Management Of Chronic Pain Conditions Research Articles

Molecular Chaperones to Pain Modulators: Heat Shock Proteins the Emerging Players in Chronic Pain Management.

Chronic pain is the most prevailing complex syndrome among clinical disorders affecting approximately 30% of people globally. Various intricate alterations in nociceptive pathways responsible for chronic pain are linked to long-term tissue damage or injury to the peripheral or central nervous systems. These include remolding in the phenotype of cells and fluctuations in the expression of proteins such as ion channels, neurotransmitters, and receptors. Heat shock proteins are important molecular chaperone proteins in cell responses to stress, including inflammation, neurodegeneration, and pain signaling. They play a key role in activating glial and endothelial cells and in the production of inflammatory mediators and excitatory amino acids in both peripheral and central nervous systems. In particular, they contribute to central sensitization and hyperactivation within the dorsal horn of the spinal cord. The expression of some HSPs plays a remarkable role in upregulating pain response by acting as scavengers of ROS, controlling inflammatory cytokines. Different HSPs act by different mechanisms and several important pathways have been implicated in targeting HSPs for the treatment of neuropathic pain including p38-mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), brain-derived neurotrophic factors (BDNF). We summarize the role of HSPs in various preclinical and clinical studies and the crosstalk of HSPs with various nociceptors and other pain models. We also highlighted some artificial intelligence tools and machine learning-assisted drug discovery methods for rapid screening of HSPs in various diseases. Thus, targeting HSPs may provide new therapeutic opportunities for the management of chronic pain conditions and expand our understanding of pain in neurological disorders and other pathological conditions.

An Update on Emerging Regenerative Medicine Applications: The Use of Extracellular Vesicles and Exosomes for the Management of Chronic Pain.

Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain. In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood.

Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.

Chronic Pain Management in Pregnancy: A Review of the Literature

Objective: This review summarizes current literature and explores issues involved in the management of pregnant women with chronic pain conditions. Methods: Articles in this review were selected through searches of Scopus, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, and MEDLINE databases. “Grey” literature such as cross-references from identified articles, clinical recommendations, professional consensus, bibliographies from review articles, and book chapters were also examined for appropriate material. Results: The search yielded 18,401 results in total; however, the majority related to management of labour pain, physiological pain in pregnancy, chronic pain in the nonpregnant population, and opioid maintenance in pregnancy for substance- dependent women. These results were therefore excluded. Sixteen relevant articles were included. A lack of high-quality research in the area, a potential for increased maternal and fetal complications, and the need for multidisciplinary input were identified as issues. Discussion: This is one of the first literature reviews to assess the management of women with chronic pain conditions who become pregnant. Poorly managed chronic pain can have adverse effects on the mother and lead to premature induction of labour and birth of the infant. Despite the apparent risks, there remains an absence of research in this field. Conclusion: It is imperative that research and clinical education are continued in this field. This will enable health care clinicians to provide women with appropriate, evidence-based options for their prenatal care, as well as effective, ongoing management of chronic pain conditions during pregnancy. This article has been peer reviewed.

Biodegradable microspheres via orally deliver celastrol with ameliorated neuropathic pain in diabetes rats.

The treatment of peripheral neuropathy resulting from diabetes primarily emphasizes neurotrophic medications. However, a growing body of clinical studies indicates that neuroinflammation plays a significant role in the pathogenesis of neuropathic pain. This has spurred active exploration of treatment strategies leveraging nanomedicine for diseases, aiming for superior therapeutic outcomes. In this context, we have developed biodegradable nanoparticles made of polylactic-co-glycolic acid, loaded with triptolide (pCel), designed to alleviate somatic cell neuropathic pain induced by diabetes. Treatment with pCel notably reduced levels of reactive oxygen species and apoptosis in vitro. Furthermore, the progression of streptozotocin-induced diabetes, characterized by elevated renal function indices (blood urea nitrogen, creatinine), liver function indices (bilirubin, alkaline phosphatase) and decreased levels of albumin and globulin, was mitigated following pCel administration. Importantly, oral treatment with pCel significantly inhibited mechanical allodynia and the activation of the sciatic glial cells in diabetic rats. These findings indicate that this synthetic, biodegradable nanomedicine exhibits excellent stability, biocompatibility and catalytic activity, making it a promising and innovative approach for the management of chronic pain conditions associated with diabetic neuropathy.

Developmental Approaches to Chronic Pain: A Narrative Review.

