation (SCS) improves aspects of sleep. How meaningful that is to patients' lives has not been ascertained.

Learn More >

Imbalance of Th1 and Th2 cytokines and stem cell therapy in pathological pain.

The pathophysiological importance of T helper 1 (Th1) and Th2 cell cytokines in pathological pain has been highly debated in recent decades. However, the analgesic strategy targeting individual cytokines still has a long way to go for clinical application. In this review, we focus on the contributions of Th1 cytokines (TNF-α, IFN-γ, and IL-2) and Th2 cytokines (IL-4, IL-5, IL-10 and IL-13) in rodent pain models and human pain-related diseases. A large number of studies have shown that Th1 and Th2 cytokines have opposing effects on pain modulation. The imbalance of Th1 and Th2 cytokines might determine the final effect of pain generation or inhibition. However, increasing evidence indicates that targeting the individual cytokine is not sufficient for the treatment of pathological pain. It is practical to suggest a promising therapeutic strategy against the combined effects of Th1 and Th2 cytokines. We summarize the current advances in stem cell therapy for pain-related diseases. Preclinical and clinical studies show that stem cells inhibit proinflammatory cytokines and release enormous Th2 cytokines that exhibit a strong analgesic effect. Therefore, a shift of the imbalance of Th1 and Th2 cytokines induced by stem cells will provide a novel therapeutic strategy against intractable pain. Thus, it is extremely important to reveal the cellular and molecular mechanisms of stem cell-mediated analgesia. The efficiency and safety of stem cell therapy should be carefully evaluated in animal models and patients with pathological pain.

Learn More >

Trends in Dispensed Prescriptions for Opioids, Sedatives, Benzodiazepines, Gabapentin, and Stimulants to Children by General Dentists, 2012-2019.

Opioids, benzodiazepines and sedatives can manage dental pain, fear and anxiety but have a narrow margin of safety in children. General dentists may inappropriately prescribe gabapentin and stimulants. National evidence on dispensing rates of these high-alert medicines by dentists to children is limited.

Learn More >

Prevention and therapy of chemotherapy-induced peripheral neuropathy: a review of recent findings.

Chemotherapy-induced peripheral neuropathy is one of the most frequent dose-limiting side effects, observed in patients receiving antineoplastic agents, persisting for up to two years after completing treatment, greatly affecting both the course of chemotherapy and patients' quality of life. Approximately 20 to 85% of patients treated with neurotoxic chemotherapy will develop peripheral neuropathy and there is considerable variability in its severity among patients. The main symptoms are numbness, paresthesia, and burning pain in a "glove and stocking" distribution. The prevalence of chemotherapy-induced peripheral neuropathy will likely increase as cancer survival rates continue to improve. Currently, there are only a few therapeutic options available for the prevention or successful therapy because the mechanisms of chemotherapy-induced peripheral neuropathy remain unclear. A better understanding of the risk factors and underlying mechanisms of chemotherapy-induced peripheral neuropathy is needed to develop effective preventive and therapeutic strategies.

Learn More >

Reversal of cold intolerance by testosterone in orchiectomized mice after tibial nerve transection.

Cold intolerance is a debilitating effect of nerve injury, has a strong impact on the life of patients and no advisable treatment exists against it. Testosterone influences pain pathways and has analgesic effects. A recent study showed testosterone as being an agonist of TRPM8, the predominant ion channel that contributes to cold hypersensitivity after injury. We investigated the effect of testosterone on cold sensitivity after nerve injury. Specifically, using the double plate test (DPT) (thermo-neutral-plate: 31C and cold-plate: 18C) we determined the thermal preference of mice at different points during the study design consisting of: orchiectomy, tibial nerve transection (TNT) (30 days after orchiectomy), 15-days-repeated subcutaneous injections of testosterone enanthate (250 or 500µg/kg/day) or vehicle (started 12hours after TNT surgery). Different parameters such as time spent on cold plates, distance traveled, animal speed on the cold- and thermo-neutral-plates were determined in naïve, sham and neuropathic animals. Neither orchiectomy nor sham TNT surgery generate effects on cold intolerance and animal activity while TNT surgery decreased the time spent on the cold-plate and the distance traveled during DPT. Testosterone administration reversed the effect of nerve injury, decreasing the cold hypersensitivity and increasing activity of TNT mice. However, the effect of testosterone on cold avoidance reduced with time and at 14 days after TNT surgery, a higher dose was needed to reverse the effect generated by nerve injury. This indicates that although testosterone administration has a positive effect on cold intolerance, it might not be suitable for prolongated treatment.

Learn More >

Is ketamine infusion effective and safe as an adjuvant of sedation in the PICU? Results from the Ketamine Infusion Sedation Study (KISS).

We aimed to evaluate the efficacy and safety of ketamine in ensuring comfort and sparing conventional drugs when used as an adjuvant for analgesia and sedation in the Pediatric Intensive Care Unit (PICU) as a continuous infusion (≥12 hours).

Learn More >

Clustering Analysis Identifies Two Subgroups of Women with Fibromyalgia with Different Psychological, Cognitive, Health-Related and Physical Features but Similar Widespread Pressure Pain Sensitivity.

Since identification of groups of patients can help to better understand risk factors related to each group and to improve personalized therapeutic strategies, this study aimed to identify subgroups (clusters) of women with fibromyalgia syndrome (FMS) according to pain-related, related-disability, neuro-physiological, cognitive, health-related, psychological or physical features.

Learn More >

Deficits in ascending pain modulation pathways in breast cancer survivors with chronic neuropathic pain: A resting-state fMRI study.

Breast cancer (BC) is the highest frequent malignancy in women globally. Approximately 25-60% of BC patients with chronic neuropathic pain (CNP) result from advances in treating BC. Since the CNP mechanism is unclear, the various treatment methods for CNP are limited. We aimed to explore the brain alternations in BC patients with CNP and the relationship between depression and CNP utilizing resting-state functional magnetic resonance imaging (rs-fMRI).

Learn More >

Sex-Specific Associations Between Preoperative Chronic Pain and Moderate to Severe Chronic Postoperative Pain in Patients 2 Years After Cardiac Surgery.

Chronic postoperative pain (CPSP) after cardiac surgery can cause severe health problems. As demonstrated in noncardiac surgeries, preoperative chronic pain can potentially lead to CPSP. However, the association between preoperative chronic pain and CPSP over follow-up in cardiac surgical settings in the context of sex differences is still lacking. This observational study aims to explore the role and sex differences of preoperative chronic pain in the occurrence and development of long-term CPSP and CPSP-related complications after cardiac surgery.

Learn More >

Pain Empathy and Its Association with the Clinical Pain in Knee Osteoarthritis Patients.

Knee osteoarthritis (KOA) is a painful chronic disorder. Evidence has shown that a history of chronic pain plays an important role in shaping empathy. Empathy, a valuable indicator of social functioning that refers to an individual's ability to share the experiences of others, however, has been overlooked in KOA patients. This study aimed to investigate empathy and its association with clinical pain in KOA patients.

Learn More >

Involvement of Brn3a-positive spinal dorsal horn neurons in the transmission of visceral pain in inflammatory bowel disease model mice.

The spinal dorsal horn plays a crucial role in the transmission and processing of somatosensory information. Although spinal neural circuits that process several distinct types of somatic sensations have been studied extensively, those responsible for visceral pain transmission remain poorly understood. In the present study, we analyzed dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) mouse models to characterize the spinal dorsal horn neurons involved in visceral pain transmission. Immunostaining for c-fos, a marker of neuronal activity, demonstrated that numerous c-fos-positive cells were found bilaterally in the lumbosacral spinal dorsal horn, and their distribution was particularly abundant in the shallow dorsal horn. Characterization of these neurons by several molecular markers revealed that the percentage of the Pit1-Oct1-Unc86 domain (POU domain)-containing transcription factor Brn3a-positive neurons among the c-fos-positive neurons in the shallow dorsal horn was 30%-40% in DSS-treated mice, which was significantly higher than that in the somatic pain model mice. We further demonstrated by neuronal tracing that, within the shallow dorsal horn, Brn3a-positive neurons were more highly represented in spino-solitary projection neurons than in spino-parabrachial projection neurons. These results raise the possibility that Brn3a-positive spinal dorsal horn neurons make a large contribution to visceral pain transmission, part of which is mediated through the spino-solitary pathway.

Learn More >

JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review.

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK-STAT signal transduction. Furthermore, JAK-STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK-STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK-STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.

Learn More >

Long-term efficacy and safety of neridronate treatment in patients with complex regional pain syndrome type 1: a pre-specified, open-label, extension study.

No data on the permanent and curative effect of bisphosphonate treatment in patients with complex regional pain syndrome type-1 (CRPS-1) are currently available. The aim of this pre-specified, open-label, observational study was to evaluate the long-term efficacy and safety of neridronate treatment.

Learn More >

Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation.

