Chronic widespread pain (CWP) is prevalent and associated with reduced life expectancy. Cardiovascular disease is one possible mechanism for this. The purpose of this study was to examine the association of CWP with arterial stiffness and carotid plaque measured using ultrasound to determine if shared environmental or genetic factors might account for any observed association. Around 3000 participants from the TwinsUK with CWP information and measures of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and plaque were considered. The relationship between CWP and cfPWV, cIMT, and plaque was determined. UK Biobank data were used to replicate the association. Cholesky decomposition and multivariate pathway twin models were examined. Using a 2-sample Mendelian randomisation approach, the causal association between CWP and coronary artery disease was assessed. TwinsUK participants demonstrated a significant association between CWP and increased cfPWV consistent with arterial stiffening (OR = 1.35, P-value = 0.012), as well as the presence of carotid plaque (OR = 1.45, P-value = 0.8e-5). The twin modelling showed a common latent component and pathway underlying CWP, cfPWV, and carotid plaque, with genetic factors accounting for 68% and 90% of the latent factor variation, respectively. The 2-sample MR revealed a potential causal association between CWP and coronary artery disease. This study found that those with CWP have increased the risk of arterial stiffness and atherosclerosis and suggests that CWP leads to an increased risk of cardiovascular disease through genetic factors.

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine whether (1) 5 consecutive days of rTMS delivered prior to experimentally induced prolonged jaw pain has a prophylactic effect on future pain intensity and (2) whether these effects were accompanied by increases in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from day 0 to 4, 40 healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. Peak alpha frequency and CME were assessed on day 0 (before rTMS) and day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor in the right masseter muscle after the final rTMS session. From days 5 to 25, participants completed twice-daily electronic diaries including pain on chewing and yawning (primary outcomes), as well as pain during other activities (eg, talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Furthermore, active rTMS led to an increase in PAF. This is the first study to show that rTMS delivered prior to prolonged pain onset can protect against future pain. Our findings suggest that rTMS may hold promise as a prophylactic intervention for pain.

Forty-five years ago, Patrick Wall published his John J Bonica lecture "On the relation of injury to pain."90 In this lecture, he argued that pain is better classified as an awareness of a need-state than as a sensation. This need state, he argued, serves more to promote healing than to avoid injury. Here I reframe Wall's prescient proposal to pain in early life and propose a set of different need states that are triggered when injury occurs in infancy. This paper, and my own accompanying Bonica lecture, is dedicated to his memory and to his unique contribution to the neuroscience of pain. The IASP definition of pain includes a key statement, "through their life experiences, individuals learn the concept of pain."69 But the relation between injury and pain is not fixed from birth. In early life, the links between nociception (the sense) and pain (the need state) are very different from those of adults, although no less important. I propose that injury evokes three pain need states in infancy, all of which depend on the state of maturity of the central nervous system: (1) the need to attract maternal help; (2) the need to learn the concept of pain; and (3) the need to maintain healthy activity dependent brain development.

The burden of pain in low- and middle income countries (LMICs) is high and expected to rise further with their ageing populations. Multidisciplinary pain management approaches based on the biopsychosocial model of pain have been shown to be effective in reducing pain-related distress and disability, but these approaches are still lacking in many LMICs due to various factors, including low levels of awareness about the role of multidisciplinary pain clinics, lack of prioritisation for pain services, and lack of healthcare professionals trained in pain management. The International Association for the Study of Pain (IASP) has several educational programs to promote multidisciplinary pain management in LMICs, in the form of education grants, pain fellowships, pain camps and, most recently, the development of a Multidisciplinary Pain Centre Toolkit. This article describes the various educational programs, focusing on Southeast Asia, that demonstrate how targeted educational programs which include skills training, follow-up and mentorship, can translate into the formation of new multidisciplinary pain management services in settings with limited resources.

