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.

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.

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.

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.

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.

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.

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.

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.

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.

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].

Transcranial direct current stimulation for provoked vestibulodynia: What roles do psychosexual factors play in treatment response?

There is growing evidence that provoked vestibulodynia (PVD), a frequent and debilitating condition, is characterized by central sensitization. This study aimed to examine predictive factors of transcranial direct current stimulation (tDCS) efficacy in this chronic pain population. Exploratory analysis derived from a randomized controlled trial was performed to assess predictors of pain reduction among 39 women with PVD who received 10 daily sessions of either active or sham tDCS. Clinical characteristics (e.g. pain intensity, duration and pain sensitivity) and psychosexual factors (e.g. pain catastrophizing, pain-related fear, anxiety, depressive symptoms and vaginal penetration cognitions) were assessed at baseline and used to predict tDCS response at 3-month follow-up. Analysis revealed that higher depressive symptoms and lower negative self-image cognitions were significant predictors of pain reduction at follow-up and accounted for 62.3% of the variance in the active tDCS group. Higher genital incompatibility cognitions were related to poorer response, regardless of treatment group. These findings suggest that women with PVD presenting higher depressive symptoms and lower levels of negative self-image cognitions could derive greater benefits from tDCS. These results suggest that tDCS could be effective in a subgroup of women with PVD - a possibility worth exploring with future prospective larger studies.

Classification of Qualitative Fieldnotes Collected During Quantitative Sensory Testing: A Step Towards the Development of a New Mixed Methods Approach in Pain Research.

PURPOSE: Quantitative sensory testing (QST) is a standardized method to assess somatosensory function. The collection of qualitative information, during the QST procedure, could be an interesting way to facilitate the characterization of altered sensory perception and the identification of different pain phenotypes. The aims of this study were 1) to classify qualitative fieldnotes of sensory abnormalities collected during an independent QST study, and 2) to generate a qualitative interview guide that could be included in the traditional QST procedure as a step towards the implementation of a mixed methods approach. PATIENTS AND METHODS: QST data were collected from 48 chronic neuropathic pain patients treated with spinal cord stimulation (SCS). Three body areas, with or without SCS, were tested: the painful limb targeted by SCS, the contralateral area, and the ipsilateral upper limb. After each trial of each QST modality, patients were encouraged to report any sensory abnormalities they could identify with a pain quality scale or using their own words. RESULTS: Qualitative self-reported sensory abnormalities were dichotomized into two groups: altered sensory intensities and altered sensory perceptions. Altered sensory intensities were classified as sensory loss or sensory gain subgroups. Altered sensory perceptions were classified as paresthesia and dysesthesia subgroups Overall, 630 qualitative fieldnotes of altered sensations were collected: 385 on the painful limb, 173 at the contralateral area, and 72 at the ipsilateral upper limb. Based on these qualitative data, we propose a standardized method to collect qualitative data involving 9 open- and close-ended questions and 21 codes. CONCLUSION: Our findings have highlighted the value of qualitative sensory evaluation during QST and constitute an important milestone in the development of a mixed methods protocol in phenotyping research.

Transcutaneous electrical nerve stimulation (TENS): towards the development of a clinic-friendly method for the evaluation of excitatory and inhibitory pain mechanisms.

Background: Temporal summation and conditioned pain modulation (CPM) can be measured using a thermode and cold pressor test (CPTest). Unfortunately, these complex and expensive tools are ill-suited for routine clinical assessments. Aims: We aimed to compare the temporal summation and CPM obtained with the thermode + CPTest paradigm to those obtained with a novel paradigm using transcutaneous electrical nerve stimulation (TENS). Methods: We assessed temporal summation and CPM in 29 healthy participants, using two paradigms (random order): TENS, and thermode + CPTest. In the TENS paradigm, both the conditioning stimulus (CS) and the test stimulus (TS) were delivered using TENS; in the thermode + CPTest paradigm, the CS consisted of a CPTest and the TS was delivered using a thermode. We compared the average temporal summation and CPM evoked by the two paradigms. Results: Average temporal summation was similar for both modalities (P = 0.90), and the number of participants showing temporal summation was similar in both paradigms (19 with thermode vs. 18 with TENS; P = 1.00). Average CPM response was larger following the thermode + CPTest than following the TENS (P = 0.005), and more participants showed CPM with the thermode + CPTest paradigm compared to the TENS paradigm (24 vs. 14; P = 0.01). Conclusions: Both paradigms were roughly equivalent in the ability to evoke temporal summation (although response to one modality did not predict response to the other), but the TENS paradigm appeared to be less apt to induce a CPM response than the thermode + CPTest paradigm.

