Papers: 26 Mar 2022 - 1 Apr 2022

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Human pluripotent stem cells (hPSCs) show promise for studying diseases affecting cell populations that are not easily available, including sensory neurons (SNs). Here, we present a differentiation protocol in chemically defined conditions to generate peripheral SNs from hPSCs. We describe four main steps: expansion of hPSCs, neural crest cell (NCC) differentiation, NCC dissociation and replating, and sensory neuron (SN) differentiation. This protocol enables generation of a mechanoreceptor-enriched culture or a population containing all three SN subtypes (nociceptors, mechanoreceptors, and proprioceptors). For complete details on the use and execution of this protocol, please refer to Saito-Diaz et al. (2021).

Chronic low back pain (CLBP) is the leading cause of years lived with disability. Recently, it has been reported that CLBP is associated with alterations in the central nervous system. The present study aimed to investigate the association between CLBP and regional brain atrophy in an older Japanese population. A total of 1106 community-dwelling participants aged ≥65 years underwent brain magnetic resonance imaging scans and a health examination in 2017 to 2018. We used the FreeSurfer software for the analysis of brain magnetic resonance imaging. Chronic pain was defined as subjective pain for ≥3 months. Participants were divided into 3 groups according to the presence or absence of chronic pain and the body part that mainly suffered from pain: a "no chronic pain (NCP)" group (n = 541), "CLBP" group (n = 189), and "chronic pain in body parts other than the lower back (OCP)" group (n = 376). The brain volumes of the ventrolateral and dorsolateral prefrontal cortex, the posterior cingulate gyrus, and the amygdala were significantly lower in the CLBP group than in the NCP group after adjustment for sociodemographic, physical, and lifestyle factors and depressive symptoms. In addition, the left superior frontal gyrus was identified as a significant cluster by the Query, Design, Estimate, Contrast interface. There were no significant differences in the brain volumes of pain-related regions between the NCP and the OCP groups. The present study suggests that CLBP is associated with lower brain volumes of pain-related regions in a general older population of Japanese.

This review highlights recent findings of different amplitude ranges, roles, and modulations of A-type K currents (I) in excitatory (GAD67-GFP) and inhibitory (GAD67-GFP) interneurons in mouse spinal cord pain pathways. Endogenous neuropeptides, such as TAFA4, oxytocin, and dynorphin in particular, have been reported to modulate I in these pain pathways, but only TAFA4 has been shown to fully reverse the opposing modulations that occur selectively in LIIo GAD67-GFP and LIIi GAD67-GFP interneurons following both neuropathic and inflammatory pain. If, as hypothesized here, Kv4 subunits underlie I in both GAD67-GFP and GAD67-GFP interneurons, then I diversity in spinal cord pain pathways may depend on the interneuron-subtype-selective expression of Kv4 auxiliary subunits with functionally different N-terminal variants. Thus, I emerges as a good candidate for explaining the mechanisms underlying injury-induced mechanical hypersensitivity.

Burrowing behaviour is employed to assess pain-associated behaviour in laboratory rodents. To gain insight in how models of disease associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (NSAID and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation (R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin and naproxen showed reduced burrowing behaviour at high doses, while ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease associated pain.

Pain-related avoidance of movements that are actually safe (i.e., overprotective behavior) plays a key role in chronic pain disability. Avoidance is reinforced through operant learning: after learning that a certain movement elicits pain, movements that prevent pain are more likely to be performed. Proprioceptive accuracy importantly contributes to motor learning and memory. Interestingly, reduced accuracy has been documented in various chronic pain conditions, prompting the question whether this relates to avoidance becoming excessive. Using robotic arm-reaching movements, we tested the hypothesis that poor proprioceptive accuracy is associated with excessive pain-related avoidance in pain-free participants. Participants first performed a task to assess proprioceptive accuracy, followed by an operant avoidance training during which a pain stimulus was presented when they performed one movement trajectory, but not when they performed another trajectory. During a test phase, movements were no longer restricted to two trajectories, but participants were instructed to avoid pain. Unbeknownst to the participants, the pain stimulus was never presented during this phase. Results supported our hypothesis. Furthermore, exploratory analyses indicated a reduction in proprioceptive accuracy after avoidance learning, which was associated with excessive avoidance and higher trait fear of pain. Perspective: This study is the first to show that poorer proprioceptive accuracy is associated with excessive pain-related avoidance. This finding is especially relevant for chronic pain conditions, as reduced accuracy has been documented in these populations, and points toward the need for research on training accuracy to tackle excessive avoidance.

