Papers: 9 Jul 2022 - 15 Jul 2022

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

Although general anesthesia is normally induced by systemic dosing, an anesthetic state can be induced in rodents by microinjecting minute quantities of GABAergic agents into the brainstem mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesions to the MPTA render rats relatively insensitive to standard anesthetic doses delivered systemically. Using a chemogenetic approach we have identified and characterized a small subpopulation of neurons restricted to the MPTA which, when excited, render the animal anesthetic by sensorimotor (immobility) and electroencephalographic (EEG) criteria. These "effector-neurons" do not express GABAδ-Rs, the likely target of GABAergic anesthetics. Rather, we report a distinct sub-population of nearby MPTA neurons which do. During anesthetic induction these likely excite the effector-neurons by disinhibition. Within the effector population ~ 70% appear to be glutamatergic, ~30% GABAergic and ~ 40% glycinergic. Most are projection neurons that send ascending or descending axons to distant targets associated with the individual functional components of general anesthesia: atonia, analgesia, amnesia, and loss-of-consciousness.

Physicians are challenged in treating pain patients due to the lack of quantifiable, objective methods of measuring pain in the clinic; pain sensation is multifaceted and subjective to each individual. There is a critical need for point-of-care quantification of accessible biomarkers to provide objective analyses beyond the subjective pain scales currently employed in clinical care settings. In the present study, we employed an animal model to test the hypothesis that circulating regulators of the inflammatory response directly associate with an objective behavioral response to inflammatory pain. Upon induction of localized paw inflammation, we measured the systemic protein expression of cytokines, and activity levels of matrix metalloproteinases (MMPs) that are known to participate in the inflammatory response at the site of injury and investigated their relationship to the behavioral response across a 24 h period. Intraplantar injection with 1% λ-carrageenan induced a significant increase in paw thickness across this timespan with maximal effects observed at the 8 h timepoint when locomotor activity was also impaired. Expression of the chemokines C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand 2 (CCL2) positively correlated with paw inflammation and negatively correlated with locomotor activity at 8 h. The ratio of MMP9 to MMP2 activity negatively correlated with paw inflammation at the 8 h timepoint. We postulate that the CXCL1 and CCL2 as well as the ratio of MMP9 to MMP2 activity may serve as predictive biomarkers for the timecourse of inflammation-associated locomotor impairment. These data define opportunities for the future development of a point-of-care device to objectively quantify biomarkers for inflammatory pain states.

Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels. Unlike other senses that decrease in sensitivity with age, sensitivity of hindpaw nociceptors to thermal and mechanical stimulation was not different between young and aged F344xBN rats. Intraplantar injection of bradykinin (BK) produced greater thermal and mechanical allodynia in aged versus young rats, whereas only mechanical allodynia was greater in aged rats following injection of prostaglandin E (PGE). Intraplantar injection of TRP channel activators, capsaicin (TRPV1), mustard oil (TRPA1) and menthol (TRPM8) each resulted in greater mechanical allodynia in aged versus young rats and capsaicin-induced heat allodynia was also greater in aged rats. A treatment-induced allodynia that was greater in young rats was never observed. The anti-allodynic effects of intraplantar injection of kappa and delta opioid receptor agonists, salvinorin-A and D-Pen,D-Pen]enkephalin (DPDPE), respectively, were greater in aged than young rats, whereas mu opioid receptor agonists, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and morphine, were not effective in aged rats. Consistent with these observations, in primary cultures of peripheral sensory neurons, inhibition of cAMP signaling in response to delta and kappa receptor agonists was greater in cultures derived from aged rats. By contrast, mu receptor agonists did not inhibit cAMP signaling in aged rats. Thus, age-related changes in nociceptors generally favor increased pain signaling in aged versus young rats, suggesting that changes in nociceptor sensitivity may play a role in the increased incidence of pain in the elderly population. These results also suggest that development of peripherally-restricted kappa or delta opioid receptor agonists may provide safer and effective pain relief for the elderly.

To characterize the effects of blocking calcitonin gene-related peptide (CGRP) activity in a mouse model of gastrointestinal transport.

