Papers: 23 Apr 2022 - 29 Apr 2022

Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch-conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders.

Rapid reduction or discontinuation of long-term opioid therapy may increase risk of opioid overdose or opioid use disorder (OUD). Current guidelines for chronic pain management caution against rapid dose reduction but are based on limited evidence.

Trigeminal neuralgia (TN) is a rare but debilitating disorder characterized by excruciating facial pain, with a higher incidence in women. Recent studies demonstrated that TN patients present mutations in the gene encoding the CaV3.2 T-type calcium channel, an important player in peripheral pain pathways. Here we characterize the role of CaV3.2 channels in TN at two levels. First, we examined the biophysical properties of CACNA1H variants found in TN patients. Second, we investigated the role of CaV3.2 in an animal model of trigeminal neuropathic pain. Whole cell patch clamp recordings from four different mutants expressed in tsA-201 cells (E286K in the pore loop of domain I, H526Y, G563R and P566T in the domain I-II linker) identified a loss-of-function in activation in the E286K mutation and gain-of-function in the G563R and P566T mutations. Moreover, a loss-of-function in inactivation was observed with the E286K and H526Y mutations. Cell surface biotinylation revealed no difference in channel trafficking among the variants. The G563R mutant also caused a gain-of-function in the firing properties of transfected trigeminal ganglion neurons. In female and male mice, constriction of the infraorbital nerve (CION) induced facial thermal heat hyperalgesia. Block of T-type channels with Z944 resulted in antihyperalgesia. The effect of Z944 was absent in CaV3.2-/- mice, indicating that CaV3.2 is the molecular target of the antihyperalgesic Z944 effect. Finally, ELISA analysis revealed increased CaV3.2 channel expression in the spinal trigeminal subnucleus caudalis. Altogether, the present study demonstrates an important role of CaV3.2 channels in trigeminal pain.

This case-control study examines if measures of subjective and objective (actigraphic) sleep difficulties mediate alterations in amygdalar connectivity in adolescents with migraine compared to healthy adolescents.

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors-a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

Chronic pain and insomnia are highly comorbid: Approximately 50% of those with chronic pain experience insomnia or clinically significant sleep disturbances, and 50% of those with insomnia experience chronic pain. Further, these conditions can be extremely disabling, particularly when they co-occur. There is increasing recognition of the need to tackle both chronic pain and insomnia together, as evidenced by growing empirical research in this area. Cognitive processing biases have been independently implicated in both chronic pain and in insomnia. Given their trans-diagnostic status, cognitive biases may therefore have a role in explaining the co-occurrence and mutual maintenance of these conditions. These biases also represent novel, potentially modifiable targets for treatment. However, the role of cognitive biases has not been adequately explored in comorbid chronic pain and insomnia. Here, we describe the state of cognitive bias research in chronic pain and insomnia, considering evidence for the roles of attentional bias, interpretation bias, expectancy bias, and memory bias. In reviewing the literature, it is apparent that similar cognitive biases operate in insomnia and chronic pain, with preliminary, albeit sparse, evidence of pain-related cognitive biases influencing sleep-related outcomes. On the basis of current findings and separate theoretical models, we present a novel, testable cognitive model of comorbid chronic pain and insomnia, to guide future research in this area. Key recommendations for the future of this relatively new field are provided. PERSPECTIVE: : Chronic pain and insomnia are highly co-morbid, suggesting an overlap in causal mechanisms. Empirical research, although sparse, suggests that cognitive biases may play a role in their development and mutual maintenance. Our novel cognitive model generates research avenues of clinical importance for treating co-morbid chronic pain and insomnia.

Despite the involvement of subcortical brain structures in the pathogenesis of classic trigeminal neuralgia (CTN), the details of morphological abnormalities of basal ganglia to this disorder are still unknown. This study aimed to investigate potential changes in terms of volume and shape of subcortical regions in patients with CTN.

