Persistent Pain Conditions Research Articles

What Is New in Classification, Diagnosis and Management of Chronic Musculoskeletal Pain: A Narrative Review.

Chronic musculoskeletal pain (CMP) is the most common type of chronic pain, defined as persistent or recurrent pain condition deriving from musculoskeletal structures such as muscles, joints or bones that lasts for more than 3 months. CMP is multifactorial and severely affects people's quality of life. CMP may be influenced by a number of factors, including contextual factors, the presence of comorbidities, arthritis coping efficacy and access to CMP care. To deepen the comprehensive understanding of CMP, this narrative review provides the latest literature on disease classification, clinical diagnosis, treatment and basic research. In terms of the classification of the disease, here we introduce the 11th edition of the International Classification of Diseases (IDC-11), in which CMP is divided into chronic primary musculoskeletal pain and chronic secondary musculoskeletal pain. In the clinical diagnosis section, the progress of central sensitization in the diagnosis of CMP will also be summarized. In addition, we summarize some recent advances in clinical treatment and basic research.

Understanding the Needs and Priorities of People Living with Persistent Pain and Long-Term Musculoskeletal Conditions during the COVID-19 Pandemic-A Public Involvement Project.

Background: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups, and this leads to research that fails to include a diversity of perspectives. Aim: The aim of this PI project was to understand the experiences and priorities of people from three seldom-heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. Methods: The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted, followed by informal individual and group discussions involving professionals and people with lived experience of (a) fibromyalgia pain, (b) those waiting for elective surgery and (c) experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Resulting narratives were developed to highlight the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. Results: The narratives describe pain as a uniformly difficult experience to share with professionals; it is described as exhausting, frustrating and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases, there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies, but opportunity and advice about safe methods are variable. Services should focus on personalised care, including self-management support and medication management, so that people’s views and needs are heard and validated by health professionals. Conclusions: More research is needed to explore the most effective pain management strategies, and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is also needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain.

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non–small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.

Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512-2 Toxin in Persistent Pain Models.

CTK 01512-2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512-2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1-4h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512-2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512-2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.

Multimodal prediction of pain and functional outcomes 6 months following total knee replacement: a prospective cohort study

BackgroundKnee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors.MethodsThis multi-site longitudinal cohort study investigated predictors of 6-month pain and functional outcomes following TKA. A wide spectrum of relevant biopsychosocial predictors was assessed preoperatively by medical history, patient-reported questionnaire, functional testing, and quantitative sensory testing in 248 patients undergoing TKA, and subsequently examined for their predictive capacity.ResultsThe majority of patients had mild or no pain at 6 months, and minimal pain-related impairment, but approximately 30% reported pain intensity ratings of 3/10 or higher. Reporting greater pain severity and dysfunction at 6 months post-TKA was predicted by higher preoperative levels of negative affect, prior pain history, opioid use, and disrupted sleep. Interestingly, lower levels of resilience-related “positive” psychosocial characteristics (i.e., lower agreeableness, lower social support) were among the strongest, most consistent predictors of poor outcomes in multivariable linear regression models. Maladaptive profiles of pain modulation (e.g., elevated temporal summation of pain), while not robust unique predictors, interacted with psychosocial risk factors such that the TKA patients with the most pain and dysfunction exhibited lower resilience and enhanced temporal summation of pain.ConclusionsThis study underscores the importance of considering psychosocial (particularly positively-oriented resilience variables) and sensory profiles, as well as their interaction, in understanding post-surgical pain trajectories.

Trigeminal neuropathic pain reduces 50-kHz ultrasonic vocalizations in rats, which are restored by analgesic drugs

Trigeminal neuralgia (TN) is a severe form of neuropathic pain frequently associated with anxiety. The chronic constriction injury of the infraorbital nerve (CCI-ION) of rodents is a well-established model to study sensory alterations related to TN. However, few studies have addressed the emotional component of pain, which is fundamental to increase its translational capability. Emission of ultrasonic vocalization (USV) is considered a reliable measure of the emotional state of rats. Rats emit 50-kHz USVs in social and appetitive situations, whereas 22-kHz USVs may index a negative state. Studies suggest that persistent pain causes reduction in 50-kHz calls, but this may also indicate anxiety-like behavior. Thus, we hypothesize that CCI-ION would decrease 50-kHz calls and that pharmacological pain relief would restore USVs, without interfering with anxiety-like behavior. On day 15 after surgery, male rats were treated with local lidocaine, midazolam or carbamazepine to determine their effect on facial mechanical hyperalgesia, USV and anxiety-like behavior. The results showed that CCI-ION induced hyperalgesia, which was attenuated by lidocaine or carbamazepine, developed anxiety-like behavior, which was reduced only by midazolam, and displayed a reduced number of 50-kHz calls, compared to sham. Lidocaine and carbamazepine increased 50-kHz calls emitted by CCI-ION rats, but midazolam failed to change them. These data add information on the translational aspects of CCI-ION model and carbamazepine treatment for trigeminal neuropathic pain. Furthermore, they suggest that the reduction of USV in persistent pain conditions is related to spontaneous pain and reinforce the idea that it reflects the emotional component of pain.