Migraine affects ∼15% of the adult population, and the standard treatment includes the use of triptans, ergotamines, and analgesics. Recently, CGRP and its receptor, the CLR/RAMP1 receptor complex, have been targeted for migraine treatment due to their critical roles in mediating migraine headaches. The effort has led to the approval of several anti-CGRP antibodies for chronic migraine treatment. However, many patients still suffer continuous struggles with migraine, perhaps due to the limited ability of anti-CGRP therapeutics to fully reduce CGRP levels or reach target cells. An alternative anti-CGRP strategy may help address the medical need of patients who do not respond to existing therapeutics. By serendipity, we have recently found that several chimeric adrenomedullin/adrenomedullin 2 peptides are potent CLR/RAMP receptor antagonists and self-assemble to form liquid gels. Among these analogs, the ADE651 analog, which potently inhibits CLR/RAMP1 receptor signaling, forms gels at a 6-20% level. Screening of ADE651 variants indicated that residues at the junctional region of this chimeric peptide are important for gaining the gel-forming capability. Gel-formation significantly slowed the passage of ADE651 molecules through Centricon filters. Consistently, subcutaneous injection of ADE651 gel in rats led to the sustained presence of ADE651 in circulation for >1 week. In addition, analysis of vascular blood flow in rat hindlimbs showed ADE651 significantly reduces CGRP-induced vasodilation. Because gel-forming antagonists could have direct and sustained access to target cells, ADE651 and related antagonists for CLR/RAMP receptors may represent promising candidates for targeting CGRP- and/or adrenomedullin-mediated headaches in migraine patients.

Learn More >

A Pilot Investigation into Targeted Muscle Reinnervation for Complex Regional Pain Syndrome, Type II.

Complex regional pain syndrome (CRPS) is a debilitating condition, characterized by severe pain with vascular, motor, or trophic changes. Varied presentations make this a diagnostic and therapeutic challenge. There is a lack of high-quality evidence demonstrating efficacy for most existing therapies, particularly with surgical intervention for type II CRPS (CRPS-II). Targeted muscle reinnervation (TMR) is a surgical technique to transfer the terminal end of a divided nerve to a recipient motor nerve, shown to limit phantom limb pain, residual limb pain, and postamputation neuroma pain.

Learn More >

Advances in research on fat infiltration and lumbar intervertebral disc degeneration.

Low back pain (LBP) is a disabling condition with no available cure, severely affecting patients' quality of life. Intervertebral disc degeneration (IVDD) is the leading cause of chronic low back pain (CLBP). IVDD is a common and recurrent condition in spine surgery. Disc degeneration is closely associated with intervertebral disc inflammation. The intervertebral disc is an avascular tissue in the human body. Transitioning from hematopoietic bone marrow to bone marrow fat may initiate an inflammatory response as we age, resulting in bone marrow lesions in vertebrae. In addition, the development of LBP is closely associated with spinal stability imbalance. An excellent functional state of paraspinal muscles (PSMs) plays a vital role in maintaining spinal stability. Studies have shown that the diminished function of PSMs is mainly associated with increased fat content, but whether the fat content of PSMs is related to the degree of disc degeneration is still under study. Given the vital role of PSMs lesions in CLBP, it is crucial to elucidate the interaction between PSMs changes and CLBP. Therefore, this article reviews the advances in the relationship and the underlying mechanisms between IVDD and PSMs fatty infiltration in patients with CLBP.

Learn More >

Preoperative Risk Factors of Persistent Pain following Total Knee Arthroplasty.

Despite good results of total knee arthroplasty (TKA) as a treatment of idiopathic osteoarthritis (OA) of the knee, significant number of patients (16-33%) complain of persistent pain of unknown origin. This phenomenon is the major cause of patient's dissatisfaction. It has been theorized that certain preoperative factors may increase the risk of persistent pain; hence, their identification should enable proper preoperative education and development of realistic expectations regarding results of TKA. This study is aimed at identifying the preoperative chronic pain predictors in patients undergoing TKA.

Learn More >

The potential mechanisms and application prospects of non-coding RNAs in intervertebral disc degeneration.

Low back pain (LBP) is one of the most common musculoskeletal symptoms and severely affects patient quality of life. The majority of people may suffer from LBP during their life-span, which leading to huge economic burdens to family and society. According to the series of the previous studies, intervertebral disc degeneration (IDD) is considered as the major contributor resulting in LBP. Furthermore, non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate diverse cellular processes, which have been found to play pivotal roles in the development of IDD. However, the potential mechanisms of action for ncRNAs in the processes of IDD are still completely unrevealed. Therefore, it is challenging to consider ncRNAs to be used as the potential therapeutic targets for IDD. In this paper, we reviewed the current research progress and findings on ncRNAs in IDD: i). ncRNAs mainly participate in the process of IDD through regulating apoptosis of nucleus pulposus (NP) cells, metabolism of extracellular matrix (ECM) and inflammatory response; ii). the roles of miRNAs/lncRNAs/circRNAs are cross-talk in IDD development, which is similar to the network and can modulate each other; iii). ncRNAs have been attempted to combat the degenerative processes and may be promising as an efficient bio-therapeutic strategy in the future. Hence, this review systematically summarizes the principal pathomechanisms of IDD and shed light on the therapeutic potentials of ncRNAs in IDD.

Learn More >

The use of pain scales in small animal veterinary practices in the USA.

Pain assessment in veterinary medicine is challenging. Uncertainty in the ability to recognise pain in animals contributes to suboptimal analgesia. Pain scales have been developed to aid in pain recognition. It is unknown if such scales are routinely utilised in veterinary practices.

Learn More >

Bone marrow mesenchymal stem cells alleviate stress-induced hyperalgesia via restoring gut microbiota and inhibiting neuroinflammation in the spinal cord by targeting the AMPK/NF-κB signaling pathway.

Aim Spinal neuroinflammation contributes to the mechanism of stress-induced hyperalgesia (SIH). Recent research has demonstrated that bone marrow mesenchymal stem cells (BMSCs) alleviate chronic pain. However, what remains unidentified is whether BMSCs could improve hyperalgesia induced by chronic restraint stress (CRS). In another dimension, our previous study proved that gut microbiota played an important role in CRS-induced hyperalgesia in mice. Yet, whether BMSCs treatments change gut microbiota composition in CRS mice remains unexplored.

Learn More >

Modelling skeletal pain harnessing tissue engineering.

Bone pain typically occurs immediately following skeletal damage with mechanical distortion or rupture of nociceptive fibres. The pain mechanism is also associated with chronic pain conditions where the healing process is impaired. Any load impacting on the area of the fractured bone will stimulate the nociceptive response, necessitating rapid clinical intervention to relieve pain associated with the bone damage and appropriate mitigation of any processes involved with the loss of bone mass, muscle, and mobility and to prevent death. The following review has examined the mechanisms of pain associated with trauma or cancer-related skeletal damage focusing on new approaches for the development of innovative therapeutic interventions. In particular, the review highlights tissue engineering approaches that offer considerable promise in the application of functional biomimetic fabrication of bone and nerve tissues. The strategic combination of bone and nerve tissue engineered models provides significant potential to develop a new class of in vitro platforms, capable of replacing in vivo models and testing the safety and efficacy of novel drug treatments aimed at the resolution of bone-associated pain. To date, the field of bone pain research has centred on animal models, with a paucity of data correlating to the human physiological response. This review explores the evident gap in pain drug development research and suggests a step change in approach to harness tissue engineering technologies to recapitulate the complex pathophysiological environment of the damaged bone tissue enabling evaluation of the associated pain-mimicking mechanism with significant therapeutic potential therein for improved patient quality of life.

Learn More >

The opposite roles of orexin neurons in pain and itch neural processing.

Pain and itch are antagonistically regulated sensations; pain suppresses itch, and inhibition of pain enhances itch. Understanding the central neural circuit of antagonistic regulation between pain and itch is required to develop new therapeutics better to manage these two feelings in a clinical situation. However, evidence of the neural mechanism underlying the pain-itch interaction in the central nervous system (CNS) is still insufficient. To pave the way for this research area, our laboratory has focused on orexin (ORX) producing neurons in the hypothalamus, which is known as a master switch that induces various defense responses when animals face a stressful environment. This review article summarized the previous evidence and our latest findings to argue the neural regulation between pain and itch and the bidirectional roles of ORX neurons in processing these two sensations. i.e., pain relief and itch exacerbation. Further, we discussed the possible neural circuit mechanism for the opposite controlling of pain and itch by ORX neurons. Focusing on the roles of ORX neurons would provide a new perspective to understand the antagonistic regulation of pain and itch in CNS.

Learn More >

Involvement of TRPM7 Channel on the Induction of Diabetic Neuropathic Pain in Mice: Protective Role of Selenium and Curcumin.

Excessive levels of the mitochondrial reactive oxygen radical (mitSOX) and Ca influx were found to cause neuropathic pain in patients with diabetes mellitus (DM). Naltriben (NLT) and mitSOX activate the transient receptor (TRP) melastatin 7 (TRPM7) channel, but antioxidants and carvacrol inhibit it. Selenium (Se) and curcumin (CRC) have been thoroughly studied for their modulator effects on streptozotocin (STZ)-induced neuropathic pain, apoptosis, and oxidative stress through the blockage of TRP channels in dorsal root ganglion (DRG) neurons. It has not yet been fully understood how Se and CRC protect against STZ-induced neuropathic pain by modulating TRPM7. Here, we assessed how Se and CRC affected the Ca influx, mitSOX-mediated oxidative damage, and apoptosis in the DRGs of mice through modifying TRPM7 activity. Seven groups (control, Se, CRC, STZ, STZ + Se, STZ + CRC, and STZ + Se + CRC) were induced from the 56 male mice. We observed that the STZ-induced stimulation of TRPM7 increased mechanical neuropathic pain (von Frey), thermal neuropathic pain (hot plate), cytosolic Ca, TRPM7 current density, TRPM7 expression, lipid peroxidation, mitSOX, cytosolic ROS, apoptosis, caspase-3, caspase-8, and caspase-9 concentrations, whereas Se and CRC therapies diminished the alterations. The STZ-mediated decreases of DRG viability, brain glutathione, glutathione peroxidase, vitamin A, and vitamin E concentrations were also upregulated in the treatment groups by the therapies. These findings collectively imply that an imbalance of neuropathic pain, oxidative neurotoxicity, and apoptosis in the mice is caused by the STZ-mediated activation of TRPM7. However, the downregulation of TRPM7 activity caused by the injections of Se and CRC reduced the neurotoxicity and apoptosis.