Whilst general anaesthesia is commonly used to undertake spine surgery, the use of neuraxial and peripheral regional anaesthesia techniques for intraoperative and postoperative analgesia is an evolving practice. Variations in practice have meant that it is difficult to know which modalities achieve optimal outcomes for patients undergoing spinal surgery. Our objective was to identify available evidence on the use of regional and neuraxial anaesthesia techniques for adult patients undergoing spinal surgery.

To review clinical practice guidelines (CPGs) and recent literature to identify common recommendations guiding "best practice" pain care for adults with spinal cord injury (SCI).

We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN).

Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody approved for the preventive treatment of migraine in adults. The PREVAIL study demonstrated a favorable safety profile with sustained reductions in overall migraine-related burden in patients with chronic migraine (CM). This post hoc analysis aimed to examine item-level changes in the Migraine Disability Assessment (MIDAS) questionnaire over 2 years in participants with CM on eptinezumab treatment.

Neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases quality of life (QOL) and is often refractory to available therapies. Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief. One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) proteins in uninjured C fibers and dorsal root ganglia causing neuronal excitability. Recent studies have found up-regulation of TRPV 1 proteins after SCI.

Buprenorphine is commonly used to control postoperative pain in rodents. Short-acting formulations of buprenorphine (bup-HCl) require frequent handling and restraint of animals for appropriate dosing, which can be stressful and confound research outcomes. Ethiqa XR (bup-ER) is an FDA-indexed extended-release buprenorphine formulation that is an alternative to bup-HCl in mice and rats. In the current study, we first evaluated the pharmacokinetics of bup-ER in male C57BL/6J mice by sampling blood at 10 time points, ranging from 30 min to 72 h after administration ( = 3 mice per time point). Average plasma concentrations fell below therapeutic levels at 48 h after administration. We also evaluated the safety of bup-ER when administered prior to surgery in combination with common anesthetics and the efficacy of bup-ER in mouse laparotomy. Anesthetic safety was studied by measuring respiratory rate, rectal temperature, and recovery time in groups of mice ( = 8) given bup-HCl, bup-ER, or saline in combination with isoflurane or ketamine-xylazine anesthesia. No differences were seen between analgesic treatment groups with either of the general anesthetics. To evaluate efficacy, mice ( = 10) were randomly allocated to receive either bup-ER (3.25 mg/kg) once presurgically, bup-HCl (0.1 mg/kg) presurgically and then every 8 h, or saline once before surgery. Mice underwent a sham laparotomy and were assessed for pain based on changes in weight, cageside ethogram, nesting consolidation test, rearing frequency, and nociception to von Frey testing at 6, 12, 24, 48, and 72 h after surgery. Cageside ethogram, rearing frequency, and von Frey testing showed significant differences between bup-ER-treated mice and saline controls in the early postoperative period. No significant effects between treatment groups were seen in daily weights or nesting consolidation scores. This study demonstrates that bup-ER can be safely administered before surgery and provides analgesia for up to 48 h after administration based on pharmacokinetic and behavioral data.

We aimed to report the accessible demographic, clinical, and radiological characteristics of reported pediatric paroxysmal hemicrania (PH).

Chronic primary pelvic pain syndrome (CPPPS) is a heterogeneous disease with unknown pathogenesis and a lack of distinct pathological features, which complicates diagnosis and therapy and has a significant impact on patients' daily life. Because pharmacological management is ineffective and long-term use may result in additional system damage, developing a more effective treatment is critical. Neuromodulation has advanced rapidly over the last few decades, and various types of neuromodulations have demonstrated efficacy in the treatment of CPPPS. In this article we discuss the evolution of neuromodulation technology in the treatment of chronic pelvic pain, its application to various subtypes of chronic pelvic pain, and the comparison of relevant efficacy and parameter differences, as well as assess the relative advantages and disadvantages of sacral neuromodulation, percutaneous tibial nerve stimulation , transcutaneous electrical nerve stimulation, electroacupuncture, and pudendal neuromodulation. Furthermore, it was noted that chronic pelvic pain should be evaluated in terms of pain, associated symptoms, psychological problems, and quality of life. Although neuromodulation approaches have been shown to be effective in treating chronic pelvic pain, more extensive multicenter trials are required to confirm this.

