Search

Introduction Neural mobilization can be performed in a way that facilitates movement through a stretching technique (tensioning) or in a way that maximizes the gliding of peripheral nerves in relation to adjacent structures (gliding). Evidence on how these techniques compare in terms of effects are scarce. The aim of this study is to compare the effects of neural gliding and neural tensioning targeting the median nerve on heat and cold temperature threshold, heat pain threshold, pressure pain thresholds and hand grip strength in asymptomatic participants. Methods Participants received 4 series of 10 repetitions of either neural gliding (n = 30) or neural tensioning (n = 30) and were assessed for heat and cold temperature threshold, heat pain threshold, pressure pain threshold, and hand grip strength at baseline, immediately after the intervention, and 30 min post-intervention. Results A significant main interaction between time and intervention was found for the PPT at the forearm (F(2,55) = 5.98; p = 0.004), favouring the tensioning neural mobilization. No significant differences were found for the other variables. Conclusions Four series of 10 repetitions of neural tensioning targeting the median nerve in asymptomatic subjects seem to be enough to induce hypoalgesia and have no negative effects on A-delta and C mediated sensory function and on hand grip strength production.

BackgroundClinicians nominate the distribution of leg pain as being important in diagnosing nerve root involvement. This study aimed to identify: (i) common unisegmental radicular pain patterns and whether they were dermatomal, and (ii) whether these radicular pain patterns assisted clinician discrimination of the nerve root level involved.MethodsA cross-sectional diagnostic accuracy study of adult patients with radicular leg pain at a hospital in Denmark. All patients had positive neurological signs (average 2.8 signs - hypoalgesia, diminished reflexes, muscle weakness, positive Straight Leg Raise test).Part 1 (pain patterns) was a secondary analysis of baseline pain pattern data collected during a clinical trial. The pain charts of 93 patients with an MRI and clinically confirmed single-level disc herniation with nerve root compression were digitised and layered to form a composite picture of the radicular patterns for the L5 and S1 nerve roots, which were then compared to published dermatomes.In Part 2 (clinical utility) we prospectively measured the discriminative ability of the identified pain patterns. The accuracy was calculated of three groups of six clinicians at classifying the nerve root affected in a randomized sequence of 53 patients, when not shown, briefly shown or continuously shown the composite pain patterns. In each group were two chiropractors, two medical doctors and two physiotherapists.ResultsThere was a wide overlap in pain patterns from compromised L5 and S1 nerve roots but some distinguishing features. These pain patterns had approximately 50 to 80% overlap with published dermatomes. Clinicians were unable to determine with any accuracy above chance whether an individual pain drawing was from a person with a compromised L5 or S1 nerve root, and use of the composite pain drawings did not improve that accuracy.ConclusionsWhile pain distribution may be an indication of radiculopathy, pain patterns from L5 or S1 nerve root compression only approximated those of sensory dermatomes, and level-specific knowledge about radicular pain patterns did not assist clinicians’ diagnostic accuracy of the nerve root impinged. These results indicate that, on their own, pain patterns provide very limited additional diagnostic information about which individual nerve root is affected.

While elite long-distance runners experience hypoalgesia and sometimes runner’s high after running, these phenomena are rarely explored in non-elite runners. Therefore, we examined the effect of a 2-h-run on mood and pain processing in 15 non-elite male runners using repeated painful and nonpainful pinprick stimulation and functional magnetic resonance imaging (fMRI). Pain ratings, pressure pain stimulus responses, and euphoria ratings were assessed immediately after a 2-h-run and at a run-free control day (RFC). Analysis of a half-standardized-interview indicates an improvement of mood. However, there was no elevation of euphoria. Neither in pain ratings nor in fMRI data, we observed less pain perception after the 2-h-run. However, endurance training increases the blood flow of the hippocampal formation. Furthermore, more pressure was required to evoke a clear pain sensation in highly trained athletes at post-run vs. RFC. In summary, we found behavioral and neuroimaging signs that underpin the positive effects of endurance exercise. However, the results also suggest that hypoalgesia and “runner’s high” experience are rather rare phenomena in non-elite endurance runners.

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.

Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes, but any treatment toward the development of DPN is not yet available. Axon degeneration is an early feature of many peripheral neuropathies, including DPN. Delay of axon degeneration has beneficial effects on various neurodegenerative diseases, but its effect on DPN is yet to be elucidated. Deficiency of Sarm1 significantly attenuates axon degeneration in several models, but the effect of Sarm1 deficiency on DPN is still unclear. In this study, we show that Sarm1 knockout mice exhibit normal glucose metabolism and pain sensitivity, and deletion of the Sarm1 gene alleviates hypoalgesia in streptozotocin-induced diabetic mice. Moreover, Sarm1 gene deficiency attenuates intraepidermal nerve fiber loss in footpad skin; alleviates axon degeneration, the change of g-ratio in sciatic nerves, and NAD+ decrease; and relieves axonal outgrowth retardation of dorsal root ganglia from diabetic mice. In addition, Sarm1 gene deficiency markedly diminishes the changes of gene expression profile induced by streptozotocin in the sciatic nerve, especially some abundant genes involved in neurodegenerative diseases. These findings demonstrate that Sarm1 gene deficiency attenuates DPN in mice and suggest that slowing down axon degeneration is a potential promising strategy to combat DPN.