Learn More >

Key domains and residues of the receptor MRGPRX1 recognizing the peptide ligand BAM8-22.

Mas-related G protein-coupled receptors (Mrgprs) are a newly discovered class of G protein-coupled receptors consisting of more than 50 members in recent years. MRGPRX1 can be activated by bovine adrenal medulla peptide 8-22 (BAM8-22), triggering Ca influx and then causing pain and itch. It is very important for the discovery of analgesic and antipruritic drugs to elucidate the molecular mechanism of MRGPRX1 recognizing BAM8-22. Here, we identified the functional domains and residues of the receptor MRGPRX1 activating BAM8-22 through molecular model, mutation and living cell calcium imaging. The molecular docking predicted that BAM8-22 interacted with N-terminus, TM4, TM5, TM6 and ECL3 of MRGPRX1. Both ECL3 and TM6 domains were further revealed to play a critical role in the BAM8-22-induced MRGPRX1 activation, whereas TM3 region performed a secondary function. Moreover, the mutation F237A of MRGPRX1 completely lost the activation ability of BAM8-22. These results were consistent with the cryogenic electron microscopy (cryo-EM) structure of MRGPRX1-G in complex with BAM8-22 reported most recently. Taken together, our work shows insights into the molecular mechanism of the interaction between the receptor MRGPRX1 and the peptide agonist BAM8-22, and will also provide some valuable clues for the design of analgesic and antipruritic drugs targeting MRGPRX1.

Learn More >

A multidisciplinary transitional pain service to improve pain outcomes following trauma surgery: a preliminary report.

Trauma (i.e., musculoskeletal injury from a blunt or penetrating force) can change the trajectory of a person's life. Patients often experience chronic pain, reduced quality of life, long-term opioid therapy, and psychiatric comorbidities after trauma surgery. This case report presents clinical outcomes of four patients who received postsurgical pain care in a transitional pain service (TPS) that provides long-term coordinated multimodal pain care, opioid tapering plans, and psychiatric care.

Learn More >

Exploring the sex differences in conditioned pain modulation and its biobehavioral determinants in healthy adults.

Females are at greater risk of chronic pain, and exhibit higher pain sensitivity compared to males. However, sex differences in conditioned pain modulation (CPM), a neurophysiological risk factor of chronic pain, are unclear. CPM is influenced by many factors, some of which are sex-dependent. This study explored the sex differences in CPM and its biobehavioral determinants, such as blood pressure responses, physical activity levels, pain catastrophizing scores, and conditioning stimulus intensity, in young, healthy, physically active males and females.

Learn More >

CROSSTALK BETWEEN MU-OPIOID RECEPTORS AND NEUROINFLAMMATION: CONSEQUENCES FOR DRUG ADDICTION AND PAIN.

Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions. Although MORs have been related to neuroinflammation their biological mechanism remains unclear. It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of pro-inflammatory mediators and cytokines during pathological conditions. Some cytokines, including TNF-α, IL-1β and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production. In addition, Neurokinin-1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking. Therefore, inflammation in the central nervous system seems to be associated with altered/increased MORs expression, which might regulate harmful processes, such as drug addiction and pain. Here, we provide a critical evaluation on MORs' role during neuroinflammation and its implication for these conditions. Understanding MORs' functioning, their regulation and implications on drug addiction and pain may help elucidate their potential therapeutic use against these pathological conditions and associated disorders.

Learn More >

Persistent intolerable abdominal pain in patients with Parkinson’s disease.

In Parkinson's disease (PD), pain is common, increases motor disability, and makes daily life unpleasant. Few patients reportedly have a low prevalence of abdominal pain. The pathophysiology of such abdominal pain has not been confirmed. We clinically studied patients with PD and persistent intolerable abdominal pain to determine the pathophysiology and effective therapy.

Learn More >

Challenges and opportunities for omics-based precision medicine in chronic low back pain.

Chronic low back pain (cLBP) is a common health condition worldwide and a leading cause of disability with an estimated lifetime prevalence of 80-90% in industrialized countries. However, we have had limited success in treating cLBP likely due to its non-specific heterogeneous nature that goes beyond detectable anatomical changes. We propose that omics technologies as precision medicine tools are well suited to provide insight into its pathophysiology and provide diagnostic markers and therapeutic targets. Therefore, in this review, we explore the current state of omics technologies in the diagnosis and classification of cLBP. We identify factors that may serve as markers to differentiate between acute and chronic cases of low back pain (LBP). Finally, we also discuss some challenges that must be overcome to successfully apply precision medicine to the diagnosis and treatment of cLBP.

Learn More >

The effectiveness of low-dosed outpatient biopsychosocial interventions compared to active physical interventions on pain and disability in adults with nonspecific chronic low back pain: a systematic review with meta-analysis.

To evaluate the effectiveness of low-dosed outpatient biopsychosocial interventions versus active physical interventions on pain intensity and disability in adults with nonspecific chronic low back pain.

Learn More >

Rizatriptan-Loaded Oral Fast Dissolving Films: Design and Characterizations.

Rizatriptan (RZT) is an efficient anti-migraine drug which belongs to the class of selective 5 HT (1B/1D) serotonin receptor agonists. Nevertheless, RZT elicits several adverse effects and RZT nasal sprays have a limited half-life, requiring repeated doses that could cause patient noncompliance or harm to the nasopharynx and cilia. The current research aimed to develop orally disintegrating films (ODFs) of RZT employing maltodextrin (MTX) and pullulan (PUL) as film-forming polymers, as well as propylene glycol (PG) as a plasticizer. The ODFs were prepared by solvent casting method (SCM). The technique was optimized using Box-Behnken design (BBD), contemplating the ratios of PUL: MTX and different levels of PG (%) as factor variables. The influence of these factors was systematically analyzed on the selected dependent variables, including film thickness, disintegration time (D-time), folding endurance (FE), tensile strength (TS), percent elongation (%E), moisture content (%), and water uptake (%). In addition, the surface morphology, solid state analysis, drug content uniformity (%), drug release (%), and pH of the RZT-ODFs were also studied. The results demonstrated a satisfactory stable RZT-ODFs formulation that exhibited surface homogeneity and amorphous RZT in films with no discernible interactions between the model drug and polymeric materials. The optimized film showed a rapid D-time of 16 s and remarkable mechanical features. The in vitro dissolution kinetics showed that 100% RZT was released from optimized film compared to 61% RZT released from conventional RZT formulation in the initial 5 min. An animal pharmacokinetic (PK) investigation revealed that RZT-ODFs had a shorter time to achieve peak plasma concentration (T), a higher maximum plasma concentration (C), and area under the curve (AUC) than traditional oral mini capsules. These findings proposed a progressive approach for developing anti-migraine drugs that could be useful in reducing the complications of dysphagia in geriatric and pediatric sufferers.

Learn More >

Segmental Upregulation of ASIC1 Channels in the Formalin Acute Pain Mouse Model.

Hindpaw injection of formalin in rodents is used to assess acute persistent pain. The response to formalin is biphasic. The initial response (first minutes) is thought to be linked to inflammatory, peripheral mechanisms, while the latter (around 30 min after the injection), is linked to central mechanisms. This model is useful to analyze the effect of drugs at one or both phases, and the involvement of ion channels in the response. Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in pain conditions. Recently, psalmotoxin-1 (Pctx-1), a toxin that inhibits ASIC1a-constituted channels, and antisense ASIC1a-RNA, intrathecal administered in mice were shown to affect both phases of the test.

Learn More >

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity.

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 &lt; 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis-Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates' efficacy in alleviating pain.

Learn More >

Vulvodynia: Pain Management Strategies.

Vulvodynia is defined in this international consensus as persistent vulvar pain that occurs for &gt;3 months without an identifiable cause and with several potential associated factors. At present there is no univocal consensus in the therapeutic treatment of vulvodynia. The methods of intervention are based on various aspects including, above all, the management of painful symptoms.

Learn More >

Bifunctional Peptidomimetic G Protein-Biased Mu-Opioid Receptor Agonist and Neuropeptide FF Receptor Antagonist KGFF09 Shows Efficacy in Visceral Pain without Rewarding Effects after Subcutaneous Administration in Mice.

There is still an unmet clinical need to develop new pharmaceuticals for effective and safe pain management. Current pharmacotherapy offers unsatisfactory solutions due to serious side effects related to the chronic use of opioid drugs. Prescription opioids produce analgesia through activation of the mu-opioid receptor (MOR) and are major contributors to the current opioid crisis. Multifunctional ligands possessing activity at more than one receptor represent a prominent therapeutic approach for the treatment of pain with fewer adverse effects. We recently reported on the design of a bifunctional MOR agonist/neuropeptide FF receptor (NPFFR) antagonist peptididomimetic, (H-Dmt-DArg-Aba-βAla-Bpa-Phe-NH), and its antinociceptive effects after subcutaneous (s.c.) administration in acute and persistent pain in mice with reduced propensity for unwanted side effects. In this study, we further investigated the antinociceptive properties of in a mouse model of visceral pain after s.c. administration and the potential for opioid-related liabilities of rewarding and sedation/locomotor dysfunction following chronic treatment. produced a significant dose-dependent inhibition of the writhing behavior in the acetic acid-induced writhing assay with increased potency when compared to morphine. We also demonstrated the absence of harmful effects caused by typical MOR agonists, i.e., rewarding effects (conditioned-place preference test) and sedation/locomotor impairment (open-field test), at a dose shown to be highly effective in inhibiting pain behavior. Consequently, displayed a favorable benefit/side effect ratio regarding these opioid-related side effects compared to conventional opioid analgesics, such as morphine, underlining the development of dual MOR agonists/NPFFR antagonists as improved treatments for various pain conditions.

