Mechanisms Of Pain Modulation Research Articles

The Link between Endogenous Pain Modulation Changes and Clinical Improvement in Fibromyalgia Syndrome: A Meta-Regression Analysis.

Conditioned pain modulation (CPM) and temporal summation (TS) tests can measure the ability to inhibit pain in fibromyalgia syndrome (FMS) patients and its level of pain sensitization, respectively. However, their clinical validity is still unclear. We studied the association between changes in the CPM and TS tests and the clinical improvement of FMS patients who received therapeutic intervention. We systematically searched for FMS randomized clinical trials with data on therapeutic interventions comparing clinical improvement (pain intensity and symptom severity reduction), CPM, and TS changes relative to control interventions. To study the relationship between TS/CPM and clinical measures, we performed a meta-regression analysis to calculate odds ratios. We included nine studies (484 participants). We found no significant changes in TS or CPM by studying all the interventions together. Our findings show that this lack of difference is likely because pharmacological and non-pharmacological interventions resulted in contrary effects. Non-pharmacological interventions, such as non-invasive neuromodulation, showed the largest effects normalizing CPM/TS. Meta-regression was significantly associated with pain reduction and symptom severity improvement with normalization of TS and CPM. We demonstrate an association between clinical improvement and TS/CPM normalization in FMS patients. Thus, the TS and CPM tests could be surrogate biomarkers in FMS management. Recovering defective endogenous pain modulation mechanisms by targeted non-pharmacological interventions may help establish long-term clinical recovery in FMS patients.

Neural dynamics of pain modulation by emotional valence.

Definitions of human pain acknowledge at least two dimensions of pain, affective and sensory, described as separable and thus potentially differentially modifiable. Using electroencephalography, we investigated perceptual and neural changes of emotional pain modulation in healthy individuals. Painful electrical stimuli were applied after presentation of priming emotional pictures (negative, neutral, positive) and followed by pain intensity and unpleasantness ratings. We found that perceptual and neural event-related potential responses to painful stimulation were significantly modulated by emotional valence. Specifically, pain unpleasantness but not pain intensity ratings were increased when pain was preceded by negative compared to neutral or positive pictures. Amplitudes of N2 were higher when pain was preceded by neutral compared to negative and positive pictures, and P2 amplitudes were higher for negative compared to neutral and positive pictures. In addition, a hierarchical regression analysis revealed that P2 alone and not N2, predicted pain perception. Finally, source analysis showed the anterior cingulate cortex and the thalamus as main spatial clusters accounting for the neural changes in pain processing. These findings provide evidence for a separation of the sensory and affective dimensions of pain and open new perspectives for mechanisms of pain modulation.

Assessing the Influence of Nonischemic A-Fiber Conduction Blockade on Offset Analgesia: An Experimental Study

Offset analgesia (OA) is believed to reflect the efficiency of the endogenous pain modulatory system. However, the underlying mechanisms are still being debated. Previous research suggested both, central and peripheral mechanisms, with the latter involving the influence of specific A-delta-fibers. Therefore, this study aimed to investigate the influence of a nonischemic A-fiber conduction blockade on the OA response in healthy participants. A total of 52 participants were recruited for an A-fiber conduction blockade via compression of the superficial radial nerve. To monitor fiber-specific peripheral nerve conduction capacity, quantitative sensory testing was performed continuously. Before, during, and after the A-fiber block, an individualized OA paradigm was applied to the dorsum of both hands (blocked and control sides were randomized). The pain intensity of each heat stimulus was evaluated by an electronic visual analog scale. A successful A-fiber conduction blockade was achieved in thirty participants. OA has been verified within time (before, during, and after blockade) and condition (blocked and control side) (P < .01, d > .5). Repeated measurements analysis of variance showed no significant interaction effects between OA within condition and time (P = .24, η²p = .05). Hence, no significant effect of A-fiber blockade was detected on OA during noxious heat stimulation. The results suggest that peripheral A-fiber afferents may play a minor role in OA compared with alternative central mechanisms or other fibers. However, further studies are needed to substantiate a central rather than peripheral influence on OA. PerspectiveThis article presents the observation of OA before, during, and after a successful A-fiber conduction blockade in healthy volunteers. A better understanding of the mechanisms of OA and endogenous pain modulation, in general, may help to explain the underlying aspects of pain disorders.