Amputationen an den Fingern und der Hand

Revision amputation, ray amputation and narrowing of the hand can be indicated for pathological alterations of fingers and thumbs due to traumatic, inflammatory or vascular causes but also for functional deficits regarding mobility, sensibility, perfusion, and/or pain. Surgical amputation is considered if reconstructive options are no longer possible, not desired and are no longer meaningful with respect to effort and risks. Patients need to be informed about the expected deficits in function and esthetic appearance due to the amputation in advance. On the other hand, surgical amputations represent a good treatment option, for which the duration of treatment and scope are well estimated. Therefore, they are good options for patients with comorbidities, with concerns about extensive reconstructive surgery and with limited compliance. It is essential to respect anatomical and functional aspects to guarantee favorable surgical results and avoid complications, which might compromise the function of the hand beyond that which is unavoidable. The most frequent complications after creating a stump or ray resection are persistent pain, unstable skin and soft tissue conditions, mobility disorders, disturbing stumps without function, uncontrolled growth of nail remnants and recurrent inflammation.

The temporal relation between pain and fatigue in individuals receiving treatment for chronic musculoskeletal pain

BackgroundNumerous investigations have revealed significant relations between pain and fatigue in individuals with persistent pain conditions. However, the direction of influence between pain and fatigue remains unclear. Shortcomings of design and analytic approaches used in previous research limit the nature of conclusions that can be drawn about possible causal or directional relations between pain and fatigue. The present study investigated the temporal relation between changes in pain and changes in fatigue in individuals with musculoskeletal pain enrolled in a 10-week behavioral activation intervention. On the basis of previous findings, it was hypothesized that analyses would support a bi-directional relation between pain and fatigue.MethodsThe study sample consisted of 104 individuals with chronic musculoskeletal pain participating in a 10-week standardized rehabilitation intervention. Measures of pain intensity and fatigue were completed pre-, mid-, and post-treatment. The three-wave data panel permitted examination of the direction of influence between pain and fatigue through the course of the intervention. A random-intercept cross-lagged panel model (RI-CLPM) was used to examine the temporal relation between pain and fatigue.ResultsConsistent with previous research, cross-sectional analyses of pre-treatment data revealed significant correlations between measures of pain and fatigue. Significant reductions in pain and fatigue were observed through the course of treatment (d = 0.33 and d = 0.66, p < .001, respectively). RI-CLPM revealed that pain severity predicted later fatigue (pre to mid-treatment standardized path coefficient (β) = 0.55, p = 0.02; mid to post-treatment β = 0.36, p = 0.001); however, fatigue did not predict later pain severity.ConclusionsDiscussion addresses the processes that might underlie the temporal relation between pain and fatigue. Clinical implications of the findings are also discussed.

A pilot pathway for people living with persistent widespread pain and fibromyalgia: Individualised assessment, care planning and stratified rehabilitation options

Keyword: Fibromyalgia Purpose: NHS Forth Valley does not have a pathway for patients with persistent widespread pain and fibromyalgia (FM). People with FM are often diagnosed and discharged by Rheumatology, as it is not an inflammatory condition. However, FM is characterised by emotional distress and/or functional disability and people often struggle to self manage due to lack of support, understanding and validation (Toye et al., 2021). The NICE (2021) and SIGN (2013) guidelines for chronic pain highlight the importance of a biopsychosocial assessment and individualised care plans that promote self-management. Pain Management Physiotherapy currently provides this; however, there is limited capacity (1.4WTE). People perceived to be coping by Consultants were often discharged with advice. The aim of this project was to address gaps and inefficiencies identified by people with FM and clinicians, through a comprehensive biopsychosocial assessment and care plan, with stratified options, including a physiotherapy-led group. Methods: A tool was developed by Pain Management and Rheumatology for GPs to help them with identification and diagnosis of FM in the community. Prior to this, people were referred to secondary care services for diagnosis. We reviewed 7 patient journeys within the Pain Management and Rheumatology caseloads. Patient feedback was collated to identify what improvements would be valued. We pragmatically developed a four session physio-led group using existing Pain Management Programme materials. Each patient was referred by a cnsulatant and assessed by a physiotherapist prior to commencing the group. Content of the group included understanding FM and the impact on people's lives. The project is currently staffed within current job plans. It is delivered via MS Teams, due to COVID 19 restrictions. A qualitative survey was completed by participants in the group. Results: Following a review of pathways for patients with FM in NHS Forth Valley, we identified inequities in patients’ healthcare experiences. As there are limited biomedical treatment options for people with FM, discussions with clinicians in Rheumatology, GPs and patients, identified that support to develop self management skills is needed. The feedback suggested that group sessions normalise symptoms, reduce isolation and stigma, validate experience and increases the access to an intervention that promotes recovery and behaviour change. Participants valued the discussion and reflection in the group format. They reported making meaningful changes to their lives. “I got more than I expected from the group” [P3] The facilitators “are very knowledgable and understanding” [P5] Conclusion(s): This pilot demonstrates that even when perceived to be functioning well, the validation, deeper understanding of their condition and guidance on how to move forward was valued by people living with FM. The physiotherapy-led group is an efficient and person-centred way to support this population. Efficacy data will continue to be collected. Impact: This project is part of a larger redesign project to equitably meet the needs of people living with FM. The physiotherapy-led group offers more options for people diagnosed with FM to learn how to self manage their persistent pain condition. The next phase of the project will involve collaboration with the Rheumatology Service to develop the pathway further. Funding acknowledgements: This project was not funded.