Evidence-based medicine is replete with studies assessing quality and bias, but few evaluating research integrity or trustworthiness. A recent Cochrane review of psychological interventions for chronic pain identified trials with a shared lead author with highly divergent results. We sought to systematically identify all similar trials from this author to explore their risk of bias, governance procedures, and trustworthiness.We searched OVID MEDLINE, EMBASE, CENTRAL and PEDro to 22/12/2021 for trials. We contacted the authors requesting details of trial registration, ethical approval, protocol, and access to the trial data for verification. We used the Cochrane Risk of Bias tool and the Cochrane Pregnancy and Childbirth group's Trustworthiness Screening Tool to guide systematic exploration of trustworthiness.Ten trials were included: nine compared cognitive behavioural therapy (CBT) and physical exercise to usual care, exercise alone, or physiotherapy, and one compared two brief CBT programmes. Eight trials reported results divergent from the evidence base. Assessment of risk of bias and participant characteristics identified no substantial concerns. Responses from the lead author did not satisfactorily explain this divergence. Trustworthiness screening identified concerns about research governance, data plausibility at baseline, the results, and apparent data duplication.We discuss the findings within the context of methods for establishing the trustworthiness of research findings generally. Important concerns regarding the trustworthiness of these trials reduce our confidence in them. They should probably not be used to inform the results and conclusions of systematic reviews, in clinical training, policy documents, or any relevant instruction regarding adult chronic pain management.

Whole-body vibration (WBV) appears to modulate reflex hyperexcitability and spasticity. Due to common underlying neural mechanisms between spasticity and neuropathic pain, WBV may also reduce chronic pain after spinal cord injury (SCI). Our objective was to determine whether there are dose-related changes in pain following WBV and to examine the relationships between neuropathic pain and reflex excitability.

Poor access to care is a top patient-oriented research priority for youth with chronic pain in Canada, and the COVID-19 pandemic has exacerbated these concerns. Our patient-oriented project team engaged with marginalized and racialized youth with chronic pain (Black youth with sickle cell disease, Indigenous youth and youth with complex medical needs) and their families to ensure that best practice recommendations for virtual care are inclusive and equitable. Input provided through virtual round-table discussions improved recommendations for leveraging, implementing and selecting best platforms for virtual care for youth with chronic pain and identified new gaps for future research, practice and policy change.

Our original patient-oriented research project identified the top 10 priorities for pediatric chronic pain research and care in Canada from the perspective of people with lived experience (patients), their family members and healthcare professionals through a modified James Lind Alliance Priority Setting Partnership. We undertook subsequent knowledge translation activities with youth, families, healthcare professionals, decision makers and researchers to (1) generate awareness and interest in the top 10 priorities and our partnership process, (2) facilitate collaborative dialogue and open innovation and (3) integrate and adopt the top 10 priorities into stakeholder activities. This paper describes our knowledge translation activities, outcomes and impact.

Despite the importance of pain management across specialties and the effect of poor management on patients, many physicians are uncomfortable managing pain. This may be related, in part, to deficits in graduate medical education (GME).

Somatostatin-positive (SOM) neurons have been proposed as one of the key populations of excitatory interneurons in the spinal dorsal horn involved in mechanical pain. However, the molecular mechanism for their role in pain modulation remains unknown. Here, we showed that the T-type calcium channel Cav3.2 was highly expressed in spinal SOM interneurons. Colocalization of (which codes for Cav3.2) and SOM was observed in the hybridization studies. Fluorescence-activated cell sorting of SOM cells in spinal dorsal horn also proved a high expression of in SOM neurons. Behaviorally, virus-mediated knockdown of in spinal SOM neurons reduced the sensitivity to light touch and responsiveness to noxious mechanical stimuli in naïve mice. Furthermore, knockdown of in spinal SOM neurons attenuated thermal hyperalgesia and dynamic allodynia in the complete Freund's adjuvant-induced inflammatory pain model, and reduced both dynamic and static allodynia in a neuropathic pain model of spared nerve injury. Mechanistically, a decrease in the percentage of neurons with Aβ-eEPSCs and Aβ-eAPs in superficial dorsal horn was observed after knockdown in spinal SOM neurons. Altogether, our results proved a crucial role of Cav3.2 in spinal SOM neurons in mechanosensation under basal conditions and in mechanical allodynia under pathological pain conditions. This work reveals a molecular basis for SOM neurons in transmitting mechanical pain and shows a functional role of Cav3.2 in tactile and pain processing at the level of spinal cord in addition to its well-established peripheral role.