Contexte: La sommation temporelle et la modulation de la douleur conditionnée (MDC) peuvent être mesurées à l'aide d'une thermode et d'un test au froid. Malheureusement, ces tests complexes et coûteux sont mal adaptés aux évaluations cliniques de routine.Objectifs: Nous avons cherché à comparer la sommation temporelle et la modulation de la douleur conditionnée obtenues avec le paradigme thermode + test au froid à ceux obtenus avec un nouveau paradigme utilisant la neurostimulation électrique transcutanée (TENS).Méthodes: Nous avons évalué la sommation temporelle et la modulation de la douleur conditionnée chez 29 participants en bonne santé, en utilisant les deux paradigmes (ordre aléatoire) : TENS, et thermode + test au froid. Dans le paradigme TENS, Le stimulus de conditionnement et le stimulus d'essai ont été transmis à l'aide de la neurostimulation électrique transcutanée ; dans le paradigme thermode + test au froid, le stimulus de conditionnement consistait en un test au froid et le stimulus d'essai était transmis à l'aide d'une thermode. Nous avons comparé la sommation temporelle et la modulation de la douleur conditionnée moyennes évoqués par les deux paradigmes.Résultats: La sommation temporelle moyenne était similaire pour les deux modalités (P = 0,90), et le nombre de participants ayant montré une sommation temporelle étaient similaires dans les deux paradigmes (19 avec la thermode contre 18 avec la TENS; P = 1,00). La réponse moyenne de modulation de la douleur conditionnée était plus importante après la thermode + test au froid qu'après la neurostimulation électrique transcutanée (P = 0,005), et un plus grand nombre de participants ont montré une modulation de la douleur conditionnée avec la thermode + test au froid par rapport au paradigme TENS (24 contre 14 ; P = 0,01).Conclusions: Les deux paradigmes sont à peu près équivalents en ce qui concerne la capacité d'évoquer la sommation temporelle (bien que la réaction à une modalité ne prévoie pas la réaction à l'autre), mais le paradigme TENS semble moins apte à induire une réponse de modulation de la douleur conditionnée que le paradigme thermode + test au froid.

The effect of conditioning stimulus intensity on conditioned pain modulation (CPM) hypoalgesia.

Background: The magnitude and duration of conditioned pain modulation (CPM) likely depends on the nature and intensity of the conditioning stimulus (CS). Aims: The aim of this study was to measure the effect of CS intensity on the duration of CPM hypoalgesia. Methods: In this single-blind, nonrandomized, repeated measures study, we assessed CPM hypoalgesia in 20 healthy participants following cold pressor tests (CPT) at 7°C and 12°C. The test stimulus, a 60-s heat stimulation, was administered before the CPT and immediately after, and again at 5-min intervals until participants' pain scores returned to pre-CS levels. Two hypoalgesia thresholds were used to establish return to pre-CS level: within -10/100 of baseline and within -20/100 of baseline. Results: CPM hypoalgesia, when defined as a reduction in pain levels >10/100, did not last longer following the more intense 7°C CPT compared to the 12°C CPT (32 min vs. 20 min, respectively; P = 0.06); similar results were obtained when CPM hypoalgesia was defined as a reduction in pain levels of >20/100 (16 min following the 7°C CPT vs. 9 min following the 12°C CPT; P = 0.33). The duration of CPM hypoalgesia was significantly longer when the 10/100 threshold was used compared to the 20/100 threshold, regardless of CPT temperature (P = 0.008 for the 12°C CPT; P < 0.001 for the 7°C CPT). Conclusions: The more intense CS did not induce CPM hypoalgesia of longer duration compared to the less intense CS. The choice of threshold for what constitutes CPM hypoalgesia did have a significant effect on the results.