Validity of central pain processing biomarkers for predicting the occurrence of oncological chronic pain: a study protocol

BackgroundDespite recent improvements in cancer detection and survival rates, managing cancer-related pain remains a significant challenge. Compared to neuropathic and inflammatory pain conditions, cancer pain mechanisms are poorly understood, despite pain being one of the most feared symptoms by cancer patients and significantly impairing their quality of life, daily activities, and social interactions. The objective of this work was to select a panel of biomarkers of central pain processing and modulation and assess their ability to predict chronic pain in patients with cancer using predictive artificial intelligence (AI) algorithms.MethodsWe will perform a prospective longitudinal cohort, multicentric study involving 450 patients with a recent cancer diagnosis. These patients will undergo an in-person assessment at three different time points: pretreatment, 6 months, and 12 months after the first visit. All patients will be assessed through demographic and clinical questionnaires and self-report measures, quantitative sensory testing (QST), and electroencephalography (EEG) evaluations. We will select the variables that best predict the future occurrence of pain using a comprehensive approach that includes clinical, psychosocial, and neurophysiological variables.DiscussionThis study aimed to provide evidence regarding the links between poor pain modulation mechanisms at precancer treatment in patients who will later develop chronic pain and to clarify the role of treatment modality (modulated by age, sex and type of cancer) on pain. As a final output, we expect to develop a predictive tool based on AI that can contribute to the anticipation of the future occurrence of pain and help in therapeutic decision making.

Impact of endogenous analgesia triggered by acupuncture, stress, or noxious stimulation on REM sleep-deprived rats.

Poor sleep increases pain, at least in part, by disrupting endogenous pain modulation. However, the efficacy of endogenous analgesia in sleep-deprived subjects has never been tested. To assess this issue, we chose three different ways of triggering endogenous analgesia: (1) acupuncture, (2) acute stress, and (3) noxious stimulation, and compared their ability to decrease the pronociceptive effect induced by REM-SD (Rapid Eye Movement Sleep Deprivation) with that to decrease inflammatory hyperalgesia in the classical carrageenan model. First, we tested the ability of REM-SD to worsen carrageenan-induced hyperalgesia: Alow dose of carrageenan (30 µg) in sleep-deprived Wistar rats resulted in a potentiated hyperalgesic effectthat was more intense and longer-lasting than that induced by a higher standard dose of carrageenan (100 µg) or by REM-SD alone. Then, we found that (1) acupuncture, performed at ST36, completely reversed the pronociceptive effect induced by REM-SD or by carrageenan; (2) immobilization stress completely reversed the pronociceptive effect of REM-SD, while transiently inhibited carrageenan-induced hyperalgesia; (3) noxious stimulation of the forepaw by capsaicin also reversed the pronociceptive effect of REM-SD and persistently increased the nociceptive threshold above the baseline in carrageenan-treated animals. Therefore, acupuncture, stress, or noxious stimulation reversed the pronociceptive effect of REM-SD, while each intervention affected carrageenan-induced hyperalgesia differently. This study has shown that while sleep loss may disrupt endogenous pain modulation mechanisms, it does not prevent theactivation of these mechanisms to induce analgesia in sleep-deprived individuals.