Nociplastic pain, a third mechanistic pain descriptor in addition to nociceptive and neuropathic pain, was adopted in 2017 by the International Association for the Study of Pain (IASP). It is defined as "pain that arises from altered nociception" not fully explained by nociceptive or neuropathic pain mechanisms. Peripheral and/or central sensitization, manifesting as allodynia and hyperalgesia, is typically present, although not specific for nociplastic pain. Criteria for possible nociplastic pain manifesting in the musculoskeletal system define a minimum of 4 conditions: (1) pain duration of more than 3 months; (2) regional, multifocal or widespread rather than discrete distribution of pain; (3) pain cannot entirely be explained by nociceptive or neuropathic mechanisms; and (4) clinical signs of pain hypersensitivity present in the region of pain. Educational endeavors and field testing of criteria are needed. Pharmacological treatment guidelines, based on the three pain types, need to be developed. Currently pharmacological treatments of nociplastic pain resemble those of neuropathic; however, opioids should be avoided. A major challenge is to unravel pathophysiological mechanisms driving altered nociception in patients suffering from nociplastic pain. Examples from fibromyalgia would include pathophysiology of the peripheral as well as central nervous system, such as autoreactive antibodies acting at the level of the dorsal root ganglia and aberrant cerebral pain processing, including altered brain network architecture. Understanding pathophysiological mechanisms and their interactions is a prerequisite for the development of diagnostic tests allowing for individualized treatments and development of new strategies for prevention and treatment.

Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called "neuroinflammation" in human pain has been an object of contention for decades. Here, I present the results of multiple positron emission tomography (PET) studies measuring the levels of the 18 kDa translocator protein (TSPO), a putative neuroimmune marker, in individuals with various pain conditions. Overall, these studies suggest that brain TSPO PET signal: (1) is elevated, compared to healthy volunteers, in individuals with chronic low back pain (with additional elevations in spinal cord and neuroforamina), fibromyalgia, migraine and other conditions characterized by persistent pain; (2) has a spatial distribution exhibiting a degree of disorder specificity; (3) is parametrically linked to pain characteristics or comorbid symptoms (eg, nociplastic pain, fatigue, depression), as well as measures of brain function (ie, functional connectivity), in a regionally-specific manner. In this narrative, I also discuss important caveats to consider in the interpretation of this work (eg, regarding the cellular source of the signal and the complexities inherent in its acquisition and analysis). While the biological and clinical significance of these findings awaits further work, this emerging preclinical literature supports a role of neuron-glia-immune interactions as possible pathophysiological underpinnings of human chronic pain. Gaining a deeper understanding of the role of neuroimmune function in human pain would likely have important practical implications, possibly paving the way for novel interventions.

There is growing acceptance for combining complementary and integrative health (CIH) therapies with standard rehabilitative care (SRC) for chronic pain management, yet little evidence on the best sequence of therapies. We investigated whether starting with CIH therapies or SRC is more effective in reducing pain impact. Participants were 280 service members with predominantly (88%) musculoskeletal chronic pain referred to an interdisciplinary pain management center who were randomized to a twice weekly program of either CIH therapies (n = 140) or SRC (n = 140) for the 3-week first stage of treatment. The composition of a second 3-week treatment stage depended upon response to the first stage. The primary outcome measure was the impact score (range 8-50) from the NIH Task Force on Research Standards for Chronic Low-Back Pain. Outcomes were measured after 3 and 6 weeks of treatment and at 3- and 6-month follow-ups. Most participants were men (76.8%) and mean age was 34.7 years (SD 8.0). At end of stage 1, pain impact decreased significantly more in the CIH group (29.8 points [SD 7.2] at baseline to 26.3 points [SD 7.9], change of -3.3 points [95% confidence interval, -4.2 to -2.5]) than in the SRC group (30.8 [SD 7.6] to 29.4 [SD 7.8], change of -0.9 points [95% confidence interval, -1.8 to -0.1]; P < 0.001). No significant between-group differences were observed after 6 weeks of treatment nor at 3- or 6-month follow-ups. Complementary and integrative health therapies may provide earlier improvement in pain impact than SRC, but this difference is not sustained.

"Somehow scientists still pursue the same questions, if now on higher levels of theoretical abstraction rooted in deeper layers of empirical evidence… To paraphrase an old philosophy joke, science is more like it is today than it has ever been. In other words, science remains as challenging as ever to human inquiry. And the need to communicate its progress… remains as essential now as then." - Tom Siegfried, Science News 2021In fact, essential questions about pain have not changed since IASP's creation in Issaquah: what causes it and how can we treat it? Are we any closer to answering these questions, or have we just widened the gap between bench and bedside? The technology used to answer questions about pain mechanisms has certainly changed, whether the focus is on sensory neurons, spinal cord circuitry, descending controls or cortical pain processing. In this paper, we will describe how transgenics, transcriptomics, optogenetics, calcium imaging, fMRI, neuroimmunology and in silico drug development have transformed the way we examine the complexity of pain processing. But does it all, as our founders hoped, help people with pain? Are voltage-gated Na channels the new holy grail for analgesic development, is there a pain biomarker, can we completely replace opioids, will proteomic analyses identify novel targets, is there a "pain matrix," and can it be targeted? Do the answers lie in our tangible discoveries, or in the seemingly intangible? Our founders could barely imagine what we know now, yet their questions remain.