Accurate diagnosis and treatment of pain is dependent on knowledge of the variables that might alter this response. Some of these variables are the locality of the noxious stimulus, the sex of the individual, and the presence of chronic diseases. Among these chronic diseases, hypertension is considered a serious and silent disease that has been associated with hypoalgesia. The main goal of this study was to evaluate the potential nociceptive differences in spontaneously hypertensive rats (SHR) regarding the locality of the stimulus, i.e., the temporomandibular joint or paw, the sex, and the role of ovarian hormones in a model of mechanical nociception (Von Frey test) or formalin-induced inflammatory nociception. Our results indicate that SHR had lower orofacial mechanical nociception beyond the lower mechanical nociception in the paw compared with WKY rats. In a model of formalin-induced inflammatory nociception, SHR also had decreased nociception compared with normotensive rats. We also sought to evaluate the influence of sex and ovarian hormones on orofacial mechanical nociception in SHR. We observed that female SHR had higher mechanical nociception than male SHR only in the paw, but it had higher formalin-induced orofacial nociception than male SHR. Moreover, the absence of ovarian hormones caused an increase in mean arterial pressure and a decrease in paw nociception in female SHR.

© 2019 World Institute of Pain Purpose: To investigate whether people with chronic low back pain (LBP) show dysfunctional exercise-induced hypoalgesia (EIH) in response to repeated contractions of their back muscles during a lifting task. Methods: In this cross-sectional observational study conducted on asymptomatic participants (n = 18) and participants with chronic LBP (n = 21), quantitative sensory testing (QST) was applied extensively over the lumbar region and a remote area before and after a repeated task that involved lifting a 5-kg box for ~7 minutes. QST included pressure pain thresholds (PPTs), thermal detection, pain thresholds, and measures of temporal summation. Topographical maps of the percentage change in PPT detected at 16 locations over the lumbar region were generated to explore regional differences and compared between groups. Results: Mean (standard deviation) PPTs measured from 16 sites over the lower back changed significantly in asymptomatic participants (+29.78 kPa [41.4]) following task completion, indicative of EIH, whereas no significant change was observed for the low back pain (LBP) group (−14.87 kPa [61.2]). No changes were detected at the remote site for either group. No changes were revealed for the thermal tests. Temporal summation data revealed decreasing pain sensitivity as the test progressed, but the test response did not change after the exercise for either group. Conclusion(s): Unlike asymptomatic individuals, participants with LBP lacked EIH over the lumbar erector spinae muscles following repeated lifting. Although these results should be considered in relation to the study limitations, particularly the absence of a control group, the findings support impaired EIH in patients with LBP.

Background sympathoexcitation observed with passive cervical mobilisations may imply activation of an endogenous pain inhibition system resulting in hypoalgesia. However, research is mostly in asymptomatic participants and there is very limited evidence of a relationship between sympathoexcitation and symptomatic improvement in people with clinical pain. Objective to investigate the effects of cervical mobilisations on the sympathetic nervous system in participants with neck pain, and to explore the relationship between symptomatic improvement and sympathoexcitation. Design double-blind randomised controlled trial. Method 40 participants with neck pain (aged 20–69 years, 25 female) were randomly allocated to either cervical mobilisations or motionless placebo. Skin conductance was measured before, during, and after intervention. After interventions were completed, their credibility was assessed. Participants were classified as responders or non-responders according to global symptom change. Results participants receiving mobilisations were more likely to be classified as responders (odds ratio: 4.33, p = 0.03) and demonstrated greater change in most outcome measures of sympathoexcitation from baseline to during the intervention but not from during to after the intervention. There was no association between sympathoexcitation and symptomatic improvement. Mobilisations and placebo were equally credible. Conclusions These findings suggest sympathoexcitatory changes may be caused by an orienting response unrelated to the activation of an endogenous pain inhibition system Alternatively, the observed lack of an association may be explained by the existence of various mechanisms for pain relief. This study used single outcome measures of sympathoexcitation and symptomatic improvement and other measures may reveal different things. ClinicalTrials.gov number M10/2016/095.

