Papers: 8 May 2021 - 14 May 2021

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

How to prevent the onset, maintenance, or exacerbation of pain is a major focus of clinical pain science. Pain prevention can be distinctly organised into primary, secondary, and tertiary prevention. Primary prevention describes avoiding hurt or pain, secondary prevention describes reducing pain when pain is unavoidable, and tertiary prevention describes preventing or reducing ongoing negative consequences such as high functional disability or distress due to chronic pain. Each poses separate challenges where unique psychological factors will play a role. In this short review article, we highlight psychological factors important to primary, secondary, and tertiary prevention and provide direction for the field. We present 2 case studies on secondary prevention in children and adolescents and tertiary prevention in adults with chronic pain. Finally, we provide research directions for progression in this field, highlighting the importance of clear theoretical direction, the identification of risk factors for those most likely to develop pain, and the importance of treatment.

Chronic pain, and the ethical management thereof, is the single most imperative health issue of this decade. Although a growing majority of individuals with chronic pain are middle-aged, the largest proportion of sufferers are older adults. Shifting tides in practice and research have led to population-focused approaches to pain management; however, the practice of many healthcare providers remains reactive and individualistic, limiting the discovery and implementation of long-term solutions for pain management in older adults. Yet, nurses and other health professionals have an opportune position to provide expert pain care by proactively providing evidence-based care for patients systematically. The purpose of this article is to stimulate discussion on three paradigms important to population-focused pain management: (1) prevention; (2) restoration and rehabilitation; and (3) palliation, which are in line with current national policy initiatives for improving patients' care experience, improving overall health and quality of life, and reducing associated health care costs.

It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.

Long-term opioid treatment (L-TOT) of chronic non-cancer pain (CNCP) patients has been suspected to alter the endocrine system. This systematic review and meta-analysis aimed at investigating the published evidence of L-TOT effects on the endocrine system in adult CNCP patients.

The inconsistent use of standardized approaches for classifying postamputation pain (PAP) has been a barrier to establishing its prevalence.

Low back pain is the leading cause for years lived in disability. Most people with acute low back pain improve rapidly, but 4% to 25% of patients become chronic. Since the previous systematic reviews on the subject, a large number of new studies have been conducted. The objective of this article was to review the evidence of the prognostic factors behind nonspecific chronic low back pain. A systematic literature search was performed without date limitation from the MEDLINE, Cochrane library, and Medic databases. Specific inclusion criteria were used, and risk factors before the onset of chronic symptoms were searched. Study quality was assessed by 2 independent reviewers. One hundred eleven full articles were read for potential inclusion, and 25 articles met all the inclusion criteria. One study was rated as good quality, 19 studies were rated as fair quality, and 5 articles were rated as poor quality. Higher pain intensity, higher body weight, carrying heavy loads at work, difficult working positions, and depression were the most frequently observed risk factors for chronic low back pain. Maladaptive behavior strategies, general anxiety, functional limitation during the episode, smoking, and particularly physical work were also explicitly predictive of chronicity. According to this systematic review, several prognostic factors from the biomechanical, psychological and psychosocial point of view are significant for chronicity in low back pain.

The COVID-19 pandemic called for drastic changes to expand and rapidly implement telehealth to prevent breach of care for chronic patients. Responding to the challenge of implementing remote care in chronic pain services, a specialty highly dependent on doctor-patient rapport, physical examination, and frequent follow-up visits requires extensive adaptation involving administrative processes and clinical routines. We present our experience of a successful rapid adaptation to telemedicine paradigm as a response to the COVID-19 pandemic during a time of marked restriction of access to ambulatory hospital services for pediatric and adult chronic pain patients. This narrative review covers current scientific evidence for the use of telehealth for chronic pain management and describes in detail the challenges to implement telemedicine in ambulatory clinics from different perspectives. Best practices for telehealth use are recommended. A proposal for remote physical examination of pain patients is made, based on available evidence in the fields of musculoskeletal medicine and neurology comparing in-person vs remote physical examination. As an internal quality control process, an informal online survey was conducted to assess thoughts and experiences among patients and caregivers using telemedicine consultation services at the pediatric pain clinic. Providing chronic pain management services through telehealth is a viable option for many patients and health care professionals. This is reliant on the availability of appropriate materials and training, with guidelines for both patients and health care workers. With the rapid pace of technological advancements, even further integration of telehealth into routine health care is possible.