The auxiliary αδ subunits of voltage-gated calcium (Ca) channels are key to augmenting expression and function of Ca1 and Ca2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The αδ proteins are translated as preproteins encoding both α and δ, and post-translationally proteolyzed into α and δ subunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-αδ-1 and αδ-3 subunits. We provide three lines of evidence: First, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Second, proteolytic cleavage of both αδ-1 and αδ-3 is markedly reduced in cell lines by knockout of but not . Third, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature αδ is essential for the enhancement of Ca function, and in agreement, knockout of ADAM17 inhibited the ability of αδ-1 to enhance both Ca2.2 and Ca1.2 calcium currents. Finally, our data also indicate that the main site of proteolytic cleavage of αδ-1 is the Golgi apparatus, although cleavage may also occur at the plasma membrane. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of αδ-1 and αδ-3, and thus a potential drug target in neuropathic pain.

Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients' quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication.

The risk of COVID-19 in those with chronic pain is unknown. We investigated whether self-reported chronic pain was associated with COVID-19 hospitalisation or mortality. UK Biobank recruited 502,624 participants aged 37-73 years between 2006-2010. Baseline exposure data, including chronic pain (>3 months, in at least 1 of 7 pre-specified body sites) and chronic widespread pain (>3 months, all over body), were linked to COVID-19 hospitalisations/mortality. Univariable/multivariable Poisson regression analyses were performed on the association between chronic pain and COVID-19 hospitalisation, and Cox regression analyses of the associations with COVID-19 mortality. Multivariable analyses adjusted incrementally for sociodemographic confounders, then lifestyle risk factors, and finally long-term condition (LTC) count. Of 441,403 UK Biobank participants with complete data; 3,180 (0.7%) were hospitalised for COVID-19; 1,040 (0.2%) died from COVID-19. Chronic pain was associated with hospital admission for COVID-19 even after adjustment for all covariates (IRR 1.16; 95% CI 1.08 to 1.24; p<0.001), as was chronic widespread pain (IRR 1.33; 95% CI 1.06 to 1.66; p=0.012). There was clear evidence of a dose-response relationship with number of pain sites (fully adjusted global p-value<0.001). After adjustment for all covariates there was no association between chronic pain (HR 1.01; 95% CI 0.89 to 1.15; p=0.834) but attenuated association with chronic widespread pain (HR 1.50, 95% CI 1.04-2.16, p-value=0.032) and COVID-19 mortality.Chronic pain is associated with higher risk of hospitalisation for COVID-19 but the association with mortality is unclear. Future research is required to investigate these findings further and determine whether pain is associated with long-COVID.

Feasibility study, consisting of random-order, cross-over study of a single intervention session, followed by a parallel-arm study of 16 sessions.

We explore recent developments in the prevention and treatment of migraine through dietary interventions.

Headache is a common presentation of postural tachycardia syndrome, yet robust prevalence data is lacking.

The objective of this study is to characterize the effects of the sleep-wake cycle on neurovascular and behavioral characteristics of cortical spreading depression (CSD).

Neuropathic pain is a complex condition that can be refractory to conventional management and can cause persistent suffering in patients. Current pharmacologic treatments can provide temporary symptomatic relief; however, the mechanism of these therapies does not address the underlying cause of neuropathic pain. The use of injectable biologics for neuropathic pain has multiple proposed mechanisms for analgesia including attenuation of inflammatory mediated processes, arrest or delay of the degenerative process, inhibition of apoptotic pathways, and augmentation of the survival and recovery of injured and uninjured nerves.

This systematic review was conducted to evaluate the best available evidence regarding the use of non-invasive neuromodulation techniques for managing chemotherapy-induced peripheral neuropathy (CIPN).

To develop and validate a diagnostic prediction model that can distinguish between juvenile idiopathic arthritis (JIA) and chronic musculoskeletal pain syndromes (CMPS based on patient-reported outcomes.