Importance Cryotherapy is one of the simplest and oldest therapeutic methods used to alleviate acute soft tissue trauma and muscle soreness. However, inconsistent outcomes have been reported due to inconsistent protocols. Objective To determine if various cryotherapy methods lead to enhanced recovery in athletes and identify optimal methods and protocol for short-term recovery in athletes. Evidence review PubMed/MEDLINE and SPORTDiscus databases were searched from 1 April 1950 to 31 December 2018. The search algorithm used was: (Icing OR Ice Therapy OR Cryotherapy) AND (Athlete OR Sports) NOT (Case Reports). Inclusion criteria was human clinical studies with level 1–4 evidence, a cohort of at least 20 athletes, who were followed to determine the effect cryotherapy had on performance, pain and/or recovery were included. Abstracts, reviews, case reports and conference proceedings were excluded. Seven studies investigating the effect cryotherapy recovery were included. Manual extraction and compilation of demographic, methodology, functional and biochemical outcomes from the studies were completed. Non-randomised trials were assessed using the Methodological Index for Non-Randomised Studies and the randomised were assessed using Oxford quality scoring system. Findings Decreased pain or muscle soreness was seen with cold water immersion(CWI) when compared with passive recovery. Other outcome variables assessed (biomarkers, functional tests) did not reveal consistent findings. Longer icing times (>10 min) were associated with detrimental effects in muscle power and activity. Conclusions and relevance Duration is the critical variable in conventional cryotherapy, with prolonged icing leading to immediate detriment in muscle power and activity. Thus, we recommend using ice cryotherapy following exercise for no longer than 10 min for pure hypoalgesia. CWI had a greater benefit on recovery than passive recovery. Furthermore, CWI has a more beneficial effect on recovery in the first 24 hours following exercise versus immediately postrecovery. We recommend using a protocol to include immersion times of 11–15 min in 11°C–15°C (52°F–59°F) water. Level of evidence Level III.

Over the last 20 years a large number of transgenic mouse models have been produced showing different degrees of congenital hypoalgesia; some of these models mimic known human conditions while others seemingly have no human counterpart. However, very little significant contributions to our understanding of pain neurobiology were obtained from this multitude of animal models; in most cases the study of these animals was limited to the characterization of its pain perception without addressing the long term consequences of their hypoalgesic condition. In this review we discuss the untapped potential that these animal models of congenital hypoalgesia hold for future studies addressing brain plasticity during permanent conditions of reduced pain perception, and that may result in important insights on the interplay between pain, emotion, and cognition. Revisiting hypoalgesia using modern techniques of functional neurophysiology in awake animals may complement the recent literature of functional clinical and preclinical studies that improve our understanding of the central malplasticity caused by pain.

Peripheral neuropathy is the most prevalent chronic complication of diabetes mellitus. Good glycemic control can delay the appearance of neuropathic symptoms in diabetic patients but it is not sufficient to prevent or cure the disease. Therefore therapeutic approaches should focus on attenuation of pathogenetic mechanisms responsible for the nerve injury. Considering the role of polyol pathway in the etiology of diabetic neuropathy, we evaluated the effect of a novel efficient and selective aldose reductase inhibitor, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (cemtirestat), on symptoms of diabetic peripheral neuropathy in Zucker Diabetic Fatty (ZDF) rats. Since the age of 5 months, male ZDF rats were orally administered cemtirestat, 2.5 and 7.5 mg/kg/day, for two following months. Thermal hypoalgesia was evaluated by tail flick and hot plate tests. Tactile allodynia was determined by a von Frey flexible filament test. Two-month treatment of ZDF rats with cemtirestat (i) did not affect physical and glycemic status of the animals; (ii) partially inhibited sorbitol accumulation in red blood cells and the sciatic nerve; (iii) markedly decreased plasma levels of thiobarbituric acid reactive substances; (iv) normalized symptoms of peripheral neuropathy with high significance. The presented findings indicate that inhibition of aldose reductase by cemtirestat is not solely responsible for the recorded improvement of the behavioral responses. In future studies, potential effects of cemtirestat on consequences of diabetes that are not exclusively dependent on glucose metabolism via polyol pathway should be taken into consideration.

Objectives The hypoalgesic effects of exercise are well described, but there are conflicting findings for different modalities of pain; in particular for mechanical vs thermal noxious stimuli, which are the most commonly used in studies of exercise-induced hypoalgesia. The aims of this study were 1) to investigate the effect of aerobic exercise on pressure and heat pain thresholds that were well equated with regard to their temporal and spatial profile and 2) to identify whether changes in the excitability of nociceptive pathways—measured using laser-evoked potentials—accompany exercise-induced hypoalgesia. Subjects Sixteen healthy adults recruited from the University of New South Wales. Methods Pressure and heat pain thresholds and pain ratings to laser stimulation and laser-evoked potentials were measured before and after aerobic cycling exercise and an equivalent period of light activity. Results Pressure pain thresholds increased substantially after exercise (rectus femoris: 29.6%, d = 0.82, P 0.06). Conclusions This is the first investigation to compare the effects of exercise on pressure and heat pain using the same stimulation site and pattern. The results show that aerobic exercise reduces mechanical pain sensitivity more than thermal pain sensitivity.

Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naive mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results: I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 (Trpa1-/- ), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1-/- mice. Conclusion: This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.