Chronic pain is an unpleasant and debilitating condition that is often poorly managed by existing therapeutics. Reciprocal interactions between the nervous system and the immune system have been recognized as playing an essential role in the initiation and maintenance of pain. In this review, we discuss how neuroimmune signaling can contribute to peripheral and central sensitization and promote chronic pain through various autoimmune mechanisms. These pathogenic autoimmune mechanisms involve the production and release of autoreactive antibodies from B cells. Autoantibodies-ie, antibodies that recognize self-antigens-have been identified as potential molecules that can modulate the function of nociceptive neurons and thereby induce persistent pain. Autoantibodies can influence neuronal excitability by activating the complement pathway; by directly signaling at sensory neurons expressing Fc gamma receptors, the receptors for the Fc fragment of immunoglobulin G immune complexes; or by binding and disrupting ion channels expressed by nociceptors. Using examples primarily from rheumatoid arthritis, complex regional pain syndrome, and channelopathies from potassium channel complex autoimmunity, we suggest that autoantibody signaling at the central nervous system has therapeutic implications for designing novel disease-modifying treatments for chronic pain.

The growing awareness of the critical role played by the innate and adaptive immune systems in the mechanisms underlying chronic pain has prompted further research examining the modalities by which immune cells communicate with neurones, the aim being to identify new players involved in inflammatory and neuropathic pain signalling. This collection of research includes 9 articles on neuroimmune interactions as the underlying mechanisms for neuropathic pain including peripheral neuropathies, pain in rheumatoid arthritis and osteoarthritis, and bone cancer pain. The immune cells under scrutiny include macrophages, microglia, osteoclasts, and B cells, and their interactions with neurones in locations such as the dorsal root ganglia, blood-spinal cord barrier, spinal cord, and brain. Our hope is that this body of work may serve to furnish existing interest while also constituting a springboard of sorts for indispensable further investigation on neuroimmune interactions in chronic pain.

This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.

Bidirectional interactions between the immune system and the nervous system are increasingly appreciated as playing a pathogenic role in chronic pain. Unraveling the mechanisms by which inflammatory pain is mediated through communication between nerves and immune cells may lead to exciting new strategies for therapeutic intervention. In this narrative review, we focus on the role of macrophages in the pathogenesis of osteoarthritis (OA) pain. From regulating homeostasis to conducting phagocytosis, and from inducing inflammation to resolving it, macrophages are plastic cells that are highly adaptable to their environment. They rely on communicating with the environment through cytokines, growth factors, neuropeptides, and other signals to respond to inflammation or injury. The contribution of macrophages to OA joint damage has garnered much attention in recent years. Here, we discuss how macrophages may participate in the initiation and maintenance of pain in OA. We aim to summarize what is currently known about macrophages in OA pain and identify important gaps in the field to fuel future investigations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Molecular and cellular interactions among spinal dorsal horn neurons and microglia, the resident macrophages of the central nervous system, contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. Emerging evidence also demonstrates that reciprocal interactions between macrophages and nociceptive sensory neurons in the dorsal root ganglion contribute to the initiation and persistence of nerve injury-induced mechanical hypersensitivity (allodynia). We previously reported that sensory neuron-derived colony-stimulating factor 1 (CSF1), by engaging the CSF1 receptor (CSF1R) that is expressed by both microglia and macrophages, triggers the nerve injury-induced expansion of both resident microglia in the spinal cord and macrophages in the dorsal root ganglion and induces their respective contributions to the neuropathic pain phenotype. Here, we review recent research and discuss unanswered questions regarding CSF1/CSF1R-mediated microglial and macrophage signaling in the generation of neuropathic pain.

Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood-spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.