Recent literature published in a variety of multidisciplinary journals has significantly influenced perioperative patient care. Distilling and synthetizing the clinically important literature can be challenging. This review summarizes practice changing articles in perioperative medicine from the years 2020 and 2021. Embase, Ovid, and EBM reviews databases were queried from January 2020 to December 2021. Inclusion criteria were original research, systematic review, metaanalysis, and important guidelines. Exclusion criteria were conference abstracts, case reports, letters, protocols, pediatric and obstetric articles, and cardiac surgery literature. Two authors reviewed each reference using the Distiller SR systematic review software (Evidence Partners Inc., Ottawa, Ontario, Canada). A modified Delphi technique was used to identify nine practice changing articles. We identified another 13 articles for tabular summaries as they were relevant to an internist's perioperative evaluation of a patient. Articles were selected to highlight the clinical implications of new evidence in each field. We have also pointed out limitations of each study and clinical populations where they are not applicable.

Chronic vulvar pain (CVP) is pain in the vulvar area exceeding three months of duration. Previous studies have reported a prevalence of 7-8% in the general population and observed an association between CVP and other chronic pain, affective disorders and early life stressors. The aim of this study was to estimate the prevalence of CVP among gynecological outpatients and to explore its association with child sexual abuse, comorbid fibromyalgia and mental health.

Fibromyalgia (FM) is an unsolved central pain processing disturbance. We aim to provide a unifying model for FM pathogenesis based on a loop network involving thalamocortical regions, i.e., the ventroposterior lateral thalamus (VPL), the somatosensory cortex (SC), and the thalamic reticular nucleus (TRN). The dynamics of the loop have been described by three differential equations having neuron mean firing rates as variables and containing Hill functions to model mutual interactions among the loop elements. A computational analysis conducted with MATLAB has shown a transition from monostability to bistability of the loop behavior for a weakening of GABAergic transmission between TRN and VPL. This involves the appearance of a high-firing-rate steady state, which becomes dominant and is assumed to represent pathogenic pain processing giving rise to chronic pain. Our model is consistent with a bulk of literature evidence, such as neuroimaging and pharmacological data collected on FM patients, and with correlations between FM and immunoendocrine conditions, such as stress, perimenopause, chronic inflammation, obesity, and chronic dizziness. The model suggests that critical targets for FM treatment are to be found among immunoendocrine pathways leading to GABA/glutamate imbalance having an impact on the thalamocortical system.

Mechanical allodynia (pain produced by innocuous stimuli such as touch) is the main symptom of neuropathic pain. Its underlying mechanism remains to be elucidated, but peripheral nerve injury (PNI)-induced malfunction of neuronal circuits in the central nervous system, including the spinal dorsal horn (SDH), is thought to be involved in touch-pain conversion. Here, we found that intra-SDH injection of adeno-associated viral vectors including a prodynorphin promoter (AAV-PdynP) captured a subset of neurons that were mainly located in the superficial laminae, including lamina I, and exhibited mostly inhibitory characteristics. Using transgenic rats that enable optogenetic stimulation of touch-sensing Aβ fibers, we found that the light-evoked paw withdrawal behavior and aversive responses after PNI were attenuated by selective ablation of AAV-PdynP-captured SDH neurons. Notably, the ablation had no effect on withdrawal behavior from von Frey filaments. Furthermore, Aβ fiber stimulation did not excite AAV-PdynP SDH neurons under normal conditions, but after PNI, this induced excitation, possibly due to enhanced Aβ fiber-evoked excitatory synaptic inputs and elevated resting membrane potentials of these neurons. Moreover, the chemogenetic silencing of AAV-PdynP neurons of PNI rats attenuated the Aβ fiber-evoked paw withdrawal behavior and c-FOS expression in superficial SDH neurons. Our findings suggest that PNI renders AAV-PdynP-captured neurons excitable to Aβ fiber stimulation, which selectively contributes to the conversion of Aβ fiber-mediated touch signal to nociceptive. Thus, reducing the excitability of AAV-PdynP-captured neurons may be a new option for the treatment of neuropathic allodynia.