Insular cortex stimulation alleviates neuropathic pain through changes in the expression of collapsin response mediator protein 2 involved in synaptic plasticity

In recent studies, brain stimulation has shown promising potential to alleviate chronic pain. Although studies have shown that stimulation of pain-related brain regions can induce pain-relieving effects, few studies have elucidated the mechanisms of brain stimulation in the insular cortex (IC). The present study was conducted to explore the changes in characteristic molecules involved in pain modulation mechanisms and to identify the changes in synaptic plasticity after IC stimulation (ICS). Following ICS, pain-relieving behaviors and changes in proteomics were explored. Neuronal activity in the IC after ICS was observed by optical imaging. Western blotting was used to validate the proteomics data and identify the changes in the expression of glutamatergic receptors associated with synaptic plasticity. Experimental results showed that ICS effectively relieved mechanical allodynia, and proteomics identified specific changes in collapsin response mediator protein 2 (CRMP2). Neuronal activity in the neuropathic rats was significantly decreased after ICS. Neuropathic rats showed increased expression levels of phosphorylated CRMP2, alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR), and N-methyl-d-aspartate receptor (NMDAR) subunit 2B (NR2B), which were inhibited by ICS. These results indicate that ICS regulates the synaptic plasticity of ICS through pCRMP2, together with AMPAR and NR2B, to induce pain relief.

Regional and widespread pain sensitivity decreases following stretching in both men and women – Indications of stretch-induced hypoalgesia

IntroductionThis study aimed to investigate the effect of sex on regional and widespread pain sensitivity following acute bouts of stretching and to investigate the acute effect of stretching on regional and widespread pain sensitivity following stretching. Methods73 healthy adults (36 females; mean age 25.6 ± 6.7 years) with an age range from 19 to 62 years were recruited for this experimental study. Regional and distant pain pressure pain thresholds, passive knee extension range of motion and passive resistive torque were measured before and 30 s after four bouts of 30-s static muscle stretching of the knee flexors with 20-s rest between bouts. ResultsNo significant sex differences were found for pressure pain thresholds (p > 0.132), range of motion (p = 0.446) or passive resistive torque (p = 0.559) between pre-stretch and post-stretch measures. There were significant increases in pressure pain thresholds (p = 0.010), range of motion (p = 0.001) and passive resistive torque (p = 0.007) between pre-stretch and post-stretch measures. ConclusionMuscle stretching significantly decreased regional and widespread pain sensitivity, indicating that central pain-modulating mechanisms are engaged during muscle stretching, resulting in stretch-induced hypoalgesia. Moreover, the results showed that the effect of stretching on regional and widespread pain sensitivity is not sex-specific.

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

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. 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 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. 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.

Enhancing pain modulation: the efficacy of synchronous combination of virtual reality and transcutaneous electrical nerve stimulation

IntroductionVirtual reality (VR) and transcutaneous electrical nerve stimulation (TENS) have emerged as effective interventions for pain reduction. However, their standalone applications often yield limited analgesic effects, particularly in certain painful...

Brain nuclei and neural circuits in neuropathic pain and brain modulation mechanisms of acupuncture: a review on animal-based experimental research.

Neuropathic pain (NP) is known to be associated with abnormal changes in specific brain regions, but the complex neural network behind it is vast and complex and lacks a systematic summary. With the help of various animal models of NP, a literature search on NP brain regions and circuits revealed that the related brain nuclei included the periaqueductal gray (PAG), lateral habenula (LHb), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC); the related brain circuits included the PAG-LHb and mPFC-ACC. Moreover, acupuncture and injurious information can affect different brain regions and influence brain functions via multiple aspects to play an analgesic role and improve synaptic plasticity by regulating the morphology and structure of brain synapses and the expression of synapse-related proteins; maintain the balance of excitatory and inhibitory neurons by regulating the secretion of glutamate, γ-aminobutyric acid, 5-hydroxytryptamine, and other neurotransmitters and receptors in the brain tissues; inhibit the overactivation of glial cells and reduce the release of pro-inflammatory mediators such as interleukins to reduce neuroinflammation in brain regions; maintain homeostasis of glucose metabolism and regulate the metabolic connections in the brain; and play a role in analgesia through the mediation of signaling pathways and signal transduction molecules. These factors help to deepen the understanding of NP brain circuits and the brain mechanisms of acupuncture analgesia.

