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Abstract: The idea that emotions can influence pain is generally recognized. However, a synthesis of the numerous individual experimental studies on this subject is lacking. The aim of the present systematic review and meta-analysis was to synthesize the existing evidence on the effect of experimental emotion induction on experimental pain in nonclinical adults. PsycInfo and PubMed were searched up until April 10, 2023, for studies assessing differences in self-reported pain between emotion induction groups and/or control groups or between conditions within group. Risk of bias was assessed for the individual studies. The literature search yielded 78 relevant records of 71 independent studies. When compared with control conditions, the pooled results revealed a statistically significant pain-attenuating effect of positive emotion induction (between-group: Hedges g = -0.48, 95% CI: -0.72; -0.25, K = 9; within-group: g = -0.24, 95% CI: -0.32; -0.15, K = 40), and a statistically significant pain-exacerbating effect of negative emotion induction in within-group analyses but not between-group analyses (between-group: g = -0.29, 95% CI: -0.66; 0.07, K = 10; within-group: g = 0.14, 95% CI: 0.06; 0.23, K = 39). Bayesian meta-analysis provided strong support for an effect of positive emotion induction but weak support for an effect of negative emotion induction. Taken together, the findings indicate a pain-attenuating effect of positive emotion induction, while the findings for negative emotion induction are less clear. The findings are discussed with reference to theoretical work emphasizing the role of motivational systems and distraction for pain. Limitations include considerable heterogeneity across studies limiting the generalizability of the findings., (Copyright © 2023 International Association for the Study of Pain.)

Objectives: Pain catastrophizing in the aging population has not been studied in great detail. Existing investigations have reported conflicting results on the effects of age on pain catastrophizing in relation to pain responses. This study investigated the relationship between pain catastrophizing, and its individual components (rumination, magnification, and helplessness), and the responses to standardized experimental pain stimuli in old and young, healthy adults., Methods: Sixty-six volunteers (32 old: 65-87, 18 females; 34 young: 20-35, 17 females) participated in the study. Pain catastrophizing including the components of rumination, magnification, and helplessness was assessed with the pain catastrophizing scale (PCS). Experimental pain was induced by applying predefined pressure stimulations to the trapezius muscle. Pain intensity and unpleasantness were assessed using numerical rating scales. Pain catastrophizing levels and pain responses were statistically compared between the two age groups., Results: Elderly individuals reported significantly ( p = 0.028) lower scores of pain catastrophizing (Med = 5; interquartile range [IQR] = 14) than younger individuals; this difference was driven by the significantly lower components of rumination (Med = 2; IQR = 4; p = 0.017) and helplessness (Med = 2; IQR = 7; p = 0.049). A larger proportion of young (57.8%) rated pain catastrophizing at high levels, with scores above the 75th percentile (Med = 20). Additionally, elderly reported the lowest pain intensity (Med = 5; p = 0.034) and pain unpleasantness (Med = 4.5; p = 0.011) responses to the experimental pressure stimuli. In the elderly group, pain unpleasantness was positively and significantly associated with pain catastrophizing ( r s = 0.416, p = 0.021), rumination ( r s = 0.42, p = 0.019), and helplessness ( r s = 0.434, p = 0.015), respectively. No associations were found in the young group., Conclusions: Elderly reported lower PCSs than young adults. Rumination and helplessness were reduced in the elderly group. The elderly population showed positive correlations between catastrophizing levels and pain unpleasantness to standardized pressure pain stimuli. Results supported the view that elderly possess resilience over specific domains of pain catastrophizing that could counteract pain perception due to physiological decline., (© 2024 the author(s), published by De Gruyter.)