Objective. Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. Methods. In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2–4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. Results. Both thermal and mechanical nociceptive thresholds showed a significant decrease (p Conclusion. Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.

AIMS To investigate whether static jaw clenching can activate endogenous pain modulation and to compare the magnitude between healthy individuals and patients with temporomandibular disorder (TMD) myalgia. METHODS Thirty-three healthy volunteers (17 women and 16 men) and 20 women with TMD myalgia participated. Exercise-induced hypoalgesia (EIH) was examined by recording pressure pain thresholds (PPTs) in the masseter (MA) and brachioradialis (BR) muscles during tooth clenching until exhaustion. Pain and fatigue were assessed before and after clenching, and pain amplification was examined by applying a painful mechanical pressure at the MA for 2 minutes while assessing pain every 30 seconds. Analyses of data included repeated measures analysis of variance. RESULTS In the contracting MA, PPTs increased over time in all three groups (P < .001), while PPTs in the relaxed BR increased only in the men (P = .045). Pain intensity and fatigue in the MA increased after contraction in all groups (P < .003) and was higher in the women with TMD than in the healthy women (P < .001). Only the women with TMD showed pain amplification (P < .001). CONCLUSION Tooth clenching until exhaustion could activate EIH locally; ie, the magnitude of EIH in the MA was similar in women with TMD myalgia and pain-free women, indicating no deficient EIH in women with TMD. However, only women with TMD showed pain amplification during application of continuous painful pressure.

Background and aims The relative contribution of patient-related factors and intraoperative nerve damage for the development of chronic pain after surgery is unclear. This study aimed to examine chronic pain after bilateral thoracotomy. We hypothesized, that individual patient-related risk factors would be important resulting in an intraindividual uniformity of pain and hyperphenomena between the two sides of the thorax. Methods Twenty patients who had undergone lung transplantation via bilateral thoracotomy 6–12 months previously were included from the Danish Lung Transplant program, Rigshospitalet, Denmark, from October 2016 to August 2017. All patients answered questionnaires about pain in and around the scar, completed the Neuropathic Pain Symptom Inventory, and underwent bedside examination for hyperphenomena (brush- and cold-evoked allodynia, pinprick hyperalgesia) and pinprick hypoalgesia. Results Nine patients reported spontaneous pain bilaterally, five patients had pain on one side only, and six patients had no pain. Hyperphenomena were present on both sides of the thorax in 13 patients, on one side in four patients, and three patients had no hyperphenomena. The intraindividual uniformity of pain (p=0.029) and hyperphenomena (p=0.011) between the two sides of the thorax suggests that patient-related factors play an important role in the development of chronic pain. Conclusions The results of the present study provide support for the hypothesis of an individual predisposition for the development of chronic pain after thoracotomy. Implications Patient-related risk factors contribute to the development of chronic pain after thoracotomy. This result most likely can be transferred to chronic pain after other surgical procedures and therefore help us understand risk factors for chronic pain after surgery.

Background and aims Prior research indicates that swearing increases pain tolerance and decreases pain perception in a cold pressor task. In two experiments, we extend this research by testing whether taboo hand gesticulations have a similar effect. Methods Study 1 focused on males and females who, across two trials, submerged an extended middle finger (taboo) and an extended index finger (control) in ice water until discomfort necessitated removal. Study 2 focused exclusively on pain perception in males who, across three trials, submerged their hand, flat, with extended middle finger and with extended index finger, for 45 s each. Results In study 1 taboo gesticulation did not increase pain tolerance or reduce pain perception compared with the index finger control condition, as a main effect or as part of an interaction with condition order. While there was a gesture×gender interaction for pain tolerance, this was driven by an increased pain tolerance for the index finger gesture for women but not men. The results of study 2 again showed that taboo gesticulation did not lower pain perception, although it did increase positive affect compared with both non-taboo gesture conditions. Conclusions Taken together these results provide only limited evidence that taboo gesticulation alters the experience of pain. These largely null findings further our understanding of swearing as a response to pain, suggesting that the activation of taboo schemas is not sufficient for hypoalgesia to occur.

The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.