Chronic pain, which can potentially develop from acute pain, subacute pain, or breakthrough pain, is generally defined as pain persisting for greater than three months with minimal relief. Chronic pain can be associated with a myriad of medical conditions. It is also one of the most common causes of disability, physical suffering, depression, and reduced quality of life. Treatment can vary depending on the underlying pathophysiology and can involve physical therapy, non-pharmaceutical approaches, pharmaceutical drugs, and invasive procedures. Currently available pharmaceutical agents have been effective for short-term management of chronic pain conditions, but few options address chronic pain with long-term efficacy. First-line pharmaceutical agents can potentially include over-the-counter (OTC) or prescription-strength non-steroidal anti-inflammatory drugs (NSAIDs), which have been linked to numerous side effects. If chronic pain persists, steroids are frequently used to provide longer relief. For more progressive or resistant chronic pain and/or in conjunction with invasive procedures, opioids have been utilized for acute treatment and for long-term maintenance. While these agents have proven to be effective for both acute and long-term use due to their modulation at various peripheral and central opioid receptors, they can be associated with numerous side effects and tied to the risk of addiction. As such, an unmet need exists to identify treatment modalities that provide opioid-like pain relief without opioid-induced adverse effects and the potential for addiction. This narrative review will provide an overview of the currently available treatment modalities for chronic pain and their adverse event profiles, as well as a review of therapies that are currently in development and/or preclinical trials for the management and treatment of chronic pain.

Systemic Allergic Reaction to a Spinal Cord Stimulator Trial: A Case Report

BACKGROUND: Spinal cord stimulation (SCS) is commonly used for the management of chronic pain conditions, such as intractable axial and radicular back pain, complex regional pain syndrome, and painful peripheral vascular disease. Patients have had adverse complications with SCS trials and permanent implants. Cases of contact dermatitis from SCS devices have been reported, but a systemic allergic reaction to an SCS trial has not yet been published to date. CASE REPORT: A 52-year-old woman with complex regional pain syndrome type II and a history of a presumed infectious reaction to a previous SCS trial 8 years prior presented with chronic right L5, S1 radicular pain. Having failed conservative measures, she underwent a repeat SCS trial. The lead was placed at the T8 vertebral body, migrated several days later to the T9 vertebral body, and was subsequently adjusted back to T8 under fluoroscopic guidance. The patient reported improvement in her back and leg pain. Three days later, she presented to the emergency department with subjective fever, headache, rigors, chills, diaphoresis, nausea, vomiting, and diarrhea. The lead was removed, and the patient’s acute symptoms resolved within 48 hours. CONCLUSIONS: Systemic allergic reactions to SCS can be significant and lead to device removal despite improvement in pain symptoms. Further case reports and studies are needed to elucidate the risks associated with SCS placement, such as allergic reaction, infection, and neurologic injury. KEY WORDS: Case report, spinal cord stimulator, chronic pain, allergic reaction

The management of chronic pain in sickle cell disease: an interview with Nadine Matthie.

Nadine Matthie, PhD, RN, CNL is an Assistant Professor in the Nell Hodgson Woodruff School of Nursing at Emory University in Atlanta, GA, USA. As a nurse scientist, she has conducted behavioral research to investigate pain and self-management in adults living with sickle cell disease, and address chronic, non vaso-occlusive pain in this population. DrMatthie is developing nonpharmacological, patient-centered, self-management strategies that incorporate virtual reality and biopsychosocial approaches to help manage chronic pain and reduce the burden of sickle cell;thereby, facilitating new, personalized approaches to management of chronic pain conditions in the home setting. Her research has been published in several national and international peer-reviewed sources for various disciplines, including nursing, medicine, music therapyand psychology.

Cannabinoids and Their Role in Chronic Pain Treatment: Current Concepts and a Comprehensive Review.

For decades, chronic pain was managed with an almost conventional approach of using a wide range of analgesic spectrum, surgical approaches and complex interventional pain techniques to modulate or even interrupt pain pathways. These different approaches carry many pharmacological hazards together with the lack of efficacy and safety of many interventional and surgical management techniques for chronic pain have mandated searching for other effective therapies including alternative treatments. Cannabinoids are naturally occurring substances that are derived from Cannabis sativa L. The usage of cannabinoids and their related synthetic chemical compounds has emerged as a choice in the management of different chronic pain conditions is being evaluated, however, the efficacy is still not consistently established. In the present investigation, therefore, we discuss the different aspects related to cannabinoids and their implications in the management of chronic pain conditions. This review will also discuss the safety profile of the cannabinoids together with the legal considerations that hinder their use in different countries.