Inflammatory bowel disease (IBD), comprising Crohn's disease and Ulcerative colitis, is a relapsing and remitting disease of the gastrointestinal tract, presenting with chronic inflammation, ulceration, gastrointestinal bleeding, and abdominal pain. Up to 80% of patients suffering from IBD experience acute pain, which dissipates when the underlying inflammation and tissue damage resolves. However, despite achieving endoscopic remission with no signs of ongoing intestinal inflammation or damage, 30-50% of IBD patients in remission experience chronic abdominal pain, suggesting altered sensory neuronal processing in this disorder. Furthermore, effective treatment for chronic pain is limited such that 5-25% of IBD outpatients are treated with narcotics, with associated morbidity and mortality. IBD patients commonly present with substantial alterations to the microbial community structure within the gastrointestinal tract, known as dysbiosis. The same is also true in irritable bowel syndrome (IBS), a chronic disorder characterized by altered bowel habits and abdominal pain, in the absence of inflammation. An emerging body of literature suggests that the gut microbiome plays an important role in visceral hypersensitivity. Specific microbial metabolites have an intimate relationship with host receptors that are highly expressed on host cell and neurons, suggesting that microbial metabolites play a key role in visceral hypersensitivity. In this review, we will discuss the techniques used to analysis the metabolome, current potential metabolite targets for visceral hypersensitivity, and discuss the current literature that evaluates the role of the post-inflammatory microbiota and metabolites in visceral hypersensitivity.

Non-coding RNAs (ncRNAs) are involved in neuropathic pain development. Herein, we systematically searched for neuropathic pain-related ncRNAs expression changes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular non-coding RNAs (circRNAs).

This paper assesses the effects of percutaneous electrical nerve stimulation (PENS) on pain- and function-related outcomes by means of a scoping review of studies with single cases, case-series, quasi-experimental, and randomized or non-randomized trial designs. We consulted the PubMed, MEDLINE and EMBASE databases. Data were extracted by two reviewers. The methodological quality of studies was assessed using the Physiotherapy Evidence Database (PEDro) scale for experimental studies and the Joanna Briggs Institute (JBI) tool for case reports or cases series. Mapping of the results included: (1), description of included studies; (2), summary of results; and, (3), identification of gaps in the existing literature. Eighteen articles (five randomized controlled trials, one trial protocol, nine case series and three case reports) were included. The methodological quality of the papers was moderate to high. The conditions included in the studies were heterogeneous: chronic low back pain, lower limb pain after lumbar surgery, chronic post-amputation pain, rotator cuff repair, foot surgery, knee arthroplasty, knee pain, brachial plexus injury, elbow pain and ankle instability. In addition, one study included a healthy athletic population. Interventions were also highly heterogeneous in terms of sessions, electrical current parameters, or time of treatment. Most studies observed positive effects of PENS targeting nerve tissue against the control group; however, due to the heterogeneity in the populations, interventions, and follow-up periods, pooling analyses were not possible. Based on the available literature, PENS interventions targeting peripheral nerves might be considered as a potential therapeutic strategy for improving pain-related and functional outcomes. Nevertheless, further research considering important methodological quality issues (e.g., inclusion of control groups, larger sample sizes and comparatives between electric current parameters) are needed prior to recommending its use in clinical practice.

Endometriosis is a chronic disease that affects about 10% of women of reproductive age. It can contribute to pelvic pain, infertility or other conditions such as asthma, cardiovascular disease, breast or ovarian cancer. Research has shown that one of the conditions for the development of endometrial lesions is the dysfunction of the immune system. It appears that immune cells, such as neutrophils, macrophages, NK cells and dendritic cells, may play a specific role in the angiogenesis, growth and invasion of endometriosis cells. Immune cells secrete cytokines and defensins that also affect the endometriosis environment. This review discusses the various components of the immune system that are involved in the formation of endometrial lesions in women.

The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α-necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α-necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.

Given the often disappointing results of pharmacotherapy, many patients with chronic pain seek to modify their lifestyle. Some lifestyle factors, such as the consumption of alcohol, tobacco, cannabis, or psychostimulants, are deleterious in this context, whereas others, such as physical activity and a balanced diet, are considered beneficial, but these require substantial effort on the part of patients. In all cases, it is important to analyse lifestyle factors in patients with chronic pain, without stigmatisation, as the co-existence of pain and inappropriate behaviour can be seen as double jeopardy in patients with pain.