Background Recent neuroimaging evidence suggests that mindfulness practice may mitigate the biasing influence of prior cognitive and emotional expectations on pain perception. The current study tested this hypothesis using a pain-cueing paradigm, which has reliably been shown to elicit conditioned hypoalgesic and hyperalgesic effects. Specifically, we aimed to investigate whether the instructed use of a mindfulness compared to a suppression strategy differentially modulates the magnitudes of conditioned hypoalgesia and hyperalgesia. Methods Sixty-two healthy non-meditators were assigned to listen to either brief mindfulness or suppression instructions, in between the conditioning and testing phases of a pain-cueing task. Participants provided ratings of anticipatory anxiety, pain intensity and pain unpleasantness throughout the task. They also completed trait and state self-report measures of mindfulness and pain catastrophizing. Results Results indicated that the paradigm was successful in inducing conditioned hyperalgesic and hypoalgesic effects. Importantly, while we found evidence of cue-induced hyperalgesia in both groups, only the suppression group reported cue-induced hypoalgesia. No group differences in pain ratings were found for unconditioned (novel-cued) stimuli. Conclusions These findings provide partial support for recently proposed predictive processing models, which posit that mindfulness may lead to a prioritization of current sensory information over previous expectations. We explore potential explanations for the asymmetrical group differences in conditioned hypoalgesia versus conditioned hyperalgesia, and discuss our results in light of recent neuroimaging insights into the neuropsychological mechanisms of mindfulness and expectancy-driven pain modulation. Significance The current study provides novel insights into the working mechanisms of mindfulness-driven pain modulation. Our data suggest that brief mindfulness training may reduce the influence of prior beliefs and expectations on pain perception. This finding adds to growing evidence suggesting that mindfulness may alleviate pain via neuropsychological mechanisms opposite to those typically observed in conditioning/placebo procedures and other cognitive manipulations. These unique mechanisms underline the potential of mindfulness as an alternative to traditional cognitive pain regulatory strategies.

The mechanisms underlying pain modulation by hypnosis and the contribution of hypnotic induction to the efficacy of suggestions being still under debate, our study aimed, (1) to assess the effects of identical hypoalgesia suggestions given with and without hypnotic induction, (2) to compare hypnotic hypoalgesia to distraction hypoalgesia and (3) to evaluate whether hypnotic suggestions of increased and decreased pain share common psychophysiological mechanisms. To this end, pain ratings, nociceptive flexion reflex amplitude, autonomic responses and electroencephalographic activity were measured in response to noxious electrical stimulation of the sural nerve in 20 healthy participants, who were subjected to four conditions: suggestions of hypoalgesia delivered with and without hypnosis induction (i.e. hypnotic-hypoalgesia and suggested-hypoalgesia), distraction by a mental calculation task and hypnotic suggestions of hyperalgesia. As a result, pain ratings decreased in distraction, suggested-hypoalgesia and hypnotic-hypoalgesia, while it increased in hypnotic-hyperalgesia. Nociceptive flexion reflex amplitude and autonomic activity decreased during suggested-hypoalgesia and hypnotic-hypoalgesia but increased during distraction and hypnotic-hyperalgesia. Hypnosis did not enhance the effects of suggestions significantly in any measurement. No somatosensory-evoked potential was modulated by the four conditions according to strict statistical criteria. The absence of a significant difference between the hypnotic hypoalgesia and hyperalgesia conditions suggests that brain processes as evidenced by evoked potentials are not invariably related to pain modulation. Time-frequency analysis of electroencephalographic activity showed a significant differentiation between distraction and hypnotic hypoalgesia in the theta domain. These results highlight the diversity of neurophysiological processes underlying pain modulation through different psychological interventions.

Hypertension-related hypoalgesia, defined as lower pain sensitivity in individuals with high blood pressure, has yet to be examined in a large-scale study of complex care residents. Here, the Continuing Care Reporting System database, which contains health information on residents of Canadian complex chronic care facilities, was used for assessment. Hypertension was reported among 77,323 residents (55.5%, total N = 139,920). Propensity score matching, with a 1:1 ratio, was used to identify a control record without hypertension for each case. Multinomial logistic regression was used to quantify the effects of hypertension and sex on four-level ordinal pain variables, controlling for potential confounders. The matched dataset included n = 40,799 cases with hypertension and n = 40,799 without hypertension, with 57% female. Residents with hypertension had significantly lower odds of reporting pain (yes/no) (OR = 0.85, 95% CI 0.81–0.90, p &lt, 0.001), including on measures of severe pain (OR = 0.69, 95% CI 0.63–0.76, p &lt, 0.001). A significant interaction between hypertension and sex (OR = 1.17, 95% CI 1.03–1.32, p = 0.014) indicated that a significantly greater proportion of females without hypertension reported severe pain (8.71%). The results confirm the relationship between hypertension and reduced pain sensitivity on a population level.

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.

Objectives The effect of stretching on joint range of motion is well documented, and although sensory perception has significance for changes in the tolerance to stretch following stretching the underlining mechanisms responsible for these changes is insufficiently understood. The aim of this study was to examine the influence of endogenous pain inhibitory mechanisms on stretch tolerance and to investigate the relationship between range of motion and changes in pain sensitivity. Methods Nineteen healthy males participated in this randomized, repeated-measures crossover study, conducted on 2 separate days. Knee extension range of motion, passive resistive torque, and pressure pain thresholds were recorded before, after, and 10 min after each of four experimental conditions; (i) Exercise-induced hypoalgesia, (ii) two bouts of static stretching, (iii) resting, and (iv) a remote, painful stimulus induced by the cold pressor test. Results Exercise-induced hypoalgesia and cold pressor test caused an increase in range of motion (p0.507, p=0.01) and exercise-induced hypoalgesia and the cold pressor test (Rho=0.562, p=0.01). A weak correlation in pressure pain thresholds and changes in range of motion were found following the cold pressor test (Rho=0.460, p=0.047). However, a potential carryover hypoalgesic effect may have affected the results of the static stretch. Conclusions These results suggest that stretch tolerance may be linked with endogenous modulation of pain. Present results suggest, that stretch tolerance may merely be a marker for pain sensitivity which may have clinical significance given that stretching is often prescribed in the rehabilitation of different musculoskeletal pain conditions where reduced endogenous pain inhibition is frequently seen.