Aim: This study aims to profile migraine patients according clinical and psychophysical characteristics., Method: In this observational study, two cohorts of migraine patients(episodic/chronic) were included. Cohort-1: ictal/perictal phase; Cohort-2: interictal phase.The following variables were assessed: headache frequency; disability; cervical active range of motion(AROM) in flexion, extension, right/left lateral flexion, right/left rotation; pressure-pain threshold(PPT) over: temporalis, two cervical areas(C1/C4 vertebral segments), and two distal pain-free areas(hand/leg). Cluster analysis was performed using the K-means algorithm. Differences across clusters were investigated., Results: Cohort-1: 100 patients were included, and two clusters were identified. Cluster-1.1 (19%), Cluster-1.2 (81%). Cluster 1.1 had a higher percentage of men (P = .037) and higher disability (P = .003) compared to Clusters 1.2. Cluster 1.2 had reduced AROM in flexion, extension, and left/right lateral flexion (P < .037), and lower PPT value in all areas (P < .001) compared to Cluster 1.1. Cohort-2: 98 patients were included and three clusters were identified. Cluster-2.1(18%), Cluster-2.2(45%), and Cluster-2.3(37%). Cluster-2.1 had a higher percentage of men compared to clusters-2.2 and 2.3 (P = .009). Cluster-2.3 had higher headache frequency, and disability compared to Cluster-2.2 (P < .006), and higher disability compared to Cluster-2.1 (P = .010). Cluster-2.3 had reduced AROM in all directions compared to Clusters-2.1 and 2.2 (P < .029). Clusters-2.2 and 2.3 have lower PPT values in all areas compared to Cluster-1.1 (P < .001)., Conclusion: In the Ictal/perictal phase, two clusters were identified according to clinical and psychophysical characteristics, with one group showing no psychophysical impairment and one with increased pain-sensitivity and cervical musculoskeletal-dysfunctions.In the interictal phase, three clusters could be identified, with one group showing no psychophysical impairment, one increased pain-sensitivity, and one increased pain sensitivity and cervical musculoskeletal-dysfunctions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: It has been hypothesized that the presence of chronic pain causes excess mortality. Since chronic pain is prevalent among patients with PsA this potential association should be explored. We aimed to investigate whether higher cumulative pain intensity is associated with an excess mortality risk in patients with PsA., Methods: A nested case-control study using data from the nationwide DANBIO Register (Danish Database for Biological Therapies in Rheumatology) Register and Danish healthcare registers. Cases were patients who died and corresponding to the date of death, matched on sex, year of birth and calendar period at the time of death with up to five controls. Exposure of interest was mean pain intensity reported during the time followed in routine rheumatology practice. Pain intensity was measured using a visual analogue scale from 0 to 100 and conditional logistic regression was used to calculate odds of mortality per 5 unit increase in pain while adjusting for confounders., Results: The cohort consisted of 8019 patients. A total of 276 cases were identified and matched with 1187 controls. Higher mean pain intensity was associated with increased odds of mortality [odds ratio 1.06 (95% CI 1.02, 1.10)] in the crude model, but there was no association [odds ratio 0.99 (95% CI 0.95, 1.03)] when adjusting for additional confounders. Factors shown to increase the odds of mortality were recent glucocorticoid use, concomitant chronic obstructive pulmonary disease, diabetes mellitus, cancer and cardiovascular disease., Conclusion: These results indicate that experienced pain in itself is not associated with premature mortality in patients with PsA. However, recent glucocorticoid use and concurrent comorbidities were., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, 2 skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in 1 placebo and 1 EMLA pretreated area, obtaining the following four areas: Capsaicin + EMLA, Capsaicin + Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-hour application of capsaicin. Warmth detection, heat pain sensitivity, and microvascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare. Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (P= .007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (P< .01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (P< .001). Twenty-four hours post application, heat pain sensitivity was normalized. However, WDT increased significantly (P< .001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (P< .05) induced by histamine compared with EMLA alone. The findings suggest that pretreatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization. PERSPECTIVE: Pretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Most patients with atrial fibrillation (AF) report symptoms, while one-third are asymptomatic. We hypothesised that sensory processing, in particular pain, differs in patients with symptomatic and asymptomatic AF., Methods: Thirty individuals with permanent AF (15 symptomatic and 15 asymptomatic) completed the Atrial Fibrillation 6 (AF6) and short form 36 Health Survey questionnaires and underwent quantitative pain sensitisation testing using pressure algometry at the sternum (referred pain area) and the tibialis anterior muscle (generalised pain area). The primary objective was to assess differences in pressure pain thresholds (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM) in the two groups. The secondary objective was to determine association of demographic and clinical parameters to measures of pain sensitisation., Results: The symptomatic group had lower PPTs at both tibialis (p=0.004) and sternum (p=0.01), and impaired CPM (p=0.025) and facilitated TSP (p=0.008) at the tibialis but not sternum, compared with the asymptomatic group. The AF6 sum score was negatively correlated to PPT on both tibialis (r=-0.50, p=0.005) and sternum (r=-0.42, p=0.02) and positively correlated to TSP on both tibialis (r=0.57, p=0.001) and sternum (r=0.45, p=0.01), but not to CPM. The physical component summary score was positively correlated to the PPT on both tibialis (r=0.52, p=0.003) and sternum (r=0.40, p=0.03) and negatively to TSP on the tibialis (r=-0.53, p=0.003) but not sternum., Conclusions: Patients with symptomatic AF exhibit lower pain tolerance than patients with asymptomatic AF, as well as impaired pain inhibitory control and facilitated summation of pain, indicating that pain sensitisation may be of importance in symptomatic AF.Trial registration numberNCT04649437., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Improving the ability to predict persistent pain after spine surgery would allow identification of patients at risk and guide treatment decisions. Quantitative sensory tests (QST) are measures of altered pain processes, but in our previous study, preoperative QST did not predict pain and disability at single time-points. Trajectory analysis accounts for time-dependent patterns. We hypothesized that QST predict trajectories of pain and disability during 1 year after low back surgery. We performed a trajectory analysis on the cohort of our previous study (n = 141). Baseline QST included electrical, pressure, heat, and cold stimulation of the low back and lower extremity, temporal summation, and conditioned pain modulation. Pain intensity and Oswestry Disability Index were measured before, and 2, 6, and 12 months after surgery. Bivariate trajectories for pain and disability were computed using group-based trajectory models. Multivariable regressions were used to identify QST as predictors of trajectory groups, with sociodemographic, psychological, and clinical characteristics as covariates. Cold pain hypersensitivity at the leg, not being married, and long pain duration independently predicted worse recovery (complete-to-incomplete, incomplete-to-no recovery). Cold pain hypersensitivity increased the odds for worse recovery by 3.8 (95% confidence intervals 1.8-8.0, P < 0.001) and 3.0 (1.3-7.0, P = 0.012) in the univariable and multivariable analyses, respectively. Trajectory analysis, but not analysis at single time-points, identified cold pain hypersensitivity as strong predictor of worse recovery, supporting altered pain processes as predisposing factor for persisting pain and disability, and a broader use of trajectory analysis. Assessment of cold pain sensitivity may be a clinically applicable, prognostic test.

Background: A method for assessing dynamic muscle hyperalgesia (dynamic pressure algometry) has been developed and applied in tension-type and migraine headaches., Objectives: To investigate differences in dynamic pressure pain assessment over the trigeminal area between men with cluster headache (CH) and headache-free controls, and the association between dynamic and static pressure pain sensitivity., Study Design: A case-control study., Setting: Tertiary urban hospital., Methods: Forty men with episodic CH and 40 matched controls participated. Dynamic pressure pain sensitivity was assessed with a dynamic pressure algometry set consisting of 8 rollers with different fixed levels (500, 700, 850, 1,350, 1,550, 2,200, 3,850, and 5,300 g). Each roller was moved at a speed of 0.5 cm/sec over a diagonal line covering the temporalis muscle from an anterior to posterior direction. The dynamic pressure threshold (DPT; load level of the first painful roller) and the pain intensity perceived at the DPT level (roller-evoked pain) were assessed. Static pressure pain thresholds (PPT) were also assessed with a digital pressure algometer applied statically over the mid-muscle belly of the temporalis. Patients were assessed in a remission phase, at least 3 months from the last cluster attack, and without preventive medication., Results: Side-to-side consistency between DPTs (r = 0.781, P < 0.001), roller-evoked pain on DPT (r = 0.586; P < 0.001), and PPTs (r = 0.874; P < 0.001) were found in men with CH. DPT was moderately, bilaterally, and side-to-side associated with PPTs (0.663 > r > 0.793, all P < 0.001). Men with CH had bilateral lower DPT and PPT and reported higher levels of roller-evoked pain (all P < 0.001) than headache-free controls., Limitations: Only men with episodic CH were included., Conclusions: This study supports that a dynamic pressure algometry is as valid as a static pressure algometry for assessing pressure pain sensitivity in patients with CH. Assessing both dynamic and static pain sensitivity may provide new opportunities for differentiated diagnostics., Key Words: Cluster headache, dynamic pressure pain, pressure pain threshold.