Improving health and wellbeing outcomes for people experiencing chronic musculoskeletal pain requires collective efforts across multiple levels of a healthcare ecosystem. System-wide barriers to care equity must however be addressed (eg, lack of co-designed services; overuse of low value care/underuse of high value care; inadequate health workforce; inappropriate funding models; inequitable access to medicines and technologies; inadequate research and innovation). In this narrative review, utilizing a systems' thinking framework, we synthesize novel insights on chronic musculoskeletal pain research contextualized through the lens of this complex, interconnected system, the "pain care ecosystem." We examine the application of systems strengthening research to build capacity across this ecosystem to support equitable person-centred care and healthy ageing across the lifespan. This dynamic ecosystem is characterized by three interconnected levels. At its centre is the person experiencing chronic musculoskeletal pain (micro-level). This level is connected with health services and health workforce operating to co-design and deliver person-centred care (meso-level), underpinned further upstream by contemporary health and social care systems (macro-level context). We provide emerging evidence for how we, and others, are working towards building ecosystem resilience to support quality musculoskeletal pain care: at the macro-level (eg, informing musculoskeletal policy and health strategy priorities); at the meso-level (eg, service co-design across care settings; health workforce capacity); and downstream, at the micro-level (eg, person-centred care). We outline the mechanisms and methodologies utilized and explain the outcomes, insights and impact of this research, supported by real world examples extending from Australian to global settings.

Voltage-gated potassium channel subfamily q member 4 (Kcnq4) is predominantly expressed by hair cells and auditory neurons and regulates the neuronal excitability in the auditory pathway. Although it is further detected in myelinated large-diameter dorsal root ganglia (DRG) neurons in the periphery, the expression and function of Kcnq4 channel in nociceptors remains unknown. Here we showed that Kcnq4 is substantially expressed by unmyelinated small-diameter DRG neurons in both human and mouse. In spite of a dispensable role in acute pain and chronic skin inflammation, Kcnq4 is specifically involved in the regulation of scratching behavior through controlling action potential firing properties, evidenced by the increased neuronal excitability in small-diameter DRG neurons isolated from Kcnq4 deficient mice. Moreover, genetic ablation of Kcnq4 in Trpv1-positive neurons exacerbates both acute and chronic itch behavior in mice. Taken together, our results uncover a functional role of Trpv1-lineage neuron-expressing Kcnq4 channel in the modulation of itch-specific neuronal excitation in the periphery.

Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature (MARCO, CD163, STAB1), indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163+MARCO+ macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+ subset implicated.

While our understanding of pain is rapidly growing, some areas of pain research are lagging behind. This article discusses two current and inter-related gaps in knowledge that are in need of addressing: first, the connections between "brain" and "body" components of pain; and second, the process of endogenous pain resolution. Historical reasons for these research gaps are discussed and solutions are outlined based on an integrative, whole person research approach. These include comprehensive mapping of the mechanosensory and nociceptive innervation of deep tissues; developing objective, non-invasive measurements to quantify the metabolic, structural and mechanical components of the peripheral tissue environment; integrating our understanding of pain pathophysiology, across whole organs and whole body, as well as across bio-psycho-social domains; and understanding the interplay of nervous system and peripheral tissue mechanisms that promote the endogenous resolution of pain and prevent its acute-to-chronic transition. Current NIH-led efforts in these areas are outlined, including several studies within the NIH HEAL (or Help End Addition Long Term) initiative and the National Center for Complementary and Integrative Health's strategic priorities in whole person research.

People with special needs, like those with Down syndrome, Parkinson disease, or dementia, frequently suffer from orofacial pain conditions and dysfunction of the masticatory system. However, the accurate assessment of orofacial pain and dysfunction in such individuals is challenging. In this review, the complexities of assessing and managing orofacial pain and dysfunction in special needs populations will be described, along with their comorbid orofacial conditions like impaired oral health, salivary problems, and movement disorders of the masticatory system. In addition, the importance of maintaining or restoring a good quality of life will be highlighted, while the urgent need for oral care as part of palliative care will be stressed as well. To accomplish all this, interdisciplinary collaboration between medical doctors and dentists should be promoted in research, education, prevention, and care provision. Therefore, this review focuses specifically on this important topic.