Differential Effects of Thermal Stimuli in Eliciting Temporal Contrast Enhancement: A Psychophysical Study

Offset analgesia (OA) is observed when pain relief is disproportional to the reduction of noxious input and is based on temporal contrast enhancement (TCE). This phenomenon is believed to reflect the function of the inhibitory pain modulatory system. However, the mechanisms contributing to this phenomenon remain poorly understood, with previous research focusing primarily on painful stimuli and not generalizing to nonpainful stimuli. Therefore, the aim of this study was to investigate whether TCE can be induced by noxious as well as innocuous heat and cold stimuli. Asymptomatic subjects (n = 50) were recruited to participate in 2 consecutive experiments. In the first pilot study (n = 17), the parameters of noxious and innocuous heat and cold stimuli were investigated in order to implement them in the main study. In the second (main) experiment, subjects (n = 33) participated in TCE paradigms consisting of 4 different modalities, including noxious heat (NH), innocuous heat (IH), noxious cold (NC), and innocuous cold (IC). The intensity of the sensations of each thermal modality was assessed using an electronic visual analog scale. TCE was confirmed for NH (P < .001), NC (P = .034), and IC (P = .002). Conversely, TCE could not be shown for IH (P = 1.00). No significant correlation between TCE modalities was found (r < .3, P > .05). The results suggest that TCE can be induced by both painful and nonpainful thermal stimulation but not by innocuous warm temperature. The exact underlying mechanisms need to be clarified. However, among other potential mechanisms, this may be explained by a thermo-specific activation of C-fiber afferents by IH and of A-fiber afferents by IC, suggesting the involvement of A-fibers rather than C-fibers in TCE. More research is needed to confirm a peripheral influence. PerspectiveThis psychophysical study presents the observation of temporal contrast enhancement during NH, NC, and innocuous cold stimuli but not during stimulation with innocuous warm temperatures in healthy volunteers. A better understanding of endogenous pain modulation mechanisms might be helpful in explaining the underlying aspects of pain disorders.

Relationship between Motor Corticospinal System, Endogenous Pain Modulation Mechanisms and Clinical Symptoms in Patients with Knee Osteoarthritis: New Perspectives on an Old Disease.

Knee osteoarthritis (OA) is a painful condition characterized by joint and bone changes. A growing number of studies suggest that these changes only partially explain the pain experienced by individuals with OA. The purpose of the current study was to evaluate if corticospinal and bulbospinal projection measurements were interrelated in patients with knee OA, and to explore the relationship between these neurophysiological measures and temporal summation (excitatory mechanisms of pain) on one hand, and clinical symptoms on the other. Twenty-eight (28) patients with knee OA were recruited. Corticospinal projections were measured using transcranial magnetic stimulation, while bulbospinal projections were evaluated with a conditioned pain modulation (CPM) protocol using a counter-irritation paradigm. Validated questionnaires were used to document clinical and psychological manifestations. All participants suffered from moderate to severe pain. There was a positive association between corticospinal excitability and the effectiveness of the CPM (rs = 0.67, p = 0.01, n = 13). There was also a positive relationship between pain intensity and corticospinal excitability (rs = 0.45, p = 0.03, n = 23), and between pain intensity and temporal summation (rs = 0.58, p = 0.01, n = 18). The results of this study highlight some of the central nervous system changes that could be involved in knee OA and underline the importance of interindividual variability to better understand and explain the semiology and pathophysiology of knee OA.