Exosomes are extracellular microvesicles implicated in intercellular communication with ability to transfer cargo molecules, including protein, lipids, and nucleic acids, at both close and distant target sites. It has been shown that exosomes are implicated in physiological and pathological processes. In recent years, the interest on exosomes' role in many pain states has increased. Their involvements in pain processes have been demonstrated by studies on different chronic pain diseases, both inflammatory and neuropathic, such as osteoarthritis, rheumatoid arthritis, inflammatory bowel diseases, neurodegenerative pathologies, complex regional pain syndrome, and peripheral nerve injury. Animal and clinical studies investigated exosomes-based treatments, showing their ability to improve painful symptoms with fewer side effects, with potential immunoprotective and anti-inflammatory effect. Specific molecular patterns characterize exosomes' cargo according to the cellular origin, epigenetic modifications, environmental state, and stressor factors. Therefore, the identification of specific cargo's profile associated to pain states may lead to recognize specific pathological states and to consider the use of exosomes as biomarkers of diseases. Furthermore, exosomes' ability to transfer information and their presence in many accessible biological fluids suggest a potential use as novel non-invasive therapeutic tools in pain field.

Objectives: Synovitis is one of the possible pain generators in osteoarthritis (OA) and is associated with upregulation of proinflammatory cytokines, which can lead to worsening of the postoperative pain. This exploratory study aimed to investigate the association between perioperative synovitis and self-reported pain 12 months after total knee arthroplasty (TKA) in patients with OA., Materials and Methods: Twenty-six knee OA patients were included in this analysis. The perioperative volume of synovitis in predefined locations was assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Perioperative synovitis was assessed histologically from biopsies of the synovium. Highest pain intensity within the last 24 hours (Visual Analog Scale, VAS, 0 to 100) was assessed before and 12 months after TKA. Patients were divided into a low-pain intensity (VAS≤30) and a high-pain intensity (VAS>30) group on the basis of 12 months postoperative VAS., Results: The high-pain intensity group had significantly lower perioperative contrast-enhanced-synovitis (P=0.025), DCE-synovitis (P<0.04), and a trend toward lower histologically assessed synovitis (P=0.077) compared with the low-pain intensity group. Perioperative synovitis scores were inversely correlated with pain intensity 12 months after TKA (P<0.05), indicating that more severe perioperative synovitis is associated with less severe pain intensity at 12 months., Discussion: Higher degrees of perioperative synovitis scores are found to be associated with less postoperative pain 12 months after TKA. Further, correlation analysis revealed that less severe perioperative CE-MRI and DCE-MRI synovitis was associated with higher pain intensity 12 months after TKA, suggesting that CE-MRI and DCE-MRI synovitis grades could be used as imaging markers for prediction of chronic postoperative pain after TKA.

Competing Interests: Competing interests: None declared.

Objectives: The aims of this study were: (1) to investigate the association between the rs4680 Val158Met polymorphism in frequent episodic tension-type headache (FETTH) and chronic tension-type headache (CTTH); and (2) to analyze the association between the rs4680 Val158Met polymorphism with clinical, psychological, or psychophysical variables., Methods: In total, 50 women with FETTH, 50 with CTTH, and 50 matched headache-free women participated. After amplifying Val158Met polymorphism by polymerase chain reaction, the genotype frequencies and allele distributions based on restriction fragment length polymorphism were assessed. Participants were classified according to the Val158Met polymorphism rs4680 genotype (Val/Val, Val/Met, or Met/Met). A headache diary collected clinical features. Disability (Headache Disability Inventory), sleep quality (Pittsburgh Sleep Quality Index), and depression/anxiety levels (Hospital Anxiety and Depression Scale) were also assessed. Pressure pain thresholds were assessed bilaterally over the temporalis, upper trapezius, second metacarpal, and tibialis anterior by a blinded assessor., Results: The distribution of rs4680 Val158Met genotype was not significantly different between women with/without headache (P=0.796). No differences in headache features, disability, anxiety, or sleep quality were observed depending on the rs4680 Val158Met genotype. Women with CTTH, but not FETTH, carrying the Met/Met genotype had lower widespread pressure pain thresholds and higher depressive symptoms than those with Val/Val or Val/Met genotype (P<0.05)., Conclusions: The Val158Met polymorphism (rs4680) does not appear to be involved in predisposition to tension-type headache; however, this genetic factor may be involved in the pathogenesis expression of CTTH, as greater pressure pain sensitivity and higher depressive levels were found in CTTH carrying the Met/Met genotype.

Background and aims Achilles tendinopathy is common among runners, but the etiology remains unclear. High mechanical pain sensitivity may be a predictor of increased risk of developing Achilles tendinopathy in this group. The purpose of this study was to investigate whether local pain sensitivity could predict the development of Achilles tendinopathy in recreational male runners. The overall hypothesis was that high pain sensitivity would be related to a higher risk of developing Achilles tendinopathy among recreational male runners. Methods Ninety-nine recreational male runners were recruited and followed prospectively for 1 year. At baseline and after 500 km of running the pressure pain threshold (PPT) was assessed at the infraspinatus and at the Achilles tendon (AT-PPT). Based on the AT-PPT at baseline, a median split was used to divide the runners into two groups. The high pain sensitivity groups was defined as runners displaying a pain pressure threshold below 441 kPa on the Achilles tendon, while the low pain sensitivity group was defined as runners displaying a pain pressure threshold above 441 kPa on the Achilles tendon, respectively. Subsequently, the cumulative risk difference between the two groups was assessed by using the pseudo-observation method. Results High pain sensitivity runners sustained 5%-point (95% CI: -0.18 to 0.08) more Achilles tendinopathy episodes during the first 1,500 km. No significant group differences in risk were found at 100, 250, 500, 1,000 and 1,500 km of running. Conclusions No significant association was found between mechanical pain sensitivity in the Achilles tendon and the risk of developing Achilles tendinopathy. However, the risk difference indicated a association between a high mechanical pain sensitivity and an increased risk of developing Achilles tendinopathy. It is plausible that changes in pain sensitivity were masked by unmeasured covariates, such as the differences in progression/regression of training volume and running speed between the two groups. This study was limited in size, which limited the possibility to account for covariates, such as differences in progression/regression of running speed between runners. With the limitations in mind, future studies should control the training volume, speed and running shoes in the design or account for it in the analysis. Implications Pain sensitivity of the Achilles tendon seems not to be related to an increased risk of developing Achilles pain in relation to running.