The underlying mechanisms of opioid-induced hyperalgesia (OIH) remain unclear. Herein, we found that the protein expression of metabotropic glutamate receptor 1 (mGluR1) was significantly increased in the right but not in the left laterocapsular division of central nucleus of the amygdala (CeLC) in OIH rats. In CeLC neurons, the frequency and the amplitude of mini-excitatory postsynaptic currents (mEPSCs) were significantly increased in fentanyl group which were decreased by acute application of a mGluR1 antagonist, A841720. Finally, the behavioral hypersensitivity could be reversed by A841720 microinjection into the right CeLC. These results show that the right CeLC mGluR1 is an important factor associated with OIH that enhances synaptic transmission and could be a potential drug target to alleviate fentanyl-induced hyperalgesia.

The glymphatic system is a recently discovered glial-dependent macroscopic interstitial waste clearance system that promotes the efficient elimination of soluble proteins and metabolites from the central nervous system. Its anatomic foundation is the astrocytes and aquaporin-4 (AQP4) water channels on the endfeet of astrocytes. The aim of this study is to evaluate the plasticity of the spinal glymphatic system in male SD rats with painful diabetic neuropathy (PDN) induced by type 2 diabetes mellitus. PDN rats were modeled under a high-fat and high-glucose diet with a low dose of streptozotocin. MRI was applied to observe the infiltration and clearance of contrast to indicate the functional variability of the glymphatic system at the spinal cord level. The paw withdrawal threshold was used to represent mechanical allodynia. The numerical change of glial fibrillary acidic protein (GFAP) positive astrocytes was assessed and the polarity reversal of AQP4 protein was measured by immunofluorescence. As a result, deceased contrast infiltration and clearance, enhanced mechanical allodynia, increased number of GFAP positive astrocytes, and reversed polarity of AQP4 protein were found in the PDN rats. The above molecular level changes may contribute to the impairment of the spinal glymphatic system in PDN rats. This study revealed the molecular and functional variations of the spinal glymphatic system in PDN rats and for the first time indicated that there might be a correlation between the impaired spinal glymphatic system and PDN rats.

Repetitive transcranial magnetic stimulation (rTMS) is one of the high-potential non-pharmacological methods for migraine treatment. The purpose of this study is to define the neuroimaging markers associated with rTMS therapy in patients with migraine based on data from functional MRI (fMRI).

This study sought to describe migrainous headache frequency and severity and to examine the relationship between trauma, discrimination, and migraine-associated disability in a sample of sexual and/or gender minority (SGM) adults.

Currently, diabetes mellitus (DM) is relevant problem, both for its prevalence and complications, including distal polyneuropathy (DPNP). At the same time, discussions continue on analgesic efficacy of transcutaneous electrical nerve stimulation (TENS) in DPNP. Aim of this study was to conduct a multi-faceted assessment of pain syndrome in these patients before and after TENS, taking into account levels of polyneuropathy, its severity and age of patients. The study was conducted in accordance with the research of the Federal State Budgetary Institution of the National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of the Russian Federation (CTR No. 121040100062-3) and with the permission of the Local Ethics Committee (IRB No. 2 dated 14.01.2021). The study included 75 patients with DM type II with DPNP, which are distributed into 3 groups of 25 people: Group 1a, patients received high-frequency TENS (HF); Group Ib, patients received low-frequency TENS (LF); as control, Group C received a standard method of pharmacological therapy without physiotherapy. Intensity of DPNP was evaluated before and after the course of treatment using a visual analog scale (VAS), the McGill Pain Questionnaire (MPQ), and a graphical linear analysis of pain on the neuropathic pain diagnostic questionnaire 4 (DN4) scale. TENS provides an analgesic effect that may exceed pharmacotherapy in terms of efficacy and safety. There was a 65.9% reduction in neuropathic pain according to VAS after a course of application, with the effects remaining up to 34% during the 6-month follow-up. HF TENS provided a higher significant analgesic effects than LF TENS, as it ensures the reduction of pain syndrome according to VAS by 25.8% (p <0.01), and total estimated characteristics – 35.5% (p <0.01), and touch – in at 58.1% (p = 0.001) and according to the scales of the MPQ (S) and DN4 – by 21% (p = 0.007). The observed differences in analgesic effects between HF TENS and LF TENS are based on analyses of pain in the immediate and long-term follow-up periods of type II DM patients with DPNP. These results, based on summation of the estimated parameters of the international pain scales support expectation of an expansion of the the use of analgesic TENS in aging patients suffering with DM of varying severity and extent of DPNP damage, a goal of great scientific and practical importance.