“INTEGRO INTEGRated Psychotherapeutic InterventiOn” on the Management of Chronic Pain in Patients with Fibromyalgia: The Role of the Therapeutic Relationship

Fibromyalgia (FM) is a chronic disease characterized by a heterogeneous set of physical and psychological conditions. The chronic experience of disability felt by patients and the impact on quality of life (QoL) of the disease may worsen the cognitive reappraisal ability and contribute to maintaining an altered pain modulation mechanism. This paper presents the study protocol of an INTEGRated psychotherapeutic interventiOn on the management of chronic pain in patients with fibromyalgia (INTEGRO). The aim of the study is to investigate the efficacy of an integrated psychotherapeutic intervention focused on pain management on QoL and pain perception, in a pilot sample of 45 FM patients with idiopathic chronic pain. The contribution of perceived therapeutic relationship (alliance) and physiological attunement, in both the patient and therapist, will be considered as possible mediators of intervention efficacy. Attachment dimensions, traumatic experiences, difficulties in emotion regulation, mindfulness attitude and psychophysiological profile will also be considered as covariates. The objectives are to evaluate longitudinally if patients will experience an increase in QoL perception (primary endpoint), pain-managing self-efficacy and emotion-regulation abilities as well as a reduction in pain intensity (secondary endpoints), considering the mediating role of perceived therapeutic alliance and physiological attunement in both the patient and therapist.

Drosophila pain sensitization and modulation unveiled by a novel pain model and analgesic drugs.

In mammals, pain is regulated by the combination of an ascending stimulating and descending inhibitory pain pathway. It remains an intriguing question whether such pain pathways are of ancient origin and conserved in invertebrates. Here we report a new Drosophila pain model and use it to elucidate the pain pathways present in flies. The model employs transgenic flies expressing the human capsaicin receptor TRPV1 in sensory nociceptor neurons, which innervate the whole fly body, including the mouth. Upon capsaicin sipping, the flies abruptly displayed pain-related behaviors such as running away, scurrying around, rubbing vigorously, and pulling at their mouth parts, suggesting that capsaicin stimulated nociceptors in the mouth via activating TRPV1. When reared on capsaicin-containing food, the animals died of starvation, demonstrating the degree of pain experienced. This death rate was reduced by treatment both with NSAIDs and gabapentin, analgesics that inhibit the sensitized ascending pain pathway, and with antidepressants, GABAergic agonists, and morphine, analgesics that strengthen the descending inhibitory pathway. Our results suggest Drosophila to possess intricate pain sensitization and modulation mechanisms similar to mammals, and we propose that this simple, non-invasive feeding assay has utility for high-throughput evaluation and screening of analgesic compounds.

Adaptive changes in sensorimotor processing in patients with acute low back pain

In low back pain (LBP), primary care and secondary prevention of recurrent and persistent LBP are not always successful. Enhanced understanding of neural mechanisms of sensorimotor processing and pain modulation in patients with acute LBP is mandatory. This explorative fMRI study investigated sensorimotor processing due to mechanosensory stimulation of the lumbar spine. We studied 19 adult patients with acute LBP (< 4 weeks of an acute episode) and 23 healthy controls. On a numeric rating scale, patients reported moderate mean pain intensity of 4.5 out of 10, while LBP-associated disability indicated mild mean disability. The event-related fMRI analysis yielded no between-group differences. However, the computation of functional connectivity resulted in adaptive changes in networks involved in sensorimotor processing in the patient group: Connectivity strength was decreased in the salience and cerebellar networks but increased in the limbic and parahippocampal networks. Timewise, these results indicate that early connectivity changes might reflect adaptive physiological processes in an episode of acute LBP. These findings raise intriguing questions regarding their role in pain persistence and recurrences of LBP, particularly concerning the multiple consequences of acute LBP pain. Advanced understanding of neural mechanisms of processing non-painful mechanosensations in LBP may also improve therapeutic approaches.

Assessment of exercise-induced hypoalgesia in chronic low back pain and potential associations with psychological factors and central sensitization symptoms: A case-control study.