Learn More >

Towards Better Sinomenine-Type Drugs to Treat Rheumatoid Arthritis: Molecular Mechanisms and Structural Modification.

Sinomenine is the main component of the vine . It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases. In the past few decades, significant advances have broadened our understanding of the molecular mechanisms through which sinomenine treats RA, as well as the structural modifications necessary for improved pharmacological activity. In this review, we summarize up-to-date reports on the pharmacological properties of sinomenine in RA treatment, document their underlying mechanisms, and provide an overview of promising sinomenine derivatives as potential RA drug therapies.

Learn More >

Meta-Analysis of Effectiveness and Safety of Botulinum Toxin in the Treatment of Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is characterized by pain, limited range of motion, swelling, skin changes, vasomotor instability, and patchy bone demineralization. Conservative management strategies for CRPS include physical and occupational therapy, psychosocial and behavioral therapy, and pharmacotherapy. However, some patients still experience CRPS symptoms after receiving conventional treatments. Therefore, botulinum toxin (BoNT) has been applied to patients with CRPS in several trials considering its analgesic effect in musculoskeletal and neuropathic pain; however, the results were controversial. We conducted the study to explore the effectiveness and safety of BoNT in patients with complex regional pain syndrome (CRPS). A search was performed using the following electronic databases up to 19 October 2022: PubMed, Embase, and Cochrane Library. We included both randomized controlled trials and nonrandomized controlled studies involving patients with complex regional pain syndrome managed with botulinum toxin. Cochrane risk-of-bias tool and Joanna Briggs Institute Critical Appraisal Checklist were used for quality assessment for randomized controlled trials and quasi-experimental studies. Only randomized controlled trials entered the meta-analysis. The primary outcome was the visual analogue scale of pain presented as a weighted mean difference (WMD) and 95% confidence interval (CI). The secondary outcome was the risk of adverse events presented as an odds ratio (OR) with 95% CI. We analyzed eight articles with 176 patients, including three randomized controlled trials with 62 participants. The age of the patients ranged from 23.8 to 51 years old. The duration of the disease ranged from 2.2 to 11.8 years. The proportion of females ranged from 16.6% to 100%. The route of administration of BoNT included: (1) lumbar sympathetic block (LSB), (2) intramuscular injection, (3) subcutaneous or intradermal injection (SC/ID). Improvement in pain was revealed in six studies, and adverse events were all self-limited and temporary. Meta-analysis revealed a significant reduction in pain at the first follow-up between 3 weeks to 1 month after intervention (WMD, -1.036, 95% CI, -1.673 to -0.400) but not at the second follow-up between 2 to 3 months after treatment (WMD, -0.895, 95% CI, -2.249 to 0.458). Subgroup analyses between LSB and SC/ID were nonsignificant at both follow-up periods ( = 0.422, 0.139). The risk of adverse events was similar between the BoNT and control group (OR, 0.698, 95% CI, 0.136 to 3.581). In conclusion, BoNT may be effective and safe for alleviating pain in patients with CRPS. However, we could not draw definite conclusions due to small sample size and high between-study heterogeneity. The limited number of participants may conceal the possibility of serious adverse events. Further large-scale randomized controlled trials are warranted to delineate the role of BoNT in CRPS.

Learn More >

Understanding the Female Physical Examination in Patients with Chronic Pelvic and Perineal Pain.

(1) Background: The objective was to compare the exploration of chronic pelvic pain syndrome (CPPS) patients in different locations and establish the role of physical examination in CPPS patients. (2) Methods: We reviewed clinical data from 107 female patients with CPPS unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain, from May 2018 to June 2022. Patients were classified into three groups: (a) pelvic pain; (b) anorectal pain; or (c) vulvar/perineal pain. (3) Results: Although the demographics of patients with CPPS were different, their physical examinations were strikingly similar. Our study observed a comorbidity rate of 36% and 79% of central sensitization of pain. Seventy-one percent of patients had vulvar allodynia/hyperalgesia. Pain on examination was identified in any pelvic floor muscle, in any pelvic girdle structure, and neuropathic pain in 98%, 96%, and 89%, respectively. Patients with vulvar and perineal pain were more different from the other groups; these patients were younger and had fewer comorbidities and less central sensitization, less anorectal pain, more pain during intercourse, and greater nulliparity ( = 0.022; = 0.040; = 0.048; = 0.000; = 0.006; = 0.005). (4) Conclusions: The findings of this study are related to the understanding of the pathophysiology of CPPS. The physical examination confirms the central sensitization of female patients with CPPS, helps us to determine the therapeutic management of the patient, and can be considered as a prognostic factor of the disease.

Learn More >

New Perspectives on the Adverse Effects of NSAIDs in Cancer Pain: An Italian Delphi Study from the Rational Use of Analgesics (RUA) Group.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for cancer pain. We used the Delphi methodology to evaluate the opinions of clinicians on NSAIDs and paracetamol, with a specific focus on their safety profile. Consensus was reached on seven statements. A high level of consensus was reached regarding the use of NSAIDs and gastrointestinal, cardiovascular, and renal risk in patients taking low-dose aspirin and assessment of liver function during long-term treatment with paracetamol. Consensus was also reached that assessment and monitoring of eGFR are important in the elderly being administered NSAIDs. It was further agreed that NSAIDs can often play a key role in association with opioids in the treatment of cancer pain and that paracetamol is the analgesic of first choice for patients with mild chronic pain. When NSAIDs are administered in combination with steroids, it was agreed that the risk of gastrointestinal damage is increased since steroids delay the healing of ulcers and that paracetamol can be used during pregnancy and does not affect the health of the fetus. This Delphi study highlights that there is poor agreement on how these drugs are routinely prescribed. However, a consensus was reached for seven key statements and may represent a valid contribution to daily practice.

Learn More >

Opioid Dose, Pain, and Recovery following Abdominal Surgery: A Retrospective Cohort Study.

The optimal dosage for opioids given to patients after surgery for pain management remains controversial. We examined the association of higher post-surgical opioid use with pain relief and recovery. We retrospectively enrolled adult patients who underwent elective abdominal surgery at our hospital between August 2021 and April 2022. Patients were divided into the "high-intensity" or "low-intensity" groups based on their post-surgical opioid use. Generalized estimating equation models were used to assess the associations between pain scores at rest and during movement on days 1, 2, 3, and 5 after surgery as primary outcomes. The self-reported recovery and incidence of adverse events were analyzed as secondary outcomes. Among the 1170 patients in the final analysis, 293 were in the high-intensity group. Patients in the high-intensity group received nearly double the amount of oral morphine equivalents per day compared to those in the low-intensity group (84.52 vs. 43.80), with a mean difference of 40.72 (95% confidence interval (CI0 38.96-42.48, &lt; 0.001) oral morphine equivalents per day. At all timepoints, the high-intensity group reported significantly higher pain scores at rest (difference in means 0.45; 95% CI, 0.32 to 0.58; &lt; 0.001) and during movement (difference in means 0.56; 95% CI, 0.41 to 0.71; &lt; 0.001) as well as significantly lower recovery scores (mean difference (MD) -8.65; 95% CI, -10.55 to -6.67; &lt; 0.001). A post hoc analysis found that patients with moderate to severe pain during movement were more likely to receive postoperative high-intensity opioid use. Furthermore, patients in the non-high-intensity group got out of bed sooner (MD 4.31 h; = 0.001), required urine catheters for shorter periods of time (MD 12.26 h; &lt; 0.001), and were hospitalized for shorter periods (MD 1.17 days; &lt; 0.001). The high-intensity group was at a higher risk of chronic postsurgical pain (odds ratio 1.54; 95% CI, 1.14 to 2.08, = 0.005). High-intensity opioid use after elective abdominal surgery may not be sufficient for improving pain management or the quality of recovery compared to non-high-intensity use. Our results strengthen the argument for a multimodal approach that does not rely so heavily on opioids.

Learn More >

Dysmenorrhoea: Can Medicinal Cannabis Bring New Hope for a Collective Group of Women Suffering in Pain, Globally?

Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.

Learn More >

Validation of Six Commercial Antibodies for the Detection of Heterologous and Endogenous TRPM8 Ion Channel Expression.

TRPM8 is a non-selective cation channel expressed in primary sensory neurons and other tissues, including the prostate and urothelium. Its participation in different physiological and pathological processes such as thermoregulation, pain, itch, inflammation and cancer has been widely described, making it a promising target for therapeutic approaches. The detection and quantification of TRPM8 seems crucial for advancing the knowledge of the mechanisms underlying its role in these pathophysiological conditions. Antibody-based techniques are commonly used for protein detection and quantification, although their performance with many ion channels, including TRPM8, is suboptimal. Thus, the search for reliable antibodies is of utmost importance. In this study, we characterized the performance of six TRPM8 commercial antibodies in three immunodetection techniques: Western blot, immunocytochemistry and immunohistochemistry. Different outcomes were obtained for the tested antibodies; two of them proved to be successful in detecting TRPM8 in the three approaches while, in the conditions tested, the other four were acceptable only for specific techniques. Considering our results, we offer some insight into the usefulness of these antibodies for the detection of TRPM8 depending on the methodology of choice.

Learn More >

Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale.