An emergent subgroup of spinal cord microglia mediates recovery from persistent pain.

Attention is known to modulate itch intensity. In contrast, the reverse relationship, i.e. the degree to which the presence of an acute itch affects attention, is currently not well understood. The aims of this study were to investigate whether acute itch induces an attentional bias towards or away from visual itch-related stimuli, and if so, whether it occurs in the early or later stages of processing. A volunteer sample of 60 healthy individuals were subjected to a skin prick (either histamine or placebo), followed by completion of a spatial cueing paradigm using itch-related and neutral words as cues, in order to obtain reaction time estimates of attentional bias. The results suggest that experience of acute itch induces attentional avoidance of visual itch threats. This attentional avoidance occurs at a later processing stage in the form of facilitated disengagement of attention from itch and/or delayed disengagement from neutral information.

The anterior cingulate cortex (ACC) is a key cortical region that plays an important role in pain perception and emotional functions. Previous studies of the ACC projections have been collected primarily from monkeys, rabbits and rats. Due to technological advances, such as gene manipulation, recent progress has been made in our understanding of the molecular and cellular mechanisms of the ACC-related chronic pain and emotion is mainly obtained from adult mice. Few anatomic studies have examined the whole-brain projections of the ACC in adult mice. In the present study, we examined the continuous axonal outputs of the ACC in the whole brain of adult male mice. We used the virus anterograde tracing technique and an ultrahigh-speed imaging method of Volumetric Imaging with Synchronized on-the-fly-scan and Readout (VISoR). We created a three-dimensional (3D) reconstruction of mouse brains. We found that the ACC projected ipsilaterally primarily to the caudate putamen (CPu), ventral thalamic nucleus, zona incerta (ZI), periaqueductal gray (PAG), superior colliculus (SC), interpolar spinal trigeminal nucleus (Sp5I), and dorsal medullary reticular nucleus (MdD). The ACC also projected to contralateral brain regions, including the ACC, reuniens thalamic nucleus (Re), PAG, Sp5I, and MdD. Our results provide a whole-brain mapping of efferent projections from the ACC in adult male mice, and these findings are critical for future studies of the molecular and synaptic mechanisms of the ACC and its related network in mouse models of brain diseases.

Opioids are commonly used as analgesics to relieve chronic pain and have high abuse potential. Due to their strong potency and trace concentration in plasma, a robust analytical method is necessary for quantification in forensic and pharmacology fields. Hence, this study developed and validated a simple, rapid, and robust method for the simultaneous determination of 12 opioids and metabolites which were available legally by prescription or abused for non-medical purposes, in plasma samples by simple liquid extraction and high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We compared the extraction recovery of our sample pre-treatment to two other sample pre-treatments (namely QuEChERS and simplified QuEChERS) and showed that the method used in our study gave the highest recoveries. The method validation followed the European Medicines Agency guidelines, including selectivity, carryover, accuracy and precision, dilution integrity, matrix effect and freeze/thaw stability. This method's accuracy ranged from 85% to 115% with a precision less than 15%, within the acceptable range of the validation protocol. The lower limit of quantification of the method ranged between 0.05 μg L and 0.38 μg L among 12 opioids/metabolites. Stability was assessed, with all opioids observed as relatively stable at 0.5 μg L and 5 μg L levels under -20 °C and 25 °C storage conditions. In summary, the developed method has the potential to achieve simultaneous analysis for monitoring opioids in forensic and pain management regimens using a simple sample pre-treatment.

