The Journal of Pain

ObjectivesBack pain is a massive public health problem. The STarT Back Screening Tool (SBST) was developed for use in primary care to triage people with lumbar pain, classifying them as low, medium or high "risk" of prolonged symptoms. This classification guides non-surgical interventions including manual treatments, exercise and cognitive behavioural therapy. Claims suggest SBST brings generic health and cost benefits. National guidance recommends STarT Back is used at the first primary care consultation but can be used at any stage. For SBST to be an effective triage tool it should distinguish structural from non-structural pain. We tested this requirement in consecutive people referred to a single triage practitioner, hypothesising it was not possible conceptually. DesignAn observational study of the relationship between routine, prospectively collected triage data and diagnosis. SettingA secondary care spinal triage service based in a teaching hospital. ParticipantsWe studied consecutive referrals with lumbar pain triaged by a single extended scope practitioner (ESP) over 22 months (Nov 2015-Sept 2017). Main Outcome MeasuresSBST and pain visual analogue scores (VAS: 0-10) were collected at the initial consultation. We compared data for people with and without surgically remedial lesions. Results1041 people were seen (61% female, mean age 53), n=234 (28%) had surgically amenable explanations for pain. People with surgical lesions were older (58 v 51yrs), more likely male (48 v 35%) and had higher VAS scores (6.8 v 6.1). Surgery and non-surgery subgroups had similar SBST total and domain score distribution profiles. The surgery subgroup had less low risk (9%v21%) and more high risk (37% v 30%) classified people. ConclusionSBST scores did not differentiate surgical from non-surgical pathologies. It seems unlikely that symptom questionnaires can estimate prognosis accurately unless everyone has the same diagnosis, not just the same symptom. Diagnosis, rather than questionnaire scores, should guide treatment and inform prognosis. O_TEXTBOXSummary Box What is already known on this topic?The symptom of low back pain is a common cause of disability worldwide. The majority if people with low back pain probably do not have a structural problem in their lumbar spine to explain the extent of their disability. National guidelines throughout the world attempt to facilitate the identification and treatment of people with, "non-specific low back pain", and prescribe treatment for people given this label. What this study adds?It seems unlikely that symptom questionnaires can estimate prognosis accurately unless everyone has the same diagnosis, not just the same symptom. The practice of recommending treatment and prognosticating in the absence of a diagnosis needs further scrutiny. C_TEXTBOX

Maladaptive stress responses may exacerbate chronic widespread pain (CWP) and deserve further investigations. Yet, existing stress induction paradigms lack relevance for individuals with this condition. Hence, we developed the Social Benefits Stress Test (SBST), adapted from the Trier Social Stress Test. Instead of a job interview, the main task consists in justifying the inability to work. Forty women with CWP in the context of hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorders were included. They underwent a 30-min baseline, the new stress task and a recovery period. The psychophysiological stress response was captured using self-reported stress ratings, salivary cortisol and - amylase levels, as well as continuous physiological monitoring of heart rate variability (HRV) and electrodermal activity (EDA). Compared to baseline, the analysis revealed a significant and transient increase in stress ratings during the stress task, associated with a peak in salivary biomarkers concentrations. The HRV signal analysis showed a significant decrease in high frequency power (HF), and increases in heart rate, low frequency power (LF) and in LF/HF ratio. The EDA analysis revealed a significant increase in skin conductance level (SCL) tonic component and skin conductance response (SCR). Subjective stress ratings positively correlated with changes in salivary biomarkers, LF/HF ratio and EDA outcomes. The SBST induced a reproducible moderate stress response across subjective and physiological measures in a population of CWP patients, validating this task as a relevant experimental model of social stress in chronic pain. The SBST is a useful tool to study the relationship between stress and chronic pain. PerspectiveThis manuscript presents the Social Benefits Stress Test (SBST) as a novel paradigm to assess stress reactivity in chronic widespread pain patients. By simulating the challenge of justifying work incapacity, it elicits a reproducible stress response, supporting its use as a model to study stress-pain interactions and evaluate therapeutic interventions.