To persist or not to persist? The dilemma of goal adjustment in chronic pain.

To persist or not to persist? The dilemma of goal adjustment in chronic pain.

Patient-centered care in musculoskeletal practice: Key elements to support clinicians to focus on the person

Musculoskeletal rehabilitation, including physiotherapy, needs to move towards a broader biopsychosocial understanding of musculoskeletal conditions and the delivery of high-value care for people with persistent pain conditions, in which a patient-centered approach is a key feature. However, it has been reported that clinicians experience difficulties with integrating patient-centered care principles into their clinical practice. Based on a focused symposium about patient-centered care for patients with musculoskeletal conditions, held during the online 2021 World Physiotherapy Congress, the purpose of this article is to share key elements of the content of this symposium with a wider audience, aimed at enabling clinicians to enhance patient-centeredness in their current practice. These key elements include establishing meaningful connections, deciding together and self-management support. Moreover, challenges on patient-centered care in low/middle income countries will be discussed and recommendations to implement patient-centered care in clinical practice will be provided.

Cannabidiol microinjection into the nucleus accumbens attenuated nociceptive behaviors in an animal model of tonic pain

Cannabidiol, the major non-psychoactive constituent of Cannabis, has attracted much attention as a therapeutic agent for intractable chronic pain in many conditions. Nucleus accumbens (NAc) as a major site of action of cannabinoids is one of the main mediators of several analgesic agents especially in the persistent pain condition. The present study aimed to investigate the effect of cannabidiol microinjection into the NAc on the modulation of nociception induced by formalin injection into the rat’s paw. Adult male Wistar rats weighing 220–250 g were underwent stereotaxic surgery for unilateral (right or left side) cannula placement into the NAc. After one week recovery period, intra-NAc administration of the cannabidiol or its vehicle, DMSO was performed in a volume of 0.5 µl, five minutes before the formalin test. The formalin test was performed using 50 µl injection of formalin (2.5%) into the plantar surface of the rat’s hind paw. Intra-accumbal administration of cannabidiol attenuated the nociceptive responses during the early and late phases of the formalin test in a dose-dependent manner. However, the antinociceptive effect of cannabidiol was significantly higher in the late phase of the formalin test than that in the early phase. Therefore, a non-psychoactive cannabinoid, cannabidiol may be developed as therapeutic agents in conditions, such as persistent inflammatory pain for which primary treatments are insufficient or not possible.

Psychological Interventions for Women with Persistent Pelvic Pain: A Survey of Mental Health Clinicians.

ObjectiveTo establish which psychological therapies mental health professionals use with reference to the treatment of women with persistent pelvic pain conditions. This research investigates overall therapies and specific techniques that clinicians believe are the most effective with this patient group, and the challenges mental health clinicians face in administering interventions. The study aims to suggest improvements to clinical practice and establish directions for targeted future research.DesignCross-sectional survey design.MethodsAn online survey was developed to ask mental health clinicians questions regarding the therapies and techniques they use with women experiencing persistent pelvic pain, their perspective on their practice in this area. The survey was advertised on relevant social media and professional websites. Survey results were tabled, and chi-square statistical analyses were undertaken to examine differences in therapy use according to country and profession.ResultsMental health clinicians predominantly utilized cognitive behavioral therapy, acceptance and commitment therapy and associated techniques for women with persistent pelvic pain conditions. The results of the chi-square analyses showed that psychologists were more likely to use cognitive behavioral therapy or acceptance and commitment therapy, than counsellors who preferred counselling interventions. Chi-square analyses showed that Australian clinicians used acceptance and commitment therapy with a higher frequency than mental health clinicians in other countries. Clinicians provided multiple insights into their experiences working with women affected by persistent pelvic pain and their opinions as to valuable future research directions.ConclusionCognitive behavioral therapy, acceptance and commitment therapy, and mindfulness therapies were most commonly used by mental health clinicians working with women with persistent pelvic pain conditions, despite severely limited evidence for the use of these psychological interventions in this client group.