Contexte: L'ampleur et la durée de la modulation de la douleur conditionnée (MDC) dépendent probablement de la nature et de l'intensité du stimulus de conditionnement.Objectifs: Le but de cette étude était de mesurer l'effet de l'intensité du stimulus de conditionnement sur la durée de l'hypoalgésie par MDC.Méthodes: Dans cette étude en simple aveugle, non randomisée, à mesures répétées, nous avons évalué l'hypoalgésie par MDC chez 20 participants en bonne santé à la suite de tests au froid à 7 ° C et 12 ° C. Le stimulus du test, une stimulation thermique de 60 secondes, a été administré avant le test au froid et immédiatement après, puis à nouveau à des intervalles de cinq minutes jusqu'à ce que les scores de douleur des participants reviennent aux niveaux antérieurs au stimulus de conditionnement.Deux seuils d'hypoalgésie ont été utilisés pour établir le retour au niveau antérieur au stimulus de conditionnement : à l'intérieur de - 10 / 100 de la situation de départ et à l'intérieur de - 20 / 100 de la situation de départ.Résultats: L'hypoalgésie par MDC, définie comme une réduction des niveaux de douleur > 10 / 100, n'a pas duré plus longtemps après le test au froid plus intense de 7 ° C que le test au froid de 12 ° C (32 minutes comparativement à 20 minutes, respectivement ; P = 0,06) ; des résultats similaires ont été obtenus lorsque l'hypoalgésie par MDC était définie comme une réduction des niveaux de douleur > 20 / 100 (16 minutes après le test au froid à 7 ° C comparativement à 9 minutes après le test au froid à 12 ° C ; P = 0,33).La durée de l'hypoalgésie par MDC était significativement plus longue lorsque le seuil 10 / 100 était utilisé comparativement au seuil 20 / 100, quelle que soit la température du test au froid (P = 0,008 pour le test au froid à 12 ° C ; P < 0,001 pour le test au froid à 7 ° C).Conclusions: Le stimulus de conditionnement plus intense n'a pas induit d'hypoalgésie par MDC de plus longue durée comparativement au stimulus de conditionnement moins intense. Le choix du seuil pour ce qui constitue une hypoalgésie par MDC a eu un effet significatif sur les résultats.

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.

Comparison of Thermal and Electrical Modalities in the Assessment of Temporal Summation of Pain and Conditioned Pain Modulation.

Temporal summation of pain (TSP) and conditioned pain modulation (CPM) can be measured using a thermode and a cold pressor test (CPT). Unfortunately, these tools are complex, expensive, and are ill-suited for routine clinical assessments. Building on the results from an exploratory study that attempted to use transcutaneous electrical nerve stimulation (TENS) to measure CPM and TSP, the present study assesses whether a "new" TENS protocol can be used instead of the thermode and CPT to measure CPM and TSP. The objective of this study was to compare the thermode/CPT protocol with the new TENS protocol, by (1) measuring the association between the TSP evoked by the two protocols; (2) measuring the association between the CPM evoked by the two protocols; and by (3) assessing whether the two protocols successfully trigger TSP and CPM in a similar number of participants. We assessed TSP and CPM in 50 healthy participants, using our new TENS protocol and a thermode/CPT protocol (repeated measures and randomized order). In the TENS protocol, both the test stimulus (TS) and the conditioning stimulus (CS) were delivered using TENS; in the thermode/CPT protocol, the TS was delivered using a thermode and the CS consisted of a CPT. There was no association between the response evoked by the two protocols, neither for TSP nor for CPM. The number of participants showing TSP [49 with TENS and 29 with thermode (p < 0.001)] and CPM [16 with TENS and 30 with thermode (p = 0.01)] was different in both protocols. Our results suggest that response to one modality does not predict response to the other; as such, TENS cannot be used instead of a thermode/CPT protocol to assess TSP and CPM without significantly affecting the results. Moreover, while at first glance it appears that TENS is more effective than the thermode/CPT protocol to induce TSP, but less so to induce CPM, these results should be interpreted carefully. Indeed, TSP and CPM response appear to be modality-dependent as opposed to an absolute phenomenon, and the two protocols may tap into entirely different mechanisms, especially in the case of TSP.