Background Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. Methods Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. Results The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. Conclusion EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.

Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms begin with hyperesthesia and pain and gradually become hypoesthesia with the loss of nerve fibers. In some cases, lower limb amputation occurs when hypoalgesia makes it impossible to be aware of trauma or mechanical stimuli. On the other hand, up to 50% of these complications are asymptomatic and tend to delay early detection. Therefore, sensitive and reliable biomarkers for diabetic neuropathy are needed for an early diagnosis of this condition. This review focuses on systemic biomarkers that may be useful at this time. It also describes research on the relationship between target gene polymorphisms and pathological conditions. Finally, we also introduce current information on regenerative therapy, which is expected to be a therapeutic approach when the pathological condition has progressed and nerve degeneration has been completed.

Not the type of the procedure (verbal suggestion or conditioning), but the direction of the last-used procedure shapes pain-related expectancies and determines placebo effects., In most experimental studies in which verbal suggestion and classical conditioning are implemented together to induce placebo effects, the former precedes the latter. In naturally occurring situations, however, the information concerning pain does not always precede but often follows the pain experience. Moreover, this information is not always congruent with experience. This study investigates whether the chronology of verbal suggestion and conditioning, as well as their congruence, affects placebo hypoalgesia and nocebo hyperalgesia. The effects induced in 15 groups were compared. The participants in 8 experimental groups were presented with verbal suggestions that were either congruent or incongruent with classical conditioning. The verbal suggestions were provided either before or after conditioning. In 2 other experimental groups, placebo conditioning or nocebo conditioning was implemented without any verbal suggestion; in 2 groups, verbal suggestion of hypoalgesia or hyperalgesia without conditioning was applied. The control groups without any suggestions or conditioning were also included. Placebo hypoalgesia induced by congruent procedures was significantly stronger when the suggestion of hypoalgesia preceded rather than followed conditioning. The order of the congruent procedures did not affect the magnitude of nocebo hyperalgesia. In the groups in which incongruent procedures were implemented, placebo hypoalgesia or nocebo hyperalgesia was in line with the direction of the last-used procedure, regardless of whether it was conditioning or verbal suggestion. The results show that not the type of the procedure (verbal suggestion or conditioning), but the direction of the last-used procedure shapes pain-related expectancies and determines placebo effects.

Background: The use of exercise is a potential treatment option to modulate pain (exercise-induced hypoalgesia). The pain threshold (PT) response is a measure of pain sensitivity that may be a useful marker to assess the effect of physical exercise on pain modulation. Aim: The aim of this systematic review and meta-analysis is to evaluate the PT response to exercise in healthy subjects. Methods: We searched in MEDLINE, EMBASE, Web of Science, Lilacs, and Scopus using a search strategy with the following search terms: "exercise" OR "physical activity" AND "Pain Threshold" from inception to December 2nd, 2019. As criteria for inclusion of appropriate studies: randomized controlled trials or quasi-experimental studies that enrolled healthy subjects; performed an exercise intervention; assessed PT. Hedge's effect sizes of PT response and their 95% confidence intervals were calculated, and random-effects meta-analyses were performed. Results: For the final analysis, thirty-six studies were included (n=1326). From this, we found a significant and homogenous increase in PT in healthy subjects (ES=0.19, 95% CI= 0.11 to 0.27, I2=7.5%). According to subgroup analysis, the effect was higher in studies: with women (ES=0.36); performing strength exercise (ES=0.34), and with moderate intensity (ES=0.27), and no differences by age were found. Confirmed by the meta-regression analysis. Conclusion: This meta-analysis provides evidence of small to moderate effects of exercise on PT in healthy subjects, being even higher for moderate strength exercise and in women. These results support the idea of modulation of the endogenous pain system due to exercise and highlight the need for clinical translation to the chronic pain population.