Chronic pain (CP) represents a socio-economic burden for affected patients along with therapeutic challenges for currently available therapies. When conventional therapies fail, modulation of the affective pain matrix using reversible deep brain stimulation (DBS) or targeted irreversible thalamotomy by stereotactic radiosurgery (SRS) and magnetic resonance (MR)-guided focused ultrasound (MRgFUS) appear to be considerable treatment options. We performed a literature search for clinical trials targeting the affective pain circuits (thalamus, anterior cingulate cortex [ACC], ventral striatum [VS]/internal capsule [IC]). PubMed, Ovid, MEDLINE and Scopus were searched (1990-2021) using the terms "chronic pain", "deep brain stimulation", "stereotactic radiosurgery", "radioneuromodulation", "MR-guided focused ultrasound", "affective pain modulation", "pain attention". In patients with CP treated with DBS, SRS or MRgFUS the somatosensory thalamus and periventricular/periaquaeductal grey was the target of choice in most treated subjects, while affective pain transmission was targeted in a considerably lower number (DBS, SRS) consisting of the following nodi of the limbic pain matrix: the anterior cingulate cortex; centromedian-parafascicularis of the thalamus, pars posterior of the central lateral nucleus and internal capsule/ventral striatum. Although DBS, SRS and MRgFUS promoted a meaningful and sustained pain relief, an effective, evidence-based comparative analysis is biased by heterogeneity of the observation period varying between 3 months and 5 years with different stimulation patterns (monopolar/bipolar contact configuration; frequency 10-130 Hz; intensity 0.8-5 V; amplitude 90-330 μs), source and occurrence of lesioning (radiation versus ultrasound) and chronic pain ethology (poststroke pain, plexus injury, facial pain, phantom limb pain, back pain). The advancement of neurotherapeutics (MRgFUS) and novel DBS targets (ACC, IC/VS), along with established and effective stereotactic therapies (DBS-SRS), increases therapeutic options to impact CP by modulating affective, pain-attentional neural transmission. Differences in trial concept, outcome measures, targets and applied technique promote conflicting findings and limited evidence. Hence, we advocate to raise awareness of the potential therapeutic usefulness of each approach covering their advantages and disadvantages, including such parameters as invasiveness, risk-benefit ratio, reversibility and responsiveness.

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g., anesthesia, sleep-disordered breathing, concurrent drug administration) add to the risk. Multiple sites can independently exert a depressive effect on breathing, making it unclear which sites are necessary for the induction of OIRD. The generator of inspiratory rhythm is the preBötzinger complex (preBötC) in the ventrolateral medulla. Other important brainstem respiratory centres include the pontine Kölliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of μ opioid receptors from neurons showed that the preBötC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBötC as inspiratory rhythm generator. Glutamatergic neurons expressing NK-1R and somatostatin involved in the autonomic function of breathing, and modulatory signal pathways involving GIRK and KCNQ potassium channels, remain poorly understood. Reversal of OIRD has relied heavily on naloxone which also reverses analgesia but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid OIRD. Maternal opioid use, which is rising, increases apneas and destabilizes neonatal breathing but opioid effects on maternal and neonatal respiratory circuits in neonatal abstinence syndrome (NAS) are not well understood. Methadone, administered to alleviate symptoms of NAS in humans, desensitizes rats to RD.

Deficits in proprioception and postural control are common in patients with different musculoskeletal pain syndromes. It has been proposed that pain can negatively affect proprioception and postural control at a peripheral level, however research is limited to animal studies. Human studies have shown that it is more likely, that the link between pain and proprioceptive deficits, lies within changes in the central nervous system where noxious and non-noxious stimuli may overlap. In clinical studies, causality cannot be determined due to other factors which could confound the assessment such as pathophysiological features of the underlying musculoskeletal disorder and different psycho-social influences especially in patients with chronic pain. On the other hand, experimentally induced pain in healthy participants is able to control most of these confounding factors and perhaps offers an assessment of the effects of pain on proprioception and postural control. The aim of this paper is to critically appraise the literature related to the effect of experimentally induced pain on proprioception and postural control. Results from these studies are discussed and limitations are highlighted for future research.

To assess the associations between pain severity or physical (pQoL) and mental (mQoL) health-related quality of life and disability status or health-care utilization among persons living with moderate/severe pain due to chronic low back pain (CLBP) or osteoarthritis (OA), who received treatments in Quebec's tertiary care pain centers.

Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.

Abdominal pain frequently co-occurs with pain in other body sites. Chronic overlapping pain conditions (COPCs) represent a group of widespread pain diagnoses. Our study characterized how patterns of somatic pain distribution are associated with COPCs and aimed to characterize predictors of widespread pain among patients with chronic abdominal pain.

