Pain Reduction With an Immersive Digital Therapeutic Tool in Women Living With Endometriosis-Related Pelvic Pain: Randomized Controlled Trial.

BACKGROUND: Chronic pelvic pain is a common and disabling condition in women living with endometriosis. Pharmacological and surgical treatments are not always effective at controlling pain and present important restrictions. Digital therapeutics (DTx) are emerging as major nonpharmacological alternatives that aim to extend the analgesic therapeutic arsenal of patients. OBJECTIVE: In this randomized controlled trial (RCT), we aimed to measure the immediate and 4-hour persisting effects of a single use 20-minute DTx (Endocare) on pain in women experiencing pelvic pain due to endometriosis. METHODS: A total of 45 women with endometriosis participated in a randomized controlled study comparing the analgesic effect of a single use of a virtual reality digital treatment named Endocare (n=23, 51%) to a 2D digital control (n=22, 49%). Perceived pain and pain relief were measured before the treatment and 15, 30, 45, 60, and 240 minutes after the end of the treatment. RESULTS: The clustered posttreatment pain was significantly reduced compared to the pretreatment for both Endocare and the control group (all P<.01). Endocare was significantly more effective than the control group (all P<.01). Endocare decreased the mean pain intensity from 6.0 (SD 1.31) before the treatment to 4.5 (SD 1.71) posttreatment, while the control only decreased it from 5.7 (SD 1.36) to 5.0 (SD 1.43). When comparing each posttreatment measures to the pretest, Endocare significantly reduced pain perception for all points in time up to 4 hours posttreatment. The differences did not reached significance for the control group. Moreover, Endocare was significantly superior to the control group 15, 30, and 45 minutes after the treatment (all P<.001). The mean perceived pain relief was significantly higher for Endocare at 28% (SD 2%) compared to the control, which was 15% (SD 1%) for all the posttreatment measurements (all P>.05). CONCLUSIONS: Our study aimed to test the effects of a single use of a DTx treatment on reported pain at different time points in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain. Importantly, our results support that Endocare, a virtual reality immersive treatment, significantly reduce pain perception compared to a digital control in women living with endometriosis. Interestingly, we are the first to notice that the effect persisted up to 4 hours posttreatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04650516; https://tinyurl.com/2a2eu9wv.

Pathophysiology of chronic pain in cerebral palsy: implications for pharmacological treatment and research.

The high prevalence of chronic pain in individuals with cerebral palsy (CP) across the lifespan has been well documented, as has its negative impact on quality of life. However, without an understanding of the underlying (possibly unique) pathophysiology of pain in CP, identification of more effective management options, such as innovative and individualized pharmacological approaches to non-opioid pain treatment, will be significantly hindered. We review, briefly, what is known about chronic pain in CP and present what we need to know with respect to the neurobiology of pain and new developments in pain treatment research that might be applied to CP. WHAT THIS PAPER ADDS: Pain conditions in cerebral palsy have differing mechanisms and will not respond to the same treatments. Novel analgesics under development include inhibitors of ion channels, nerve growth factor, and calcitonin gene-related peptide.

Altered autonomic nervous system reactivity to pain in trigeminal neuralgia.

BACKGROUND: In the past two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. METHODS: Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. RESULTS: At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p values >0.05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared with healthy controls (all p values <0.05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r=-.58, p<0.05). CONCLUSIONS: These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain.

Individual differences in pain sensitivity vary as a function of precuneus reactivity.

Although humans differ widely in how sensitive they are to painful stimuli, the neural correlates underlying such variability remains poorly understood. A better understanding of this is important given that baseline pain sensitivity scores relate closely to the risk of developing refractory, chronic pain. To address this, we used a matched perception paradigm which allowed us to control for individual variations in subjective experience. By measuring subjective pain, nociceptive flexion reflexes, and, somatosensory evoked brain potentials (with source localization analysis), we were able to map the brain's sequential response to pain while also investigating its relationship to pain sensitivity (i.e. change in the stimulation strength necessary to experience pain) and spinal cord activity. We found that pain sensitivity in healthy adults was closely tied to pain-evoked responses in the contralateral precuneus. Importantly, the precuneus did not contribute to the actual representation of pain in the brain, suggesting that pain sensitivity and pain representation depend on separate neuronal sub-systems.