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools. We profiled antibodies for immunodetection of RAMP1 using Western blotting, immunocytochemistry and immunohistochemistry, including using RAMP1 knockout mouse tissue. Most antibodies could detect RAMP1 in Western blotting and immunocytochemistry using transfected cells. Two antibodies (844, ab256575) could detect a RAMP1-like band in Western blots of rodent brain but not RAMP1 knockout mice. However, cross-reactivity with other proteins was evident for all antibodies. This cross-reactivity prevented clear conclusions about RAMP1 anatomical localization, as each antibody detected a distinct pattern of immunoreactivity in rodent brain. We cannot confidently attribute immunoreactivity produced by RAMP1 antibodies (including 844) to the presence of RAMP1 protein in immunohistochemical applications in brain tissue. RAMP1 expression in brain and other tissues therefore needs to be revisited using RAMP1 antibodies that have been comprehensively validated using multiple strategies to establish multiple lines of convincing evidence. As RAMP1 is important for other GPCR/ligand pairings, our results have broader significance beyond the CGRP field.

Learn More >

The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain.

The G protein-coupled receptor kinase 6 is associated with inflammation and pathological pain. Impairment of GRK6 expression was described in chronic inflammatory diseases such as rheumatoid arthritis and this was shown to be accompanied by an imbalance of downstream signaling pathways. Here, we discuss novel aspects of GRK6 interaction and its impact upon hyperalgesia and inflammatory processes. In this review, we compile important findings concerning GRK6 regulation for a better pathophysiological understanding of the intracellular interaction in the context of inflammation and show clinical implications-for example, the identification of possible therapy goals in the treatment of chronic inflammatory hyperalgesia.

Learn More >

The Iridoid Glycoside Loganin Modulates Autophagic Flux Following Chronic Constriction Injury-Induced Neuropathic Pain.

Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on the autophagic-lysosomal pathway in the rat CCI model. Sprague-Dawley rats were divided into sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was intraperitoneally injected once daily, and rats were sacrificed on day 7 after CCI. This study focused on the mechanism by which loganin modulates autophagic flux after CCI. CCI enhanced the autophagic marker LC3B-II in the ipsilateral spinal cord. The ubiquitin-binding protein p62 binds to LC3B-II and integrates into autophagosomes, which are degraded by autophagy. CCI caused the accumulation of p62, indicating the interruption of autophagosome turnover. Loganin significantly attenuated the expression of Beclin-1, LC3B-II, and p62. Double immunofluorescence staining was used to confirm that LC3B-II and p62 were reduced by loganin in the spinal microglia and astrocytes. Loganin also lessened the CCI-increased colocalization of both proteins. Enhanced lysosome-associated membrane protein 2 (LAMP2) and pro-cathepsin D (pro-CTSD) in CCI rats were also attenuated by loganin, suggesting that loganin improves impaired lysosomal function and autophagic flux. Loganin also attenuated the CCI-increased apoptosis protein Bax and cleaved caspase-3. Loganin prevents CCI-induced neuropathic pain, which could be attributed to the regulation of neuroinflammation, neuronal autophagy, and associated cell death. These data suggest autophagy could be a potential target for preventing neuropathic pain.

Learn More >

Plasma and Peritoneal Fluid Fibronectin and Collagen IV Levels as Potential Biomarkers of Endometriosis.

Laparoscopy as a diagnostic tool for patients with suspected endometriosis is associated with several potentially life-threatening complications. Therefore, it is imperative to identify reliable, non-invasive biomarkers of the disease. The aim of this study was to analyse the concentrations of fibronectin and type IV collagen in peritoneal fluid and plasma to assess their role as potential biomarkers in the diagnosis of endometriosis. Fibronectin and collagen IV protein levels were assessed by surface plasmon resonance imaging (SPRi) biosensors with the usage of monoclonal antibodies. All patients enrolled in the study were referred for laparoscopy for the diagnosis of infertility or chronic pelvic pain (n = 84). The study group included patients with endometriosis confirmed during surgery (n = 49). The concentration of fibronectin in the plasma (329.3 ± 98.5 mg/L) and peritoneal fluid (26.8 ± 11.1 μg/L) in women with endometriosis was significantly higher than in the control group (251.2 ± 84.0 mg/L, 7.0 ± 5.9 μg/L). Fibronectin levels were independent of endometriosis stage ( = 0.874, = 0.469). No significant differences were observed in collagen IV levels ( = 0.385, = 0.465). The presence of elevated levels of fibronectin may indicate abnormalities in cell-ECM signalling during the course of endometriosis, and may be a potential biomarker for early detection.

Learn More >

µ-Opioid Receptors Expressed by Intrinsically Photosensitive Retinal Ganglion Cells Contribute to Morphine-Induced Behavioral Sensitization.

Opioid drugs are the most effective tools for treating moderate to severe pain. Despite their analgesic efficacy, long-term opioid use can lead to drug tolerance, addiction, and sleep/wake disturbances. While the link between opioids and sleep/wake problems is well-documented, the mechanism underlying opioid-related sleep/wake problems remains largely unresolved. Importantly, intrinsically photosensitive retinal ganglion cells (ipRGCs), the cells that transmit environmental light/dark information to the brain's sleep/circadian centers to regulate sleep/wake behavior, express μ-opioid receptors (MORs). In this study, we explored the potential contribution of ipRGCs to opioid-related sleep/circadian disruptions. Using implanted telemetry transmitters, we measured changes in horizontal locomotor activity and body temperature in mice over the course of a chronic morphine paradigm. Mice lacking MORs expressed by ipRGCs (McKO) exhibited reduced morphine-induced behavioral activation/sensitization compared with control littermates with normal patterns of MOR expression. Contrastingly, mice lacking MORs globally (MKO) did not acquire morphine-induced locomotor activation/sensitization. Control mice also showed morphine-induced hypothermia in both the light and dark phases, while McKO littermates only exhibited morphine-induced hypothermia in the dark. Interestingly, only control animals appeared to acquire tolerance to morphine's hypothermic effect. Morphine, however, did not acutely decrease the body temperature of MKO mice. These findings support the idea that MORs expressed by ipRGCs could contribute to opioid-related sleep/wake problems and thermoregulatory changes.

Learn More >

Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition.

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out in our previous work for the most potent inhibitor 2-amino-3-chloropyridine amide (TPA14), we have investigated its non-competitive mechanism of action using molecular dynamics, thermodynamic integration and QM-MM/GBSA calculations. The computational studies highlighted the impact of mutations on the receptor binding pockets and elucidated the molecular basis of the non-competitive inhibition mechanism of TPA14, which prevents the endocannabinoid anandamide (AEA) from reaching its pro-active conformation. Our study provides a rationale for the design of non-competitive potent FAAH inhibitors for the treatment of neuropathic pain and chronic inflammation.

Learn More >

Overview of Anti-Inflammatory and Anti-Nociceptive Effects of Polyphenols to Halt Osteoarthritis: From Preclinical Studies to New Clinical Insights.

Knee osteoarthritis (OA) is one of the most multifactorial joint disorders in adults. It is characterized by degenerative and inflammatory processes that are responsible for joint destruction, pain and stiffness. Despite therapeutic advances, the search for alternative strategies to target inflammation and pain is still very challenging. In this regard, there is a growing body of evidence for the role of several bioactive dietary molecules (BDMs) in targeting inflammation and pain, with promising clinical results. BDMs may be valuable non-pharmaceutical solutions to treat and prevent the evolution of early OA to more severe phenotypes, overcoming the side effects of anti-inflammatory drugs. Among BDMs, polyphenols (PPs) are widely studied due to their abundance in several plants, together with their benefits in halting inflammation and pain. Despite their biological relevance, there are still many questionable aspects (biosafety, bioavailability, etc.) that hinder their clinical application. This review highlights the mechanisms of action and biological targets modulated by PPs, summarizes the data on their anti-inflammatory and anti-nociceptive effects in different preclinical in vitro and in vivo models of OA and underlines the gaps in the knowledge. Furthermore, this work reports the preliminary promising results of clinical studies on OA patients treated with PPs and discusses new perspectives to accelerate the translation of PPs treatment into the clinics.

Learn More >

Differences in Cognitive Function in Women and Men with Diabetic Peripheral Neuropathy with or without Pain.

The aim of this study was to analyse the differences in cognitive function between women and men with type-2 diabetes mellitus (DMT2) and diabetic peripheral neuropathy (DPN) with and without diabetic neuropathic pain (DNP), and the factors associated with cognitive function in each sex. A cross-sectional study of 149 patients with DMT2 and DPN was performed. Sociodemographic and clinical variables, Test Your Memory (TYM) for cognitive assessment, anxiety and depression (HADS), quality of life (SF-12v2) and sleep characteristics (MOS-sleep) were measured. A high percentage of women presented cognitive impairment (50% vs. 36.1%) and they scored lower on the TYM (mean = 40.77; SD = 6.03 vs. mean = 42.49; SD = 6.05). Women with DNP scored lower on calculation tasks (3.17 vs. 3.52) than men with DNP, while women without DNP scored lower on retrograde memory (2.70 vs. 3.74), executive function (3.83 vs. 4.25) and similarities (2.51 vs. 3.12) than men without DNP. Being older (B = -0.181) and presenting cardiovascular risk factors (B = -5.059) were associated with worse cognitive function in women, while in men this was associated with older age (B = -0.154), a longer duration of diabetes (B = -0.319) and the presence of depression (B = -0.363). Women with and without DNP obtained worse results in cognitive function. However, the presence of pain had a greater impact on the different dimensions in men.