Hintergrund: Schizophrenie wird in der Literatur vielfach mit einem verminderten Schmerzempfinden (Hypo-/Analgesie) in Verbindung gebracht. Der Großteil der bis Dato durchgeführten Studien bestätigt dies. Dennoch konnte eine Hypo- oder Analgesie bei schizophrenen PatientInnen bisher nicht einheitlich belegt werden. Ebenso gibt es bezüglich der zugrundeliegenden Mechanismen keine klaren Erklärungen. Ziel dieser Arbeit ist es, die aktuelle Evidenzlage zum Thema Schmerzempfinden bei PatientInnen mit Schizophrenie aufzuzeigen, um Schlussfolgerungen für die physiotherapeutische Behandlung von Betroffenen zu ziehen. Methode: Zur Beantwortung der Forschungsfrage - "Wie beeinflusst Schizophrenie das Schmerzempfinden?" – wurde eine systematische Literaturrecherche auf den Datenbanken PubMed, ScienceDirect und ResearchGate mit verschiedensten Kombinationen von Schlüsselwörtern durchgeführt. Eingeschlossen wurden Systematic Reviews/Metaanalysen ab dem Jahr 2000, welche einem gewissen Evidenzlevel und entsprechender Qualitätskriterien entsprachen. Ergebnisse: Insgesamt zwei Systematic Reviews und zwei Metaanalysen entsprachen den Anforderungen. Diese stellen integrative Publikationen der bis Dato durchgeführten Studien zu diesem Thema dar. Conclusio: Der Großteil der bisher vorliegenden Studien zu diesem Thema bestätigen ein vermindertes Schmerzempfinden bei Schizophrenie. Dennoch gibt es Studien mit Ergebnissen, welche auf keine Unterschiede im Schmerzempfinden oder sogar auf eine Hyperalgesie hindeuten. Diese Heterogenität der Ergebnisse kann auf die generell geringe Anzahl bisher durchgeführter Studien und deren qualitative Mängel zurückgeführt werden. Dies ist bei Interpretation und weiteren Forschungsarbeiten zu berücksichtigen. Es gibt zahlreiche Ursachenhypothesen zum verminderten Schmerzempfinden, jedoch eine klare Erklärung wie Schizophrenie das Schmerzempfinden beeinflusst gibt es noch nicht. Hierzu braucht es weitere differenziertere und qualitativ hochwertigere Forschung. Background: Schizophrenia is often associated with a reduced sensitation of pain (hypo-/analgesia). This is confirmed by the majority of conducted studies. Nevertheless, hypoal-gesia or analgesia in schizophrenic patients has not yet been consistently proven. Fur-thermore, there are no clear explanations regarding the underlying mechanisms. The aim of this work is to show the current evidence on the subject of pain perception in patients with schizophrenia in order to draw conclusions for the physiotherapeutic treatment of those affected. Method: To answer the research question - "How does schizophrenia influence the per-ception of pain?" – a systematic literature search on the databases PubMed, ScienceDi-rect and ResearchGate with various combinations of key words was carried out. System-atic reviews/meta-analyses with publication date after 1999, which corresponded to a cer-tain level of evidence and quality criteria, were included. Results: Two systematic reviews and two meta-analyses, covering as integrative publications in large part studies carried out to this topic so far, matched the requirements. Conclusion: The majority of the studies on this topic confirms a reduced pain perception in schizophrenia. Nevertheless, there are studies with results that indicate no differences in pain perception or even hyperalgesia. This heterogeneity of results can be attributed to the generally small number of studies carried out to date and their qualitative deficiencies. This must be taken into account for interpretation and further research work. There are numerous hypotheses concerning the underlying mechanisms of decreased pain perception in schizophrenia, but there is still no clear explanation of how schizophrenia affects pain perception. This requires more differ-entiated and higher quality research.

Aims/hypothesis The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein. Methods Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months. Results In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p p 1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p p Conclusions/interpretation This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers. Graphical abstract

International audience; ABSTRACT: The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire. A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia are just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy, whereas hyperalgesia was more frequent in painful mononeuropathy (compared with painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions. Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide and that painful and painless neuropathic conditions may mechanistically blend into one another. Copyright

Pain is essential for our survival because it helps to protect us from severe injuries. Nociceptive signals may be exacerbated by continued physical activities but can also be interrupted or overridden by physical movements, a process called movement-induced hypoalgesia. Several neural mechanisms have been proposed to account for this effect, including the reafference principle, non-nociceptive interference, and top-down descending modulation. Given that the hypoalgesic effects of these mechanisms temporally overlap during movement execution, it is unclear whether movement-induced hypoalgesia results from a single neural mechanism or from the joint action of multiple neural mechanisms. To address this question, we conducted five experiments on 129 healthy humans by assessing the hypoalgesic effect after movement execution. Combining psychophysics and electroencephalographic recordings, we quantified the relationship between the strength of voluntary movement and the hypoalgesic effect, as well as the temporal and spatial characteristics of the hypoalgesic effect. Our findings demonstrated that movement-induced hypoalgesia results from the joint action of multiple neural mechanisms. This investigation is the first to disentangle the distinct contributions of different neural mechanisms to the hypoalgesic effect of voluntary movement, which extends our understanding of sensory attenuation arising from voluntary movement and may prove instrumental in developing new strategies for pain management.