Many common cancers such as breast, prostate, and lung cancer metastasize to bones at advanced stages, producing severe pain and functional impairment. At present, the current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. In this narrative review, we discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain. In particular, we highlight the reciprocal interactions between tumor cells, bone-resorbing osteoclasts, and pain-sensing sensory neurons (nociceptors), which drive bone cancer pain. We discuss how tumor cells present within the bone TME accelerate osteoclast differentiation (osteoclastogenesis) and alter osteoclast activity and function. Furthermore, we highlight how this perturbed state of osteoclast overactivation contributes to bone cancer pain through (1) direct mechanisms, through their production of pronociceptive factors that act directly on sensory afferents; and (2) by indirect mechanisms, wherein osteoclasts drive bone resorption that weakens tumor-bearing bones and predisposes them to skeletal-related events, thereby driving bone cancer pain and functional impairment. Finally, we discuss some potential therapeutic agents, such as denosumab, bisphosphonates, and nivolumab, and discuss their respective effects on bone cancer pain, osteoclast overactivation, and tumor growth within the bone TME.

The peripheral nervous system comprises an infinity of neural networks that act in the communication between the central nervous system and the most diverse tissues of the body. Along with the extension of the primary sensory neurons (axons and cell bodies), a population of resident macrophages has been described. These newly called sensory neuron-associated macrophages (sNAMs) seem to play an essential role in physiological and pathophysiological processes, including infection, autoimmunity, nerve degeneration/regeneration, and chronic neuropathic pain. After different types of peripheral nerve injury, there is an increase in the number and activation of sNAMs in the sciatic nerve and sensory ganglia. The activation of sNAMs and their participation in neuropathic pain development depends on the stimulation of pattern recognition receptors such as Toll-like receptors and Nod-like receptors, chemokines/cytokines, and microRNAs. On activation, sNAMs trigger the production of critical inflammatory mediators such as proinflammatory cytokines (eg, TNF and IL-1β) and reactive oxygen species that can act in the amplification of primary sensory neurons sensitization. On the other hand, there is evidence that sNAMs can produce antinociceptive mediators (eg, IL-10) that counteract neuropathic pain development. This review will present the cellular and molecular mechanisms behind the participation of sNAMs in peripheral nerve injury-induced neuropathic pain development. Understanding how sNAMs are activated and responding to nerve injury can help set novel targets for the control of neuropathic pain.

Pain plays an indispensable role as an alarm system to protect us from dangers or injuries. However, neuropathic pain, a debilitating pain condition caused by damage to the nervous system, persists for a long period even in the absence of dangerous stimuli or after injuries have healed. In this condition, pain becomes a disease itself rather than the alarm system and is often resistant to currently available medications. A growing body of evidence indicates that microglia, a type of macrophages residing in the central nervous system, play a crucial role in the pathogenesis of neuropathic pain. Whenever microglia in the spinal cord detect a damaging signal within the nervous system, they become activated and cause diverse alterations that change neural excitability, leading to the development of neuropathic pain. For over a decade, several lines of molecular and cellular mechanisms that define microglial activation and subsequently altered pain transmission have been proposed. In particular, P2X4 receptors (a subtype of purinergic receptors) expressed by microglia have been investigated as an essential molecule for neuropathic pain. In this review article, we describe our understanding of the mechanisms by which activated microglia cause neuropathic pain through P2X4 receptors, their involvement in several pathological contexts, and recent efforts to develop new drugs targeting microglia and P2X4 receptors.

Growing evidence implicates the renin-angiotensin system (RAS) in multiple facets of neuropathic pain (NP). This narrative review focuses primarily on the major bioactive RAS peptide, Angiotensin II (Ang II), and its receptors, namely type 1 (AT1R) and type 2 (AT2R). Both receptors are involved in the development of NP and represent potential therapeutic targets. We first discuss the potential role of Ang II receptors in modulation of NP in the central nervous system. Ang II receptor expression is widespread in circuits associated with the perception and modulation of pain, but more studies are required to fully characterize receptor distribution, downstream signaling, and therapeutic potential of targeting the central nervous system RAS in NP. We then describe the peripheral neuronal and nonneuronal distribution of the RAS, and its contribution to NP. Other RAS modulators (such as Ang (1-7)) are briefly reviewed as well. AT1R antagonists are analgesic across different pain models, including NP. Several studies show neuronal protection and outgrowth downstream of AT2R activation, which may lead to the use of AT2R agonists in NP. However, blockade of AT2R results in analgesia. Furthermore, expression of the RAS in the immune system and a growing appreciation of neuroimmune crosstalk in NP add another layer of complexity and therapeutic potential of targeting this pathway. A growing number of human studies also hint at the analgesic potential of targeting Ang II signaling. Altogether, Ang II receptor signaling represents a promising, far-reaching, and novel strategy to treat NP.