Migraine is a leading cause of disability among the adult population and is a significant burden on the economies of the world. Studies into the underlying causes of migraine have spanned centuries but its underlying mechanisms are still not fully understood. In recent years, accumulating evidence implicates that microbiota-mediated gut-brain crosstalk may contribute to the pathogenesis of migraine. This review provides a brief account of the history of migraine theories and summarizes the recent studies showing how gut microbiota is involved in the pathophysiology of migraine. Future research perspectives for better understanding the role of the gut microbiota in migraine are also discussed.

Neurovascular compression (NVC) is considered as the main factor leading to the classical trigeminal neuralgia (CTN), and a part of idiopathic TN (ITN) may be caused by NVC (ITN-nvc). This study aimed to explore the risk factors for unilateral CTN or ITN-nvc (UC-ITN), which have bilateral NVC, using machine learning (ML).

Neuropathic pain can be defined as pain related to abnormal somatosensory processing in either the peripheral or central nervous system. In this review article, with neuropathic cancer pain (NCP), we refer to pain due to nervous tissue lesions caused by the tumor or its metastases. Nervous tissue damage is the cause of cancer pain in approximately 40% of those experiencing cancer pain. Recognizing a neuropathic pathophysiology in these cases may be difficult and requires specific criteria that are not homogenously applied in clinical practice. The management of this type of pain can be challenging, requiring the use of specific non-opioid adjuvant drugs. The majority of the criteria for NCP diagnosis and management have been based mainly on results from the noncancer population, risking the failure of addressing the specific needs of this population of patients. In this review, we summarize current management options available for NCP and provide some insights on new promising treatments.

Percutaneous balloon compression (PBC) is a popular treatment option for trigeminal neuralgia. However, the efficacy of PBC is widely considered to be associated with the occurrence of sensitive complications, although neither this correlation nor the underlying mechanisms have been established. The objectives of the present study were to identify factors predicting time to pain recurrence after PBC and identify factors predicting a severe sensitive complication.

Social touch-the affiliative skin-to-skin contact between individuals-can rapidly evoke emotions of comfort, pleasure, or calm, and is essential for mental and physical well-being. Physical isolation from social support can be devastating. During the COVID-19 pandemic, we observed a global increase in suicidal ideation, anxiety, domestic violence, and worsening of pre-existing physical conditions, alerting society to our need to understand the neurobiology of social touch and how it promotes normal health. Gaining a mechanistic understanding of how sensory neuron stimulation induces pleasure, calm, and analgesia may reveal untapped therapeutic targets in the periphery for treatment of anxiety and depression, as well as social disorders and traumas in which social touch becomes aversive. Bridging the gap between stimulation in the skin and positive affect in the brain-especially during naturally occurring social touch behaviors-remains a challenge to the field. However, with advances in mouse genetics, behavioral quantification, and brain imaging approaches to measure neuronal firing and neurochemical release, completing this mechanistic picture may be on the horizon. Here, we summarize some exciting new findings about social touch in mammals, emphasizing both the peripheral and central nervous systems, with attempts to bridge the gap between external stimulation and internal representations in the brain.

Research indicates a complex nexus between chronic pain, depression, anxiety, and somatic amplification (PDAS) symptoms, marked by high rates of co-morbidity and mutually maintaining mechanisms. Although recent frameworks have attempted to explain co-occurrence rates of pain and other comorbid disorders, the interrelations between PDAS and their impacts on pain outcomes have not been adequately examined with a person-centered approach. Using nationally representative data, this study assessed the heterogeneity in PDAS symptomatology and examined links among risk and protective factors in different profiles.

The Spanish health authorities are concerned by the off-label use of immediate-release formulations of fentanyl (IRF) in noncancer pain and cancer pain in patients with no chronic pain therapy. To evaluate the impact of different interventions to improve appropriateness of IRF prescription on off-label prescription. We used interrupted time series (ITS) to estimate immediate and trend changes of IRF prescription for noncancer pain (NCP) and breakthrough cancer pain (BCP) in patients with and without chronic cancer pain therapy associated with two medication reviews (I1 and I2) and the issue of a safety warning letter (I3) with data from a Spanish region with 5 million inhabitants, from 2015 to 2018. The use of IRF for NCP in the region Valencia was reduced from about 1,800 prescriptions per week to around 1,400. The first medication review was followed by an immediate level change of -192.66 prescriptions per week ( < 0.001) and a downward trend change of -6.75 prescriptions/week ( < 0.001), resulting in a post-intervention trend of -1.99 ( < 0.001). I2 was associated with a trend change of -23.07 ( < 0.001) prescriptions/week. After I3, the trend changed markedly to 27.23 additional prescriptions/week, for a final post-intervention trend of 2.17 ( < 0.001). Controlled-ITS provided comparable results. For potentially inappropriate BCP use, the second medication review was followed by a downward, immediate level change of -10.10 prescriptions/week ( = 0.011) and a trend change of 2.31 additional prescriptions/week ( < 0.001) and the issue of the safety warning (I3) was followed by a downward trend change of -2.09 prescriptions/week ( = 0.007). Despite IRF prescription for NCP decreased, the interventions showed modest and temporary effect on off-label prescription. Our results call for a review of the design and implementation of safety interventions addressing inappropriate opioid use.

We do not yet know whether or the extent to which multimodal therapy changes the health behaviors and health service use of chronic headache patients in the long term. Associations are expected between pain symptoms and pain management abilities for patients who are categorized as successfully treated and those who remain unchanged.

The present meta-analysis analyzed the efficacy and safety of wrist-ankle acupuncture (WAA) as an additional therapy for postoperative multimodal analgesia following orthopedic surgery.

Despite the well-known efficacy of spinal cord stimulation (SCS) in chronic pain management, patient selection in clinical practice remains challenging. The aim of this review is to provide an overview of the factors that can influence the process of patient selection for SCS treatment. A sequential decision-making model is presented within a tier system that operates in clinical practice. The first level incorporates the underlying disease as a primary indication for SCS, country-related reimbursement rules, and SCS screening-trial criteria in combination with underlying psychological factors as initial selection criteria in evaluating patient eligibility for SCS. The second tier is aligned with the individualized approach within precision pain medicine, whereby individual goals and expectations and the potential need for preoperative optimizations are emphasized. Additionally, this tier relies on results from prediction models to provide an estimate of the efficacy of SCS in the long term. In the third tier, selection bias, MRI compatibility, and ethical beliefs are included, together with recent technological innovations, superiority of specific stimulation paradigms, and new feedback systems that could indirectly influence the decision-making of the physician. Both patients and physicians should be aware of the different aspects that influence patient selection in relation to SCS for pain management to make an independent decision on whether or not to initiate a treatment trajectory with SCS.

To investigate the literature in terms of describing new ways to organize pain treatment for patients with chronic nonmalignant pain and the effect on opioid consumption.

We thank Dr. Jensen for his interest […].

Acupuncture is an analgesic technique that has long been utilized in Eastern medicine. In recent times, various acupuncture techniques have been used in integrated pain management approaches in Western medicine. It has even been adopted as an analgesic method in surgical patients. Currently, no review exists regarding various acupuncture techniques used in perioperative pain management and data describing the utility of these techniques. This paper synthesizes the latest literature regarding the role of acupuncture in perioperative pain management. The authors sought to describe various acupuncture modalities used to help manage surgical pain and synthesize the current body of literature to help readers make informed judgements on the topic.

This article presents differences in clinical characteristics based on a simple self-report method of classifying pain mechanisms for Urologic Chronic Pelvic Pain Syndrome patients. This method can be easily applied to other chronic pain conditions and may be useful for exploring pathophysiology in pain subtypes.

Disorders of the gut-brain interaction negatively impact quality of life and carry a substantial socioeconomic burden. Irritable bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) are common functional abdominal pain disorders in childhood. The pathophysiology is not fully understood, and high-quality intervention trials and international guidelines are missing. Therefore, the management of these disorders remains challenging. This review aims to provide an up-to-date overview of therapeutic possibilities for pediatric IBS or FAP-NOS and recommends management strategies. To prevent unnecessary referrals and extensive costs, it is fundamental to make a positive diagnosis of IBS or FAP-NOS in children with chronic abdominal pain with only minimal investigations. A tailor-made approach for each patient, based on the accompanying physical and psychological symptoms, is proposed to date.