For decades, clinicians and researchers have observed bidirectional relationships between child development and the pain experience in childhood. Pain in childhood is an inherently developmental phenomenon, embedded in an iterative, time-dependent process that reflects individual biological, behavioral, social, psychological, and environmental characteristics that unfold across the early life span. Childhood pain can have wide ranging effects on brain development in ways that contribute-for better and worse-to social, emotional, and cognitive well-being in childhood and on into adulthood. Atypical trajectories of development in the context of disorders such as autism, cerebral palsy, ADHD, and mood/anxiety disorders also contribute to unique childhood pain experiences. In this paper, pain will be considered as a determinant of development, and conversely development will be considered as a key determinant of a child's pain experience. We will discuss how intersectional identities (eg, gender, race, socioeconomic status) and associated social, structural, systemic, and physical environments influence the relationship between development and pain. Finally, we will identify what might be needed to think "developmentally" in ways that extend from the "bench side" in the lab to the "curb side" in the community, integrating a developmental perspective into research and clinical practice to achieve health accessibility and equity in pain care for all children across the developmental spectrum.

Spinal cord injury (SCI) results in permanent neurological dysfunction and neuropathic pain. To address this pathology, we recently conducted a clinical study in which we transplanted neural precursor cells (NPCs) derived from human induced pluripotent stem cells into patients during the subacute phase of SCI. One of the therapeutic mechanisms of cell transplantation is the formation of synaptic connections with the host's neural tissues, which we demonstrated using a chemogenetic tool. In addition, we have developed innovative strategies to enhance the effectiveness of cell transplantation through gene therapy. Moreover, our current study is focused on developing cell therapy for chronic SCI, a more challenging pathology characterized by the formation of cavities and scar tissue. In such situations, transplanting NPCs with neurogenic properties could effectively penetrate scar tissue and form functional synapses with the host neurons. To improve the outcomes of cell transplantation alone, we have found that incorporating rehabilitation is beneficial. In animal models of SCI, we have established an effective rehabilitative training program in which NPCs were transplanted during the chronic phase. Robotic rehabilitation has demonstrated improvements in gait ability and trunk function in clinical situations. Therefore, regenerative medicine shows promise for chronic SCI, particularly when rehabilitation strategies are incorporated.

Advancements in clinical science have shown the necessity for a paradigm shift away from a biomedical toward a biopsychosocial approach. Yet, the translation from clinical science into clinical practice is challenging. The aim of this study was to assess the short-term and mid-term changes in pain knowledge and attitudes and guideline-adherent recommendations of healthcare professionals (HCP) by means of an interdisciplinary training program (ITP) about chronic pain. Belgian HCPs, with a priority for medical doctors, physiotherapists, occupational therapists, nurses, psychologists, and pharmacists in primary care, participated in the ITP, which contained 2 e-learning modules and two 7-hour workshops provided in small interdisciplinary groups in 5 cities. The objective of ITP was to improve HCP's competencies for integrating biopsychosocial chronic pain management with a cognitive behavioral approach into clinical practice. Primary outcomes were changes in knowledge and attitudes about pain and guideline-adherent recommendations for continuation of physical activity, sports, and work; avoiding bed rest; and not supporting opioid usage measured through 2 clinical vignettes. They were measured before, immediately after, and 6 months after the ITP. Changes were analyzed using (generalized) linear mixed models. A total of 405 HCPs participated. The knowledge and attitudes about pain scores improved at post-training (Δ = 9.04, 95% confidence interval 7.72-10.36) and at 6-month follow-up (Δ = 7.16, 95% confidence interval 5.73-8.59). After the training program, HCPs provided significantly more recommendations in accordance with clinical guidelines. Thus, an ITP can improve the biopsychosocial perspective of chronic pain management among HCPs in the short-term and mid-term.

The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)- appraisals of pain as threatening, overwhelming, and unmanageable- and review the evidence that these thoughts are learned in childhood through experience and observation of others, particularly caretakers and parents. For children who have learned pCAT, repeated exposures to pain over time activate pCAT and likely contribute to further amplification of pain through changes in the neurobiological pain regulatory systems, which overlap with those regulating the stress response. We propose that repeated pain and stress exposures throughout childhood, adolescence, and into adulthood alter the neurobiology of pain via a repetitive positive feedback loop that increases risk for heightened pain sensitivity over time with repeated exposures. At some point, often precipitated by an acute episode of pain and possibly influenced by allostatic load, pCAT contributes to persistence of episodic or acute pain and exacerbates pain-related suffering. This developmental trajectory is not inevitable, as the impact of pCAT on pain and pain-related suffering can be influenced by various factors. We also present future directions for work in this area.