Effects of Vancomycin on Persistent Pain-Stimulated and Pain-Depressed Behaviors in Female Fischer Rats With or Without Voluntary Access to Running Wheels

The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. PerspectiveThe narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.

Flupirtine as a Potential Treatment for Fibromyalgia

Fibromyalgia is a complex disorder characterised by chronic pain, fatigue, sleep disturbance and cognitive dysfunction with limited benefit gained with current therapies. The mean global prevalence of 2.7% is estimated for this chronic condition. Pharmacological and non-pharmacological therapeutic approaches are often required as treatments of the challenges associated with fibromyalgia. Flupirtine, a non-opioid drug, exhibits effective analgesia in a range of acute and persistent pain conditions, and evidence as treatment of fibromyalgia is considered. Activation of Kv7 potassium channels and agonism at gamma-aminobutyric acid receptor A leading to indirect N-methyl-D-aspartate receptor antagonism is responsible for the analgesic effects of flupirtine and appears to be involved in other symptoms associated with fibromyalgia. Patients with fibromyalgia reported improved control of their symptoms without significant adverse effects in an observational audit in clinical practice. This article presents evidence that flupirtine, or related drugs, is a therapeutic option for the treatment of fibromyalgia. The pharmacology of flupirtine and mechanisms of action involved provide a spectrum of effects that would not only control the chronic pain characteristic of fibromyalgia but many of the other symptoms. Thus, further investigation of the efficacy of flupirtine or related drugs exhibiting a similar pharmacology as a treatment of fibromyalgia would be of interest.

Neuropathic pain modeling: Focus on synaptic and ion channel mechanisms.

Animal models of pain consist of modeling a pain-like state and measuring the consequent behavior. The first animal models of neuropathic pain (NP) were developed in rodents with a total lesion of the sciatic nerve. Later, other models targeting central or peripheral branches of nerves were developed to identify novel mechanisms that contribute to persistent pain conditions in NP. Objective assessment of pain in these different animal models represents a significant challenge for pre-clinical research. Multiple behavioral approaches are used to investigate and to validate pain phenotypes including withdrawal reflex to evoked stimuli, vocalizations, spontaneous pain, but also emotional and affective behaviors. Furthermore, animal models were very useful in investigating the mechanisms of NP. This review will focus on a detailed description of rodent models of NP and provide an overview of the assessment of the sensory and emotional components of pain. A detailed inventory will be made to examine spinal mechanisms involved in NP-induced hyperexcitability and underlying the current pharmacological approaches used in clinics with the possibility to present new avenues for future treatment. The success of pre-clinical studies in this area of research depends on the choice of the relevant model and the appropriate test based on the objectives of the study.

The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea.

PurposeWomen bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC50 for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill.Patients and MethodsFifty-six women aged 16–35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1–2 and Days 7–10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3β-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass–Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1β output was determined.ResultsNon-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7–10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1β (lower EC50).ConclusionThis is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache.

Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

Interaction of new sigma ligands with biomembrane models evaluated by differential scanning calorimetry and Langmuir-Blodgett studies

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a selective sigma 1 (σ1) antagonist with antinociceptive effect, able to increase selective opioid receptor agonist-mediated analgesia. The parent compound (−)-MRV3 [(−)-methyl (1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)-methyl]-1-phenylcyclopropanecarboxylate], a σ1 antagonist with an improved σ1/σ2 selectivity respect to (+)-MR200, play a role in both central sensitization and pain hypersensitivity, suggesting a potential use of σ1 antagonists for the treatment of persistent pain conditions. With the intention to assessing the membrane absorption of compounds and their ability to cross it, the interaction of (+)-MR200 and (−)-MRV3 with dimyristoylphosphatidylcholine phospholipids (DMPC), used as biomembrane models was studied by Differential Scanning Calorimetry (DSC) and Langmuir-Blodgett (LB).

Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis

To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain. A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults ≥ 18 years old. Risk of Bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis. Nine studies (n = 863) were included (5 randomized controlled trials [RCTs], 2 open-label non-comparative studies and 2 comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of 3 RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% CI -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain. While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine.