Higher Pain Sensitivity Research Articles

Individual Variation in Pain Sensitivity and Implicit Negative Bias Toward Pain.

Although previous studies have shown the linkage between pain sensitivity and pain-related cognitions, this study investigated whether individual variation in pain sensitivity is related to implicit negative bias toward pain. Two groups of participants with low (LPS) or high (HPS) pain sensitivity (LPS group: n = 33; HPS group: n = 31) were recruited based on their scores on pain sensitivity questionnaires. This categorization was later confirmed via pain ratings to electrical stimulations. Implicit negative bias toward pain was assessed using the Implicit Association Test (IAT) involving target (pain and nonpain) and attribute (negative and neutral-affect) concept words. Behavioral and event-related potential responses for congruent and incongruent pairings during the IAT were compared between the LPS and HPS groups. Relative to the LPS group, participants in the HPS group exhibited greater D-score (Cohen's d = 0.364, p = .004). Event-related potential results showed that, although P3 amplitudes to congruent and incongruent pairings differed significantly for the HPS group (Cohen's d = 0.757, p < .001), this difference was not observed for the LPS group (Cohen's d = 0.089, p = .29). Mediation analysis further revealed that the IAT effect on P3 responses accounted for 17.58% of the association between pain sensitivity and D-score (confidence interval = [0.009-0.051]). Individual variation in pain sensitivity relates to implicit negative bias. This linkage is partially accounted for by the electrophysiological response that has been related to cognitive process of stimulus evaluation and categorization. Pain treatment might benefit from techniques designed to alter implicit bias.

Myalgia in 30 Patients with Suspected Myopathy.

Background: In patients with neuromuscular disorder, only little data of myalgia frequency and characterization exists. To date, only a weak correlation between pain intensity and pressure pain threshold has been found, and it remains enigmatic whether high pain intensity levels are equivalent to high pain sensitivity levels in neuromuscular disorders. Methods: 30 sequential patients with suspected neuromuscular disorder and myalgia were analyzed with regard to myalgia characteristics and clinical findings, including symptoms of depression and anxiety and pain- threshold. Results: A neuromuscular disorder was diagnosed in 14/30 patients. Muscular pain fasciculation syndrome (MPFS) without evidence for myopathy or myositis was diagnosed in 10/30 patients and 6/30 patients were diagnosed with pure myalgia without evidence for a neuromuscular disorder (e.g., myopathy, myositis, MPFS, polymyalgia rheumatica). Highest median pain scores were found in patients with pure myalgia and polymyalgia rheumatica. Pressure pain threshold measurement showed a significant difference between patients and controls in the biceps brachii muscle. Conclusion: Only a weak correlation between pain intensity and pressure pain threshold has been suggested, which is concordant with our results. The hypothesis that high pain intensity levels are equivalent to high pain sensitivity levels was not demonstrated.

Mouth Pain in Horses: Physiological Foundations, Behavioural Indices, Welfare Implications, and a Suggested Solution.

Simple SummaryMouth pain in horses, specifically that caused by bits, is evaluated as a significant welfare issue. The conscious experiences of pain generated within the body generally, its roles, and its assessment using behaviour, as well as the sensory functionality of the horse’s mouth, are outlined as background to a more detailed evaluation of mouth pain. Bit-induced mouth pain elicited by compression, laceration, inflammation, impeded blood flow, and the stretching of tissues is considered. Observable signs of mouth pain are behaviours that are present in bitted horses and absent or much less prevalent when they are bit-free. It is noted that many equestrians do not recognise that these behaviours indicate mouth pain, so that the magnitude of the problem is often underestimated. The negative experiences that are most responsible for welfare compromise include the pain itself, but also, related to this pain, potentially intense breathlessness, anxiety, and fear. Finally, a series of questions is proposed to clarify issues that are relevant to increasing the adoption of bit-free bridles in order to avoid bit-induced mouth pain. A proposition addressed here is that, although bitted horses are viewed by many equestrians as being largely free of bit-related mouth pain, it seems likely that most behavioural signs of such pain are simply not recognised. Background information is provided on the following: the major features of pain generation and experience; cerebrocortical involvement in the conscious experience of pain by mammals; the numerous other subjective experiences mammals can have; adjunct physiological responses to pain; some general feature of behavioural responses to pain; and the neural bases of sensations generated within the mouth. Mouth pain in horses is then discussed. The areas considered exclude dental disease, but they include the stimulation of pain receptors by bits in the interdental space, the tongue, the commissures of the mouth, and the buccal mucosa. Compression, laceration, inflammation, impeded tissue blood flow, and tissue stretching are evaluated as noxious stimuli. The high pain sensitivity of the interdental space is described, as are likely increases in pain sensitivity due to repeated bit contact with bruises, cuts, tears, and/or ulcers wherever they are located in the mouth. Behavioural indices of mouth pain are then identified by contrasting the behaviours of horses when wearing bitted bridles, when changed from bitted to bit-free bridles, and when free-roaming unbitted in the wild. Observed indicative behaviours involve mouth movements, head-neck position, and facial expression (“pain face”), as well as characteristic body movements and gait. The welfare impacts of bit-related pain include the noxiousness of the pain itself as well as likely anxiety when anticipating the pain and fear whilst experiencing it, especially if the pain is severe. In addition, particular mouth behaviours impede airflow within the air passages of the upper respiratory system, effects that, in their turn, adversely affect the air passages in the lungs. Here, they increase airflow resistance and decrease alveolar gas exchange, giving rise to suffocating experiences of breathlessness. In addition, breathlessness is a likely consequence of the low jowl angles commonly maintained during dressage. If severe, as with pain, the prospect of breathlessness is likely to give rise to anxiety and the direct experience of breathlessness to fear. The related components of welfare compromise therefore likely involve pain, breathlessness, anxiety, and fear. Finally, a 12-point strategy is proposed to give greater impetus to a wider adoption of bit-free bridles in order to avoid bit-induced mouth pain.

Identifying pain perceptual biases related to fear of pain and threat in a pain-free sample.

The association between fear of pain (FOP) and pain intensity has remained unclear. This study aimed to examine whether highly pain-fearful participants showed pain perceptual biases to general painful stimulus or to specific threatening painful stimulus. Fifty-nine undergraduates were recruited into low (n=30) and high (n=29) FOP groups and completed a threatening pain perception task with two tasks. Task 1 assessed pain perceptual biases by calculating the percentage of near-threshold pain stimulus judged as painful and assessing the average pain intensity ratings to those painful stimuli. Task 2 assessed pain perceptual biases by measuring pain ratings to each single threshold (low intensity) and twice-threshold (high intensity) pain stimulus. Results from task 1 indicated that higher FOP levels were associated with higher pain sensitivity when pain was appraised as a threat, reflected as high FOP group reporting higher pain intensity to those stimuli judged as painful in high threat condition than in low threat condition. Consistently, results from task 2 observed that when noxious stimulus intensity increased to threshold pain and twice threshold pain levels, high FOP group also generally reported higher pain intensity in high threat condition than in low threat condition. However, for both tasks, no such threat level differences were observed in low FOP group. The current research emphasized that participants with higher FOP level showed pain perceptual biases to specific threatening painful stimulus. Threat appraisal of pain played a key role in the positive association between pain-related fear and pain perceptual biases. The findings highlight the modulatory influence of threat appraisal of pain in the positive association between pain-related fear and pain perceptual biases.

OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery.

Aim: Investigate the potential role of OPRM1 (mu-opioid receptor) and COMT (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. Methods: A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Results: Patients in the fentanyl group with the COMT high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.4 [16.5; 23.0] vs 34.6 [26.2; 41.4]; p=0.00768), but not to the low-pain sensitivity group (30.1 [19.1; 37.7]; p=0.13). No association was found between COMT haplotype and other pain outcomes or OPRM1 polymorphisms and the different pain modalities. Conclusion:COMT haplotype appears to explain part of the variability in acute postoperative pain in adult cardiac surgery patients.

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome.

Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required. We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity. In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions. Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

Shared Sensitivity to Physical Pain and Social Evaluation

Many studies have demonstrated a link between experiences of physical pain and those of social rejection, both of which can trigger cognitive processes involved in detecting, orienting toward, or reacting to potentially threatening events. This study tested the hypothesis that healthy individuals who are more sensitive to physical pain are also more sensitive to social rejection. We recruited participants with high or low pain-sensitivity (HPS and LPS), as assessed by scores on a pain-sensitivity questionnaire and confirmed by experimental pain-sensitivity assessment. A modified social-judgment task was adopted in which participants first provided expectations about being liked/disliked by “peers”, and then received “peers” feedback indicating acceptance or rejection. While both groups rated rejection as more unpleasant than acceptance, this difference was greater in the HPS group. Electroencephalographic results showed that only participants in the HPS group exhibited greater early delta/theta-oscillations (δ/θ-oscillations) in response to rejection than to acceptance, regardless of whether the feedback was expected or unexpected. However, both groups consistently exhibited greater late δ/θ-oscillations in response to rejection when the feedback was unexpected. These results suggest that participants in the HPS group were more sensitive to social cues signaling acceptance or rejection at early stages of information processing. Furthermore, neither early nor late δ/θ-oscillations following nonsocial feedback (correct or incorrect time-estimation) differed between groups. Altogether, these results supported the idea of shared sensitivity in detecting potentially physical and social threats in the environment. PerspectivesThis study showed the greater emotional reactions and early-latency δ/θ-oscillations in response to social evaluation among healthy individuals with high pain sensitivity. It supports the idea of shared sensitivity to physical pain and social evaluation, which could be governed by a common system for detecting and monitoring potentially environmental threats.

High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice.

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

The association of early life stressors with pain sensitivity and pain experience at 22 years.

Early life stress (ELS) can significantly influence biological pathways associated with nociception, increasing vulnerability to future heightened pain sensitivity and subsequent risk of pain events. However, very little human research has investigated the association of ELS, measured across multiple domains, with future pain sensitivity. Data from Gen1 and Gen2 of the Raine Study were used to assess the association between a wide range of early life stressors, including antenatally, and pressure and cold pain sensitivity at young adulthood. Participants were classified into 2 groups according to their cold pain sensitivity. In addition, the interaction between ELS, pain sensitivity, and pain experience (based on Örebro Musculoskeletal Pain Questionnaire) at age 22 years was examined. Analysis was performed using both a complete case and multiple imputation approach, adjusting for contemporaneous 22-year correlates, with comparable results in each model. More problematic behaviour at age 2 years was associated with less pressure pain sensitivity at 22 years (13.7 kPa, 95% CI: 1.0-27.0, P = 0.037), with no interaction between problematic behaviour and pain experience at 22 years. For those reporting a moderate/high pain experience at 22 years, poor family functioning increased the odds ratio for high cold pain sensitivity (3.0, 95% CI: 1.6-5.6), but for those reporting no/low pain experience, it did not (OR:1.2, 95% CI: 0.8-1.8). This study provides the most comprehensive investigation of the relationship between ELS and pressure and cold pain sensitivity in young adults supporting early life as a critical period of development influencing future nociceptive processing.