Background and ObjectiveThe neuroimmune system plays a critical role at all phases of chronic pain including at its onset. We therefore hypothesized that preemptive immunomodulation could decrease susceptibility and/or offer protection to pain. Materials and MethodsSix days before the spared nerve injury (SNI), Wistar Han rats were treated with either the immunomodulator minocycline (MIN) or vehicle (VEH). After that, half of the animals from each group switch treatments for additional 7 days, resulting in 4 groups: continuous treatment (MIN/MIN), pretreatment (MIN/VEH), early treatment (VEH/MIN) and the control (VEH/VEH). Mechanical allodynia was recorded using Von Frey test until 4 weeks after SNI where depressive-like behaviors of the animals were also assessed using sucrose preference test. ResultsThe continuous treatment provided sustained protection against mechanical allodynia, with rats in this group showing a significantly higher threshold to pain sensitivity compared to those in VEH/VEH. In contrast, pain relief effects were not observed with MIN/VEH and VEH/MIN. Additionally, animals in MIN/MIN, and VEH/MIN exhibited decreased anhedonic-like behavior at 30 days after SNI, relative to the control. ConclusionsThe exposure to an anti-inflammatory drug circa the installation of a neuropathic lesion had a positive impact on allodynia and on anhedonic behavior for a relatively long period after treatment cessation. The results support the assertions that pain trajectories can be altered at pain early stages by targeting the neuroimmune system. This proof-of-concept has the potential to be broadened to other drugs and/or therapeutical schemes. HighlightsChronic pain susceptibility varies across individuals. (endo)phenotypes of susceptibility manifest prior/circa pain onset. Preemptive minocycline treatment transiently decreases allodynia. Preemptive minocycline treatment provides sustained reduction of depressive-like behavior. Immune system modulation prior to pain onset or at early stages have beneficial outcomes.

Objective: Myofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck/shoulder pain and associated myofascial component(s). Design: Prospective cross-sectional study of adults reporting neck/shoulder pain and pain-free individuals. Outcomes Measures: Pain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST). Results: Of the 96 adults recruited for the study, 82 had complete records (age 32.2 +/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups. Conclusions: The symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.

Acute low back pain (LBP) is a common experience, however, the associated pain severity, pain frequency, and characteristics of individuals with acute LBP in community settings have yet to be well understood. In this manuscript, three acute LBP severity categorization definitions were used based on LBP frequency combined with either 1) pain impact frequency (impact-based) or 2) pain intensity (intensity-based), as well as LBP pain interference frequency (interference only-based) severity categories. The purpose of this manuscript is to describe and then compare these acute LBP severity groups in the following characteristics: 1) sociodemographic, 2) general and physical health, and 3) psychological. This cross-sectional study used baseline data from 131 community-based participants with acute LBP (<4 weeks duration before screening and [&ge;]30 pain-free days before acute LBP onset). Descriptive associations were calculated as prevalence ratios for categorical variables and Hedges g for continuous variables. Our analyses identified several large associations for impact-based and intensity-based categories with global mental health, global physical health, STarT Back Screening Tool risk category, and general health. Larger associations were found with social constructs (racially and ethnically minoritized, performance of social roles, and isolation) when using the intensity-based versus impact-based categorization. The interference-based category did not capture as much variability between acute LBP severity categories. This study adds to the literature by providing standard ways to characterize community-based individuals experiencing acute LBP. The robust differences observed between these categorization approaches suggest that how we define acute LBP severity is consequential; these different approaches may be used to improve the early identification of factors potentially contributing to the development of chronic LBP.