Unlocking hypnotizability: Transcranial brain stimulation for enhanced impact in chronic pain.

Hypnosis provides a therapeutic option for health issues like chronic pain, but individual responsiveness, termed hypnotizability, varies. Faerman et al.'s1 study showed that transcranial magnetic stimulation (TMS) can significantly improve hypnotizability, offering potential for patients with limited response to hypnosis in pain management.

The impact of an immersive digital therapeutic tool on experimental pain: a pilot randomized within-subject experiment with an active control condition.

Background: Pain is a complex and multifaced sensory and emotional experience. Virtual reality (VR) has shown promise in reducing experimental pain and chronic pain. This study examines an immersive VR environment initially designed for endometriosis patients, which demonstrated short-term analgesic effects. The research aims to determine the impact of the VR environment on experimental pain intensity and unpleasantness both during and after VR exposure (3D with binaural beats), while using an active control condition (2D with no binaural beats). Additionally, a secondary objective of the study was to identify the psychological and psychophysical factors that predict the analgesic effects of the immersive digital therapeutic tool. Methods: The study involved twenty-one healthy individuals and used a within-subject design, comparing a VR treatment with an active control condition. Continuous heat stimulation was applied to the left forearm with a Peltier thermode. Pain ratings were collected for immediate and short-term effects. Results: In both the VR and Control conditions, there were no significant differences in pain intensity before, during, and after exposure. However, during VR exposure, there was a significant decrease in pain unpleasantness as compared to before exposure (p < 0.001), with a 27.2% pain reduction. In the Control condition, there were no significant differences in pain unpleasantness during and after exposure. Furthermore, no psychological and psychophysical factors predicted the analgesic effects. Discussion: The study investigated how a VR environment affected experimentally induced pain in healthy volunteers. It showed that VR reduced pain unpleasantness during exposure but had no lasting impact. The VR environment mainly influenced the emotional aspect of pain, possibly due to its inclusion of binaural beats and natural stimuli. The study suggests that the VR environment should be tested in chronic pain population with high distress levels. Registration number clinicaltrialsgov: NCT06130267.

Beyond numbers: integrating qualitative analysis into quantitative sensory testing for neuropathic pain.

This article investigates the benefits of adopting qualitative and quantitative sensory testing (QQST) in sensory assessment, with a focus on understanding neuropathic pain. The innovative QQST method combines participant qualitative experiences with quantitative psychophysical measurements, offering a more varied interpretation of sensory abnormalities and normal sensory function. This article also explores the steps for the optimization of the method by identifying qualitative signs of sensory abnormalities and standardizing data collection. By leveraging the inherent subjectivity in the test design and participant responses, the QQST method contributes to a more holistic exploration of both normal and abnormal sensory experiences. This article positions the QQST approach as a foundational element within the Sensory Evaluation Network, uniting international experts to harmonize qualitative and quantitative sensory evaluation methods.

Sensory stimulations potentializing digital therapeutics pain control.

For the past two decades, using Digital Therapeutics (DTx) to counter painful symptoms has emerged as a novel pain relief strategy. Several studies report that DTx significantly diminish pain while compensating for the limitations of pharmacological analgesics (e.g., addiction, side effects). Virtual reality (VR) is a major component of the most effective DTx for pain reduction. Notably, various stimuli (e.g., auditory, visual) appear to be frequently associated with VR in DTx. This review aims to compare the hypoalgesic power of specific stimuli with or without a VR environment. First, this review will briefly describe VR technology and known elements related to its hypoalgesic effect. Second, it will non-exhaustively list various stimuli known to have a hypoalgesic effect on pain independent of the immersive environment. Finally, this review will focus on studies that investigate a possible potentialized effect on pain reduction of these stimuli in a VR environment.

Serotonin Transporter mRNA Expression Is Reduced in the Peripheral Blood Mononuclear Cells of Subjects with Major Depression but Normal in Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression. METHODS: PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models. RESULTS: SERT mRNA expression was significantly reduced in MDD subjects compared to controls (p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression. CONCLUSIONS: These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Add-on treatment of quetiapine for fibromyalgia: a pilot, randomized, double-blind, placebo-controlled 12-week trial.

Recently, second-generation antipsychotic drugs have attracted interest in the treatment of chronic pain, including fibromyalgia (FM). Preliminary uncontrolled studies have shown that quetiapine treatment may be helpful for FM patients. In this trial, we sought to examine-for the first time-the efficacy and tolerability of quetiapine as a treatment for FM and its associated psychiatric symptoms. This was a 12-week double-blind, randomized, placebo-controlled trial of quetiapine XR as an add-on treatment for FM syndrome. Fifty-one female FM patients were randomized, and a flexible dosage of 50 to 300 mg/d was used. The primary outcome was the change from baseline to end point in the Fibromyalgia Impact Questionnaire total score. Secondary outcomes included mood symptoms, sleep disturbances, and tender points. Using a low dose (mean = 132.2 mg) of quetiapine, we observed significant benefits of drug treatment on sleep, uncertain effects on FM and mood symptoms, but no effects on pain, in a small group of polymedicated FM patients. Quetiapine was generally well tolerated.

Pain perception in schizophrenia: evidence of a specific pain response profile.

OBJECTIVE: Ever since the characterization of schizophrenia, clinicians have noted abnormal pain sensitivity in their patients. The published literature, however, is inconsistent concerning the nature of the change reported. The objective of this study was to characterize the pain response profile of schizophrenic patients by providing both acute and prolonged (i.e., rapidly repeating) painful stimuli to schizophrenic participants and control subjects. PARTICIPANTS: Twelve schizophrenic subjects and eleven controls were included in the final analysis. Diagnosis was made according to Diagnostic and Statistical Manual of mental disorders-4th edition, text revision (DSM-IV-TR) criteria. METHODS: Intermittent, transcutaneous stimulations of the left sural nerve were administered to all participants. Painful sural nerve stimulations provoked a nociceptive flexion reflex response which was measured using an electromyographic recording of the bicep femoris muscle. Pain ratings were obtained using a 0-10 verbal numerical scale. Among schizophrenic participants, the relationship between subjective pain, reflex amplitude, and clinical features was investigated. The Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Subjective Scale to Investigate Cognition in Schizophrenia were used to evaluate clinical features. RESULTS: Compared with controls, schizophrenic subjects showed increased sensitivity to acute pain (i.e., lower pain thresholds; P = 0.019), but decreased subjective pain sensitization (P = 0.027). Group differences in subjective pain sensitization were not accompanied by group differences in nociceptive reflex activity (P = 0.260), suggesting supraspinal origins to the change in pain experienced by schizophrenic subjects. Moreover, positive symptoms correlated negatively with pain threshold values among schizophrenic participants (r = -0.696, P = 0.012), suggesting that distortions of thought and function relate to pain sensitivity in schizophrenic patients. CONCLUSION: Results indicate that schizophrenic subjects present a specific experimental pain response profile, characterized by elevated sensitivity to acute pain but reduced sensitivity to prolonged pain.

Virtual Reality and the Mediation of Acute and Chronic Pain in Adult and Pediatric Populations: Research Developments.

The use of virtual reality (VR) in the mediation of acute pain in adults has shown real benefit to patients for the past 20 years. This review of the literature provides a descriptive synthesis of the types of VR technology, the mechanisms by which VR mediates pain, and a history of early research in the area. A review of the use of VR to mediate chronic pain in adults, and both acute and chronic pain in pediatric populations follows. The studies reviewed provide mixed results and it is noted that many studies have small sample sizes, are case studies, and do not control for extraneous variables such as the dosage and type of VR technology used. Although VR is an exciting area of inquiry that promises to yield multiple applications, there is a necessity to conduct larger random controlled trials to better understand the use cases for which VR is most effective.

A web app-based music intervention reduces experimental thermal pain: A randomized trial on preferred versus least-liked music style.