Learn More >

Selective CB Receptor Agonist, HU-308, Reduces Systemic Inflammation in Endotoxin Model of Pneumonia-Induced Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines is associated with systemic complications including sepsis, multi-organ failure, and death. Thus, dampening pro-inflammatory cytokine release is a viable strategy to improve outcome. Activation of cannabinoid type II receptor (CB) has been shown to reduce cytokine release in various in vivo and in vitro studies. Herein, we investigated the effect of HU-308, a specific CB agonist, on systemic and pulmonary inflammation in a model of pneumonia-induced ALI. C57Bl/6 mice received intranasal endotoxin or saline, followed by intravenous HU-308, dexamethasone, or vehicle. ALI was scored by histology and plasma levels of select inflammatory mediators were assessed by Luminex assay. Intravital microscopy (IVM) was performed to assess leukocyte adhesion and capillary perfusion in intestinal and pulmonary microcirculation. HU-308 and dexamethasone attenuated LPS-induced cytokine release and intestinal microcirculatory impairment. HU-308 modestly reduced ALI score, while dexamethasone abolished it. These results suggest administration of HU-308 can reduce systemic inflammation without suppressing pulmonary immune response in pneumonia-induced ALI and systemic inflammation.

Learn More >

The Impact of Chronic Pain, Stiffness and Difficulties in Performing Daily Activities on the Quality of Life of Older Patients with Knee Osteoarthritis.

Osteoarthritis causes a number of physical ailments, which result in the deterioration of a persons' general health and reduction of their ability to move freely. This cross-sectional study was designed to assess the impact of physical ailments in the course of knee osteoarthritis (KOA) on the quality of life (QoL) of patients in early old age. An anonymous survey was conducted by the use of the recognized research tools: Western Ontario scale and McMaster Osteoarthritis Index (WOMAC), The Index of Severity for Knee Disease (ISK) and World Health Organization Quality of Life-BEFF (WHOQOL-BREF). The study involved 300 people aged between 60 and 75 years old, including 150 patients diagnosed with gonarthrosis and 150 people without lower limb complaints. The significant intensification of the symptoms of knee osteoarthritis was associated with a worse assessment of health ( &lt; 0.001), overall quality of life ( &lt; 0.001) and in the following domains: physical ( &lt; 0.001), mental ( &lt; 0.001) and environmental ( &lt; 0.001) in a group of patients with KOA. These findings suggest that taking measures to reduce knee pain and improve function may have an impact on improving the overall quality of the life of people in their early old age.

Learn More >

Diosgenin Exerts Analgesic Effects by Antagonizing the Selective Inhibition of Transient Receptor Potential Vanilloid 1 in a Mouse Model of Neuropathic Pain.

Diosgenin is a botanical steroidal saponin with immunomodulatory, anti-inflammatory, anti-oxidative, anti-thrombotic, anti-apoptotic, anti-depressant, and anti-nociceptive effects. However, the effects of diosgenin on anti-nociception are unclear. Transient receptor potential vanilloid 1 (TRPV1) plays an important role in nociception. Therefore, we investigated whether TRPV1 antagonism mediates the anti-nociceptive effects of diosgenin. In vivo mouse experiments were performed to examine nociception-related behavior, while in vitro experiments were performed to examine calcium currents in dorsal root ganglion (DRG) and Chinese hamster ovary (CHO) cells. The duration of capsaicin-induced licking (pain behavior) was significantly reduced following oral and intraplantar administration of diosgenin, approaching levels observed in mice treated with the TRPV1 antagonist -(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide. Additionally, oral administration of diosgenin blocked capsaicin-induced thermal hyperalgesia. Further, diosgenin reduced capsaicin-induced Ca currents in a dose-dependent manner in both DRG and CHO cells. Oral administration of diosgenin also improved thermal and mechanical hyperalgesia in the sciatic nerve constriction injury-induced chronic pain model by reducing the expression of TRPV1 and inflammatory cytokines in DRG cells. Collectively, our results suggest that diosgenin exerts analgesic effects via antagonism of TRPV1 and suppression of inflammation in the DRG in a mouse model of neuropathic pain.

Learn More >

Including a Three-Party Meeting Using the Demand and Ability Protocol in an Interdisciplinary Pain Rehabilitation Programme for a Successful Return to Work Process.

The Demand and Ability Protocol (DAP) is used in three-party meetings involving an employee, an employer, and a representative from the rehabilitation team. The aim of this study is to investigate the inclusion of an intervention using the DAP in an interdisciplinary pain rehabilitation programme (IPRP) compared to usual care. This non-randomised controlled trial included patients assigned to an IPRP in Sweden. The intervention group received a DAP intervention targeting their work situation in addition to the usual care provided by the IPRP. The control group received IPRP only. Outcome measures were collected from the Swedish Quality Registry for Pain Rehabilitation. Results demonstrated improvements in both groups regarding self-reported anxiety, depression and EQ5D. Sleep was improved in the intervention group but not in the control group. No statistical differences in outcomes were observed between the groups. In conclusion, adding the DAP intervention to IPRP seemed to have the potential to improve sleep among the patients, which may indicate an overall improvement regarding health outcomes from a longer perspective. The results were less clear, however, regarding the work-related outcomes of sickness absence and workability.

Learn More >

A Forehead Wearable Sensor for the Objective Measurement of Chronic Pain.

Chronic pain impacts one in five Americans and is difficult to manage, costing ~USD 600 billion annually. The subjective experience of pain is a complex processing of central nervous system input. Recent advances in magnetic resonance imaging revealed the prefrontal cortex as vital to the perception of pain and that changes in the cerebral hemodynamics can be used to detect painful sensations. Current pain monitoring is dependent on the subjective rating provided by patients and is limited to a single time point. We have developed a biomarker for the objective, real-time and continuous chronic pain assessment using proprietary algorithms termed ROPA and cerebral optical spectrometry. Using a forehead sensor, the cerebral optical spectrometry data were collected in two clinical sites from 41 patients (19 and 22, respectively, from sites 1 and 2), who elected to receive an epidural steroid injection for the treatment of chronic pain. Patients rated their pain on a numeric rating scale, ranging from 0-10, which were used to validate the ROPA objective pain scoring. Multiple time points, including pre- and post-procedure were recorded. The steroid injection was performed per standard medical practice. There was a significant correlation between the patient's reported numeric rating scale and ROPA, for both clinical sites (Overall ~0.81). Holding the subjective pain ratings on a numeric rating scale as ground truth, we determined that the area under the receiver operator curves for both sites revealed at least good (AUC: 64%) to excellent (AUC &gt; 98%) distinctions between clinically meaningful pain severity differentiations (no/mild/moderate/severe). The objective measure of chronic pain (ROPA) determined using cerebral optical spectrometry significantly correlated with the subjective pain scores reported by the subjects. This technology may provide a useful method of detection for the objective and continuous monitoring and treatment of patients with chronic pain, particularly in clinical circumstances where direct assessment is not available, or to complement the patient-reported pain scores.

Learn More >

Bipolar Spectrum Symptoms in Patients with Fibromyalgia: A Dimensional Psychometric Evaluation of 120 Patients.

Fibromyalgia Syndrome (FMS) is characterized by chronic widespread pain, fatigue, unrefreshing sleep and cognitive dysfunction. Depressive and manic symptoms are often reported in FMS patients' history. The aim of this study was to evaluate the prevalence of bipolar spectrum symptoms (BSS) and to correlate these with quality of life (QoL) scores and antidepressant treatment.

Learn More >

Clinical Diagnosis and Early Medical Management for Endometriosis: Consensus from Asian Expert Group.

This work provides consensus guidance regarding clinical diagnosis and early medical management of endometriosis within Asia. Clinicians with expertise in endometriosis critically evaluated available evidence on clinical diagnosis and early medical management and their applicability to current clinical practices. Clinical diagnosis should focus on symptom recognition, which can be presumed to be endometriosis without laparoscopic confirmation. Transvaginal sonography can be appropriate for diagnosing pelvic endometriosis in select patients. For early empiric treatment, management of women with clinical presentation suggestive of endometriosis should be individualized and consider presentation and therapeutic need. Medical treatment is recommended to reduce endometriosis-associated pelvic pain for patients with no immediate pregnancy desires. Hormonal treatment can be considered for pelvic pain with a clinical endometriosis diagnosis; progestins are a first-line management option for early medical treatment, with oral progestin-based therapies generally a better option compared with combined oral contraceptives because of their safety profile. Dienogest can be used long-term if needed and a larger evidence base supports dienogest use compared with gonadotropin-releasing hormone agonists (GnRHa) as first-line medical therapy. GnRHa may be considered for first-line therapy in some specific situations or as short-term therapy before dienogest and non-steroidal anti-inflammatory drugs as add-on therapy for endometriosis-associated pelvic pain.

Learn More >

Systemic Lidocaine Infusions for Pediatric Patients with Cancer-Related Pain.

Pediatric patients with cancer experience significant distress from both treatment and cancer-related pain. Careful selection of an analgesic regimen should be based upon individual patient factors, including the level of pain, response to therapy, and physiologic profile. Refractory pain is a therapeutic dilemma frequently encountered in the pediatric cancer setting. Systemic lidocaine infusions have been described as both safe and efficacious, as prior studies show patients reporting decreased pain scores and improved quality of life after lidocaine treatment. Given the favorable side effect profile of lidocaine, it has the potential to be considered for analgesia in the setting of refractory pain. This review discusses the use of systemic lidocaine infusions for analgesia in pediatric oncology patients with cancer-related pain.

Learn More >

Aligning with Patients and Families: Exploring Youth and Caregiver Openness to Pediatric Headache Interventions.