Background and aims Offset analgesia (OA) is a pain modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a minor decrease in stimulus intensity. Precise mechanisms of OA are still not elucidated and studies are needed to evaluate factors modulating OA. The aim of this study was to investigate OA before and during tonic cold pain (thought to induce descending inhibition), in a group of healthy volunteers. Methods A randomized, crossover study was performed in 17 healthy participants (8 males and 9 females). The OA paradigm lasted 35 s and was induced by the traditional method using thermal stimulation applied to the forearm. A constant control heat stimulus (CTL) paradigm was used as control to assess adaptation. Pain intensity was assessed continuously. For induction of tonic cold pain, the participants immersed their hand into 2°C water for 2 min. After 1 min and 25 s, the heat stimulation (OA or CTL paradigm) was repeated to assess the modulatory effect of the cold pressor test. Results It was possible to induce OA both before and during the cold pressor test. Tonic cold pain modulated the peak pain reported during both the OA (p=0.015) and CTL paradigms (p=0.001) reflecting endogenous pain modulation. However, the magnitude of OA was not modulated by tonic cold pain (p>0.05). Conclusions The offset analgesia magnitude was not modulated by simultaneously tonic cold pain, thought to reflect another endogenous pain modulation mechanism. Implications Neither offset analgesia magnitude nor adaptation were modulated by cold pressor induced endogenous analgesia. This could be explained by the fact, that offset analgesia was already at maximum in healthy participants. Hence, offset analgesia may not be a suitable assessment tool to investigate modulation induced by experimental methods or pharmacology in healthy participants.

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.

Objective: To investigate variables associated at baseline (cross-sectional design) and at one year (longitudinal design) with the quality of sleep in chronic tension-type headache (CTTH)., Methods: One hundred and eighty (n = 180) and 135 individuals with CTTH participated in the cross-sectional and longitudinal design respectively. Clinical features were collected with a 4-weeks headache diary at baseline and one-year follow-up. Sleep quality was assessed at baseline and 1-year follow-up with the Pittsburgh Sleep Quality Index. Anxiety and depression (Hospital Anxiety and Depression Scale-HADS), burden of headache (Headache Disability Inventory-HDI), quality of life (SF-36 questionnaire), and pressure pain thresholds (PPTs) at trigeminal, extra-trigeminal and widespread area were assessed at baseline. Hierarchical regression analyses were conducted to determine the associations between variables at baseline and 1-year follow-up with sleep quality., Results: At baseline positive correlations between sleep quality and headache intensity, headache frequency, headache duration, emotional and physical burden of headache and depression were observed. The regression analyses found that depression and emotional burden of headache explained 27.5% of the variance in sleep quality at baseline (r2 = .262; F = 23.72 P < .001). At one-year, sleep quality was significantly associated with baseline burden of headache, depression, widespread PPTs, vitality and mental health domains. Regression analyses revealed that vitality, PPT over the second metacarpal and PPT over the neck explained 30.0% of the variance of sleep quality at one-year (r2 = .269, F = 9.71, P < .001)., Conclusions: It seems that sleep quality exhibits a complex interaction in individuals with CTTH since depression and the emotional burden were associated with sleep quality at baseline, but vitality and PPTs over extra-trigeminal areas were associated with the quality of sleep at one-year., Competing Interests: The authors have declared that no competing interests exist.

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre-established inflammatory hyperalgesia (ultraviolet-B-irradiation; "UVB") and non-inflammatory neurotrophic pain sensitization (nerve growth factor; "NGF") alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non-irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 μg intradermally injected (4 × 50 μL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB- and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Little is known about endogenous descending control of itch. In chronic pain, descending pain inhibition is reduced as signified by lowered conditioned pain modulation. There are indications that patients with chronic itch may also exhibit reduced endogenous descending inhibition of itch and pain. This study aimed to investigate whether and the extent to which itch can be modulated by conditioning itch and pain stimuli. Twenty-six healthy volunteers participated. The study consisted of 5 conditions designed to systematically assess endogenous modulation of itch or pain: 1) itch-induced modulation of contralateral itch, 2) pain-induced modulation of contralateral itch, 3) pain-induced modulation of ipsilateral itch, 4) pain-induced modulation of contralateral pain, and 5) itch-induced modulation of contralateral pain. Conditioning stimuli were cold pressor-induced pain and histamine-evoked itch, whereas the test stimuli were electrical stimulation paradigms designed to evoke itch or pain. Pain was significantly reduced (conditioned pain modulation-effect) by the conditioning pain stimulus (P < .001), but not by the conditioning itch stimulus (negative control condition). Itch was significantly reduced (conditioned itch modulation-effect) by contra- as well as ipsilateral applied conditioning pain (both P < .001), whereas conditioning itch stimulation only marginally reduced itch. Endogenous descending itch inhibition through mechanisms that are independent of segmental gating can be readily evoked by heterotopic conditioning pain stimulation. However, robust descending inhibition of itch cannot be evoked with conditioning itch stimulation., Perspective: The study showed a hierarchical prioritization favoring pain-induced central descending modulation of itch as well as pain in humans. Future studies addressing potential aberrations in pain-evoked descending modulation of itch in chronic itch patients are warranted., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. In addition, a comprehensive battery of quantitative sensory tests was conducted, including assessment of mechanical and thermal sensitivity. Neurogenic inflammation was quantified using full-field laser perfusion imaging. Erythema and hyperpigmentation were assessed before, immediately after, and ≈64 hours after AITC exposure. AITC induced significant dose-dependent, moderate-to-severe spontaneous burning pain, mechanical and heat hyperalgesia, and dynamic mechanical allodynia (P < 0.05). No significant differences in induced pain hypersensitivity were observed between the 50% and 90% AITC concentrations. Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.

Treating chronic musculoskeletal pain, and chronic joint pain (osteoarthritis (OA)) in particular, is challenging as the peripheral and central pain mechanisms are not fully discovered, and safe and as efficient analgesic drugs are not available. In general, the preclinical models of OA are limited to provide fundamental understanding of the pain mechanisms involved in patients with chronic joint pain (1). The pain associated with joint discomfort is highly variable, often underestimated by clinicians, and shows only modest association with crude radiological scorings. One reason for the disconnect between the extent of structural damage and pain is neuroplastic changes occurring in the peripheral and central nervous system resulting in pain sensitisation impacting the patient's experience of pain. In recent years, a variety of human quantitative and mechanistic pain assessment tools (Quantitative Sensory Testing, QST) have been developed, providing new opportunities for diagnostic phenotyping of OA patients and the associated degree of sensitisation. Mechanistic phenotyping has revealed specific subgroups of specifically sensitised OA patients, and been used as a predictive guideline to evaluate which patients are most likely to experience continued chronic pain after an otherwise technically successful knee replacement (chronic postoperative pain). Furthermore, such techniques may be used to profile new or existing drugs together with other e.g. cognitive or behavioural therapies with the potential to manage joint pain.