To determine the prevalence of neuropathic-like pain(NP) and pain sensitisation(PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint.

Numerous studies have examined the influence of pain on spinal reflex excitability, motor unit behaviour and corticospinal excitability. Nevertheless, there are inconsistencies in the conclusions made. This systematic review sought to understand the effect of pain on spinal and supraspinal projections to motoneurons and motor unit properties by examining the influence of clinical or experimental pain on the following three domains: H reflex, corticospinal excitability and motor unit properties.

Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress.

The concept of inflammatory back pain (IBP) describes a cohort of patients with chronic back pain (CBP) who have distinct clinical characteristics, rather than being a diagnosis in and of itself. IBP is a common and important feature of axial spondyloarthritis (axSpA) but this is not the only differential. This review examines the utility of IBP in both primary and secondary care settings.

The number of applications for peripheral nerve stimulation (PNS) in the pain management field is ever-growing. With the increasing number of clinical applications for peripheral nerve stimulation, the purpose of this article is to review the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes.

Integrated care is a continuum of services delivered by a system organized around the health needs of people rather than diseases. People with chronic musculoskeletal pain often live with co-existing chronic health conditions. Current care for musculoskeletal pain remains narrowly focused on individual painful conditions despite the complex health needs of patients. We explore the challenges to delivering integrated care to people with musculoskeletal pain and co-existing chronic health conditions. We discuss these challenges in relation to 3 areas: (i) understanding the relationships between musculoskeletal conditions and other chronic health conditions, (ii) factors that impact the clinician's capacity to provide integrated care for musculoskeletal conditions, (iii) system level constraints impacting on both the clinician's delivery of care and the patient's healthcare experience. We suggest ways for clinicians and researchers to move towards better integrated care for musculoskeletal pain and co-existing chronic health conditions. .

Chronic low back pain (CLBP) has been recognized as the leading cause of disability. Up to 90% of patients with CLBP are classified as having non-specific CLBP (NSCLBP). Motor control exercise (MCE) is one of the most popular and widespread treatment options, and has many advantages in alleviating pain and disability. This meta-analysis is aimed to investigate the effectiveness of MCE on NSCLBP, disability, and core muscles reported in randomized controlled trials (RCTs).

In the management of human immunodeficiency virus (HIV) infection around the world, chronic complications are becoming a new problem along with the prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those with a low viral load undergoing long-term treatment with antiviral drugs, negatively influencing the adherence to disease management and quality of life. A large proportion of chronic pain is neuropathic pain, which defined as chronic pain caused by nervous system lesions or diseases, presenting a series of nervous system symptoms including both positive and negative signs. Injury caused by HIV protein, central and peripheral sensitization, and side effects of antiretroviral therapy lead to neuroinflammation, which is regarded as a maladaptive mechanism originally serving to promote regeneration and healing, constituting the main mechanism of HIV-related neuropathic pain. Gp120, as HIV envelope protein, has been found to be the major toxin that induces neuropathic pain. Particularly, the microglia, releasing numerous pro-inflammatory substances (such as TNFα, IL-1β, and IL-6), not only sensitize the neurons but also are the center part of the crosstalk bridging the astrocytes and oligodendrocytes together forming the central sensitization during HIV infection, which is not discussed detailly in recent reviews. In the meantime, some NRTIs and PIs exacerbate the neuroinflammation response. In this review, we highlight the importance of clarifying the mechanism of HIV-related neuropathic pain, and discuss about the limitation of the related studies as future research directions.