Anterior insula stimulation increases pain threshold in humans: a pilot study.

Chronic pain results in an enormous societal and financial burden. Opioids are the mainstay of treatment, but opioid abuse has led to an epidemic in the United States. Nonpharmacological treatment strategies like deep brain stimulation could be applied to refractory chronic pain if safe and effective brain targets are identified. The anterior insula is a putative mediator of pain-related affective-motivational and cognitive-evaluative cerebral processing. However, the effect of anterior insula stimulation on pain perception is still unknown. Here, the authors provide behavioral and neurophysiological evidence for stimulating the anterior insula as a means of potential therapeutic intervention for patients with chronic pain. Six patients with epilepsy in whom intracerebral electrodes had been implanted for seizure localization were recruited to the study. The direct anterior insula stimulations were performed in the inpatient epilepsy monitoring unit while subjects were fully awake, comfortable, and without sedating medications. The effects of anterior insula stimulation were assessed with quantitative sensory testing for heat pain threshold, nociceptive-specific cutaneous laser-evoked potentials, and intracranial electroencephalogram (EEG) recordings. Control stimulation of noninsular brain regions was performed to test stimulation specificity. Sham stimulations, in which no current was delivered, were also performed to control for potential placebo effects. The safety of these stimulations was evaluated by bedside physicians, real-time intracranial EEG monitoring, and electrocardiogram recordings. Following anterior insula stimulations, the heat pain threshold of each patient significantly increased from baseline (p < 0.001) and correlated with stimulation intensity (regression analysis: β = 0.5712, standard error 0.070, p < 0.001). Significant changes in ongoing intracranial EEG frequency band powers (p < 0.001), reduction in laser pain intensity, and attenuated laser-evoked potentials were also observed following stimulations. Furthermore, the observed behavioral and neurophysiological effects persisted beyond the stimulations. Subjects were not aware of the stimulations, and there were no cardiovascular or untoward effects. Additional, nonpharmacological therapies are imperative for the future management of chronic pain conditions and to mitigate the ongoing opioid crisis. This study suggests that direct stimulation of the anterior insula can safely alter cerebral pain processing in humans. Further investigation of the anterior insula as a potential target for therapeutic neuromodulation is underway.

(E)-3-furan-2-yl-N-phenylacrylamide (PAM-4) decreases nociception and emotional manifestations of neuropathic pain in mice by α7 nicotinic acetylcholine receptor potentiation

ABSTRACT Clinical intervention of pain is often accompanied by changes in affective behaviors, so both assays of affective and sensorial aspects of nociception play an important role in the development of novel analgesics. Although positive allosteric modulation (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) has been recognized as a novel approach for the relief of sensorial aspects of pain, their effects on affective components of pain remain unclear. Therefore, we investigated whether PAM-4, a highly selective α7-nAChR PAM, attenuates inflammatory and neuropathic pain, as well as the concomitant depressive/anxiety comorbidities. The anti-nociceptive activity of PAM-4 was assessed in mice using the formalin test and chronic constriction injury (CCI)-induced neuropathic pain model. The anxiolytic- and antidepressant-like activity of PAM-4 was evaluated using the marble burying test and forced swimming test. Acute systemic administration of PAM-4 dose-dependently reversed formalin-induced paw licking behavior and CCI-induced mechanical allodynia without development of any motor impairment. PAM-4 reversed the decreased swimming time and number of buried marbles in CCI-treated mice, suggesting that this ligand attenuates chronic pain-induced depression-like behavior and anxiogenic-like effects. The effects of PAM-4 were inhibited by the α7-selective antagonist methyllycaconitine, indicating molecular mechanism mediated by α7-nAChRs. Indeed, electrophysiological recordings showed the PAM-4 enhances human α7 nAChRs with higher potency and efficacy compared to rat α7 nAChRs. These findings suggest that PAM-4 reduces both sensorial and affective behaviors induced by chronic pain in mice by α7-nAChR potentiation. PAM-4 deserves further investigations for the management of chronic painful conditions with comorbidities.