GABAergic system disinhibition played an important role in the pathogenesis of remifentanil-induced hyperalgesia (RIH). K-Cl-cotransporter-2 (KCC2) has the potential to enhance the strength of GABAergic signaling function. However, few reports have focused on the additive analgesic effect of KCC2 enhancer and GABAA receptor agonist on the spinal dorsal horn. Therefore, we evaluated the role of GABA type A receptor (GABAAR) agonist (muscimol), KCC2 enhancer (CLP257) in remifentanil-induced hyperalgesia, as well as GABA and KCC2 receptors responses in the dorsal spinal horn. Remifentanil started to reduce paw withdrawal mechanical thresholds at postoperative 4 h and lasted to 72 h. The RIH associated decreases in spinal GABA release was transient. The amount of spinal GABA transmitter by microdialysis was observed to be decreased at the beginning and reached bottom at 150 min, then returned to the baseline level at 330 min. The synthesis and transportation of GABA transmitter were inhibited, characterized as spinal GAD67 and GAT1 downregulation after the establishment of RIH model. The effect of RIH on GABA receptor downregulation was linked to the reduced expression of spinal KCC2 receptor. This decrease in KCC2 expression has coincided with an early loss of GABA inhibition. KCC2 enhancer, which is reported to lead to a reduction in intracellular Cl, can enhance GABA-mediated inhibitory function. Both muscimol and CLP257 could dose-dependently inhibit mechanical hypersensitivity caused by remifentanil-induced downregulation of GABAAα2R and KCC2, respectively. Compared with muscimol acting alone, the joint action of CLP257 and muscimol showed a higher pain threshold and less c-fos expression via upregulation of KCC2 and GABAAα2R. Taken together, these findings suggested that the RIH was initiated by decreased GABA release. Downregulation of GABAAα2R and KCC2 receptor contributed to spinally mediated hyperalgesia in RIH. KCC2 enhancer was proved to potentiate antinociceptive effect of GABAAR agonist in RIH.

The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.

A large proportion of patients with burn injuries develop chronic itch, which impacts quality of life. The underlying pathophysiological mechanisms are poorly understood. This cross-sectional pilot study investigates whether altered cortical oscillatory processes are involved in chronic post-burn itch. Continuous electroencephalography (EEG) data were recorded during rest and stimulation of non-injured skin, inducing itch (histamine and electrical) and cold-pressor task pain for 15 adults with chronic post-burn itch and 15 matched healthy controls. Quantitative metrics comprised oscillatory power and peak frequencies in theta, alpha, and beta bands. No statistical differences between patients and healthy controls were found in oscillatory activity during rest or stimulation, with Bayesian analysis suggesting equivocal evidence. However, post-traumatic stress symptoms and duration of chronic itch may be associated with changes in oscillatory activity. A lack of differences in cortical oscillatory processing and itch levels at non-injured sites, suggests that itch symptoms have a localised character in this sample of patients with post-burn itch. For future studies, a biopsychological approach with integration of peripheral and central nervous system techniques, linear and non-linear EEG analysis, injured and non-injured stimulation sites, and incorporation of individual characteristics is recommended. Insight into pathophysiological mechanisms underlying chronic post-burn itch could improve diagnostics and treatments.

Pain, fatigue and depression in chronic inflammatory demyelinating polyneuropathy (CIDP) are often underestimated, as the focus lies on sensorimotor dysfunction and gait instability. The aim of this study was to investigate their prevalence, characteristics and contribution to disability in a prospective cohort of 84 patients with CIDP.

The aim of this meta-analysis was to study the evidence on pain sensitization in knee osteoarthritis (OA), providing a quantitative synthesis of its prevalence and impact. Factors associated with pain sensitization were also investigated.

Chronic pain is characterized by an impaired functional state (pain, mood, sleep, cognition, and metabolism) affecting different brain networks relevant for pain perception and neural pain processing […].

Pediatric inflammatory bowel disease (p-IBD) is a chronic relapsing gastrointestinal disorder of childhood with long-term morbidity. Several extraintestinal manifestations are described, the most common being joint pain and/or inflammation. However, patient and disease characteristics, treatments, and outcomes of p-IBD-associated musculoskeletal disease are not well established. Our study aims to summarize the recent literature on the epidemiology of musculoskeletal manifestations in p-IBD in the era of biologics.