Primary headache disorders are common yet underestimated in youth, resulting in functional disability, decreased quality of life, and caregiver burden. Despite the ubiquity of options, adherence remains challenging for families. One potential factor impacting willingness to engage in recommended treatments is openness. This study explored openness to multidisciplinary headache interventions and the relationships with demographic, pain-related, and psychological variables, among youth and their caregivers. Participants ( = 1087) were youth/caregiver dyads presenting for initial headache evaluation. They completed assessments of openness to headache treatments, medical information, functional disability, and pain-related distress. Overall openness was moderately high for youth and caregivers, and highly correlated between them (r = 0.70). Relationships between youth/caregiver openness to specific interventions were moderate-high (r = 0.42-0.73). These were stronger for interventional techniques but weaker for lifestyle changes. In hierarchical regression models predicting youth and caregiver openness, we found that counterpart openness accounted for the largest portion of variance in their own openness (31-32%), beyond demographic (3%), pain-related (10%), and psychological variables (2-3%). Our findings highlight the importance of involving caregivers in pediatric headache management, given their influence on youth openness and potential involvement in adherence. Awareness of youth/caregiver openness may guide clinicians providing recommendations.

Learn More >

Expression and Kinetics of Endogenous Cannabinoids in the Brain and Spinal Cord of a Spare Nerve Injury (SNI) Model of Neuropathic Pain.

The role of endogenous cannabinoids in neuropathic pain has been actively studied, among which 2-arachidonoyl glycerol (2-AG) has received the most attention. However, owing to its chemical properties, direct detection of 2-AG distribution in tissues is difficult. Moreover, although desorption electrospray ionization mass spectrometry imaging (DESI-MSI) has enabled the detection of 2-AG, its distribution in the brain and spinal cord of neuropathic pain models has not been reported. In this study, the expression and distribution of 2-AG in the brain and spinal cord of a spare nerve injury (SNI) mice model of neuropathic pain was examined using DESI-MSI. The brain and lumbar spinal cord were collected and analyzed on days 3, 7, and 21 after treatment. On days 3 and 7 after treatment, 2-AG expression in the SNI model was decreased in the hypothalamus, midbrain, and especially in the periaqueductal gray (PAG) region but increased in the lumbar spinal cord. On day 21, the SNI model showed decreased 2-AG expression in the hypothalamus, but the difference from the control was not significant. Furthermore, there were no differences in 2-AG expression between the lumbar spinal cord, midbrain, or PAG. These data suggest that 2-AG might be involved in pain control.

Learn More >

A Fenchone Derivative Effectively Abrogates Joint Damage Following Post-Traumatic Osteoarthritis in Lewis Rats.

In a previous report, we have identified the cannabinoid receptor 2 (CB2) agonist HU308 to possess a beneficial effect in preventing age and trauma-induced osteoarthritis (OA) in mice. The effects of HU308 were largely related to the capacity of this compound to induce cartilage anabolism which was dependent on the CREB/SOX9 axis, and exhibited pro-survival and pro-proliferative hallmarks of articular cartilage following treatment. Here, we utilized the novel cannabinoid-fenchone CB2 agonists (1B, 1D), which were previously reported to render anti-inflammatory effects in a zymosan model.

Learn More >

Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy.

Cancer patients undergoing paclitaxel infusion usually experience peripheral nerve degeneration and serious neuropathic pain termed paclitaxel-induced peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for paclitaxel do not eliminate PIPN, and no therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the paclitaxel-induced inhibition of KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of paclitaxel-induced peripheral sensory fiber degeneration and chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.

Learn More >

Identification of Spinal Inhibitory Interneurons Required for Attenuating Effect of Duloxetine on Neuropathic Allodynia-like Signs in Rats.

Neuropathic pain is a chronic pain condition that occurs after nerve damage; allodynia, which refers to pain caused by generally innocuous stimuli, is a hallmark symptom. Although allodynia is often resistant to analgesics, the antidepressant duloxetine has been used as an effective therapeutic option. Duloxetine increases spinal noradrenaline (NA) levels by inhibiting its transporter at NAergic terminals in the spinal dorsal horn (SDH), which has been proposed to contribute to its pain-relieving effect. However, the mechanism through which duloxetine suppresses neuropathic allodynia remains unclear. Here, we identified an SDH inhibitory interneuron subset (captured by adeno-associated viral (AAV) vectors incorporating a rat promoter; AAV-NpyP neurons) that is mostly depolarized by NA. Furthermore, this excitatory effect was suppressed by pharmacological blockade or genetic knockdown of α-adrenoceptors (ARs) in AAV-NpyP SDH neurons. We found that duloxetine suppressed Aβ fiber-mediated allodynia-like behavioral responses after nerve injury and that this effect was not observed in AAV-NpyP SDH neuron-selective α-AR-knockdown. These results indicate that α-AR and AAV-NpyP neurons are critical targets for spinal NA and are necessary for the therapeutic effect of duloxetine on neuropathic pain, which can support the development of novel analgesics.

Learn More >

Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain.

Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat's hind paw on the neuropathic pain induced by L5 nerve injury. The results showed that intraplantar injection of RTX (0.002%, 100 µL) (1) completely reversed the development of chronic thermal and mechanical hypersensitivity; (2) completely prevented the development of nerve-injury-induced thermal and mechanical hypersensitivity when applied one week earlier; (3) caused downregulation of nociceptive pain markers, including TRPV1, IB4 and CGRP, and upregulation of VIP in the ipsilateral dorsal horn of spinal cord and dorsal root ganglion (DRG) immunohistochemically and a significant reduction in the expression of TRPV1 mRNA and protein in the ipsilateral DRG using Western blot and qRT-PCR techniques; (4) caused downregulation of PGP 9.5- and CGRP-immunoreactivity in the injected skin; (5) produced significant suppression of c-fos expression, as a neuronal activity marker, in the spinal neurons in response to a second intraplantar RTX injection two weeks later. This work identifies the ability of cutaneous injection of RTX to completely alleviate and prevent the development of different types of neuropathic pain in animals and humans.

Learn More >

Examining the Nocebo Effect in Trials of Neuromodulators for Use in Disorders of Gut-Brain Interaction.

Nocebo effects are thought to influence the rate of reported adverse events (AEs) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCTs). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBIs), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm versus the treatment arm of RCTs of neuromodulators for DGBIs. We also sought to estimate the risk of developing any AE in the placebo arm of these studies as well as the rate of specific individual adverse events.

Learn More >

Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain.

The racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture (MP-101). In vitro, dimiracetam was more potent than its R- or S-enantiomers in reducing the NMDA-induced [H]D-aspartate release in rat spinal cord synaptosomes. Similarly, acute oral administration of dimiracetam was more effective than a single enantiomer in the sodium monoiodoacetate (MIA) paradigm of painful osteoarthritis. Then, we compared the in vitro effects of a broad range of non-racemic enantiomeric mixtures on the NMDA-induced [H]D-aspartate release. Dimiracetam was a more potent blocker than each isolated enantiomer but the R:S 3:1 non-racemic mixture (MP-101) was even more potent than dimiracetam, with an IC in the picomolar range. In the chronic oxaliplatin-induced neuropathic pain model, MP-101 showed a significantly improved anti-neuropathic profile, and its effect continued one week after treatment suspension. MP-101 also performed better than dimiracetam in animal models of cognition and depression. Based on the benign safety and tolerability profile previously observed with racemic dimiracetam, MP-101 appears to be a novel, promising clinical candidate for the prevention and treatment of several neuropathic and neurological disorders.

Learn More >

Vestibular migraine or Meniere’s disease: a diagnostic dilemma.

Meniere's disease (MD) represents one of the vertigo disorders characterized by triad symptoms (recurrent vertigo, fluctuating hearing loss, tinnitus or ear fullness). The diagnosis of MD relies on the accurate and detailed taking of medical history, and the differentiation between MD and vestibular migraine (VM) is of critical importance from the perspective of the treatment efficacy. VM is a highly prevalent vertigo condition and its typical symptoms (headache, vestibular symptoms, cochlear symptoms) mimic those of MD. Furthermore, the misdiagnosis in MD and VM could lead to VM patients mistakenly receiving the traumatic treatment protocol designed for MD, and sustaining unnecessary damage to the inner ear. Fortunately, thanks to the advances in examination technologies, the barriers to their differentiation are being gradually removed. These advances enhance the diagnostic accuracy of vertigo diseases, especially VM and MD. This review focused on the differentiation of VM and MD, with an attempt to synthesize existing data on the relevant battery of differentiation diagnosis (covering core symptoms, auxiliary tests [audiometry, vestibular tests, endolymphatic hydrops tests]) and longitudinal follow-up. Since the two illnesses are overlapped in all aspects, no single test is sufficiently specific on its own, however, patterns containing all or at least some features boost specificity.

Learn More >

Current and Emerging COX inhibitors for Treating Postoperative Pain Following Oral Surgery.

The numerous drugs in the NSAID class are often used to treat acute postoperative pain associated with oral surgery such as impacted third-molar extractions. These drugs are effective in this setting and dental pain studies often serve as models for acute pain relief and for registration of analgesics. With numerous cyclooxygenase (COX) inhibitors available as monotherapy, for use in combination analgesic regimens, and in different doses and formulations, it was our aim to determine if there were clear-cut distinctions among these products and dosing regimens.

Learn More >

Photobiomodulation enhanced endogenous pain modulation in healthy volunteers.