Persistent pain has a significant impact on quality of life and places considerable demand on the NHS (National Health Service). In 2023, Welsh Government published their guidance Living with Persistent Pain, marking persistent pain as a national priority. The research aimed to provide evidence to help inform NHS leads in Wales around current and future services, capacity planning, and to aid in implementing health policies. We conducted a retrospective cohort study covering the period 2010-2023. Anonymised, individual- level, population-scale linked routinely-collected electronic health records and administrative data from the SAIL Databank was used. The population included people living in Wales and registered with a General Practice (GP) that provides data to SAIL. Three cohorts of people were created. These were i) people with diagnostic codes relevant to persistent pain, ii) people prescribed opioids or gabapentinoids for 3 months or more, and iii) people referred to specialist outpatient pain services. A comparator group included people who did not meet any of these criteria. We measured the proportion of the population living with persistent pain, demographic details, and health status. Healthcare use data included GP appointments and prescriptions, hospital admissions, emergency department visits, and outpatient appointments. The results showed that 15% of the population of Wales are living with persistent pain. Persistent pain was more common among older adults, women, and individuals living in more deprived areas. A higher burden of frailty and comorbid conditions was observed in the persistent pain cohort compared to the general population. People living with persistent pain had 63% more GP events than those without. Those referred to pain services had more healthcare interactions overall and were younger and less frail compared to those not referred. Trends over time showed small but statistically significant decline was observed in the prevalence of persistent pain over the study period. After adjusting for demographics and seasonal changes--there were small but significant monthly increases in GP events, hospital admissions, emergency attendances, for the persistent pain cohort. Outpatient attendances showed small but statistically significant month-on-month decreases. Findings may point to unmet need in accessing specialist care, particularly among older adults and individuals from more deprived areas. Patterns of pain prevalence and service use reflect existing inequalities across age, sex, and socioeconomic status. There is a need for further research, service improvements and policy development. Funding statementThe authors and their Institutions were funded for this work by the Health and Care Research Wales Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government.

Most animal models of neuropathic pain use targeted nerve injuries quantified with motor reflexive measures in response to an applied noxious stimulus. These motor reflexive measures can only accurately represent a pain response if motor function in also intact. The commonly used spared nerve injury (SNI) model, however, damages the tibial and common peroneal nerves that should result in motor phenotypes (i.e., an immobile or "flail" foot) not typically captured in sensory assays. To test the extent of these issues, we used DeepLabCut, a deep learning-based markerless pose estimation tool to quantify spontaneous limb position in C57BL/6J mice during tail suspension following either SNI or sham surgery. Using this granular detail, we identified the expected flail foot-like impairment, but we also found SNI mice hold their injured limb closer to the body midline compared to shams. These phenotypes were not present in the Complete Freunds Adjuvant model of inflammatory pain and were not reversed by multiple analgesics with different mechanisms of action, suggesting these SNI-specific phenotypes are not directly related to pain. Together these results suggest SNI causes previously undescribed phenotypes unrelated to altered sensation that are likely underappreciated while interpreting preclinical pain research outcomes.

BackgroundNLX-204 is a highly selective, high efficacy biased agonist at serotonin 5-HT1A receptors, which are well-established modulators of pain processing. ObjectiveTo evaluate the analgesic activity of NLX-204 in two rat models of nociceptive/inflammatory pain: the monoiodoacetate (MIA)-induced knee osteoarthritis (KOA) and the Brennans plantar incision model, using morphine as an active comparator, in both male and female rats. MethodsKOA was induced by left intra-articular MIA injection. Analgesic effects of NLX-204 (0.1-3 mg/kg p.o.) or morphine (6 mg/kg s.c.) were assessed on days 5 and 8 by measuring withdrawal threshold (WT) using von Frey filaments and dynamic weight bearing (DWB) on injured and contralateral limbs. In the Brennans model, the plantar surface of the left hind limb was incised with elevation and incision of the plantaris muscle. Mechanical allodynia (WT) and guarding behavior (GB) were assessed 24 h post-surgery. ResultsIn the MIA-KOA model, NLX-204 significantly attenuated DWB imbalance in males at 1-3 mg/kg (acute) and 0.1-3 mg/kg (repeated dosing), and in females at 3 mg/kg (repeated dosing only). NLX-204 demonstrated anti-allodynic activity (VF filaments) from 0.3 mg/kg in males (acute and repeated) and from 1 mg/kg in females. In the Brennans model, NLX-204 reduced GB scores at 1 mg/kg (males) and 0.3-1 mg/kg (females), and showed anti-allodynic effects from 0.3 mg/kg in both sexes. Morphine was effective in both models under acute and repeated administration. ConclusionsOral NLX-204 demonstrates dose-dependent analgesic and anti-allodynic activity in two rat models of nociceptive/inflammatory pain, supporting the therapeutic potential of selective, high-efficacy 5-HT1A receptor agonists as a novel non-opioid strategy for pain management.