This article reviews PTPS demographics, diagnosis, pathophysiology, surgical and anesthetic techniques, and their role in preventing PTPS along with updated treatment options.

Describe concerns, advantages, and disadvantages encountered in an evidence-based PT program for persons with chronic low back pain (cLBP) delivered by telehealth.

Pain is the main symptom of entheseal diseases (enthesopathies) despite a paucity of nerve endings in the enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammatory and repeated non-physiological mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to the enthesis or but also trigger a "neuro-vascular invasion" that allows spreading of nerves and blood vessels into the enthesis. Nociceptive pseudo-unipolar neurons support this process by releasing neurotransmitters from peripheral endings that induce neovascularization and peripheral pain sensitization. This process may explain the frequently observed dissociation between subjective symptoms, i.e. pain and the structural findings in imaging in entheseal disease.

Chronic pain symptoms account up to half of all health care visits, afflicts >10% of US adults, at a higher prevalence in women with current analgesic drugs rarely provide enough efficacy in the absence of serious side effects. Chronic pain is also the root cause of the national opioid health crisis, which adds to health care costs and deaths. Thus, new pain therapies based on detailed understanding of nociceptive mechanisms are needed as alternatives to opioid analgesics and are of great societal importance. Chronic pain is one of the most prevalent human health problems that often is associated by the concomitant decline in cognitive and motor functions. Pain is strongly associated with other diseases that can lack of awareness to its pathology. Despite a successful reduction of pain with available medications, majority of treated patients were seeking professional help again. The average time duration between the onset of pain symptoms and the diagnosis is couple of years despite the fact that majority of patients with chronic pain suffer every day. Efficacious and reliable therapeutic intervention is still unavailable despite the tremendous economic burden imposed on healthcare to treat many diseases associated with chronic pain.

The neurotrophin brain-derived neurotrophic factor (BDNF), which acts as a transducer, is responsible for improving cerebral stroke, neuropathic pain, and depression. Exercise can alter extracellular nucleotide levels and purinergic receptors in central nervous system (CNS) structures. This inevitably activates or inhibits the expression of BDNF via purinergic receptors, particularly the P2X receptor (P2XR), to alleviate pathological progression. In addition, the significant involvement of sensitive P2X4R in mediating increased BDNF and p38-MAPK for intracerebral hemorrhage and pain hypersensitivity has been reported. Moreover, archetypal P2X7R blockade induces mouse antidepressant-like behavior and analgesia by BDNF release. This review summarizes BDNF-mediated neural effects via purinergic receptors, speculates that P2X4R and P2X7R could be priming molecules in exercise-mediated changes in BDNF, and provides strategies for the protective mechanism of exercise in neurogenic disease.

Accelerated transcranial magnetic stimulation (aTMS) is an emerging delivery schedule of repetitive TMS (rTMS). TMS is "accelerated" by applying two or more stimulation sessions within a day. This three-part review comprehensively reports the safety/tolerability, efficacy, and stimulation parameters affecting response across disorders.

There has been a growing interest in the use of complementary and alternative medicine in modern pain management strategies on behalf of both patients and clinicians. Nonpharmacologic modalities such as cryotherapy, acupuncture, music, and mind-body therapies have been shown to aid in symptom control and improve quality of life in patients suffering from acute and chronic pain, and there is a growing body of literature demonstrating their feasibility, acceptability, and efficacy in the perioperative period. Here, we provide a brief review of the current evidence supporting the use of complementary therapies within existing perioperative pain management strategies and highlight evidence-based protocols to facilitate implementation into modern surgical practice.

