Exploring pain mechanisms in hypermobile Ehlers-Danlos syndrome: A case-control study.

BACKGROUND: The hypermobile type of Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder, associated with joint hypermobility and prominent chronic pain. Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood. OBJECTIVE: The present study assesses endogenous pain facilitation and pain inhibition in hEDS, using a protocol for temporal summation of pain (TSP), conditioned pain modulation (CPM) and exercise-induced hypoalgesia (EIH). METHODS: Twenty women with hEDS and 20 age-matched healthy controls participated. After evaluating thermal and mechanical pain thresholds (PPT), TSP was assessed using 10 repetitive painful pressure stimuli. CPM was provoked using pressure as the test stimulus and hand immersion in hot water (46°) as the conditioning stimulus. EIH was assessed after a submaximal cycling protocol. RESULTS: The hEDS group demonstrated reduced PPTs and showed significantly more TSP after repeated painful stimuli than the control group. In comparison to the healthy control group, the hEDS group demonstrated significantly less EIH at the quadriceps test location. At the trapezius, EIH did not significantly differ between groups. No significant differences were found between the hEDS group and control group in the CPM response. CONCLUSION: The results demonstrate increased TSP in hEDS, suggesting increased central pain facilitation. EIH should be studied more extensively but may be disturbed when evaluated in the muscles that are activated during exercise. The CPM results are inconclusive and require more research. SIGNIFICANCE: Studies regarding the mechanisms that underlie pain in hEDS are scarce, although it is the most prevalent and disabling symptom in this patient population. This study demonstrates increased temporal summation in hEDS and suggests that exercise-induced hypoalgesia may be reduced. Because exercise is a cornerstone in the multidisciplinary treatment of heritable connective tissue disorders, gaining knowledge in this field is important. Pressure stimuli were used to facilitate the international usability of the protocols, allowing for future data acquisition in large cohorts.

Developing and Pilot Testing of a Mini Massive Open Online Course (MOOC) on Occupational Epidemiology.

OBJECTIVE: Massive Open Online Courses (MOOCs) offer a flexible method of providing education to large numbers of people around the world. This study aimed to develop and pilot test a mini MOOC in order to teach knowledge and skills in occupational epidemiology. METHODS: Using instructional design principles, an open online course was developed. RESULTS: Four modules have been designed and delivered in a pilot version requiring an 8-hour time commitment. Thirty postgraduate students evaluated different aspects of the MOOC. They appreciated the active learning approach, gave high rates of approval for learning effects and structure but would welcome more feedback and interaction. CONCLUSIONS: Although students were satisfied, developing the MOOC entailed a considerable amount of time. A multi-institutional approach and international collaboration would be beneficial to improve the present MOOC and develop new ones.

Neonatal brachial plexus palsy and hand representation in children and young adults.

AIM: To assess the impact of neonatal brachial plexus palsy (NBPP) on higher-order hand representation. METHOD: Eighty-two left-handed children and adolescents with and without right-sided NBPP were recruited. Thirty-one participants with NBPP (mean age [SD] 11y 4mo [4y 4mo]; age range 6y 2mo-21y 0mo; 15 females; C5-6, n=4, C5-7, n=12, C5-T1, n=11, C5-T1 with Horner sign, n=4) were assessed along with 30 controls (mean age 11y 5mo [4y 4mo]; age range 6y 7mo-21y 7mo; 14 females). Participants' estimated hand size and shape on measure of implicit and explicit hand representation was assessed. A linear mixed model (LMM) was used to investigate the effect of condition, sensorimotor impairment, and age. RESULTS: Individuals with NBPP showed a significant difference in implicit hand representation between affected and non-affected hands. LMM confirmed a significant influence of the severity of sensorimotor injury. Only the estimated implicit hand representation was associated with age, with a significant difference between 6- to 8-year-olds and 9- to 10-year-olds. INTERPRETATION: The effect of sensorimotor impairment on central hand representation in individuals with NBPP is specific due to its implicit component and is characterized by finger length underestimation in the affected hand compared to the characteristic underestimation in the unaffected hand. Neither NBPP nor age impacted the explicit hand estimate. This study confirms the importance of sensorimotor contribution to the development of implicit hand representation.

Comparison of five conditioned pain modulation paradigms and influencing personal factors in healthy adults.

BACKGROUND: Conditioned pain modulation (CPM) methods are experimental procedures to assess presumed descending nociceptive modulatory pathways. Various CPM-methods are currently used, making the comparison of results difficult. The aim of this study was to compare five conditioning stimuli and to evaluate the influencing effects of personal factors on CPM-efficacy. METHODS: 101 healthy pain-free adults (50 males, 51 females) participated in this cross-sectional study with repeated measures design. The CPM-method consisted of hot water immersion (46°C, HWI), cold pressor test (12°C, CPT), cold pack application, and single and double ischemic occlusion as conditioning stimuli in randomized order. Pressure pain threshold was used as test stimulus at the mm. trapezius and quadriceps for all CPM-protocols. RESULTS: All CPM-protocols resulted in effective CPM, although cold pack application revealed smaller CPM-magnitudes compared to all other methods at both muscles, except single ischemic occlusion at the m. quadriceps. A smaller CPM-effect at the m. trapezius was shown when CPM was provoked by single ischemic occlusion compared to the CPT. Chronic stress, gender, attentional focus, age, physical activity and perceived pain are all influencing factors, in various conditioning stimuli at the mm. trapezius and quadriceps. CONCLUSIONS: CPT and HWI seem to be the most appropriate conditioned pain modulation paradigms for research settings, while single and double ischemic occlusion seem to be more useful for clinical settings. Influencing factors to be considered are gender, age, stress, physical activity, perceived pain and attentional focus to the conditioning stimulus, but depend on the test site and exerted method. SIGNIFICANCE: Hot water immersion, cold pressor test, and single and double ischemic occlusion result in comparable CPM-effects at the mm. trapezius and quadriceps. Anti-nociceptive effects of the cold pack are mainly a result of attention towards the cold pack. Chronic stress, attentional focus towards the conditioning stimulus and perceived pain of the conditioning stimulus influenced the anti-nociceptive effects at the m. trapezius. Gender and level of physical activity influenced the anti-nociceptive effects with the other methods at the m. quadriceps.

Hand size representation in healthy children and young adults.

Whereas we experience our body as a coherent volumetric object, the brain appears to maintain highly fragmented representations of individual body parts. Little is known about how body representations of hand size and shape are built and evolve during infancy and young adulthood. This study aimed to investigate the effect of hand side, handedness, and age on the development of central hand size representation. The observational study with comparison groups was conducted with 90 typically developing Belgian school children and young adults (48 male and 42 female; age range = 5.0-23.0 years; 49 left-handed and 41 right-handed). Participants estimated their hand size and shape using two different tasks. In the localization task, participants were verbally cued to judge the locations of 10 anatomical landmarks of an occluded hand. An implicit hand size map was constructed and compared with actual hand dimensions. In the template selection task, the explicit hand shape was measured with a depictive method. Hand shape indexes were calculated and compared for the actual, implicit, and explicit conditions. Participants were divided into four age groups (5-8 years, 9-10 years, 11-16 years, and 17-23 years). Implicit hand maps featured underestimation of finger length and overestimation of hand width, which is already present in the youngest children. Linear mixed modeling revealed no influence of hand side on finger length underestimation; nonetheless, a significant main effect of age (p = .001) was exposed. Sinistrals aged 11 to 16 years showed significantly less underestimation (p = .03) than dextrals of the same age. As for the hand shape, the implicit condition differed significantly with the actual and explicit conditions (p < .001). Again, the implicit shape index was subjected to handedness and age effects, with significant differences being found between sinistrals and dextrals in the age groups of 9 and 10 years (p = .029) and 11 to 16 years (p < .001). In conclusion, the implicit metric component of the hand representation in children and young adults is misperceived, featuring shortened fingers and broadened hands since a very young age. Crucially, the finger length underestimation increases with age and shows a different developmental trajectory for sinistrals and dextrals. In contrast, the explicit hand shape is approximately veridical and seems immune from age and handedness effects. This study confirms the dual character of somatoperception and establishes a point of reference for children and young adults.

The Result of Acute Induced Psychosocial Stress on Pain Sensitivity and Modulation in Healthy People.

BACKGROUND: Pain can be influenced by several factors, including stress. Stress can have various reactions on pain. These reactions are influenced by several internal factors such as gender, age, and experience with stress or pain. OBJECTIVES: To determine the effect of acute stress on mechanical hyperalgesia (with pressure pain thresholds [PPT]), endogenous pain facilitation (measured by temporal summation [TS]), and inhibition (measured by conditioned pain modulation [CPM]) in healthy people and to determine which factors are responsible for this stress result. STUDY DESIGN: Pre-posttest design. SETTING: Healthy volunteers from Belgium. METHODS: One hundred and one healthy pain-free patients underwent a modified Trier Social Stress Test. Prior and following the stress manipulation, PPT, TS, and CPM efficacy were determined in the mm. trapezius and quadriceps and overall. Furthermore, possible explanatory factors, such as fear of pain, pain catastrophizing, pain hypervigilance, and daily activity levels, were assessed using questionnaires. RESULTS: We found a significant stress result on widespread pain sensitivity, with an increase of PPT (P < 0.001), unchanged TS (P > 0.05), and a decrease in CPM efficacy (P < 0.001). Factors associated with the stress result were age, previous surgery, attentional focus on the conditioning stimulus during CPM, fear of pain, and daily activity levels. LIMITATIONS: The efficacy of the stress manipulation was not examined, and the lack of a control group prevented to examine a real stress-effect. Furthermore, no physiologic parameters were measured as possibly influencing internal factors for the stress-result. CONCLUSIONS: The increase in PPT was not a clinically significant change, whereas the decrease in CPM was meaningful. None of the factors predicted the stress result in all experimental pain measurements, and the predictions that were observed only explained a small proportion of the observed effects.

Influence of Morphine and Naloxone on Pain Modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia, and Controls: A Double-Blind, Randomized, Placebo-Controlled, Cross-Over Study.

BACKGROUND: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown. METHODS: A randomized, double-blind, placebo-controlled cross-over trial was carried out. Ten chronic fatigue syndrome (CFS)/fibromyalgia (FM) patients, 11 rheumatoid arthritis (RA) patients and 20 controls were randomly allocated to the experimental (10 mg morphine or 0.2 mg/mL Naloxone) and placebo (2 mL Aqua) group. Pressure pain thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned pain modulation (CPM) efficacy and deep tissue pain pressure were assessed by adding ischemic occlusion at the opposite upper arm. RESULTS: Deep tissue pain pressure was lower and temporal summation higher in CFS/FM (P = 0.002 respectively P = 0.010) and RA patients (P = 0.011 respectively P = 0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (P time = 0.034). Accordingly, PPTs increased after placebo (P time = 0.015), and no effects on the other pain parameters were objectified. There were no significant effects of naloxone nor nocebo on PPT, deep tissue pain, temporal summation or CPM in the control group. CONCLUSIONS: This study revealed anti-hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA.

An Overview of Offset Analgesia and the Comparison with Conditioned Pain Modulation: A Systematic Literature Review.

BACKGROUND: Offset analgesia (OA) is an increasingly described phenomenon to measure endogenous pain inhibition, in which a greater decrease in pain intensity is experienced than would be predicted by the decrease in painful stimulation. The temporal filtering in this OA phenomenon differs from the spatial filtering in the commonly described conditioned pain modulation (CPM). Yet, the knowledge on the efficacy of OA in chronic pain patients is scarce, compared to CPM efficacy. OBJECTIVE: This systematic review has been conducted to provide an overview of the current knowledge regarding OA, and to compare it to CPM. STUDY DESIGN: A systematic review of research studies that investigated the application or mechanisms of OA. SETTING: The present study took place at Ghent University and the University of Antwerp. METHODS: This systematic review follows the PRISMA guidelines. The electronic databases Pubmed and Web of Science were searched in January 2015. Full text clinical reports addressing OA were included. The checklists for randomized controlled trials, case-control studies, and cohort-studies provided by the Dutch Institute for Healthcare Improvement and the Dutch Cochrane Centre were used to assess methodological quality. The articles received a level of evidence A1, A2, B, C, or D, based on study design and risk of bias. These levels were used to determine the strength of conclusion (level 1 to 4). RESULTS: Seventeen articles met the inclusion criteria. Sixteen studies used quantitative sensory testing to provoke OA; however, differences in protocols are present. OA can function as a non-opioid mediated assessment tool for endogenous pain inhibition, and activates brain regions such as periaqueductal gray (PAG), dorsolateral prefontral cortex, insula, medulla, pons and cerebellum, indicating strong brain derived pain modulation. The primary somatosensory cortex is, conversely, less activated during OA. OA is decreased in neuropathic patients. Nonetheless, evidence for the influence of individual factors on OA is limited. OA and CPM seem to rely on different mechanisms. LIMITATIONS: Search strategy was taken wide, wherefore a large variety of research perspectives were included. CONCLUSIONS: This systematic review displays OA as a temporal filtering mechanisms that is more brain-derived compared to the spatial assessment method CPM. There is strong evidence for reduced OA in neuropathic patients, however, evidence regarding OA in (sub)acute and central sensitization patients, and the influence of personal factors on OA is currently scarce and needs further investigation.

Exercise- and Stress-Induced Hypoalgesia in Musicians with and without Shoulder Pain: A Randomized Controlled Crossover Study.

BACKGROUND: Professional and pre-professional musicians are characterized by physical and psychological demands inherent to their musical activity, and therefore at risk for developing performance related musculoskeletal pain. Physical and psychological demands are known to influence human pain modulation. OBJECTIVES: In this study we compared the influence of a physically and emotionally stressful task on pain thresholds in musicians with and without shoulder pain. STUDY DESIGN: A single-blinded randomized and controlled crossover study design was used to compare the effects of a physical versus emotional testing procedure on pressure pain thresholds (PPTs) in musicians with and without shoulder pain. SETTING: All data were obtained in the field (e.g., at the physiotherapy accommodation in the Royal Conservatory). METHODS: During the physical testing procedure, the subjects performed an isometric exercise of the glenohumeral external rotators. The emotional task comprised watching "unpleasant" images selected from the International Affective Picture System. The outcome was the assessment of change in PPTs before and after the physical and emotional task. RESULTS: Our results indicate similar effects of both protocols in either group, i.e., musicians with and without shoulder pain (P > 0.05). All musicians showed elevated PPTs at local and remote areas after isometric exercise (P < 0.05). The emotional stress task increased PPTs at remote areas only (P < 0.05). LIMITATIONS: Despite the small sample size of musicians without shoulder pain, a power of 78.5% was achieved to detect the necessary effect size of Cohen's d = 1. Furthermore, comparing these results with those of non-musicians (both healthy subjects and patients with shoulder pain) might reveal information regarding the specific adaptations. Finally a high variability was observed in shoulder disability (i.e., SDQ-scores) as typically seen in a population with shoulder pain. CONCLUSIONS: In musicians with and without regional shoulder pain, no significant differences were found with respect to pain modulation during a physically and an emotionally stressful task. Both interventions adequately activated central and widespread pain inhibitory mechanisms in both groups.

Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review.

BACKGROUND: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. METHODS: This systematic review follows the PRISMA guidelines. "Pubmed" and "Web of Science" were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. RESULTS: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. CONCLUSION: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required.

Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: a double-blind randomized controlled trial.

OBJECTIVE: Temporal summation (TS) of pain, conditioned pain modulation (CPM), and exercise-induced analgesia (EIA) are often investigated in chronic pain populations as an indicator for enhanced pain facilitation and impaired endogenous pain inhibition, respectively, but interactions are not yet clear both in healthy controls and in chronic pain patients. Therefore, the present double-blind randomized placebo-controlled study evaluates pains cores, TS, and CPM in response to exercise in healthy controls, patients with chronic fatigue syndrome and comorbid fibromyalgia (CFS/FM), and patients with rheumatoid arthritis (RA), both under placebo and paracetamol condition. METHODS: Fifty-three female volunteers - of which 19 patients with CFS/FM, 16 patients with RA, and 18 healthy controls - underwent a submaximal exercise test on a bicycle ergometer on 2 different occasions (paracetamol vs. placebo), with an interval of 7 days. Before and after exercise, participants rated pain intensity during TS and CPM. RESULTS: Patients with rheumatoid arthritis showed decreased TS after exercise, both after paracetamol and placebo (P < 0.05). In patients with CFS/FM, results were less univocal. A nonsignificant decrease in TS was only observed after taking paracetamol. CPM responses to exercise are inconclusive, but seem to worsen after exercise. No adverse effects were seen. CONCLUSION: This study evaluates pain scores, TS, and CPM in response to submaximal exercise in 2 different chronic pain populations and healthy controls. In patients with RA, exercise had positive effects on TS, suggesting normal EIA. In patients with CFS/FM, these positive effects were only observed after paracetamol and results were inconsistent.

Applying modern pain neuroscience in clinical practice: criteria for the classification of central sensitization pain.

BACKGROUND: The awareness is growing that central sensitization is of prime importance for the assessment and management of chronic pain, but its classification is challenging clinically since no gold standard method of assessment exists. OBJECTIVES: Designing the first set of classification criteria for the classification of central sensitization pain. METHODS: A body of evidence from original research papers was used by 18 pain experts from 7 different countries to design the first classification criteria for central sensitization pain. RESULTS: It is proposed that the classification of central sensitization pain entails 2 major steps: the exclusion of neuropathic pain and the differential classification of nociceptive versus central sensitization pain. For the former, the International Association for the Study of Pain diagnostic criteria are available for diagnosing or excluding neuropathic pain. For the latter, clinicians are advised to screen their patients for 3 major classification criteria, and use them to complete the classification algorithm for each individual patient with chronic pain. The first and obligatory criterion entails disproportionate pain, implying that the severity of pain and related reported or perceived disability are disproportionate to the nature and extent of injury or pathology (i.e., tissue damage or structural impairments). The 2 remaining criteria are 1) the presence of diffuse pain distribution, allodynia, and hyperalgesia; and 2) hypersensitivity of senses unrelated to the musculoskeletal system (defined as a score of at least 40 on the Central Sensitization Inventory). LIMITATIONS: Although based on direct and indirect research findings, the classification algorithm requires experimental testing in future studies. CONCLUSION: Clinicians can use the proposed classification algorithm for differentiating neuropathic, nociceptive, and central sensitization pain.

The influence of sprint interval training on body composition, physical and metabolic fitness in adolescents and young adults with intellectual disability: a randomized controlled trial.