Chronic migraine (CM) diagnosis is nowadays based on the threshold of 15 headache days/month for three consecutive months, of which at least eight have migraine headache features. In recent years, proposals for reducing the threshold to 8 days/month have been proposed. The sole frequency parameter, however, is partial considering the variability in frequency, pain severity, associated symptoms, such as nausea, osmophobia, and photophobia, and presence of aura, but also the variable response to treatment and the association with several comorbidities. Therefore, in our opinion, a multiparameter perspective has to be taken into account that considers the underlying pathophysiology, in particular the presence of tension-type-like pain, cutaneous allodynia, and reduced pain threshold. A paradigm change in the definition of chronic migraine moves far beyond the mere 8 vs. 15 days/month, but has ethical and practical implications for treatment: should patients be treated with the most effective prophylactic drugs, i.e., monoclonal antibodies (MABs), if they enter into a new definition of CM? How should clinicians deal with treatment escalation towards MABs? What is the role of associated conditions, response to treatments, lifestyle issues, and psychological factors? And, finally, which endpoint should we use to define effectiveness? Is improvement in headache frequency enough, or should we move towards disability, quality of life, or workplace productivity?

Chronic low back pain (cLBP) impacts millions of adults annually. Several nonsurgical interventions are recommended for treating this condition, however, limited literature exists regarding the impact patient-led goals may have on outcomes in the treatment of cLBP. The purpose of this narrative review is to identify gaps and synthesize literature examining the associations of patient-led goals combined with care for cLBP. A total of 12 studies were reviewed and findings were synthesized. Patient-led goal setting may serve as an effective intervention for adults with cLBP. Current outcome measures may not align with patient-led goals. Further investigation is required to understand patient-led goals with ancillary treatments and specific age groups, such as adults over age 65.

Neuropathic pain (NP) is a chronic condition that affects ~ 1% of the general population globally. Several conditions such as chronic diabetes, herpes zoster (HZ), cancer, HIV, stroke, multiple sclerosis, physical compression or damage of nerves and certain surgical procedures can lead to neuropathy and related pain. The condition is difficult to treat with traditional analgesic drugs. Typically, non-traditional analgesics are used in treating pain in this condition such as antidepressants and antiepileptic drugs. Opioids are useful in some patients, but the risk of addiction and the risk of both short-term and long-term adverse effects make it a low priority drug class in the treatment of NP. In the current review we discuss the pharmacology and pharmaceutical care aspects of various classes of drugs used in the treatment of NP, counselling points for these drug classes, and future prospects in the treatment of NP.

Spinal cord injuries incite varying degrees of symptoms in patients, ranging from weakness and incoordination to paralysis. Common amongst spinal cord injury (SCI) patients, neuropathic pain (NP) is a debilitating medical condition. Unfortunately, there remain many clinical impediments in treating NP because there is a lack of understanding regarding the mechanisms behind SCI-induced NP (SCINP). Given that more than 450,000 people in the United States alone suffer from SCI, it is unsatisfactory that current treatments yield poor results in alleviating and treating NP.

Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.

Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain. However, whether such processing is associated with neuronal and/or synaptic plasticity is still unknown. We addressed this issue in a chronic facial inflammatory pain model (complete Freund's adjuvant model) in rats, by combining behavior, Fos protein immunochemistry and ex vivo intracellular recordings in rACC slices prepared from these animals. Facial mechanical allodynia occurs immediately after CFA injection, peaks at post-injection day 3 and progressively recovers until post-injection days 10-11, whereas anxiety is delayed, being present at post-injection day 10, when sensory hypersensitivity is relieved, but, notably, not at post-injection day 3. Fos expression reveals that neuronal activity follows a bi-phasic time course in bilateral rACC: first enhanced at post-injection day 3, it gets strongly depressed at post-injection day 10. Ex vivo recordings from lamina V pyramidal neurons, the rACC projecting neurons, show that both their intrinsic excitability and excitatory synaptic inputs have undergone long-term depression (LTD) at post-injection day 10. Thus chronic pain processing is associated with dynamic changes in rACC activity: first enhanced and subsequently decreased, at the time of anxiety-like behavior. Chronic pain-induced anxiety might thus result from a rACC deactivation-cACC hyperactivation interplay.