BackgroundThe insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization. Objective/HypothesisInvestigate the effect of low-intensity focused ultrasound (LIFU) pressure to the anterior insula (AI), posterior insula (PI) or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). MethodsN = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 minute LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. ResultsLIFU to the PI significantly attenuated pain ratings in both TSP and the CPM protocols. LIFU to the dACC only affected TSP pain ratings. LIFU to AI had no effect on either TSP or CPM pain ratings. LIFU pressure modulated group means but did not affect overall group differences. ConclusionsLIFU to the PI and dACC differentially affected central sensitization. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.

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 i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF 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 (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. 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. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain.

Pain resulting from tissue damage, including surgical incision, is often only partially responsive to standard treatments focusing on inflammation, suggesting additional mechanisms are involved. Tissue damage leads to expression in dorsal root ganglion (DRG) sensory neurons of activating transcription factor 3 (ATF3), a known injury-induced transcription factor. ATF3 expression is associated with sensitization of cellular physiology and enhanced amplitude/duration of a nociceptive reflex. It is unclear how tissue damage leads to these changes in the sensory neurons, but it could include direct damage to the tissue-innervating axons and inflammation-associated retrograde biochemical signalling. We examined the necessity and sufficiency of incision, inflammation, and axonal conduction for induction of ATF3 in response to skin incision. Incision outside of a single dermatome, but close enough to induce inflammation inside the dermatome, was not sufficient to induce ATF3 expression in the corresponding DRG. Incision inside the dermatomeled to strong expression of ATF3. Anti-inflammatory treatments did not prevent this induction of ATF3. In rodent models of repeated injury - a major etiological factor for chronic pain - ATF3 expression was synergistically increased and the threshold for paw-withdrawal to mechanical stimulation was significantly decreased for an extended duration. Together, these results suggest that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3, expression of which appears additionally increased by repeated injury. Further, pre-treatment of the nerves innervating the incised skin with bupivacaine, a local anesthetic commonly used to reduce surgical pain, did not prevent induction of ATF3, indicating that conduction of action potentials is not necessary for induction of ATF3. We also determined that closure of incision with surgical glue significantly reduced incision-induced expression of ATF3 and GAP-43. Intriguingly, treatment with polyethylene glycol (PEG), known to enhance membrane integrity after injury among other effects, reduced incision-associated ATF3 expression and electrophysiological changes. These results suggest that pain resulting from tissue damage may arise from a mix of ATF3-independent inflammation-related mechanisms as well as ATF3-/axonal-damage-associated mechanism and therefore require a mix of approaches to achieve more complete control some of which we suggest here.. FundingJCP NIH R01NS109936, R21NS120498, KSCHIRT 10-10 BJH NIH R01NS121533 SCOPE statementPain resulting from tissue damage, including surgical incision, is often only partially responsive to anti-inflammatory treatments, suggesting multiple mechanisms at work, including neuropathic. Cutaneous tissue damage leads to expression in DRG sensory neurons of the injury marker ATF3 - associated with physiological sensitization and enhancement of a nociceptive reflex. We examined some of the conditions for induction of ATF3 in response to incision of skin and the impact of interventions. Treatment with anti-inflammatory ketoprofen and/or local anesthetic did not prevent the induction of ATF3, together suggesting that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3. Repeated incision induced unique changes in expression of ATF3- and pain-associated genes. Closure with surgical glue reduced incision-induced gene expression compared to closure with staples. Treatment with polyethylene glycol (PEG), known to enhance membrane integrity after axonal injury, reduced induction of ATF3 and electrophysiological changes. These experiments were designed to identify distinct pain-related mechanisms with pre-clinical animal models that reflect existing clinical practice and feasible future practice. These results suggest that pain resulting from tissue damage likely arises from mixed mechanisms - including neuropathic - and therefore require a mix of approaches to achieve more complete control.