Digital technologies are increasingly being used to strengthen national health systems. Music is used as a management technique for pain. The objective of this study is to demonstrate the effects of a web app-based music intervention on pain. The participants were healthy adults and underwent three conditions: Conditioned Pain Modulation (CPM), Most-Liked Music (MLM) and Least-Liked Music (LLM). The music used is MUSIC CARE©, a web app-based personalized musical intervention ("U" Sequence based on a musical composition algorithm). Thermal pain was measured before starting the 20-min music intervention and after three time points for each music condition: 2.20, 11.30, and 20 min. Mean pain perceptions were significantly reduced under both LLM and MLM conditions. Pain decrease was more important under MLM condition than LLM condition at 2.20 min with a mean difference between both conditions of 9.7 (±3.9) (p = 0.0195) and at 11.30 min [9.2 (±3.3), p = 0.0099]. LLM is correlated with CPM but not MLM, suggesting different mechanisms between LLM and MLM. Musical intervention, a simple method of application, fits perfectly into a multidisciplinary global approach and helps to treat the pain and anxiety disorders of participants. Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT04862832], ClinicalTrials.gov [NCT04862832].

Inter-subject variability of pleasant pain relief using a data-driven approach in healthy volunteers.

Background: The offset of a painful and unpleasant sensation can elicit pleasure. This phenomenon, namely pleasant pain relief (PPR), is attracting growing interest in research. While the cold pressor test (CPT) has been frequently used to study the inhibition of pain by the administration of another painful stimulation (inhibitory conditioned pain modulation; ICPM), a preliminary study from our research team has shown that CPT can also elicit a robust and long-lasting PPR. However, its effects on pain relief and inhibition vary greatly between subjects. Although substantial research has been carried out on inter-individual variability in the case of ICPM, the same cannot be said of PPR. Therefore, the current study sought to identify clusters of healthy volunteers with similar dynamic pain responses during the CPT, using a data-driven approach, and to investigate the inter-subject variability for PPR and ICPM. Methods: One hundred and twenty-two healthy volunteers were recruited. A sequential ICPM paradigm was carried out with CPT (water at 10°C) and a Peltier Thermode to evaluate pain intensity and unpleasantness. Moreover, PPR was measured for four minutes at CPT offset. Statistical analyses were performed using group-based trajectory modelling. Results: Four trajectories (groups) were identified for CPT pain intensity and unpleasantness ratings with varying levels of tonic pain and pain sensitization (e.g., temporal summation). PPR scores were correlated with both pain ratings trajectories (p < 0.001). On the other hand, no differences were found between groups regarding ICPM efficacy (percentage pain inhibition). Discussion: This study has provided a first step into the investigation of PPR and ICPM interindividual variability. Using a data-driven approach, it was shown that PPR at CPT offset differs between clusters of participants identified based on dynamic pain intensity and unpleasantness responses from CPT. Thus, it was brought to light that both the levels of tonic pain and pain sensitization underlie individual differences in PPR. The lack of correlation between CPT pain trajectories and ICPM efficacy may be explained by the hypotheses that eliciting ICPM requires only a certain threshold of stimulation which doesn't need to be noxious. In the future, studies on the inter-subject variability of PPR in large samples of chronic pain patients are warranted.

Sex-Related Effects of Adrenergic Drugs on Conditioned Pain Modulation: A Randomized Controlled Cross-Over Double-Blind Trial.

Objective: Endogenous pain inhibition can be investigated using conditioned pain modulation (CPM). CPM efficacy has been reported to be influenced by various factors, such as gender and cardiovascular (autonomic) activity. The aim of this study is to describe the effect of pharmacological manipulations of autonomic activity on CPM efficacy. Methods: Thirty healthy participants were enrolled to assess CPM efficacy in 4 experimental sessions. The first session consisted of the determination of baseline CPM effectiveness. The three following sessions were performed in a randomized order and consisted of the injection of (1) esmolol, (2) ephedrine, or (3) placebo, before the conditioning stimulus. Pain intensity induced by using a contact heat stimulation thermode was compared before and after a cold-pressure conditioning stimulus to evaluate CPM effectiveness. Results: Our results show that inhibiting sympathetic nervous activity with esmolol did not have a significant effect on CPM. Conversely, enhancing sympathetic nervous activity with ephedrine increased CPM effectiveness in healthy women but decreased it in men. Conclusions: Increasing sympathetic activity with adrenergic agonists, such as ephedrine, could improve CPM effectiveness in women. It will be interesting to verify if the same results are present in patients suffering from chronic pain and if adrenergic agonists could have better therapeutic effects in women showing reduced CPM effectiveness.

Clusters of facilitatory and inhibitory conditioned pain modulation responses in a large sample of children, adolescents, and young adults with chronic pain.