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PC-FACS

µ-Opioid Activity in Chronic TMD Pain Is Associated with COMT Polymorphism

Clinicians have the dilemma of prescribing opioid or nonopioid analgesics to chronic pain patients; however, the impact of pain on our endogenous µ-opioid system and how our genetic profile (specifically catechol-O-methyltransferase [COMT] polymorphisms) impacts its activation are currently unknown. Twelve chronic temporomandibular disorder (TMD) patients and 12 healthy controls (HCs) were scanned using positron emission tomography (PET) with [11C]carfentanil, a selective radioligand for µ-opioid receptors (µORs). The first 45 min of each PET measured the µOR nondisplaceable binding potential (BPND) at resting state, and the last 45 min consisted of a 20-min masseteric pain challenge with an injection of 5% hypertonic saline. Participants were also genotyped for different COMT alleles. There were no group differences in µOR BPND at resting state (early phase). However, during the masseteric pain challenge (late phase), TMD patients exhibited significant reductions in µOR BPND (decreased [11C]carfentanil binding) in the contralateral parahippocampus (P = 0.002) compared to HCs. The µOR BPND was also significantly lower in TMD patients with longer pain chronicity (P < 0.001). When considering COMT genotype and chronic pain suffering, TMD patients with the COMT 158Met substitution had higher pain sensitivity and longer pain chronicity with a 5-y threshold for µOR BPND changes to occur in the parahippocampus. Together, the TMD diagnosis, COMT 158Met substitution, and pain chronicity explained 52% of µOR BPND variance in the parahippocampus (cumulative R2 = 52%, P < 0.003, and HC vs. TMD Cohen’s effect size d = 1.33 SD). There is strong evidence of dysregulation of our main analgesic and limbic systems in chronic TMD pain. The data also support precision medicine by helping identify TMD patients who may be more susceptible to chronic pain sensitivity and opioid dysfunction based on their genetic profile.

Obstructive Urolithiasis in Horse

Background: Obstructive urinary tract disease in horses is a rare and low prevalence pathology in the species, but potentially severe. It is an emergency condition that presents variable clinical signs and depends on the anatomical location of the obstruction. The bladder calculus are the most common followed by the urethra and less commonly seen are the kidney or ureteral. The main crystalloid component of uroliths in horses is calcium carbonate. The higher prevalence of urolithiasis in male horses is justified by some anatomical differences between genders. The urethra of males is narrower and longer than that of females. The tissue injury is the most important factor for the development of uroliths in horses. Desquamation of epithelial cells, presence of leukocyte and necrotic cell debris are relevant contributors to crystal growth. Urinary stasis favors nucleation by increasing the chance of contact between crystalloid material and urinary epithelium. Once crystal growth has begun, the urine alkalinity of the equines favors the crystallization and further deposition of other components, especially calcium carbonate. Typical clinical signs of urolithiasis include tenesmus, dysuria, strangury and polaquiuria. Hematuria is often present, mainly observed after exercise and at the end of urination. In addition signs of colic are quite frequent in the acute bladder and urethral urolithiasis due to bladder distension. Upper urinary tract surgery may be technically challenging due to limited structural exposure, especially in adult horses The prognosis for horses with urolithiasis depends on the location of the urolith and the degree of renal injury that occurred.Case: This report aims to describe a rare case of obstructive urolithiasis in a 8-year-old castrated male horse with 24 h evolution. The horse was expressing signs of abdominal pain and during the transretal examination through palpation, it was possible to notice great distension and turgidity of the bladder, in addition to a high pain sensitivity to the palpation of the kidneys. Was perform urethral catheterization, but it was unproductive. The diagnosis was made through perineal ultrasonography and treated surgically by perineal urethrotomy. The animal presented an excellent evolution after being discharged after 10 days of hospitalization and did not present any complication or recurrence of the disease after one year of the procedure.Discussion: Urolithiasis in horses has a prognosis dependent on the location of the urolith and the degree of renal damage. Cases of obstructive urolithiasis in horses are rare and require prompt and appropriate intervention. Therefore, a rapid and accurate diagnosis is directly related to the success of the treatment. In the present case, the animal had characteristic clinical signs of an acute abdomen. Transrectal palpation, for evaluation of the intestinal portions, was important to diagnose an excessively distended urinary vesicle with no intestinal changes. Transcutaneous ultrasonography of the perineum allowed visualization of the calculus, and then a case of perineal urolithiasis was diagnosed. The choice for perineal urethrotomy was performed because of the ease of palpation of the calculus through the skin below the anus and because it is a non-invasive technique. The urethra was sutured to guide the cicatricial process and the urethral catheter was maintained, reducing the risks of occlusion of the urethral lumen.

The pain trajectory of juvenile idiopathic arthritis (JIA): translating from adolescent patient report to behavioural sensitivity in a juvenile animal model

BackgroundWhile pain is a common symptom in JIA patients, it remains unclear why some JIA patients develop ongoing or persistent pain. Complex clinical and social settings confound analysis of individual factors that may contribute to this pain. To address this, we first undertook a retrospective analysis of pain reports in a JIA patient cohort with the aim of identifying potential factors contributing to persistent pain. We then carried out an experimental laboratory study, using joint inflammatory pain behaviour in rodents, to validate the role of these factors in the onset of persistent pain under controlled conditions.MethodsPatients: Retrospective analysis of anonymised pain visual analogue scale (VAS) scores and accompanying clinical scores from 97 JIA patients aged 13–19 (mean: 16.40 ± 1.21) collected over 50 weeks. Rats: Experimental study of pain behaviour following intra-articular microinjection of complete Freund’s adjuvant (CFA) in adolescents (n = 25) and young adults (n = 43). Some animals (n = 21) had been previously exposed to joint inflammation in infancy or adolescence.ResultsPatients: Cluster analysis of patient pain VAS scores revealed three trajectories over 50 weeks: consistently low pain (n = 45), variable pain (n = 30) and persistently high pain (n = 22). Number of actively inflamed joints did not differ in the three groups. High pain at a single visit correlated with greater physician global assessment of disease activity, while a high pain trajectory over 50 weeks was associated with more limited joints but fewer actively inflamed joints. Rats: Rodents administered ankle joint CFA also exhibit low, medium and high joint pain sensitivities, independent of joint inflammation. Prolonged inflammatory pain behaviour was associated with high background pain sensitivity, following joint inflammation at an earlier stage in life.ConclusionsBoth JIA patients and rodents differ in their individual pain sensitivity independent of the concurrent joint inflammation. Using experimental animal models allows us to isolate physiological factors underlying these differences, independently of social or clinical factors. The results suggest that a history of prior arthritic activity/joint inflammation may contribute to high pain sensitivity in adolescents with JIA.

Abscesso subcutâneo por Trueperella pyogenes em bovino na Amazônia Ocidental: relato de caso

Trueperella pyogenes is a pathogenic bacterium that causes suppurative infections in domestic and wild animals as well as humans. This paper describes a clinical case of subcutaneous abscess by T. pyogenes in a bovine in the Western Amazon, Brazil. During anamnesis, intramuscular injectable drug administration in the middle third of the left gluteal biceps muscle and the practice of reusing needles were reported. The clinical examination revealed edema, hyperthermia and high pain sensitivity to the touch in the region. A sample was collected through a puncture incision for the bacterial culture, during which T. pyogenes was isolated. The therapeutic approach was the use of a systemic antimicrobial and topical care, with a good prognosis. This report is the first description of infection by T. pyogenes in cattle in the Western Amazon and underscores the importance of appropriate sanitary management in herds, especially the use of disposable needles and hygiene at the site of parenteral drug application.

&lt;p&gt;Chronic widespread pain patients show disrupted cortical connectivity in default mode and salience networks, modulated by pain sensitivity&lt;/p&gt;

Purpose: The remodeling of functional neuronal connectivity in chronic widespread pain (CWP) patients remains largely unexplored. This study aimed to investigate functional connectivity in CWP patients in brain networks related to chronic pain for changes related to pain sensitivity, psychological strain, and experienced pain.Patients and methods: Functional connectivity strength of the default mode network (DMN) and the salience network (SN) was assessed with functional magnetic resonance imaging. Between-group differences were investigated with an independent component analysis for altered connectivity within the whole DMN and SN. Then, changes in connectivity between nodes of the DMN and SN were investigated with the use of a seed-target analysis in relation to the covariates clinical pain intensity, pressure pain sensitivity, psychological strain, and as an effect of experienced experimental cuff-pressure pain.Results: CWP patients showed decreased connectivity in the inferior posterior cingulate cortex (PCC) in the DMN and increased connectivity in the left anterior insula/superior temporal gyrus in the SN when compared to controls. Moreover, higher pain sensitivity in CWP when compared to controls was related to increased connectivity within the SN (between left and right insula) and between SN and DMN (between right insula and left lateral parietal cortex).Conclusion: This study shows that connectivity within the DMN was decreased and connectivity within the SN was increased for CWP. Furthermore, we present a novel finding of interaction of pain sensitivity with SN and DMN-SN functional connectivity in CWP.