BackgroundThe exact mechanisms underlying paediatric abdominal pain (AP) remain unclear due to patient heterogeneity. This study aimed to identify AP phenotypes and develop predictive models to explore associated factors. MethodsIn 13,790 children from a large birth cohort, data on paediatric and maternal demographics and comorbidities were extracted from general practitioner records. Machine learning (ML) clustering was used to identify distinct AP phenotypes, and an ML-based predictive model was developed using demographics and clinical features. Results1,274 children experienced AP (9.2 %) (average age: 8.4 {+/-} 1.1 years, male/female: 615/659), who clustered into three distinct phenotypes: Phenotype 1 with an allergic predisposition (n = 137), Phenotype 2 with maternal comorbidities (n = 676), and Phenotype 3 with minimal other comorbidities (n = 340). As the number of allergic diseases or maternal comorbidities increased, so did the frequency of AP, with 17.6% of children with [&ge;] 3 allergic diseases and 25.6% of children with [&ge;] 3 maternal comorbidities. The predictive model demonstrated moderate performance in predicting paediatric AP (AUC 0.67), showing that a childs ethnicity, paediatric allergic diseases, and maternal comorbidities were key predictive factors. When stratified by ML-predicted probability, observed AP rates were 18.9% in the <40% group, 44.8% in the 40-50% group, 60.6% in the 50-60% group, and 100.0% in the >60% group. ConclusionsOur findings reveal distinct phenotypes and associated factors of paediatric AP by an ML approach. These insights suggest potential targets for future research to clarify the underlying mechanisms of paediatric AP.

Two-pore domain potassium channels (K2P) regulate neuronal excitability by acting as hyperpolarizing leak channels. Among them, THIK2 remain poorly characterized. Although no study has yet clearly linked them to excitability or pain, their selective expression in nociceptive neurons of the Dorsal Root Ganglia (DRG) suggests a role in nociception and pain regulation. This project investigates THIK2 channels in pain pathophysiology through molecular, electrophysiological, and behavioral approaches. We mapped THIK expression patterns and in THIK2 knock-out mice, we examined DRG neuron excitability and pain sensitivity. Results reveal thermal hypersensitivity under both naive and inflammatory conditions, indicating that THIK2 normally limits neuronal hyperexcitability. These findings position THIK2 as a potential therapeutic target in chronic inflammatory pain, with peripheral inhibition potentially offering analgesia without central opioid side effects.

BackgroundGenome targeting strategies to address NaV 1.7 mediated signaling in nociceptive afferents produce highly selective and persistent analgesic outcomes. Here, we analyze the concentration-dependent effects of the reduction of primary afferent NaV 1.7 channel expression by intrathecal delivery of an antisense oligonucleotide on pain behaviors and the covariance of Scn9a knock-down on NaV 1.7 message expression and channel binding. MethodsMale Sprague-Dawley rats were implanted with lumbar intrathecal catheters and dosed with different NaV 1.7 ASO concentrations (100 to 3000 g;10 L). Pain behavior assays were conducted 0-28 days after ASO injections. Brain, spinal cords (SC) and dorsal root ganglia (DRGs) were collected. Quantification of ASO knock-down was assessed through RT-qPCR. NaV 1.7 expression was assessed by binding of NaV 1.7 fluorescent labeled antagonist (ATTO488PTx-II). Distribution studies were performed using anti-ASO antibody staining in brain, SCs and DRGs. ResultsNaV 1.7 message was detected in nerve, DRG and SC. Intrathecal ASO induced a concentration dependent gradient of knock down in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488PTx-II binding in small DRG neurons, and in spinal parenchyma, and a suppression of pain behaviors initiated by mechanical compression, inflammation and following intraplantar NaV1.7 agonist (OD1) or formalin. At 1000 {micro}g, there was a 47% reduction in phase 2 flinching, a 60% reduction in DRG mRNA and a 36% reduction in ATTO488PTx-II DRG binding in comparison with mismatch controls. Although marked changes were seen at the sensory ganglia level and spinal dorsal horn, no changes in NaV 1.7 binding or mRNA were detected in sciatic nerves. Reduction in DRG message displayed a rostrocaudal gradient that corresponded with ASO distribution. ConclusionsThe study presents how NaV 1.7 ASOs reduce primary afferent channel binding through an effective knock-down on Scn9a mRNA, and channel binding leading to a covariate reduction in pain behavior.