Capsaicin is a natural compound found in chili peppers and is used in the diet of many countries. The important mechanism of action of capsaicin is its influence on TRPV1 channels in nociceptive sensory neurons. Furthermore, the beneficial effects of capsaicin in cardiovascular and oncological disorders have been described. Many recent publications show the positive effects of capsaicin in animal models of brain disorders. In Alzheimer's disease, capsaicin reduces neurodegeneration and memory impairment. The beneficial effects of capsaicin in Parkinson's disease and depression have also been described. It has been found that capsaicin reduces the area of infarction and improves neurological outcomes in animal models of stroke. However, both proepileptic and antiepileptic effects of capsaicin in animal models of epilepsy have been proposed. These contradictory results may be caused by the fact that capsaicin influences not only TRPV1 channels but also different molecular targets such as voltage-gated sodium channels. Human studies show that capsaicin may be helpful in treating stroke complications such as dysphagia. Additionally, this compound exerts pain-relieving effects in migraine and cluster headaches. The purpose of this review is to discuss the mechanisms of the beneficial effects of capsaicin in disorders of the central nervous system.

The aim of this review is to provide an updated review of the epigenetic factors involved in the onset and development of osteoarthritis (OA). OA is a prevalent degenerative joint disease characterized by chronic inflammation, ectopic bone formation within the joint, and physical and proteolytic cartilage degradation which result in chronic pain and loss of mobility. At present, no disease-modifying therapeutics exist for the prevention or treatment of the disease. Research has identified several OA risk factors including mechanical stressors, physical activity, obesity, traumatic joint injury, genetic predisposition, and age. Recently, there has been increased interest in identifying epigenetic factors involved in the pathogenesis of OA. In this review, we detail several of these epigenetic modifications with known functions in the onset and progression of the disease. We also review current therapeutics targeting aberrant epigenetic regulation as potential options for preventive or therapeutic treatment.

Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was carried out to investigate the possible role of FPR2/ALX in nociception in mice. Intrathecal administration of the formyl peptide receptor type 1 (FPR1) agonist fMLF and the FPR2/ALX agonist BML-111 relieved nociception and these effects were reduced by contemporary administration of the FPR2/ALX antagonist WRW. Furthermore, measurement of cytokines and brain-derived neurotrophic factor (BDNF) in the spinal cord of neuropathic mice demonstrated that the antinociceptive effects of BML-111 might depend on the reduction in cytokine release and BDNF in the spinal cord. These results suggest a possible role of FPR2/ALX for pain control in the spinal cord.

Chronic pain remains a very difficult condition to manage for healthcare workers and patients. Different options are being considered and a biopsychosocial approach seems to have the most benefit, since chronic pain influences biological, psychological and social factors. A conservative approach with medication is the most common type of treatment in chronic pain patients; however, a lot of side effects are often induced. Therefore, a premium is set on novel nonpharmacological therapy options for chronic pain, such as psychological interventions. Previous research has demonstrated that resilience is a very important aspect in coping with chronic pain. A more recent type of cognitive-behavioural therapy is Acceptance and Commitment Therapy, in which psychological flexibility is intended to be the end result. In this manuscript, current evidence is used to explain why and how a comprehensive and multimodal treatment for patients with chronic pain can be applied in clinical practice. This multimodal treatment consists of a combination of pain neuroscience education and cognitive-behavioural therapy, more specifically Acceptance and Commitment Therapy. The aim is to provide a clinical guideline on how to contribute to greater flexibility and resilience in patients with chronic pain.

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis.

Opioids remain an essential part of the treatment of chronic pain. However, their use and increasing rates of misuse are associated with high morbidity and mortality. The development of tolerance to opioids and analgesics further complicates dosing and the need to reduce side effects. First-generation digital systems were developed to improve analgesics but are not always capable of making clinically relevant associations and do not necessarily lead to better clinical efficacy. A lack of improved clinical outcomes makes these systems less applicable for adoption by clinicians and patients. There is a need to enhance the therapeutic regimens of opioids. In the present paper, we present the use of a digital analgesic that consists of an analgesic administered under the control of a second-generation artificial intelligence system. Second-generation systems focus on improved patient outcomes measured based on clinical response and reduced side effects in a single subject. The algorithm regulates the administration of analgesics in a personalized manner. The digital analgesic provides advantages for both users and providers. The system enables dose optimization, improving effectiveness, and minimizing side effects while increasing adherence to beneficial therapeutic regimens. The algorithm improves the clinicians' experience and assists them in managing chronic pain. The system reduces the financial burden on healthcare providers by lowering opioid-related morbidity and provides a market disruptor for pharma companies.