Increased pressure pain sensitivity and impaired descending pain control have been associated with chronic pain, but knowledge on the variability in the adult general population is lacking. Pressure pain thresholds (PPTs) and descending pain control assessed using conditioned pain modulation (CPM) were recorded in a randomly selected sample (n = 2,199, 53% female) of the Danish adult general population aged 18 to 70 years. PPTs were recorded over the tibialis anterior muscle and the upper trapezius muscle. CPM was defined as the difference between PPT assessments before and during conditioning with cold pressor pain (hand) for 2 minutes. Conditioning pain intensity was assessed using a visual analog scale and questionnaire data were collected. Female sex (P < .001) and younger age (P ≤ .02) was associated with lower PPTs at both body sites. For the trapezius muscle, high perceived stress was associated with lower PPTs (P < .02), whereas an interaction was found between body mass index and sex. CPM potency was lower in female compared with male participants (P ≤ .003), whereas no association with age was found. Higher level of education (P ≤ .05), premature withdrawal from the cold pressor test (P ≤ .02), and high visual analog scale score (P ≤ .02) were associated with a larger CPM response., Perspective: Data from this large population-based study provide new insight into the gender and age variation in pain sensitivity and CPM response. Decreased CPM potency and increased pain sensitivity in female participants were found, emphasizing the need to improve the understanding of its clinical consequences., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate widespread pressure hyperalgesia in the trigemino-cervical and extra-trigeminal (distant pain-free) regions in women with episodic and chronic migraine., Methods: Fifty-one women with episodic migraine, 52 women with chronic migraine, and 52 healthy women without headache history were recruited. Pressure pain thresholds (PPT) were bilaterally assessed over the trigeminal area (i.e., temporalis muscle), cervical area (i.e., C5/C6 zygapophyseal joint), and two extra-trigeminal areas (i.e., second metacarpal, tibialis anterior muscle) in a blinded design. Clinical features of migraine and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) were also assessed., Results: The multivariate analysis of covariance (ANCOVA) revealed that PPTs were significantly decreased bilaterally over trigeminal and extra-trigeminal points in migraine patients compared to healthy women (all sites, P < 0.001). No differences between episodic and chronic migraine were observed (all, P > 0.919). The presence of neck pain (all, P > 0.282), anxiety (P > 0.425) or depression (all, P > 0.316) did not influence the results. The intensity of migraine pain was negatively associated with widespread pressure pain sensitivity: The greater the intensity of migraine attacks, the lower the widespread PPT levels, i.e., the greater the widespread sensitization., Conclusions: This study found similar widespread pressure hypersensitivity in women with episodic or chronic migraine suggesting that central manifestations are involved both in episodic and chronic migraine., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

The COX-2 inhibitor etoricoxib modulates the peripheral and central nociceptive mechanisms in animals. This interaction has not been studied in patients with pain. This randomized, double-blind, placebo-controlled, 2-way crossover, 4-week treatment study investigated the pain mechanisms modulated by etoricoxib in patients with painful knee osteoarthritis. Patients were randomized to group A (60 mg/d etoricoxib followed by placebo) or B (placebo followed by 60 mg/d etoricoxib). The quantitative, mechanistic pain biomarkers were pressure pain thresholds, temporal summation (TS), and conditioning pain modulation. Clinical readouts were Brief Pain Inventory, WOMAC, painDETECT questionnaire (PD-Q), and time and pain intensity during walking and stair climbing. Etoricoxib as compared with placebo significantly modulated the pressure pain thresholds (P = 0.012, localized sensitization) at the knee and leg (control site) (P = 0.025, spreading sensitization) and TS assessed from the knee (P = 0.038) and leg (P = 0.045). Conditioning pain modulation was not modulated. The Brief Pain Inventory (pain scores), PD-Q, WOMAC, and walking and stair climbing tests were all significantly improved by etoricoxib. Based on a minimum of 30% or 50% pain alleviation (day 0-day 28), responders and nonresponders were defined. The nonresponders showed a significant association between increased facilitation of TS and increased pain alleviation. None of the other parameters predicted the degree of pain alleviation. Generally, a responder to etoricoxib has the most facilitated TS. In conclusion, etoricoxib (1) modulated central pain modulatory mechanisms and (2) improved pain and function in painful osteoarthritis. Stronger facilitation of TS may indicate a better response to etoricoxib, supporting the central mode-of-action of the drug.

Objective: Pain sensitization is associated with pain severity in knee osteoarthritis (OA), but its cause in humans is not well understood. We examined whether inflammation, assessed as synovitis and effusion on magnetic resonance imaging (MRI), or mechanical load, assessed as bone marrow lesions (BMLs), was associated with sensitization in knee OA., Methods: Subjects in the Multicenter Osteoarthritis Study, a National Institutes of Health-funded cohort of persons with or at risk of knee OA, underwent radiography and MRI of the knee, and standardized quantitative sensory testing (temporal summation and pressure pain threshold [PPT]) of the wrist and patellae at baseline and 2 years later. We examined the relation of synovitis, effusion, and BMLs to temporal summation and PPT cross-sectionally and longitudinally., Results: There were 1,111 subjects in the study sample (mean age 67 years, mean body mass index 30 kg/m(2) , 62% female). Synovitis was associated with a significant decrease in PPT at the patella (i.e., more sensitized) over 2 years (adjusted β -0.30 [95% confidence interval (95% CI) -0.52, -0.08]). Effusion was similarly associated with a decrease in PPT at the wrist (adjusted β -0.24 [95% CI -0.41, -0.08]) and with risk of incident temporal summation at the patella (adjusted OR 1.54 [95% CI 1.01, 2.36]). BMLs were not associated with either quantitative sensory testing measure., Conclusion: Inflammation, as evidenced by synovitis or effusion, is associated with pain sensitization in knee OA. In contrast, BMLs do not appear to contribute to sensitization in knee OA. Early targeting of inflammation is a reasonable strategy to test for prevention of sensitization and through this, reduction of pain severity, in knee OA., (© 2016, American College of Rheumatology.)

Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington's disease (HD), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA), is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed.

Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1°C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1°C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1°C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity.

Background: We tested the hypothesis that pressure sensitivity of the sternum (PPS) is associated with autonomic nervous system (ANS) function as assessed by tilt table test (TTT). in patients with stable ischemic heart disease., Objectives: (1) To evaluate an association between PPS and systolic blood pressure (SBP) and heart rate (HR) responses to TTT; and (2) to test the hypothesis that a reduction of resting PPS raises the PPS, SBP and HR responses to TTT response and lowers risk factors for ANS dysfunction (ANSD)., Methods: Cross-sectional study: In 361 patients with stable ischemic heart disease we measured PPS, SBP, and HR during TTT. Intervention study: We reassessed subjects with persistent stress who concluded a stress intervention trial by a second TTT., Results: Cross-sectional study: Resting PPS and the PPS response to TTT were correlated (r = - 0.37). The PPS response to TTT was correlated with that of SBP (r = 0.44) and HR (r = 0.49), and with the number of risk factors for ANSD (r = - 0.21) (all p < 0.0001). Intervention study: A reduction in resting PPS was associated with an increment in PPS response to TTT (r = - 0.52, p < 0.0001). The greater this increment, the greater was the reduction in ANSD risk factors (r = - 0.23; p = 0.003)., Conclusion: The results are consistent with the hypothesis that PPS at rest and in response to TTT reflects ANS function.

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Objective: Methods of blinding have been infrequently investigated. This study assessed data collector blinding within an investigation of endogenous pain modulation., Design: Participants (N = 33; 52% women) were randomly assigned to an order of an exercise bout with intramuscular control injections, quiet rest with intramuscular algesic injections, and a control condition. Data collectors (N = 4; 50% women) recorded participants' pain responses and then left the room before the injection and exercise procedures were administered by other personnel. Immediately after the procedures, the data collectors returned to collect additional pain responses and record their suspicions regarding the assigned condition, their confidence level in their suspicions (0-100 mm scale), and the reason/s for their suspicions., Results: Data collectors correctly identified control and algesic injections in 90.4 and 73.1% of the sessions, respectively, and quiet rest and exercise in 94.2 and 69.2% of the sessions, respectively. The confidence of the data collectors in their suspicions was 60.17 mm (SD = 34.54) for injections and 62.19 mm (SD = 34.95) for exercise. However, data collectors only had correct suspicions and confidence of at least 90 mm for 26.2% of the injections and 29.4% of the exercise bouts. Participants' pain responses were the primary reason for data collectors' suspicions. Neither the amount of experience nor the sexual composition of the participant-data collector dyad influenced the blinding., Conclusions: Collection of participants' pain responses led to frequent episodes of unblinding. However, it may be misleading to only consider the frequency of correct suspicions as successful or unsuccessful blinding., (Wiley Periodicals, Inc.)

Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

Exercise is often used for pain rehabilitation but the link between physical activity level and pain sensitivity is still not fully understood. Pressure pain sensitivity to cuff algometry and conditioned pain modulation (CPM) were evaluated in highly active men (n=22), normally active men (n=26), highly active women (n=27) and normally active women (n=23) based on the Godin Leisure-Time Exercise Questionnaire. Cuff pressure pain sensitivity was assessed at the arm and lower leg. The subjects scored the pain intensity on an electronic Visual Analogue Scale (VAS) during ten minutes with 25 kPa constant cuff pressure and two minutes with zero pressure. The maximal VAS score and area under the VAS-curve were extracted. Pressure pain thresholds (PPT) were recorded by manual pressure algometry on the ipsilateral tibialis anterior muscle before, during and after the tonic arm stimulation. Tonic cuff stimulation of the arm and leg resulted in higher VAS peak scores in women compared with men (p<0.04). In all groups the PPTs were reduced during and after the cuff stimulation compared with baseline (p=0.001). PPT were higher in men compared with women (p=0.03) and higher in highly physical active compared with normal active (p=0.048). Besides the well-known gender difference in pressure pain sensitivity this study demonstrates that a high physical fitness degree in non-athletic subjects is associated with increased pressure pain thresholds but does not affect cuff pressure pain sensitivity in healthy people.

Background It is unknown why an acute pain condition under various circumstances can transition into a chronic pain condition. There has been a shift towards neuroinflammation and hence glial cell activations specifically in the dorsal root ganglion and spinal cord as a mechanism possibly driving the transition to chronic pain. This has led to a focus on non-neuronal cells in the peripheral and central nervous system. Besides infiltrating macrophages, Schwann cells and satellite glial cells release cytokines and therefore important mechanisms in the maintenance of pain. Activated Schwann cells, satellite glial cells, microglia, and astrocytes may contribute to pain sensitivity by releasing cytokines leading to altered neuronal function in the direction of sensitisation. Aims of this perspective paper 1) Highlight the complex but important recent achievement in the area of neuroinflammation and pain at spinal cord level and in the dorsal root ganglion. 2) Encourage further research which hopefully may provide better understanding of new key elements driving the transition from acute to chronic pain. Recent results in the area of neuroinflammation and pain Following a sciatic nerve injury, local macrophages, and Schwann cells trigger an immune response immediately followed by recruitment of blood-derived immune cells. Schwann cells, active resident, and infiltrating macrophages release proinflammatory cytokines. Proinflammatory cytokines contribute to axonal damage and also stimulate spontaneous nociceptor activity. This results in activation of satellite glial cells leading to an immune response in the dorsal root ganglia driven by macrophages, lymphocytes and satellite cells. The anterograde signalling progresses centrally to activate spinal microglia with possible up regulation of glial-derived proinflammatory/pronociceptive mediators. An important aspect is extrasegmental spreading sensitisation where bilateral elevations in TNF-α, IL-6, and IL-10 are found in dorsal root ganglion in neuropathic models. Similarly in inflammatory pain models, bilateral up regulation occurs for TNF-α, IL-1 β, and p38 MAPK. Bilateral alterations in cytokine levels in the DRG and spinal cord may underlie the spread of pain to the uninjured side. An important aspect is how the opioids may interact with immune cells as opioid receptors are expressed by peripheral immune cells and thus can induce immune signaling changes. Furthermore, opioids may stimulate microglia cells to produce proinflammatory cytokines such as IL-1. Conclusions The present perspective paper indicates that neuroinflammation and the associated release of pro-inflammatory cytokines in dorsal root ganglion and at the spinal cord contribute to the transition from acute to chronic pain. Neuroinflammatory changes have not only been identified in the spinal cord and brainstem, but more recently, in the sensory ganglia and in the nerves as well. The glial cell activation may be responsible for contralateral spreading and possible widespread sensitisation. Implications Communication between glia and neurons is proposed to be a critical component of neuroinflammatory changes that may lead to chronic pain. Sensory ganglia neurons are surrounded by satellite glial cells but how communication between the cells contributes to altered pain sensitivity is still unknown. Better understanding may lead to new possibilities for (1) preventing development of chronic pain and (2) better pain management.