BackgroundManaging postoperative pain after spine surgery is challenging, and up to 40% of operated patients develop failed back surgery syndrome (FBSS) resulting in intractable back and/or leg pain. While spinal cord stimulation (SCS) has been shown to effectively alleviate such chronic pain, it is unknown if intraoperative SCS can mitigate the development of central sensitization that potentially causes intense postoperative pain and FBSS after spine surgery. MethodsAs an experimental spine surgery, unilateral T13 laminectomy was performed in mice to expose the dorsal part of L4-5 spinal segments that receive sensory inputs from the hind limb. After the laminectomy, a group of mice received intraoperative SCS epidurally applied to the exposed side of the dorsal part of the spinal cord for an hour under anesthesia before closing the surgical wounds. Secondary mechanical hypersensitivity, a behavioral manifestation of central sensitization, was measured in hind paws using von Frey assay one day before and at predetermined times after surgery. In addition, because von Frey assay is a nocifensive reflex-based analysis that primarily assesses the sensory-discriminative domain of pain, we also performed a conflict avoidance test to capture the affective-motivational domain of pain at selected timepoints post-laminectomy. ResultsMice that underwent unilateral T13 laminectomy developed mechanical hypersensitivity in both hind paws, which gradually resolved in 1-2 weeks. The extent of the hypersensitivity was significantly less in the contralateral hind paw (relative to the laminectomy) than in the ipsilateral hind paw only in females. Intraoperative SCS applied to the exposed side of the dorsal -spinal cord significantly inhibited the development of hind paw mechanical hypersensitivity only in the SCS-applied side. When paws were mechanically stimulated in their preferred place to present a conflict between pain/discomfort and natural preference, mice avoided the conflict after laminectomy, spending less time in the place than before the surgery. However, mice treated with intraoperative SCS after laminectomy did not avoid the conflict. ConclusionThese results demonstrate that spine surgery for unilateral laminectomy induces central sensitization that results in postoperative pain hypersensitivity. Intraoperative SCS after laminectomy can mitigate the development of this hypersensitivity in the SCS-applied side.

1Chronic pain is a debilitating disease that is usually comorbid to anxiety and depression. Current treatment approaches primarily rely on analgesics, but they often neglect emotional aspects. Non-pharmacological interventions have been incorporated into clinics to provide a more comprehensive management of chronic pain. Among these interventions, listening to music is a well-accepted and cost-effective option. However, the underlying mechanisms of music-mediated pain relief remain insufficiently understood. Here, our aim was to evaluate the effects of music exposure in an animal model of chronic pain. First, we injected mice with the inflammatory agent complete Freunds adjuvant (CFA) into the hind paw and housed them for 14 days with background music during their active period (Mozart K.205, overnight), or silence. The impact of music exposure on nociception and anxiety-like and depression-like behaviors was evaluated through different paradigms, including the hot plate, Von Frey, elevated plus maze, splash, and tail suspension tests. Additionally, we investigated whether music influences dopamine dynamics in the nucleus accumbens (NAcc), a pivotal region involved in pain processing, anhedonia, and reward. Our findings indicate that music exposure prevents the decreased NAcc activity observed in CFA-injected mice, linking with a sex-dependent reduction of allodynia, anxiety- and depression-like behaviors. Thus, females were more sensitive to music exposure. Collectively, our findings provide compelling evidence for the integration of music listening as a non-pharmacological intervention in chronic pain conditions. Moreover, the observed impact on the NAcc suggests its potential as a therapeutic target for addressing chronic pain and its associated symptoms.

There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data in a sex-aware fashion. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data in a sex-aware fashion. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data in a sex-aware fashion have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex-awareness in data analysis. The preclinical literature identifies a sex difference in prostaglandin D2 synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and sex-aware analysis in data analysis in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.

