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.

Nocebo Effect on Pain Perception and Attention with Children With and Without Attention Deficit And/Or Hyperactivity Disorder.

OBJECTIVE: Attention deficit disorder with or without hyperactivity (ADHD) has negative consequences for children. The effectiveness of medical interventions and educational outcomes are strongly influenced by expectations, which can be modulated by nocebo effects. The aims of this study were to compare the nocebo effect on pain perception and attention in children with and without ADHD as well as to characterize the associations of the nocebo effect with personal variables, such as anxiety, sleep, and pain catastrophizing. METHODS: Data were collected from 30 children with and without ADHD. The nocebo effect was induced using an inactive pill, "increasing" pain perception and attention deficits. Experimental thermal pain was evoked using a thermode and recorded using a computerized visual analog scale. Attention abilities were measured with the Stop-Signal Task. We also used questionnaires to measure personal variables. RESULTS: When combining groups, the nocebo treatment led to comparable nocebo effects for pain (increased pain perception) and attention (increased time needed for inhibition). When comparing groups, the nocebo effect on pain perception was similar for children with and without ADHD. Inattention, learning problems, anxiety, and sleep problems were associated with the nocebo response for pain and attention. CONCLUSION: This exploratory study conducted in an experimental setting emphasizes the importance of managing children's expectations for pain perception and attention as well as the potentially deleterious impact of negative suggestions on elementary school children.

Reliability and minimal detectable change of dynamic temporal summation and conditioned pain modulation using a single experimental paradigm.

BACKGROUND: Quantitative sensory tests (QST) are frequently used to explore alterations in somatosensory systems. Static and dynamic QST like pain threshold and temporal summation (TS) and conditioned pain modulation (CPM) are commonly used to evaluate excitatory and inhibitory mechanisms involved in pain processing. The aim of the present study was to document the reliability and the minimal detectable change (MDC) of these dynamic QST measurements using a standardized experimental paradigm. MATERIAL AND METHODS: Forty-six (46) pain-free participants took part in 2 identical sessions to collect TS and CPM outcomes. Mechanical (pressure pain threshold [PPT]) and thermal (constant 2-minute heat pain stimulation [HPS]) nociceptive stimuli were applied as test stimuli, before and after a cold-water bath (conditioning stimulus). TS was interpreted as the change in pain perception scores during HPS. CPM were determined by calculating the difference in pain perception between pre- and post- water bath for both PPT and HPS. Relative and absolute reliability were analyzed with intra-class correlation coefficient (ICC2, k), standard error of the measurements (SEMeas) and MDC. RESULTS: Results revealed a good to excellent relative reliability for static QST (ICC ≥ 0.73). For TS, a poor to moderate relative reliability depending on the calculation methods (ICC = 0.25 ≤ ICC ≤ 0.59), and a poor relative reliability for CPM (ICC = 0.16 ≤ ICC ≤ 0.37), both when measured with mechanical stimulation (PPT) and thermal stimulation (HPS). Absolute reliability varied from 0.73 to 7.74 for static QST, 11 to 22 points for TS and corresponded to 11.42 points and 1.56 points for thermal and mechanical-induced CPM, respectively. MDC analyses revealed that a change of 1.58 to 21.46 point for static QST, 31 to 52 points for TS and 4 to 31 points for CPM is necessary to be interpreted as a real change. CONCLUSION: Our approach seems well-suited to clinical use. Although our method shows equivalent relative and absolute reliability compared to other protocols, we found that the reliability of endogenous pain modulation mechanisms is vulnerable, probably due to its dynamic nature.

Data-driven dynamic profiles of tonic heat pain perception in pain-free volunteers are associated with differences in anandamide levels.

Our laboratory previously developed a method for assessing experimentally induced pain perception through a 2-min constant heat pain stimulation. However, the traditional analysis relying on group means struggles to interpret the considerable inter-individual variability due to the dynamic nature of the response. Recently, trajectory analysis techniques based on extended mixed models have emerged, providing insights into distinct response profiles. Notably, these methods have never been applied to pain paradigms before. Furthermore, various socio-demographic and neurobiological factors, including endocannabinoids, may account for these inter-individual differences. This study aims to apply the novel analysis to dynamic pain responses and investigate variations in response profiles concerning socio-demographic, psychological, and blood endocannabinoid concentrations. 346 pain-free participants were enrolled in a psychophysical test involving a continuous painful heat stimulation lasting for 2 min at a moderate intensity. Pain perception was continuously recorded using a computerized visual scale. Dynamic pain response analyses were conducted using the innovative extended mixed model approach. In contrast to the traditional group-mean analysis, the extended mixed model revealed three pain response trajectories. Trajectory 1 is characterized by a delay peak pain. Trajectory 2 is equivalent to the classic approach (peak pain follow by a constant and moderate increase of pain perception). Trajectory 3 is characterized by extreme responses (steep peak pain, decrease, and increase of pain perception), Furthermore, age and blood anandamide levels exhibited significant variations among these three trajectories. Using an innovative statistical approach, we found that a large proportion of our sample had a response significantly different from the average expected response. Endocannabinoid system seems to play a role in pain response profile.

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.

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].

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.

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.

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.

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.