Exercise is the most recommended treatment for chronic low back pain (CLBP) and is effective in reducing pain, but the mechanisms underlying its effects remain poorly understood. Exercise-induced hypoalgesia (EIH) may play a role and is thought to be driven by central pain modulation mechanisms. However, EIH appears to be disrupted in many chronic pain conditions and its presence in people with CLBP remains unclear. As people suffering from chronic pain often exhibit psychological factors and central sensitization symptoms influencing pain perception, EIH might be associated with these factors. The aim of this study is to compare the level of EIH between participants with and without CLBP following back and wrist exercises and to assess the associations between EIH, psychological factors, and symptoms of central sensitization (using the central sensitization inventory - CSI) in CLBP. Twenty-eight participants with CLBP and 23 without pain were recruited. Pressure pain thresholds (PPT) were measured at 4 sites (2 bony sites=capitate, S1|2 muscle sites=wrist flexors, lumbar erector spinae) before and after each of two exercises (wrist flexion and lumbar extension). Exercise-induced hypoalgesia was defined as percent change in PPT from pre- to post-exercise. Participants with CLBP also completed questionnaires to measure psychological factors (e.g., kinesiophobia, catastrophizing, anxiety, and self-efficacy) and symptoms of central sensitization (CSI), and correlations with EIH were calculated. After wrist exercise, EIH measured at the muscle sites was lower in the CLBP group compared with the pain-free group (p=0.047) but no differences were found at bony sites (p=0.49). No significant differences for EIH were observed following back exercise at muscle sites (p=0.14) or at bony sites (p=0.65). Exercise-induced hypoalgesia was not correlated with any psychological factors or with the CSI score. The lower EIH following wrist exercises may represent an alteration in pain modulation control in CLBP. However, psychological factors and central sensitization symptoms may not explain the differences observed.

Anti- and Pro-Nociceptive mechanisms in neuropathic pain after human spinal cord injury.

Deficient endogenous pain modulation and increased nociceptive excitability are key features of central sensitization and can be assessed in humans by conditioned pain modulation (CPM, anti-nociceptive) and temporal summation of pain (TSP, pro-nociceptive), respectively. This study aimed to investigate these measures as proxies for central sensitization in subjects with chronic neuropathic pain (NP) after spinal cord injury (SCI). In paraplegic subjects with NP (SCI-NP; n= 17) and healthy controls (HC; n= 17), parallel and sequential sham-controlled CPM paradigms were performed using pressure pain threshold at the hand, that is, above lesion level, as test stimulus. The conditioning stimulus was a noxious cold (verum) or lukewarm water bath (sham) applied contralaterally. Regarding pro-nociceptive mechanisms, a TSP protocol with individually-adjusted pressure pain stimuli at the thenar eminence was used. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP. Neither the parallel nor sequential sham-controlled CPM paradigm showed any significant inhibition of above-level pressure pain thresholds for SCI-NP or HC. Accordingly, no group difference in CPM capacity was found, however, subjects with more intense spontaneous NP showed lower inhibitory CPM capacity. TSP was observed for both groups but was not enhanced in SCI-NP. Our results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared with HC; however, they also highlight the relevance of spontaneous NP intensity with regards to the capacity of endogenous pain modulation in SCI subjects. Central sensitization encompasses deficient endogenous pain modulation and increased nociceptive excitability. These two mechanisms can be assessed in humans by conditioned pain modulation and temporal summation of pain, respectively. Our data demonstrates a lack of descending pain inhibition only in subjects with severe neuropathic pain which may hint towards central sensitization at spinal and/or supra-spinal levels. Disentangling the mechanisms of endogenous pain modulation and neuronal hyperexcitability might improve mechanism-based treatment of neuropathic pain in subjects with spinal cord injury.