Chemotherapy causes sensory disturbances in cancer patients that results in neuropathies and pain. As cancer survivorships has dramatically increased over the past 10 years, pain management of these patients is becoming clinically more important. Current analgesic strategies are mainly ineffective and long-term use is associated with severe side effects. The issue being that common analgesic strategies are based on ubiquitous pain mediator pathways, so when applied to clinically diverse neuropathic pain and neurological conditions, are unsuccessful. This is principally due to the lack of understanding of the driving forces that lead to chemotherapy induced neuropathies. It is well documented that chemotherapy causes sensory neurodegeneration through axonal atrophy and intraepidermal fibre degeneration causing alterations in pain perception. Despite the neuropathological alterations associated with chemotherapy-induced neuropathic pain being extensively researched, underlying causes remain elusive. Resent evidence from patient and rodent studies have indicated a prominent inflammatory cell component in the peripheral sensory nervous system in effected areas post chemotherapeutic treatment. This is accompanied by modulation of auxiliary cells of the dorsal root ganglia sensory neurons such as activation of satellite glia and capillary dysfunction. The presence of a neuroinflammatory component was supported by transcriptomic analysis of dorsal root ganglia taken from mice treated with common chemotherapy agents. With key inflammatory mediators identified, having potent immunoregulatory effects that directly influences nociception. We aim to evaluate the current understanding of these immune-neuronal interactions across different cancer therapy drug classes. In the belief this may lead to better pain management approaches for cancer survivors.

Patients with knee osteoarthritis are constantly looking for ways to combat their pain and improve their quality of life. As newer treatments present themselves, it is up to the orthopaedic specialists to provide the best treatment possible. Radiofrequency ablation, usually administered by a pain management specialist, has shown to be an acceptable alternative treatment and should be considered in the management of osteoarthritis. It should be considered for patients who have failed nonoperative treatments and are not interested in pursuing total knee arthroplasty, and possibly for patients who have persistent pain after total knee arthroplasty.

Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges.

Poorly controlled postoperative pain is associated with increased morbidity, negatively affects quality of life and functional recovery, and is a risk factor for persistent pain and longer-term opioid use. Up to 10% of opioid-naïve patients have persistent opioid use after many types of surgeries. Opioid-related side-effects and the opioid abuse epidemic emphasise the need for alternative, opioid-minimising, multimodal analgesic strategies, including neuraxial (epidural/intrathecal) techniques, truncal nerve blocks, and lidocaine infusions. The preference for minimally invasive surgical techniques has changed anaesthetic and analgesic requirements in abdominal surgery compared with open laparotomy, leading to a decline in popularity of epidural anaesthesia and an increasing interest in intrathecal morphine and truncal nerve blocks. Limited research exists on patient quality of recovery using specific analgesic techniques after intra-abdominal surgery. Poorly controlled postoperative pain after major abdominal surgery should be a research priority as it affects patient-centred short-term and long-term outcomes (including quality of life scores, return to function measurements, disability-free survival) and has broad community health and economic implications.

Piezo1 and Piezo2 are recently discovered mechanosensory ion channels. Piezo channels transduce mechanical stimulation into cellular signaling in a variety of tissues and organ systems. The functional roles of Piezo1 and Piezo2 have been revealed in both developmental and physiological scenarios by using mouse genetic models. Mechanotransduction by Piezo1 channels regulates osteoblast/osteocyte activity and, thus, strengthens the skeleton enabling it to adapt to a wide range of mechanical loadings. Deletion of the Piezo1 gene in the developing skeleton causes bone malformations that lead to spontaneous bone fractures, while inactivity of Piezo1 in adulthood results in osteoporosis. Furthermore, Piezo2 channels in sensory neurons might provide another route of skeletal regulation. Piezo channels also regulate the proliferation and differentiation of various types of stem cells. PIEZO1 and PIEZO2 mutations and channel malfunctions have been implicated in an increasing number of human diseases, and PIEZO channels are currently emerging as potential targets for disease treatment. This review summarizes the important findings of Piezo channels for skeletal development and homeostasis using the mouse genetic model system.