Biochemical and pain biomarkers can be applied to patients with painful osteoarthritis profiles and may provide more details compared with conventional clinical tools. The aim of this study was to identify an optimal combination of biochemical and pain biomarkers for classification of patients with different degrees of knee pain and joint damage. Such profiling may provide new diagnostic and therapeutic options. A total of 216 patients with different degrees of knee pain (maximal pain during the last 24 hours rated on a visual analog scale [VAS]) (VAS 0-100) and 64 controls (VAS 0-9) were recruited. Patients were separated into 3 groups: VAS 10 to 39 (N = 81), VAS 40 to 69 (N = 70), and VAS 70 to 100 (N = 65). Pressure pain thresholds, temporal summation to pressure stimuli, and conditioning pain modulation were measured from the peripatellar and extrasegmental sites. Biochemical markers indicative for autoinflammation and immunity (VICM, CRP, and CRPM), synovial inflammation (CIIIM), cartilage loss (CIIM), and bone degradation (CIM) were analyzed. WOMAC, Lequesne, and pain catastrophizing scores were collected. Principal component analysis was applied to select the optimal variable subset, and cluster analysis was applied to this subset to create distinctly different knee pain profiles. Four distinct knee pain profiles were identified: profile A (N = 27), profile B (N = 59), profile C (N = 85), and profile D (N = 41). Each knee pain profile had a unique combination of biochemical markers, pain biomarkers, physical impairments, and psychological factors that may provide the basis for mechanism-based diagnosis, individualized treatment, and selection of patients for clinical trials evaluating analgesic compounds. These results introduce a new profiling for knee OA and should be regarded as preliminary.

Objective: To determine the presence of widespread pressure hyperalgesia in multiple sclerosis (MS) patients with and without pain and its association with pain and fatigue., Methods: A total of 108 individuals with definite MS, 49 men and 59 women (mean age, 44±8 y) and 108 age-matched and sex-matched pain-free controls (mean age, 44±9 y) were included. Fifty patients (n=58, 54%) reported pain and 50 (46%) did not. Pressure pain threshold (PPT) was bilaterally assessed over supraorbital, infraorbital, mental, median, radial and ulnar nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscle by an assessor blinded to the patient's condition. The intensity of pain was assessed with a numerical pain rate scale (0 to 10), fatigue was determined with the Fatigue Impact Scale, and depression was evaluated with the Beck Depression Inventory., Results: The analyses of covariance revealed that PPT were significantly decreased bilaterally over the supraorbital, infraorbital, mental, median, ulnar and radial nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscles in patients with MS compared with pain-free controls (all, P<0.001). No significant differences existed between MS patients with pain and those without pain (all P>0.944). Patients with pain exhibited higher fatigue and depression than those patients without pain (P<0.05). PPT was not associated with any clinical variable, that is, pain, depression, or fatigue., Conclusions: Our study found widespread pressure pain hyperalgesia in individuals with MS as compared with pain-free controls. No differences existed between MS patients with pain and those without pain in the presence of widespread pressure sensitivity. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems.

The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain. Trial registration: Clinical Trials.gov NCT01636440.

This study investigated the relationship between pain sensitivity, adaptability, and potency of endogenous pain inhibition, including conditioned pain modulation (CPM) and local pain inhibition. Forty-one healthy volunteers (20 male, 21 female) received conditioning stimulation (CS) over 2 sessions in a random order: tonic heat pain (46 °C) on the right leg for 7 minutes and cold pressor pain (1 °C to 4 °C) on the left hand for 5 minutes. Participants rated the intensity of pain continuously using a 0 to 10 electronic visual analogue scale. The primary outcome measures were pressure pain thresholds (PPT) measured at the heterotopic and homotopic location to the CS sites before, during, and 20 minutes after CS. Two groups of participants, pain adaptive and pain nonadaptive, were identified based on their response to pain in the cold pressor test. Pain-adaptive participants showed a pain reduction between peak pain and pain at end of the test by at least 2 of 10 (n=16); whereas the pain-nonadaptive participants reported unchanged peak pain during 5-minute CS (n=25). Heterotopic PPTs during the CS did not differ between the 2 groups. However, increased homotopic PPTs measured 20 minutes after CS correlated with the amount of pain reduction during CS. These results suggest that individual sensitivity and adaptability to pain does not correlate with the potency of CPM. Adaptability to pain is associated with longer-lasting local pain inhibition., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: The analgesic action of botulinum neurotoxin type A (BoNTA) has been linked to the blockade of peripheral release of neuropeptides and neurotransmitters in animal models; however, there is no direct evidence of this in humans., Objectives: To investigate the effect of BoNTA on glutamate release in humans, using an experimental model of pain and sensitization provoked by capsaicin plus mild heat., Methods: Twelve healthy volunteers (six men, six women) were pretreated with BoNTA (10 U) on the volar forearm and with a saline control on the contralateral side. Dermal microdialysis was applied one week later to collect interstitial samples before and after the application of a capsaicin patch (8%) plus mild heat (40°C⁄60 min) to provoke glutamate release, pain and vasodilation. Samples were collected every hour for 3 h using linear microdialysis probes (10 mm, 100 kD). Dialysate was analyzed for glutamate concentration. Pain intensity and skin vasomotor reactions (temperature and blood flow changes) were also recorded., Results: BoNTA significantly reduced glutamate release compared with saline (P<0.05). The provoked pain intensity was lower in the BoNTA-pretreated arm (P<0.01). The reduction in pain scores was not correlated with glutamate level. Cutaneous blood flow (P<0.05), but not cutaneous temperature (P≥0.05), was significantly reduced by BoNTA. There was a correlation between glutamate level and skin blood flow (r=0.58⁄P<0.05) but not skin temperature (P≥0.05). No differences according to sex were observed in any response., Conclusions: The present study provided the first direct evidence supporting the inhibitory effect of BoNTA on glutamate release in human skin, which is potentially responsible for some of the analgesic action of BoNTA.