This meta-analysis compared pressure pain sensitivity in trigeminal, cervical spine and remote pain-free areas between migraine patients and headache-free controls considering diagnosis (episodic versus chronic) and sex. Electronic databases were searched for cross-sectional or prospective case-control studies comparing pressure pain thresholds between migraine and headache-free controls. Data were extracted by two reviewers. The risk of bias and methodological quality was assessed by Newcastle-Ottawa Quality Assessment Scale. Meta-analyses of trigeminal, extra-trigeminal (cervical spine) and remote pain-free areas were compared. Frequency of migraine and sex were taken into account. Mean differences (MD) and random effects were calculated.

Nav1.3, encoded by the SCN3A gene, is a voltage-gated sodium channel on the cell membrane. It is expressed abundantly in the fetal brain but little in the normal adult brain. It is involved in the generation and conduction of action potentials in excitable cells. Nav1.3 plays an important role in many neurological diseases. The aim of this review is to summarize new findings about Nav1.3 in the field of neurology. Many mutations of SCN3A can lead to neuronal hyperexcitability and then cause epilepsy. The rapid recovery from inactivation and slow closed-state inactivation kinetics of Nav1.3 leads to a reduced activation threshold of the channel and a high frequency of firing of neurons. Hyperactivity of Nav1.3 also induces increased excitability of sensory neurons, a lower nociceptive threshold, and neuropathic pain. This review summarizes the structure and the function of Nav1.3 and focuses on its relationship with epilepsy and neuropathic pain.

Multimorbidity (multiple coexisting chronic health conditions) is common and increasing worldwide, and makes care challenging for both patients and healthcare systems. To ensure care is patient-centred rather than specialty-centred, it is important to know which conditions commonly occur together and identify the corresponding patient profile. To date, no studies have described multimorbidity clusters within an unselected hospital population. Our aim was to identify and characterise multimorbidity clusters, in a large, unselected hospitalised patient population. Linked inpatient hospital episode data were used to identify adults admitted to hospital in Grampian, Scotland in 2014 who had ≥ 2 of 30 chronic conditions diagnosed in the 5 years prior. Cluster analysis (Gower distance and Partitioning around Medoids) was used to identify groups of patients with similar conditions. Clusters of conditions were defined based on clinical review and assessment of prevalence within patient groups and labelled according to the most prevalent condition. Patient profiles for each group were described by age, sex, admission type, deprivation and urban-rural area of residence. 11,389 of 41,545 hospitalised patients (27%) had ≥ 2 conditions. Ten clusters of conditions were identified: hypertension; asthma; alcohol misuse; chronic kidney disease and diabetes; chronic kidney disease; chronic pain; cancer; chronic heart failure; diabetes; hypothyroidism. Age ranged from 51 (alcohol misuse) to 79 (chronic heart failure). Women were a higher proportion in the chronic pain and hypothyroidism clusters. The proportion of patients from the most deprived quintile of the population ranged from 6% (hypertension) to 14% (alcohol misuse). Identifying clusters of conditions in hospital patients is a first step towards identifying opportunities to target patient-centred care towards people with unmet needs, leading to improved outcomes and increased efficiency. Here we have demonstrated the face validity of cluster analysis as an exploratory method for identifying clusters of conditions in hospitalised patients with multimorbidity.

The endocannabinoid system (ECS) influences many biological functions, and hence, its pharmacological modulation may be useful for several disorders, such as migraine. Preclinical studies have demonstrated that the ECS is involved in the modulation of trigeminal excitability. Additionally, clinical data have suggested that an endocannabinoid deficiency is associated with migraine. Given these data, phytocannabinoids, as well as synthetic cannabinoids, have been tried as migraine treatments. In this narrative review, the current clinical evidence of potential ECS involvement in migraine pathogenesis is summarized. Furthermore, studies exploring the clinical effects of phytocannabinoids and synthetic cannabinoids on migraine patients are reviewed.

