Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future.

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Arthritis is a common clinical disease that affects millions of people in the world. The most common types of arthritis are osteoarthritis and rheumatoid arthritis. Inflammatory arthritis (IA), a chronic painful disease, is characterized by synovitis and cartilage destruction in the early stages. Pathologically, IA causes inflammatory changes in the joints and eventually leads to joint destruction. Pain is associated with inflammation and abnormal regulation of the nervous system pathways involved in pain promotion and inhibition. In addition, the occurrence of pain is associated with depression and anxiety. We found that there are many factors affecting pain, in addition to inflammatory factors, glutamate receptor may be the possible cause of long-term chronic pain caused by IA. N-methyl-d-aspartate receptor subunit 2B (NR2B) has been reported to involved in IA and nervous system diseases, especially peripheral neuropathic pain. In this review, we summarized the mechanisms of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in peripheral nerve sensitization during IA and chronic pain.

Chronic pain is a long-standing unpleasant sensory and emotional feeling that has a tremendous impact on the physiological functions of the body, manifesting itself as a dysfunction of the nervous system, which can occur with peripheral and central sensitization. Many recent studies have shown that a variety of common immune cells in the immune system are involved in chronic pain by acting on the peripheral or central nervous system, especially in the autoimmune diseases. This article reviews the mechanisms of regulation of the sensory nervous system by neutrophils, macrophages, mast cells, B cells, T cells, and central glial cells. In addition, we discuss in more detail the influence of each immune cell on the initiation, maintenance, and resolution of chronic pain. Neutrophils, macrophages, and mast cells as intrinsic immune cells can induce the transition from acute to chronic pain and its maintenance; B cells and T cells as adaptive immune cells are mainly involved in the initiation of chronic pain, and T cells also contribute to the resolution of it; the role of glial cells in the nervous system can be extended to the beginning and end of chronic pain. This article aims to promote the understanding of the neuroimmune mechanisms of chronic pain, and to provide new therapeutic ideas and strategies for the control of chronic pain at the immune cellular level.

OBJECTIVE: This meta-analysis aimed to evaluate quantitative sensory testing (QST) evidence for pain processing in patients with the muscle pain subtype of temporomandibular disorders (mTMD).
METHODS: A comprehensive systematic electronic search strategy was performed in online literature databases. All full-text observational studies published up to July 2021 with the aim of investigating pain sensitization in humans with mTMD using QST measures were eligible for inclusion. Meta-analysis of QST data was performed using a random effects model, which included results comparing patients with mTMD to healthy controls, and standard mean difference (SMD) results were analyzed.
RESULTS: Twelve studies with 732 participants (371 patients with mTMD and 361 healthy controls) were analyzed following screening and quality appraisal. Compared with healthy controls, patients with mTMD had significantly lower pressure pain threshold (SMD - 1.10, 95% confidence interval [CI] - 1.52 to - 0.68) with high heterogeneity (Tau2 = 0.61, I2 = 86%), and significantly lower mechanical pain threshold (SMD - 0.64, 95% CI - 0.95 to - 0.32) with no heterogeneity (Tau2 = 0.00, I2 = 0%). No difference was observed in the cold pain threshold (SMD 0.16, 95% CI - 0.13 to 0.45), heat pain threshold (SMD - 0.13, 95% CI - 0.40 to 0.15), and wind-up ratio (SMD 0.63, 95% CI - 0.11 to 1.38) between patients with mTMD and healthy controls. Other QST parameters were also discussed.
CONCLUSIONS: The study results suggest that the pain processing of deep tissues is likely sensitized in mTMD and calls for more QST studies with standard procedures to reduce inter-study heterogeneity.
CONCLUSIONS: The major findings of this meta-analysis support using PPT to examine the pain processing in patients with mTMD in clinical scenario.

Chronic pelvic pain (CPP) is a highly prevalent condition which is underdiagnosed and poorly understood. The purpose of this review is to outline the various aspects of the nature of CPP, including its etiologies, clinical presentation, and nonoperative treatment options. For data collection, a PubMed search was conducted using indexing terms such as chronic pelvic pain and pelvic pain. Literature reviews and studies focusing on etiologies, clinical presentation, and/or the diagnosis of CPP were compiled for review by a team of 3 physiatrists. Studies investigating conservative treatments, medications, and interventional procedures for CPP and related conditions with comparable etiologies were also included. Of the 502 articles retrieved, 116 were deemed suitable by the team for this study. Although CPP is a complex, multifaceted condition, a particular susceptibility to nociceptive stimuli was demonstrated as an underlying theme in its evolution. There are many treatment options currently used; however, more robust evidence, such as randomized controlled trials, are needed before creating comprehensive guidelines for treating CPP.

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients\' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were \"topical AND pain\", \"topical AND neuropathic\", \"topical AND treatment\", \"topical AND mechanism\", \"peripheral neuropathic\", and \"mechanism\". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.

BACKGROUND: Due to advances in oncological therapy options and increasing survival rates, the number of cancer patients with persistant pain, who are in need of analgesic therapy has increased. It has been proven that biopsychosocial mechanisms exist in patients with persistant non-cancer pain leading to chronification. Furthermore, addiction has been identified as a complication of analgesic therapy.
OBJECTIVE: Can the multidimensional model of chronic pain enhancement and chronification be used for patients with cancer pain, analogue to patients with non-cancer pain? Can addiction sydromes as a result of analgesic treatment be demonstrated?
METHODS: In this non-systematic review, a literature search was carried out for somatic and psychosocial chronification mechanisms in patients with cancer pain. Indications for potential addiction syndromes in cancer patients are demonstrated based on selected publications. A Medline search provided a number of relevant publications that are listed (see Supplementary Material).
CONCLUSIONS: Somatic chronification mechanisms, such as pain intensity, repetitive algesic stimuli, topical and demographic factors, are found both in persistant non-cancer pain and cancer pain. Cancer-induced peripheral and central sensitization mechanisms that can be due to underlying genetic variations, are specific for cancer pain. With regard to psychosocial determinants for pain chronification, both cancer and non-cancer patients show similar patterns. Furthermore, data from the literature support the existence of addiction in cancer patients.
CONCLUSIONS: In order to optimize treatment more attention should be paid to the risk of chronification and addiction in cases of chronic persistant cancer pain.