Expectations affect pain sensitivity changes during massage

ABSTRACT Background Pain-inducing massage produces comparable changes in pain sensitivity as a cold pressor task, suggesting shared neurophysiological mechanisms of conditioned pain modulation. Manual therapy and conditioned pain modulation are influenced by positive and negative expectations. Therefore, the purpose of this study was to examine the effects of positive and negative expectations on pain-free and pain-inducing massage. Methods 56 healthy participants were randomly assigned to receive a positive or negative expectation instructional set followed by a pain-inducing or a pain-free massage. Pressure pain threshold (PPT) was measured followed by each interval of massage. A repeated measures ANCOVA controlling for post-randomization differences in sex tested for massage x expectation set x PPT interaction effects, as well as two-way interaction effects. Results A significant three-way interaction effect (p = 0.04) and time x expectation interaction effect was observed for individuals receiving pain inducing massage (p = 0.02). Individuals who received the positive expectation instructional set demonstrated significantly higher PPT at minutes 3 and 4 of massage compared to individuals who received the negative expectation instructional set. Conclusions Expectations impact pain sensitivity changes produced during massage. Clinicians planning to provide pain-inducing massage should consider the role of expectations in modulating pain sensitivity changes.

Temporal Summation in Fibromyalgia Patients: Comparing Phasic and Tonic Paradigms.

IntroductionFibromyalgia (FM) is associated with dysfunctional pain modulation mechanisms, including central sensitization. Experimental pain measurements, such as temporal summation (TS), could serve as markers of central sensitization and have been previously studied in these patients, with conflicting results. Our objective in this study was to explore the relationships between two different protocols of TS (phasic and tonic) and test the associations between these measures and other clinical variables.Materials and MethodsIn this cross-sectional analysis of a randomized clinical trial, patients were instructed to determine their pain-60 test temperature, then received one train of 15 repetitive heat stimuli and rated their pain after the 1st and 15th stimuli: TSPS-phasic was calculated as the difference between those. We also administered a tonic heat test stimulus at the same temperature continuously for 30 s and asked them to rate their pain levels after 10 s and 30 s, calculating TSPS-tonic as the difference between them. We also collected baseline demographic data and behavioral questionnaires assessing pain, depression, fatigue, anxiety, sleepiness, and quality of life. We performed univariable analyses of the relationship between TSPS-phasic and TSPS-tonic, and between each of those measures and the demographic and clinical variables collected at baseline. We then built multivariable linear regression models to find predictors for TSPS-phasic and TSPS-tonic, while including potential confounders and avoiding collinearity.ResultsFifty-two FM patients were analyzed. 28.85% developed summation during the TSPS-phasic protocol while 21.15% developed summation during the TSPS-tonic protocol. There were no variables associated TSPS phasic or tonic in the univariable analyses and both measures were not correlated. On the multivariate model for the TSPS-phasic protocol, we found a weak association with pain variables. BPI-pain subscale was associated with more temporal summation in the phasic protocol (ß = 0.38, p = 0.029), while VAS for pain was associated with less summation in the TSPS-tonic protocol (ß = −0.5, p = 0.009).ConclusionOur results suggest that, using heat stimuli with pain-60 temperatures, a TSPS-phasic protocol and a TSPS-tonic protocol are not correlated and could index different neural responses in FM subjects. Further studies with larger sample sizes would be needed to elucidate whether such responses could help differentiating subjects with FM into specific phenotypes.

INFLUENCE OF PRE-SURGICAL CONDITIONED PAIN MODULATION ON POST-SURGICAL OUTCOMES FOLLOWING TOTAL KNEE REPLACEMENT: A SYSTEMATIC REVIEW

Purpose: Chronic pain after total knee replacement (TKR) surgery is prevalent in approximately 20-35% of patients undergoing surgery. Endogenous pain modulation mechanisms in the central nervous system influences the ultimate pain experience. Accordingly, pre-operative central pain modulatory processes may influence longitudinal outcomes following TKR surgery. The objective of this systematic review is to identify the association between preoperative central modulation of pain as measured by conditioned pain modulation (CPM) and post-operative outcomes (pain and function) in patients who underwent TKR due to knee osteoarthritis (OA).