A newly developed specialized psychosocial aftercare program (PAC) for pediatric patients with chronic pain following an intensive interdisciplinary pain treatment (IIPT) was found to be significantly more effective than IIPT alone. This qualitative study aimed to gain further insight into the mechanisms and prerequisites for the effectiveness of this specialized aftercare program. We conducted structured telephone interviews with patients, parents, and health care professionals conducting PAC. A total of 16 interviews were conducted-seven interviews with parents, six interviews with patients, and three interviews with health care professionals-and transcribed verbatim. Data were analyzed using reflexive thematic analysis. Four major themes consisting of 20 subcategories were identified, namely (1) frame conditions, (2) person factors, (3) stabilization and (4) catalyst. The foundations of treatment success are frame conditions, such as flexibility or constancy, and person factors, such as respect or expertise. Based on these foundations, stabilization is achieved through security, mediation, orientation and support. Altogether, these components of PAC reveal their potential as catalysts for further improvement even after discharge from IIPT. Overall, patients and their families emphasized widespread personal relevance and acceptance of the PAC program. The findings of this study may be employed in the development of other aftercare programs or interventions involving families in the context of psychotherapeutic and psychosocial health care.

Recently, a growing body of evidence has emerged regarding the interplay between microbiota and the nervous system. This relationship has been associated with several pathological conditions and also with the onset and regulation of pain. Dysregulation of the axis leads to a huge variety of diseases such as visceral hypersensitivity, stress-induced hyperalgesia, allodynia, inflammatory pain and functional disorders. In pain management, probiotics have shown promising results. This narrative review describes the peripheral and central mechanisms underlying pain processing and regulation, highlighting the role of the gut-brain axis in the modulation of pain. We summarized the main findings in regard to the stress impact on microbiota's composition and its influence on pain perception. We also focused on the relationship between gut microbiota and both visceral and inflammatory pain and we provided a summary of the main evidence regarding the mechanistic effects and probiotics use.

How should endometriosis be diagnosed and managed based on the best available evidence from published literature?

Stratified approaches to spinal pain that address psychosocial risk factors reduce long-term disability to a moderate extent. Identifying and managing other risk factors might help improve outcomes.

For many medical conditions, clinicians can collect quantitative indicators of disease, such as heart rate, body temperature, or levels of a specific protein in a blood sample. For chronic pain, however, such biological markers have not yet been identified. This information gap occurs even though chronic pain is one of the most common reasons why adults seek medical care [1]. If they could be identified, biological markers (or "biomarkers") for chronic pain could improve patient care by giving doctors a more complete picture of a particular patient's condition.

Tacrolimus is associated with optic neuropathy. The clinical features of tacrolimus-induced optic neuropathy (TION) are unclear. The purpose of this article is to explore the clinical features of TION.

Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.

Pain is a distressing, subjective and complex phenomenon that all nurses will encounter in their clinical practice. Effective pain management requires nurses to undertake a structured assessment to identify the probable causes of pain and guide management. Interventions used to reduce pain can be varied and multimodal. This article provides an overview of pain including its definition, classifications, assessment and management. It emphasises the importance of a person-centred approach to care which reflects Margo McCaffery's seminal quote that pain is 'whatever the experiencing person says it is'.

Migraine frequency increases after the cessation of successful preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs). In this study, we aimed to evaluate the course of migraine after treatment resumption.

To determine the extent to which quantitative sensory testing (QST) predicted attrition in an interdisciplinary pain program (IPP). Participants (n = 53) enrolled in an IPP completed pretreatment assessments of QST and the PROMIS-29 quality of life survey. Compared with completers, non-completers (24.5%) reported significantly higher pain intensity (7.1, 95% CI [5.8, 8.4] versus 5.4, 95% CI [4.8, 6.1]) and cold hyperalgesia (14.6°C, 95% CI [8.8, 20.4] versus 7.5°C, 95% CI [4.8, 6.1]), with both variables also predicting attrition. This finding highlights a potentially novel and clinically significant use of QST. Higher overall pain intensity and the presence of remote cold hyperalgesia may identify patients at risk for dropping out of an IPP.