Sensory Modulation: An Important Piece of the Disability Puzzle for Adolescents With Persistent Pain.

Sensory modulation patterns contribute to altered pain perception and disengagement in activities; atypical sensory modulation patterns have been associated with higher pain sensitivity, catastrophizing, and reduced function. Objectives of this study were to ascertain whether: adolescents with persistent pain had atypical sensory modulation patterns, atypical sensory modulation was associated with reduced functioning and higher pain, and pain catastrophizing mediated the relationship between sensory modulation and functional disability. Adolescents (N=70, females=63, males=7) attending tertiary level interdisciplinary team assessment for persistent pain completed sensory modulation (Adolescent/Adult Sensory Profile), pain catastrophizing (Bath Adolescent Pain Questionnaire), pain intensity, functional disability (Functional Disability Index), and quality of life (QOL) (Pediatric QOL Scales) questionnaires. Adolescents with persistent pain had atypical patterns of sensory modulation compared with normative data. Sensory modulation patterns were not associated with pain intensity; however, higher sensitivity was associated with greater disability (r=0.36, P<0.01), and lower registration of sensation was associated with poorer emotional (r=0.31, P<0.01), social (r=0.35, P<0.01), and school-related (r=0.49, P<0.001) QOL. Sensory modulation, pain intensity, and catastrophizing contributed independently to disability; catastrophizing mediated sensory sensitivity and both functional disability and emotional QOL. This study is the first to show that atypical sensory modulation patterns are associated with poorer function for adolescents with persistent pain, suggesting that individualized sensory-informed interventions can potentially facilitate participation in daily activities and improve QOL.

Association of Catechol-O-methyltransferase single nucleotide polymorphisms, ethnicity, and sex in a large cohort of fibromyalgia patients

BackgroundFibromyalgia (FM) is a complex, centralized pain condition that is often difficult to diagnose and treat. FM is considered to have a genetic background due to its familial aggregation and due to findings from multiple candidate-gene studies implicating catecholaminergic and serotonergic neurotransmitter systems in chronic pain. However, a multi-factorial analysis of both genetic and environmental risk factors is lacking. A better characterization of the interplay of risk factors may assist in understanding the pathophysiology of FM, its clinical course, and assist in early diagnosis and treatment of the disorder.MethodsThis retrospective study included 60,367 total participants from 237 clinics across the USA. Of those, 2713 had been diagnosed with fibromyalgia, as indicated by ICD code. Logistic regression was used to test for associations of diagnosed FM in study subjects with COMT SNPs and COMT haplotypes, which were previously found to be linked with pain sensitivity, as well as demographics such as age, sex, and ethnicity. The minor allele frequencies of COMT SNPs in the FM population were compared with 1000 Genomes data using a χ2 test to determine significant deviations from the estimated population allelic frequencies.ResultsFM diagnosis was strongly associated with sex, age, and ethnicity. Females, those between 49 and 63 years, and non-Caucasians were at higher risk of FM. Females had 1.72 increased odds of FM (p = 1.17 × 10− 30). African-Americans were 1.52 times more likely to have a diagnosis of FM compared to Caucasians (p = 3.11 × 10− 12). Hispanics were less likely to have a diagnosis of FM compared to Caucasians (p = 3.95 × 10− 7). After adjusting for sex and ethnicity, those in the low age group and mid age group had 1.29 (p = 1.02 × 10− 5) and 1.60 (p = 1.93 × 10− 18) increased odds of FM, respectively, compared to the high age group, where age was categorized by tertile (low (< 49), mid (49–63), and high (> 63)). The COMT haplotypes associated with pain sensitivity were not associated with FM, but African-Americans were 11.3 times more likely to have a high pain sensitivity COMT diplotype, regardless of FM diagnosis. However, the minor alleles of COMT SNPs rs4680, rs4818, rs4633 and rs6269 were overrepresented in the FM population overall, and varied when compared with ethnically-similar populations from 1000 Genomes.ConclusionsThis is the largest study, to date, that examines demographic and genetic associations of FM in a diverse population. While pain sensitivity-associated COMT haplotypes were not found to be directly associated with FM diagnosis, the minor alleles that make up the COMT haplotypes were overrepresented in the FM population, suggesting a role of COMT in FM. Future studies are needed to elucidate the exact role of COMT variation in widespread pain conditions, such as FM. Clinically, this information can be used to provide insight into the pathways underlying FM and to identify those at greater risk of developing FM.