Development and Validation of a Predictive Model of Pain Modulation Profile to Guide Chronic Pain Treatment: A Study Protocol.

Introduction: Quantitative sensory testing is frequently used in research to assess endogenous pain modulation mechanisms, such as Temporal Summation (TS) and Conditioned Pain Modulation (CPM), reflecting excitatory and inhibitory mechanisms, respectively. Numerous studies found that a dysregulation of these mechanisms is associated with chronic pain conditions. In turn, such a patient's "profile" (increased TS and/or weakened CPM) could be used to recommend different pharmacological treatments. However, the procedure to evaluate these mechanisms is time-consuming and requires expensive equipment that is not available in the clinical setting. In this study, we aim to identify psychological, physiological and socio-demographic markers that could serve as proxies to allow healthcare professionals to identify these pain phenotypes in clinic, and consequently optimize pharmacological treatments. Method: We aim to recruit a healthy participant cohort (n = 360) and a chronic pain patient cohort (n = 108). Independent variables will include psychological questionnaires, pain measurements, physiological measures and sociodemographic characteristics. Dependent variables will include TS and CPM, which will be measured using quantitative sensory testing in a single session. We will evaluate one prediction model and two validation models (for healthy and chronic pain participants) using multiple regression analysis between TS/CPM and our independent variables. The significance thresholds will be set at p = 0.05, respectively. Perspectives: This study will allow us to develop a predictive model to compute the pain modulation profile of individual patients based on their biopsychosocial characteristics. The development of the predictive model is the first step toward the overarching goal of providing clinicians with a set of quick and cheap tests, easily applicable in clinical practice to orient pharmacological treatments.

Medial Orbitofrontal De-Activation During Tonic Cold Pain Stimulation: A fMRI Study Examining the Opponent-Process Theory.

BACKGROUND: While the concomitant administration of painful and rewarding stimuli tends to reduce the perception of one another, recent evidence shows that pleasant pain relief is experience after the interruption of noxious stimuli. On neurobiological grounds, these opponent processes should translate into decreased activity in brain reward regions during nociceptive stimulation and increased activity in these regions after its interruption. While growing evidence supports the latter assumption, evidence is lacking in humans in support of the former. METHODS: Twenty-six healthy individuals underwent a functional magnetic resonance imaging (fMRI) session during which they were administered a cold pain stimulation, using a novel paradigm which consisted in a cold gel applied on the right foot of participants. RESULTS: After the interruption of noxious stimulation, participants experienced significant levels of pleasant pain relief. During cold pain stimulation, brain activations were observed in key regions of the pain matrix (eg, thalamus, primary somatosensory cortex and insula). Conversely, the medial orbitofrontal cortex was found to be de-activated. Medial orbitofrontal de-activations were negatively correlated with subclinical pain symptoms. DISCUSSION: Our results show that a key brain reward region (eg, medial orbitofrontal cortex) is de-activated during cold pain stimulation, a result which is consistent with one of the central assumptions of the opponent-process theory. On methodological grounds, our results show that the cold gel applied to the foot can be used to trigger activations in the pain matrix, and that the interruption of the cold pressor test elicits significant levels of pleasant pain relief. fMRI studies on pain-reward interactions in chronic pain patients are warranted.