Acceptance and commitment therapy for chronic pain: A systematic review

IntroductionChronic pain is common, costly, and associated with significant disability and negative effects on well-being and mental health. The treatment is challenging, requiring a multidisciplinary approach. Acceptance and commitment therapy (ACT) aims to help patients in engaging in a flexible and persistent pattern of values-directed behavior while in contact with continuing pain and discomfort.ObjectivesTo provide an updated review on the efficacy of ACT for the management of chronic pain.MethodsWe conducted a systematic review based on the PubMed® and EBSCO databases up to April 2020.ResultsFifteen trials were included. The results were in favour of ACT in pain acceptance, functioning and pain intensity with small to large effect sizes. Few studies evaluated quality of life, but half of those were favourable to ACT. We also focused our analysis on ACT online interventions, considering the current demands due to the COVID-19 pandemic.ConclusionsThe current systematic review points in favour of ACT for the management of chronic pain conditions, though the studies included suffered from methodological limitations, which may have led to overestimated effects. Methodologically robust trials are required to further understand the clinical efficacy of ACT for chronic pain and which patients most benefit from this intervention.

What is ‘chronic primary pain’ and why is NICE guidance on it causing controversy?

The latest guidance from the National Institute for Health and Care Excellence (NICE) marks a step-change in the assessment and management of chronic pain conditions. For the first time, the guideline divides chronic pain into two different pathways: one with an identifiable underlying cause, and one without. The latter has been termed “chronic primary pain”, and includes conditions such as fibromyalgia, […]

A Comprehensive Review of Alternative Therapies for the Management of Chronic Pain Patients: Acupuncture, Tai Chi, Osteopathic Manipulative Medicine, and Chiropractic Care.

IntroductionNon-pharmacologic alternative therapies for pain have been around for a long time, some for hundreds of years. They have been used throughout history to treat many issues.Recent FindingsCurrently, alternative medicine is most frequently used to treat musculoskeletal pain, and between 59 and 90% of patients utilizing alternative therapies for chronic pain claimed they were helpful and can serve as an effective adjunctive for the treatment of chronic pain. Some examples of alternative therapies that will be discussed in this review include acupuncture, tai chi, osteopathic manipulation, and chiropractic care. Acupuncture, traditionally a Chinese practice, is becoming more popular across the world to attempt to relieve pain. It involves the placement of thin needles at various points in the body. The efficacy of acupuncture for pain is heavily debated. More research and discussion are necessary to determine the exact role it plays in the treatment of chronic pain. Tai chi is also a traditional Chinese practice that is often used as a form of meditation and for potential health benefits. Tai chi involves a series of complex movements such as squatting combined with deep breathing to achieve relaxation and pain reduction. Osteopathic manipulative treatment (OMT) is a technique used by both osteopathic physicians (DO) as well as other health professionals to manage a wide range of conditions in any given patient. The technique involves utilization and manipulation of the musculoskeletal system to achieve potential health benefits. OMT has been used as therapy for many issues but is commonly used for pain conditions.SummaryAlternative therapies may serve as an effective adjunctive treatment modality for the management of chronic pain conditions. There has been a tremendous amount of research dictating the effectiveness of alternative therapies for chronic pain management. The purpose of this review is to provide a comprehensive evidence-based update of alternative therapy used for the management of chronic pain conditions.

Biopsychosocial Characteristics of Patients With Chronic Pain Expecting Different Levels of Pain Relief in the Context of Multidisciplinary Treatments.

Evidence suggests that patients' expectations predict chronic pain treatment outcomes. Although patients vary in terms of expected pain relief, little is known about individual factors related to such variations. This study aims to investigate how patients with various levels of pain relief expectations differ on the basis of biopsychosocial baseline characteristics in the context of multidisciplinary chronic pain treatment. Data from 3110 individuals with chronic pain attending one of 3 multidisciplinary pain treatment centers were considered. Participants completed a self-reported measure of pain relief expectations and provided information pertaining to biological, psychological, and social variables. A backward stepwise regression helped identify biopsychosocial variables that significantly predicted expected pain relief. Subsequent analyses suggest that patients reporting low, moderate, high, and very high expectations of pain relief differed significantly in terms of pain duration and depressive symptoms. Significant between-group differences were also found with regard to overall physical health, age, sex, and ethnicity. Identifying characteristics related to different levels of pain relief expectations is a fundamental step in generating a more comprehensive understanding of how expectations can be of use in the successful management of chronic pain conditions.

A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain.