BackgroundExercise is recommended to promote and maintain health and as treatment for more than 25 diseases and pain conditions. Exercise-induced hypoalgesia (EIH), a measure of descending pain inhibitory control, has been found to be impaired in some chronic pain conditions, but it is currently unclear if EIH is modifiable. This study investigated whether a long-term exercise intervention could modulate EIH in healthy subjects.MethodsIn 38 healthy subjects, EIH was assessed as change in pressure pain threshold (PPT) after a three-minute isometric wall squat within the first week and after approximately seven weeks of military training (MT). Further, temporal summation of pain (TSP) and Knee injury and Osteoarthritis Outcome Score (KOOS) were assessed. Physical performance capacity was assessed using the Endurance 20-m shuttle run fitness test (20MSR). Hypoalgesic (EIH > 0.0 kPa) and hyperalgesic (EIH ≤ 0.0 kPa) subgroups were defined based on baseline EIH. Change in EIH following MT was used as the primary outcome.ResultsIncreased EIH (P = 0.008), PPT (P 0.05). Subjects with a hyperalgesic EIH response at baseline (26% of the participants) presented significantly improved EIH following MT (P = 0.010). Finally, an association between 20MRS change and EIH change was found (r = 0.369, P = 0.023).ConclusionsMT increased EIH, especially in subjects who demonstrated a hyperalgesic response at baseline. Improvement in physical performance capacity was associated with an improvement in EIH, indicating that improvement in physical performance capacity may improve central pain mechanisms.

Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). Methods: A novel PAR1 modulator (PARIN5) was designed based on the thrombin PAR1 recognition site. Coagulation, motor and sensory function and small fiber loss were evaluated by employing the murine streptozotocin diabetes model. Results: PARIN5 showed a safe coagulation profile and showed no significant effect on weight or glucose levels. Diabetic mice spent shorter time on the rotarod (p &lt, 0.001), and had hypoalgesia (p &lt, 0.05), slow conduction velocity (p &lt, 0.0001) and reduced skin innervation (p &lt, 0.0001). Treatment with PARIN5 significantly improved rotarod performance (p &lt, 0.05), normalized hypoalgesia (p &lt, 0.05), attenuated slowing of nerve conduction velocity (p &lt, 0.05) and improved skin innervation (p &lt, 0.0001). Conclusion: PARIN5 is a novel pharmacological approach for prevention of DPN development, via PAR1 pathway modulation.

No large-cohort studies that examine potential racial effects on placebo hypoalgesic effects exist. To fill this void, we studied placebo effects in healthy and chronic pain participants self-identified as either African American/black (AA/black) or white. We enrolled 372 study participants, 186 with a diagnosis of temporomandibular disorder (TMD) and 186 race-, sex-, and age-matched healthy participants to participate in a placebo experiment. Using a well-established paradigm of classical conditioning with verbal suggestions, each individual pain sensitivity was measured to calibrate the temperatures for high- and low-pain stimuli in the conditioning protocol. These 2 temperatures were then paired with a red and green screen, respectively, and participants were told that the analgesic intervention would activate during the green screens to reduce pain. Participants then rated the painfulness of each stimulus on a visual analog scale ranging from 0 to 100. Racial influences were tested on conditioning strength, reinforced expectations, and placebo hypoalgesia. We found that white participants reported greater conditioning effects, reinforced relief expectations, and placebo effects when compared with their AA/black counterparts. Racial effects on placebo were observed in TMD, although negligible, short-lasting, and mediated by conditioning strength. Secondary analyses on the effect of experimenter-participant race and sex concordance indicated that same experimenter-participant race induced greater placebo hypoalgesia in TMDs while different sex induced greater placebo hypoalgesia in healthy participants. This is the first and largest study to analyze racial effects on placebo hypoalgesia and has implications for both clinical research and treatment outcomes.

OBJECTIVE Spontaneous or experimentally induced high blood pressure (BP) is associated with reduced pain perception, known as BP-related hypoalgesia. Despite its clinical implications, such as the interference with early detection of myocardial infarction in 'at risk' groups, the size of the association between high BP and pain has not yet been quantified. Moreover, the distinct association between high BP and physiological or psychological components of pain has not yet been considered so far. The aim of this study was to overcome this gap by performing separate meta-analyses on nociceptive response versus quantifiable perceptual measures of pain in relation to high BP. METHODS PubMed and Web of Knowledge databases were searched for English language studies conducted in humans. Fifty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges' g) were compared. Random effect models were used. Results show that higher BP is significantly associated with lower nociceptive response (g = 0.38; k = 6) and reduced pain perception, assessed by quantifiable measures (g = 0.48; k = 59). RESULTS The association between BP and pain perception, derived from highly heterogeneous studies, was characterized by significant publication bias. BP assessment, pain assessment, site of pain stimulation, percentage of female participants in the sample, and control for potential confounders were significant moderators. CONCLUSION Current meta-analytic results confirm the presence of BP-related hypoalgesia and point towards the need for a better understanding of its underlying mechanisms.