BackgroundPain is one of the primary symptoms of endometriosis, a chronic inflammatory condition characterised by the presence of endometrial tissue outside the uterus. Endometriosis-associated pain is commonly considered as nociceptive in nature but its clinical presentation suggests that it might have neuropathic-like properties in a subgroup of patients. MethodsThis is a cross sectional study using an online survey. The survey was distributed by patient support websites. The survey was composed of validated questionnaires assessing pain symptoms, psychological measures and questions about number of surgeries. Main results and the role of chanceWe had 1417 responses which met the inclusion criteria. Using standard painDETECT cut-off scores, we found that pain was classified as neuropathic in 40% of patients and as mixed neuropathic/nociceptive in a further 35%. In line with observations in other neuropathic conditions, the neuropathic subgroup reported higher pain intensities, greater psychological distress and cognitive impairment. Neuropathic pain was also more likely in those with more surgeries to the abdomen and a longer history of pain. As revealed by a cluster analysis, those with a neuropathic pain component could further be divided into two subgroups based on their sensory profile. ConclusionsThe data presented here indicate that endometriosis-associated pain includes a neuropathic-like component in a substantial proportion of women. Although further investigation is required, our finding challenges the current conceptualisation of endometriosis-associated pain as nociceptive and advocates for a new perspective on this type of pain, which is so debilitating to a large number of women.

We performed the first systematic review and meta-analysis of the prevalence of pain with neuropathic characteristics using Bayesian methods to correct prevalence estimates for the use of screening tools with imperfect sensitivity and specificity (CRD42023416845). We searched major databases for national or regional epidemiological studies that reported the prevalence of pain with neuropathic characteristics, as identified by the PainDETECT, S-LANSS, or DN4-interview. Of the 1,251 unique records retrieved, 8 were finally extracted. The uncorrected (apparent) prevalence data were pooled using a random-effects meta-analysis for proportions. The corrected (true) prevalence was estimated using Bayesian models incorporating sensitivity and specificity distributions under non-informative [beta(1,1)] and informative priors [beta(4.389, 29.522); based on apparent prevalence]. Using the mean values from Bayesian credible intervals, a pooled estimate of true prevalence was generated using a random-effects model. The pooled estimate for the apparent prevalence was 10.6% (95% CI: 8.5; 12.9). The pooled estimate for true prevalence was 4.9% (95% CI: 3.8; 6.1) using informative priors, and 2.3% (95% CI: 1.5; 3.2) using non-informative priors. The use of imperfect screening tools may have overestimated the prevalence of neuropathic pain. PerspectiveThe prevalence of neuropathic pain may be lower than previously estimated. A lower prevalence should not be equated with reduced societal or clinical significance, but it may have implications for healthcare resource allocation and research funding policies for neuropathic pain.

Neuropathic Pain (NP) affects 10% of the general population, decreasing quality of life for millions of Americans and contributing to higher physical and mental health care costs. The most widely used treatments for NP involve medications that show limitations in efficacy and burdensome side effects. This randomized controlled trial explored the efficacy of a wearable Audio-Visual Stimulation neuromodulation device (Sana) as a novel intervention for chronic NP in 64 participants. Outcomes were assessed at baseline, after 8-weeks of daily use of the assigned Sana or Sham device, and after 4 weeks of discontinued use. For the main outcome (Neuropathic Pain Symptom Inventory total), there were statistically significant improvements in the Active arm that were greater than those in the Sham Arm at Week-14 (Mean Difference = 10.04, p = 0.01). Both groups showed significant improvements at the end of the treatment period (Week-10), and the Active arm maintained this improvement after an additional 4 weeks of non-use, while the Sham arm almost returned to baseline (Active Change = 13.26, p <=0.001 | Sham Change = 3.22, p = 0.214). Participants in the Active arm had significant decreases in use of anxiolytic, opiate, antidepressant, and anticonvulsant medications compared to the Sham arm. The study provides strong evidence supporting the efficacy of a novel AVS Device in generating durable improvements in NP, with superiority over Sham at 14 weeks. The Sana device may also reduce the reliance on pain medications and is a safe and easy to use treatment option for patients.