The 20% prevalence of chronic pain in the general population is a major health concern given the often profound associated impairment of daily activities, employment status, and health-related quality of life in sufferers. Resource utilization associated with chronic pain represents an enormous burden for healthcare systems. Although analgesia based on the World Health Organization’s pain ladder continues to be the mainstay of chronic pain management, aside from chronic cancer pain or end-of-life care, prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain is rarely sustainable. As the endocannabinoid system is known to control pain at peripheral, spinal, and supraspinal levels, interest in medical use of cannabis is growing. A proprietary blend of cannabis plant extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal cannabinoids is formulated as an oromucosal spray (USAN name: nabiximols) and standardized to ensure quality, consistency and stability. This review examines evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain conditions. Cumulative evidence from clinical trials and an exploratory analysis of the German Pain e-Registry suggests that add-on THC:CBD oromucosal spray (nabiximols) may have a role in managing chronic neuropathic pain, although further precise clinical trials are required to draw definitive conclusions.

Enhancing Motivation for Change in the Management of Chronic Painful Conditions: a Review of Recent Literature.

The purpose of this review is to evaluate and summarize recent empirical research investigating motivational factors for management of chronic pain and headache disorders. Research on motivation for non-pharmacological treatment of chronic pain and headache disorders has identified factors that influence initiation of and adherence to treatment. To address common factors that inhibit initiation of treatment (i.e., cost, time commitment), several electronic treatments have been developed. Self-efficacy is the most commonly studied psychosocial influence on treatment adherence, with evidence that it is positively correlated with adherence. Other studies have sought to improve adherence to treatment using motivational interviewing interventions. There is currently limited research on how to enhance motivation for initial adherence to non-pharmacological treatment for chronic pain and headache disorders. Instead of enhancing motivation, researchers have looked to reduce barriers to treatment with electronic health treatments; however, many of these studies have focused on intervention feasibility, rather than efficacy or effectiveness. Numerous studies have identified a relationship between self-efficacy and treatment adherence. Although motivational interviewing interventions have been shown to improve adherence to treatment, there is little evidence that they improve treatment outcomes. Recommendations for further investigation include improving interventions to enhance accessibility and adherence to treatment with the goal of improving outcomes, as well as identifying ways to improve treatment initiation and adherence in patients who are currently engaged in long-term opioid therapy.

An Update on Cognitive Therapy for the Management of Chronic Pain: a Comprehensive Review.

Psychological approaches to the management of chronic pain have proven to be very effective in allowing patients to better manage their symptoms and with overall functioning. Cognitive functional therapy (CFT) is centered on a three-step process, beginning with cognitive training, then progressing to functional movement training and exposure with control, and ending with physical activity and lifestyle changes. Cognitive behavioral therapy (CBT) as a technique focuses on identifying and changing maladaptive behaviors, thought patterns, and situations that contribute to psychiatric dysfunction, which may lead to further progression of pain. The purpose of this review is to provide a comprehensive update of recent advances in the use of both CFT and CBT for the management of chronic pain conditions.

Evolving Spinal Cord Stimulation Technologies and Clinical Implications in Chronic Pain Management.

Spinal cord stimulation (SCS), based on the gate theory of nociception, has been shown to be effective in the management of chronic pain conditions. While early-generation technology offered many patients improvement in their pain and symptoms, limitations including paresthesia, dependence on mapping, decreased chronological efficacy, and inadequate coverage left many patients with persistent pain and overt therapeutic failure. New advances in neuromodulation technology circumvent many of these previous limitations and offer patients improved pain relief and quality of life. In this review, an update on recent technological developments in the field of SCS and peripheral neuromodulation is presented with discussion on differentiating characteristics which may help guide applicability to individual patient needs.

The role of neurologists in tackling the opioid epidemic.

The opioid crisis constitutes a public health challenge at the intersection of two interrelated medical problems - opioid addiction and chronic pain. Overlap of the reward and pain circuits in the brain underlies the frequent comorbidity of chronic pain and opioid addiction, whereas inadequate support, treatment and health-care reimbursement for both of these conditions are major contributors underlying the magnitude of the problem. Neurologists are uniquely positioned to help address the opioid crisis, not only through their involvement in the management of chronic pain conditions but also because they can screen for and manage opioid use disorders. The new NIH Helping to End Addiction Long-term (HEAL) Initiative will support research into pain and opioid use disorders to help address the opioid crisis. Neurologists' involvement in basic, translational and clinical research is needed for the development of new pain therapeutics and biomarkers and interventions to prevent chronic pain and to prevent and treat opioid addiction.