To examine the effects of photobiomodulation (PBM) in healthy volunteers using photonic stimulation of acupuncture points on conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA), which reflect some aspects of endogenous pain modulation. We included 15 men and 15 women (age, 31.5 [27.3-37.0], body mass index, 25.7 [24.4-27.1], Fitzpatrick skin typing, II: 20, III: 8, IV: 2). CPM, TSP, and OA were evaluated after a sham procedure (control session) and after acupuncture point stimulation (LI4 and LI10 on the non-dominant forearm) using linear polarized near-infrared light irradiation (LPNILI; wavelengths peaked at approximately 1000 nm, output: 1.4 W/cm, spot diameter: 10 mm, spot size: 1.02 cm, maximum temperature: 40.5 °C, pulse width: 1 s, frequency: 0.2 Hz) (PBM session). Differences in CPM, TSP, and OA between the two sessions were evaluated by the paired t-test and Fisher's exact test (statistical significance: p < 0.05). Values indicate median [interquartile range]. LPNILI significantly increased CPM in all participants (control session: 12.1 [-4.5-37.4], PBM session: 23.9 [8.3-44.8], p < 0.05) and women (control session: 16.7 [-3.4-36.6], PBM session: 38.7 [24.6-52.1], p < 0.05). The CPM effect increment was significantly higher in women than in men (p = 0.0253). LPNILI decreased TSP in participants with higher TSP ratios (p = 0.0219) and increased OA in participants with lower OA scores (p = 0.0021). LPNILI enhanced endogenous pain modulation in healthy volunteers, particularly in women, as evaluated using CPM. CPM, TSP, and OA evaluations are potentially useful for discriminating PBM responders from non-responders.

Learn More >

Global pain and aging: A cross-sectional study on age differences in the intensity of chronic pain among middle-aged and older adults in 20 countries.

This study aims to examine age differences in the intensity of chronic pain among middle-aged and older adults, where intensity is measured on a scale differentiating between chronic pain that is often troubling and likely requires intervention versus more endurable sensations. We aim to explore whether individual health and national gross domestic product (GDP) explain these differences as well.

Learn More >

Theoretical Schemas to Guide BACPAC Chronic Low Back Pain Clinical Research.

Chronic low back pain (cLBP) is a complex with a heterogenous clinical presentation. A better understanding of the factors that contribute to cLBP is needed for accurate diagnosis, optimal treatment, and identification of mechanistic targets for new therapies. The Back Pain Consortium (BACPAC) Research Program provides a unique opportunity in this regard as it will generate large clinical datasets including a diverse set of harmonized measurements. The Theoretical Model Working Group (TMWG) was established to guide BACPAC research, and to organize new knowledge within a mechanistic framework. This article summarizes the initial works of the TMWG. It includes a three-stage integration of expert opinion and an umbrella literature review of factors that affect cLBP severity and chronicity. During Stage 1, experts from across BACPAC established a taxonomy for risk and prognostic factors (RPFs) and preliminary graphical depictions. During Stage 2, a separate team conducted a literature review according to PRISMA guidelines to establish working definitions, associated data elements (ADEs), and overall strength-of-evidence (SOE) for identified RPFs. These were subsequently integrated with expert opinion during Stage 3. The majority (∼80%) of RPFs had little SOE confidence, while 7 factors had substantial confidence for either a positive association (pain-related anxiety, serum c-reactive protein, diabetes, and anticipatory/compensatory postural adjustments) or no association (serum interleukin 1-beta/interleukin 6, transversus muscle morphology/activity, and quantitative sensory testing) with cLBP. This theoretical perspective will evolve over time as BACPAC investigators link empirical results to theory, challenge current ideas of the biopsychosocial model, and utilize a systems approach to develop tools and algorithms that disentangle the dynamic interactions between cLBP factors.

Learn More >

Changes in postoperative opioid prescribing across three diverse healthcare systems, 2010-2020.

The opioid crisis brought scrutiny to opioid prescribing. Understanding how opioid prescribing patterns and corresponding patient outcomes changed during the epidemic is essential for future targeted policies. Many studies attempt to model trends in opioid prescriptions therefore understanding the temporal shift in opioid prescribing patterns across populations is necessary. This study characterized postoperative opioid prescribing patterns across different populations, 2010-2020.

Learn More >

Which outcome variables are associated with psychological inflexibility/flexibility for chronic pain patients? A three level meta-analysis.

The psychological flexibility model can be seen as a basis for an integrated and progressive psychological approach to chronic pain management. Some researchers suggest that psychological flexibility and inflexibility represent distinct processes and constructs. This meta-analysis is the first to provide a summary estimate of the overall effect size for the relationship between psychological (in)flexibility and common outcomes among chronic pain patients. The research protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, https://www.crd.york.ac.uk/PROSPERO/), registration number CRD42021285705. Four databases were searched (PsycINFO; PubMed; Web of Science, CINAHL) along with reference lists. Thirty-six cross-sectional studies were included (7,779 participants). Meta-analyses (random effects model) indicated a significant medium negative association between psychological flexibility and pain intensity or functional impairment. The present study also indicated a significant small to medium association between psychological inflexibility and pain intensity, a nearly large association between psychological inflexibility and functional impairment as well as the quality of life, and a large association between psychological inflexibility and anxiety/depression. Due to the limited number of included studies, the relationship between risk behavior and psychological inflexibility may not be significant. Types of countries and instruments measuring psychological inflexibility may explain part of the heterogeneity. These findings may carry significant implications for chronic pain patients regarding the potential relationship between psychological inflexibility or flexibility and these outcomes. It may consequently form the basis for more robust testing of causal and manipulable relationships.

Learn More >

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Learn More >

Clinical Outcomes of Amniotic Membrane/Umbilical Cord Particulate in Spinal Disorders: A Retrospective Study.

Musculoskeletal spinal disorders significantly impact patient populations from everyday workers to military soldiers. Effective treatment is critical to minimize the time between injury and returning to work and daily activities. Injection of amniotic membrane/umbilical cord (AMUC) tissue has demonstrated great potential in reducing patients' pain and has become an increasingly popular treatment option for painful orthopedic disorders.

Learn More >

Oral splints in the management of nociceptive pain and migraines: A scoping review.

Temporomandibular disorders (TMDs) are characterized by numerous pain manifestations. Their treatment often involves the use of an oral splint. Recent research has found a relationship between migraines, nociceptive pain and TMDs. The aim of the present study was to perform a scoping review of studies in order to evaluate the effectiveness of the various types of oral splint in the treatment of migraine or nociceptive pain. Publications were retrieved from seven databases (PubMed, Web of Science, EMBASE, Scopus, ProQuest, SpringerLink and Ovid). Out of the 15 included publications, three studies were before and after studies, with no control group, whereas the other twelve studies were clinical trials, among which two publications were crossover studies. A clear, single distinction of pain was difficult to describe. Therefore, numerous publications focused on a combination of various types of pains, including myofascial, temporomandibular joint, headaches and migraine-like symptoms, all of which mimicked TMD pain. Overall, six studies used the stabilization splint (SS), three explored the comparison between the SS and the nociceptive trigeminal inhibition splint (NTIS) and two the NTIS. The majority of publications reported a positive outcome of splint therapy. Regarding the type of oral splint usage, the most commonly used one was the SS, followed by the NTIS. The definition and assessment of pain were heterogenous in the identified articles. The findings of the current study showed that occlusal splints may help with pain management, and that effective treatment of TMD-related pain at an early stage can enhance the quality of life of patients.

Learn More >

The efficacy and safety of epidural morphine/hydromorphone in the treatment of intractable postherpetic neuralgia: A single-center, double-blinded, randomized controlled, prospective, and non-inferiority study.

Postherpetic neuralgia (PHN) is a clinical puzzle, especially in patients who still suffered from moderate and severe pain after standard treatment. This single-center, double-blinded, randomized controlled, prospective, and non-inferiority study observed the safety and effectiveness of the epidural application of morphine or hydromorphone, trying to provide an alternative method for those patients with refractory PHN. Eighty PHN patients with a visual analogue scale (VAS) still greater than 50 mm after routine management were randomly divided into two groups according to 1:1, respectively. One group received epidural morphine (EMO group), and the other group received epidural hydromorphone (EHM group). VAS, the number of breakthrough pain, quality of life (QOL), and anxiety/depression assessment (GAD-7 and PHQ-9 scores) were also observed before treatment, at 1, 3, 7, 14, 21, 28, 60, and 90 days after treatment, as well as side effects. Opioid withdrawal symptoms (OWSs) were also measured from 3 to 28 days after treatment. The EHM group was non-inferior to the EMO group in terms of the VAS decrease relative to baseline (VDRB) after 1-week treatment. The VAS of the two groups on all days after treatment was significantly lower than the corresponding baseline findings ( < 0.05). The breakthrough pain (BTP) decreased significantly after treatment and lasted until 14 days after treatment ( < 0.05). There was no significant difference in BTP between the two groups at each time point ( > 0.05). In terms of the QOL, GAD-7, and PHQ-9 outcomes, those were significantly improved after treatment ( < 0.05), and there was no difference between the two groups ( > 0.05). No significant AE difference across the two groups was observed in this study. Few reports of OWS were found in this trial, and there were no significant differences between the two groups ( > 0.05). EHM was non-inferior to EMO in terms of the VDRB after 1-week treatment. For patients with VAS still greater than 50 mm after standard treatment, short-term application of EMO or EHM can ameliorate intractable pain, improve the quality of life, and have no obvious side effects. Short-term epidural opioid application will not lead to the appearance of OWS.

Learn More >

Cost-Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run-In Period.

Run-In (RI) periods can be used to improve the validity of randomized controlled trials (RCTs), but their utility in Chronic Pain (CP) RCTs is debated. Cost-effectiveness analysis (CEA) methods are commonly used in evaluating the results of RCTs, but they are seldom used for designing RCTs. We present a step-by-step overview to objectively design RCTs via CEA methods and specifically determine the cost effectiveness of a RI period in a CP RCT.

Learn More >

Search