Epidural stimulation of the motor cortex (eMCS) was devised in the 1990s, and has now largely supplanted thalamic stimulation for neuropathic pain relief. Its mechanisms of action involve activation of multiple cortico-subcortical areas initiated in the thalamus, with involvement of endogenous opioids and descending inhibition toward the spinal cord. Evidence for clinical efficacy is now supported by at least 7 RCTs; benefits may persist up to 10 years, and can be reasonably predicted by preoperative use of non-invasive repetitive magnetic stimulation (rTMS). rTMS first developed as a means of predicting the efficacy of epidural procedures, then as an analgesic method on its own right. Reasonable evidence from at least 6 well-conducted RCTs favours a significant analgesic effect of high-frequency rTMS of the motor cortex in neuropathic pain (NP), and less consistently in widespread/fibromyalgic pain. Stimulation of the dorsolateral frontal cortex (DLPFC) has not proven efficacious for pain, so far. The posterior operculo-insular cortex is a new and attractive target but evidence remains inconsistent. Transcranial direct current stimulation (tDCS) is applied upon similar targets as rTMS and eMCS; it does not elicit action potentials but modulates the neuronal resting membrane state. tDCS presents practical advantages including low cost, few safety issues, and possibility of home-based protocols; however, the limited quality of most published reports entails a low level of evidence. Patients responsive to tDCS may differ from those improved by rTMS, and in both cases repeated sessions over a long time may be required to achieve clinically significant relief. Both invasive and non-invasive procedures exert their effects through multiple distributed brain networks influencing the sensory, affective and cognitive aspects of chronic pain. Their effects are mainly exerted upon abnormally sensitised pathways, rather than on acute physiological pain. Extending the duration of long-term benefits remains a challenge, for which different strategies are discussed in this review.

During the COVID-19 pandemic, social distancing has been employed to decrease the spread of COVID-19, especially within the geriatric population; however, the resulting loneliness and isolation carry their own detrimental effects. Loneliness resulting from the COVID-19 pandemic may also have negative implications on those with chronic musculoskeletal pain.

Despite the overwhelming female-predominance in chronic pain disorders, preclinical pain studies have historically excluded females as research subjects. Male-biased explanations of pathological pain mechanisms may not fully translate to pain processes in females, necessitating the exploration of pain processing and modulation in both sexes at the preclinical and clinical levels. This review highlights historical trends in the study of sex differences within the pain field and examines the current literature regarding new techniques for the mechanistic analysis of pain modulation in males and females. A large body of evidence suggests that sex differences exist at the molecular, cellular, and systems levels of pain processing, likely influenced by a combination of genetic, hormonal, and neuroimmune factors that may differ at distinct levels of the neuraxis.

Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management.

The opioid use disorder is an international public health problem. Over the past 20 years it has been the subject of numerous publications concerning patients treated for chronic pain other than cancer-related. Patients with cancer-related pain are also at risk of opioid use disorder. The primary objective of this literature review was to determine the prevalence of opioid use disorder in patients with cancer-related chronic pain. Its secondary objective was to identify the characteristics of these opioid users.

Fibromyalgia syndrome (sFM) is one of the most common causes of chronic pain. This study aimed to assess the presence of small and large fiber impairment in fibromyalgic patients by applying validated scores used in the screening for diabetic neuropathy. The endpoints for the study were the assessment of neuropathy prevalence in sFM patients using the NerveCheck Master (NCM), the Michigan Neuropathy Screening Instrument (MNSI), the Diabetic Neuropathy Symptom (DNS) and the Douleur Neuropathique 4 Questions (DN4). The sample was composed of 46 subjects: subjects with sFM ( = 23) and healthy controls (HC) ( = 23). The positivity rates in each group for DN4 were significantly different ( < 0.001), with a prevalence in symptomatic subjects of 56.3% ( = 9) among sFM individuals. A similar difference was also observed with the DNS total score ( < 0.001). NCM and MNSI did not disclose significant differences between the two groups. This finding seems to confirm the data regarding the prevalence of a neuropathic pain in sFM patients.