Prediction of running-induced Achilles tendinopathy with pain sensitivity - a 1-year prospective study.

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.

Epidermal Expression of TRPM8 But Not of TRPA1 Ion Channels is Associated with Human Cold Pain Sensitivity Patterns

Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed at peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are the members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Reproducibly observed distinct cold pain phenotype groups hinted at inter individually differing molecular bases. In 28 subjects displaying either high or medium cold pain sensitivity, the density of TRPM8 but not that of TRPA1 expression at dermal nerve fibers correlated significantly with the cold pain threshold. Moreover, a reproducible grouping of the subjects based on high or medium cold pain sensitivity was reflected in an analogous grouping based on high or low TRPM8 expression at dermal nerve fibers. The distribution of TRPM8 expression in dermal nerve fibers provided a sufficient explanation of the previously observed and presently reproduced (bi)modal distribution of human cold pain thresholds. Considering current controversies about the role of human TRPA1 ion channels in cold pain perception, the present observations with a lack of association of TRPA1 channel expression with pain related measures fuels doubts about its involvement in cold pain in humans. Considering that TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, known species differences, in particular in the function of TRPA1, emphasize an increasing importance of research methods developed to approach TRPs directly in humans. Funding Statement: This work has been funded by the Else Kroner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP, JL) and by the Landesoffensive zur Entwicklung wissenschaftlich - okonomischer Exzellenz (LOEWE), LOEWE-Zentrum fur Translationale Medizin und Pharmakologie (JL). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: The study followed the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Faculty of the Goethe – University Frankfurt am Main, Germany (protocol number 110/16).

Does pain sensitivity increase during ictal period? Evidence from absence epileptic WAG/Rij rats

ObjectiveThe hyperexcitable brain provides a common ground for comorbidity of pain syndromes and epilepsy. There are controversial reports about pain sensitivity during the ictal period. We analyzed the pain sensitivity during the ictal period in the genetic absence epilepsy animal model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. MethodsThe ictal and interictal pain sensitivities of symptomatic WAG/Rij rats (8 months old, n = 19) were determined and compared with those of age-matched control Wistar rats (n = 19). Pain sensitivity was assessed by applying heat stimulation to hind paws and measuring the paw-withdrawal latency using a thermal plantar analgesia meter in awake and freely moving animals. All measurements were made during the interictal and ictal periods and confirmed by simultaneous electroencephalography (EEG) through intracranially implanted electrodes. ResultsThe nociceptive stimulus-induced withdrawal latency during the ictal period in absence epilepsy WAG/Rij rats was significantly shorter when compared with that during the interictal period (p = 0.007) and when compared with that in the control Wistar rats (p = 0.001). ConclusionOur data indicate higher pain sensitivity during the ictal period in absence epilepsy rats. Considering the fact that subjects are less responsive during spike–wave discharges, there is a decrease in the level of consciousness and/or responsiveness ictally during all generalized genetic seizures, this increased pain sensitivity is rather surprising during the ictal period. Although the mechanism remains unknown, this novel finding deserves further investigation.