Introduction: When investigating the role of facilitatory and inhibitory pain mechanisms such as conditioned pain modulation (CPM) and temporal summation of pain (TSP), it is important to take both into consideration in a single experimental model to provide the most information on subgroups of patients. Therefore, the objective of this study was to identify subgroups in a large population of pediatric patients with chronic pain based on their facilitatory and inhibitory pain mechanisms and compare them with control subjects. Methods: Five hundred twenty-one female subjects and 147 male subjects between 8 and 21 years old underwent a CPM assessment using a 2-minute tonic noxious heat stimulation as the test stimulus and a 2-minute cold-pressor task (CPT) (12°C) as the conditioning stimulus. Results: The best partition of clusters of patients was 3 clusters accounting for 27.15% of the total variation in the data. Cluster 1 (n = 271) was best characterized by high pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 2 (n = 186) was best characterized by low pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 3 (n = 151) was best characterized by high pain intensity during the CPT, presence of TSP during the test stimuli, and inefficient inhibitory CPM. Discussion: A single thermal CPM experimental design can identify combinations of facilitatory and inhibitory pain modulation responses. Findings from the current study add to the literature by describing different clinical phenotypes of central pain mechanisms of youth with chronic pain.

Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis.

PURPOSE: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA). METHODS: Female rats were ovariectomized and pre-emptive 17ß-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17ß-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A). RESULTS: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17ß-estradiol. Interestingly, the 17ß-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018). CONCLUSION: These results clearly indicate that 17ß-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

[Descriptive study of the postoperative pain assessment and documentation process in a university hospital]. / Étude descriptive du processus d'évaluation et de documentation de la douleur postopératoire dans un hôpital universitaire.

Several studies have shown that patients often receive inadequate treatment of postoperative pain. The aim of the present descriptive study was to examine and analyze various data related to the postoperative pain assessment of 40 patients who underwent elective surgery. Pain journals were to be completed by patients during every waking hour for the first three postoperative days to assess both pain intensity and pain unpleasantness. A post hoc analysis of patient records permitted verification of pain assessment by nurses for each patient. The results showed that not only was postoperative pain rarely assessed using a valid scale, it was also poorly documented. In addition, when nurses assessed and documented postoperative pain using a numerical scale, their results were very different from patients' assessments. For the first postoperative day, the mean (± SD) pain intensity documented by nurses on a 0 to 10 numerical scale was 1.57±0.23, while the mean pain intensity noted by patients using the same scale was 3.82±0.41. Statistical analysis showed that there was no significant correlation between mean pain intensity documented by nurses and the mean pain intensity noted by patients.

Glial and neuroimmune cell choreography in sexually dimorphic pain signaling.

Chronic pain is a major global health issue that affects all populations regardless of sex, age, ethnicity/race, or country of origin, leading to persistent physical and emotional distress and to the loss of patients' autonomy and quality of life. Despite tremendous efforts in the elucidation of the mechanisms contributing to the pathogenesis of chronic pain, the identification of new potential pain targets, and the development of novel analgesics, the pharmacological treatment options available for pain management remain limited, and most novel pain medications have failed to achieve advanced clinical development, leaving many patients with unbearable and undermanaged pain. Sex-specific susceptibility to chronic pain conditions as well as sex differences in pain sensitivity, pain tolerance and analgesic efficacy are increasingly recognized in the literature and have thus prompted scientists to seek mechanistic explanations. Hence, recent findings have highlighted that the signaling mechanisms underlying pain hypersensitivity are sexually dimorphic, which sheds light on the importance of conducting preclinical and clinical pain research on both sexes and of developing sex-specific pain medications. This review thus focuses on the clinical and preclinical evidence supporting the existence of sex differences in pain neurobiology. Attention is drawn to the sexually dimorphic role of glial and immune cells, which are both recognized as key players in neuroglial maladaptive plasticity at the origin of the transition from acute pain to chronic pathological pain. Growing evidence notably attributes to microglial cells a pivotal role in the sexually dimorphic pain phenotype and in the sexually dimorphic analgesic efficacy of opioids. This review also summarizes the recent advances in understanding the pathobiology underpinning the development of pain hypersensitivity in both males and females in different types of pain conditions, with particular emphasis on the mechanistic signaling pathways driving sexually dimorphic pain responses.