Translational research has not yet elucidated whether alterations in central pain processes are related to peripheral inflammatory processes in chronic pain patients. We tested the hypothesis that the concentration of cytokines in the peritoneal fluid of endometriosis patients with chronic pain correlate with parameters of hyperexcitability of the nociceptive system. The concentrations of 15 peritoneal fluid cytokines were measured in 11 patients with chronic pelvic pain and a diagnosis of endometriosis. Six parameters assessing central pain processes were recorded. Positive correlations between concentration of some cytokines in the peritoneal fluid and amplification of central pain processing were found. The results suggest that inflammatory mechanisms may be important in the pathophysiology of altered central pain processes and that cytokines produced in the environment of endometriosis could act as mediators between the peripheral lesion and changes in central nociceptive processes.

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P<.05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P<.05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P<.05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P<.05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Recent advances in understanding the pathophysiology of pain have led to a wealth of molecular targets for novel analgesic drugs and many clinical drug trials. There have been successes, like the gabapentinoids for neuropathic pain and calcium channel blockers for otherwise intractable pain states; and drugs which show promise in clinical trials, like nerve growth factor inhibitors and p38 kinase inhibitors. Unfortunately there have also been a number of failures. We suggest factors which might predispose to success, for example some clinical precedence for the mechanism in pain or a genetic link for the mechanism, for example a mutation linked to a pain syndrome. We also stress the importance of demonstrating molecular target engagement with a novel compound and suggest pain biomarkers which can be used for mechanistic drug profiling., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The aim of the study was to systematically investigate the effect of craniofacially evoked conditioned pain modulation on somatosensory function using a quantitative sensory testing (QST) protocol applied to the trigeminal area in healthy humans. Pressure pain evoked by a mechanical compressive device was applied as conditioning stimulus (CS) in the craniofacial region, with a pain intensity of 5 on a visual analogue scale (VAS: 0-10 cm) (painful session) or with VAS score of 0 (control session). A full QST battery of 13 parameters was performed as test stimuli on the dominant-side cheek. The individual QST data from 11 men and 12 women were transformed into z scores, and the QST data and z scores were tested using analyses of variance. Analyses of variance of pressure pain threshold (PPT) data (log-transformed values and z scores) indicated significant session (P ≤ .003) and time (P < .001) effects with a session-time interaction (P < .001), but no main effect of sex (P ≥ .053, effect size ≥ .166). The session-time interaction showed that the PPTs in the painful session were associated with significantly higher log-transformed PPT values and significantly lower z scores compared with the control session at the time point during CS (hypoalgesia) (P < .001). No other QST parameters were significantly modulated by the CS. Sex differences were not detected in this study; a larger sample size may be needed to further explore this possibility. However, the findings indicate that when extensive QST protocols are applied, PPT may be the most sensitive measure to detect endogenous pain inhibitory mechanisms., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Our aim was to investigate whether migraine adolescents with pain directed inside (imploding pain--IP) and outside (exploding pain--EP) the head may have different levels of cortical excitability underlying their migraineous syndrome. Ten migraine children referring prevalent EP (mean age 14.5 ± 1.4 years, 3 girls, 7 boys), 10 patients with IP (mean age 14.1 ± 2.2 years, 4 girls, 6 boys), and 13 control subjects (mean age 13 ± 1.8 years, 6 males, 7 females) participated to the study. The recovery cycle of the somatosensory evoked potentials to electrical median nerve stimuli at interstimulus intervals of 5, 20, and 40 ms was measured. Anger expression, anxiety, and somatic concerns were investigated in migraine patients. Overall, SEP recovery cycle was shorter in migraineurs than in healthy controls. The recovery cycle of the frontal N30 SEP component was significantly shorter in IP than in EP patients. While among the EP patients those with faster N30 recovery cycle had higher Trait-Anger score, the opposite was found among the IP patients. Our results suggest that the inhibitory mechanisms within the somatosensory cortex are more impaired in IP than in EP migraine adolescents. The pathophysiological difference between IP and EP migraineurs was strengthened also by the opposite correlations between the brain excitability and the anger expression., (Copyright © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Chronic pelvic pain presents difficulties for women suffering its complex presentation. It also presents difficulties for clinicians involved in diagnosing and managing the problem. We review here clinically relevant information related to visceral pathology and its association with peripheral and central aspects of pain hypersensitivity. We address why surgery appears to be successful in some cases but less than successful in others, and what cautionary indicators should be taken into account. A categorization of chronic pelvic pain based on our understanding of pain physiology and mechanisms involved is proposed. The benefits of multidimensional sensory and pain testing in gynaecological care are reviewed.

Background: Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included., Results: Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain., Conclusion: This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

The aim of this study was to develop a human experimental bone pain model. Fourteen healthy men were included in two study sessions. Pressure pain threshold (PPT) was estimated using probes of different sizes. Computer-controlled and hand-held algometry were applied to the skin area covering right and left medial tibia before and after local anaesthesia (LA) of the skin and reproducibility was evaluated. Pain experience (McGill questionnaire) was compared between healthy volunteers and 12 patients with vertebral fractures. Computer-controlled algometer: No differences in PPT between study sessions for 6 and 8-mm probes (p = 0.43 and 0.32) were seen. There was a difference in PPT before and after LA for the 6-mm probe (p = 0.008), but not for the 8-mm probe (p = 0.26). Hand-held algometer: A difference in PPT between study sessions was observed for 4- and 8-mm probes (p = 0.03 and 0.007), but not for 2, 6 and 10-mm probes (p = 0.19, 0.05 and 0.25). No differences in PPT were seen before and after LA for 2, 4, 8 and 10-mm probes (p = 0.35, 0.15, 0.08 and 0.53), but LA significantly influenced PPT with the 6-mm probe (p = 0.01). Similar words were chosen in the McGill pain questionnaire by healthy volunteers and patients, qualitatively describing the deep pain sensation. The pain evoked by hand-held algometer and the 2-mm probe was not influenced by LA, and PPT was reproducible between sessions and is recommended for studies of experimentally evoked bone-associated pain., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)