OBJECTIVE: In this study we evaluated the effect of sprint interval training on metabolic and physical fitness in adolescents and young adults with intellectual disabilities when compared with continuous aerobic training and no training (control). METHODS: Fifty-four persons with intellectual disabilities (age: 17 (3.0), body mass index: 27.7 (3.7), intelligence quotient: 59 (8.6)) were matched based on age, gender and intelligence quotient between sprint interval training (n = 17), continuous aerobic training (n = 15) and control (n = 14). Sprint interval training was composed of three blocks of 10 minutes at ventilatory threshold (blocks 1 and 3: 10 sprint bouts of 15 seconds, followed by 45 seconds relative rest; block 2: continuous training) twice a week for 15 weeks. Continuous aerobic training was composed of three blocks of 10 minutes continuous training. After eight weeks, intensity was increased to 110% of ventilatory threshold. The control group did not participate in supervised exercise training. Before and after the training period, body composition, physical and metabolic fitness were evaluated. RESULTS: Sprint interval training showed a significant positive evolution for waist circumference, fat%, systolic blood pressure, lipid profile, fasting insulin, homeostasis model assessment of insulin resistance, peak VO2, peak Watt, ventilatory threshold, 6-minute walk distance and muscle fatigue resistance when compared with no training (P < 0.01). The sprint interval training group demonstrated significant improvements for fat%, systolic blood pressure, low-density lipoprotein, fasting insulin, peak VO2 and peak power and ventilatory threshold (P < 0.01) when compared with continuous aerobic training. CONCLUSION: In this study we could observe that sprint interval training has stronger beneficial effects on body composition, physical fitness and metabolic fitness compared with control. Compared with continuous aerobic training, sprint interval training seems to result in better outcome.

The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets?

INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are characterized by persistent pain and fatigue. It is hypothesized that reactive oxygen species (ROS), caused by oxidative and nitrosative stress, by inhibiting mitochondrial function can be involved in muscle pain and central sensitization as typically seen in these patients. AREAS COVERED: The current evidence regarding oxidative and nitrosative stress and mitochondrial dysfunction in CFS and FM is presented in relation to chronic widespread pain. Mitochondrial dysfunction has been shown in leukocytes of CFS patients and in muscle cells of FM patients, which could explain the muscle pain. Additionally, if mitochondrial dysfunction is also present in central neural cells, this could result in lowered ATP pools in neural cells, leading to generalized hypersensitivity and chronic widespread pain. EXPERT OPINION: Increased ROS in CFS and FM, resulting in impaired mitochondrial function and reduced ATP in muscle and neural cells, might lead to chronic widespread pain in these patients. Therefore, targeting increased ROS by antioxidants and targeting the mitochondrial biogenesis could offer a solution for the chronic pain in these patients. The role of exercise therapy in restoring mitochondrial dysfunction remains to be explored, and provides important avenues for future research in this area.

Central sensitization in urogynecological chronic pelvic pain: a systematic literature review.

BACKGROUND: Chronic pelvic pain (CPP) is a complex pain syndrome. Since its pathogenesis is still poorly understood and structural alterations in pain related brain regions may be present, there is a greater acceptance that sensitization of the central nervous system (CNS) plays an important role in the development and maintenance of chronicity. OBJECTIVE: The purpose of this study is to systematically review the scientific evidence regarding central sensitization (CS) in female patients with urogynecological CPP. STUDY DESIGN: Systematic review of the literature. METHODS: A systematic literature search was conducted in PubMed and Web of Science using different keyword combinations related to urogynecological CPP and central sensitization. Full text clinical reports addressing CS in adult women with urogynecological CPP were included and assessed for methodological quality by 2 independent reviewers. RESULTS: After screening for the eligibility, a total of 29 full-text articles with low to good methodological quality were retained. All studies were observational, 27 of which were case-control and 2 of which were cohorts. Sensitivity of the CNS was investigated by using a variety of methods. Although different central mechanisms seem to be involved in pain processing, the present evidence suggests hyperexcitability of the CNS in patients with urogynecological CPP. Altered brain morphology and function, generalized hyperalgesia to different type of stimuli, overactive bottom-up nociceptive mechanisms, and autonomic dysregulation were established in patients with urogynecological CPP. Nevertheless, diffuse noxious inhibitory control seemed normal, and therefore the contribution of an impaired endogenous pain inhibition mechanism to CPP requires further study. The same goes for the contribution of psychological factors. LIMITATIONS: The level of evidence of retained studies is low due to the observational study designs and a wide range of diagnoses and assessment methods. CONCLUSION: Although the majority of the literature provides evidence for the presence of CS in urogynecological CPP with changes in brain morphology/function and sensory function, it is unclear whether these changes in central pain processing are secondary or primary to CPP, especially since evidence regarding the function of endogenous pain inhibition and the role of psychosocial pain facilitation is scarce. Further studies with good methodological quality are needed in order to clarify exact mechanisms.

Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review.

OBJECTIVE: The goal of this systematic literature review is to determine whether there are differences and similarities in heart rate variability (HRV) between adult patients with fibromyalgia (FM), chronic fatigue syndrome (CFS), and healthy pain-free control subjects. METHODS: To obtain relevant articles, PubMed and Web of Knowledge were searched for case-control studies. Selection of the literature was based on selection criteria ascertaining studies with adult human patient groups comparing HRV. Risk of bias and levels of evidence were determined. RESULTS: Sixteen case-control studies were included, 10 comparing FM patients to controls and 6 comparing CFS patients to controls. Methodological quality was moderate to good. Both time domain and frequency domain measurements were used. The majority of the researchers observed lower HRV in FM patients compared to healthy control persons, as well as increased sympathetic activity and a blunted autonomic response to stressors. Resistance training improved HRV in FM patients. In CFS patients HRV was only reduced during sleep. CONCLUSION: FM patients show more HRV aberrances and indices of increased sympathetic activity. Increased sympathetic activity is only present in CFS patients at night. Since direct comparisons are lacking and some confounders have to be taken into account, further research is warranted. The role of pain and causality can be subject of further research, as well as therapy studies directed to reduced HRV.

Does acetaminophen activate endogenous pain inhibition in chronic fatigue syndrome/fibromyalgia and rheumatoid arthritis? A double-blind randomized controlled cross-over trial.

BACKGROUND: Although enhanced temporal summation (TS) and conditioned pain modulation (CPM), as characteristic for central sensitization, has been proved to be impaired in different chronic pain populations, the exact nature is still unknown. OBJECTIVES: We examined differences in TS and CPM in 2 chronic pain populations, patients with both chronic fatigue syndrome (CFS) and comorbid fibromyalgia (FM) and patients with rheumatoid arthritis (RA), and in sedentary, healthy controls, and evaluated whether activation of serotonergic descending pathways by acetaminophen improves central pain processing. STUDY DESIGN: Double-blind randomized controlled trial with cross-over design. METHODS: Fifty-three women (19 CFS/FM patients, 16 RA patients, and 18 healthy women) were randomly allocated to the experimental group (1 g acetaminophen) or the placebo group (1 g dextrose). Participants underwent an assessment of endogenous pain inhibition, consisting of an evaluation of temporal summation with and without conditioned pain modulation (CPM). Seven days later groups were crossed-over. Patients and assessors were blinded for the allocation. RESULTS: After intake of acetaminophen, pain thresholds increased slightly in CFS/FM patients, and decreased in the RA and the control group. Temporal summation was reduced in the 3 groups and CPM at the shoulder was better overall, however only statistically significant for the RA group. Healthy controls showed improved CPM for both finger and shoulder after acetaminophen, although not significant. LIMITATIONS: The influence of acetaminophen on pain processing is inconsistent, especially in the patient groups examined. CONCLUSION: This is the first study comparing the influence of acetaminophen on central pain processing in healthy controls and patients with CFS/FM and RA. It seems that CFS/FM patients present more central pain processing abnormalities than RA patients, and that acetaminophen may have a limited positive effect on central pain inhibition, but other contributors have to be identified and evaluated.