Osteoarthritis is the 12th leading cause of years lived with disability globally and by 2040 more than 10 million Canadians will have knee osteoarthritis (KOA). Pain in persons with KOA is well-recognized, persistent and chronic with central sensitization (CS) being prevalent in ~30%. CS is measured by psychophysical testing and patient-reported methods such as the Central Sensitization Inventory (CSI). The CSI was developed using subgroups of people with chronic pain, but not those with KOA. Therefore, validity of the CSI in people with KOA is lacking. CS as indicated by psychophysical tests is associated with CSI scores lower than the recommended cut score. Therefore, we aimed to evaluate the validity of the CSI through Rasch analysis in persons with KOA. We then sought to determine the agreement of the Rasch calibrated (RC-CSI) version of the CSI with the original and to evaluate the validity of the RC-CSI with psychophysical tests in people with KOA. In the first study, the CSI was able to fit Rasch model. After iterative analysis, we found the CSI to be a singular construct with acceptable unidimensionality while retaining all 25 items. Only two items - frequent urination (item 21) and Skin problems (item 19) showed a pattern of uniform differential item functioning by age and sex respectively. Moreover, we generated a RC-CSI cut score of 31.37 that we used to compare with the original cut score of 40. In second study, the findings suggested a lack of agreement between the two versions of the CSI demonstrating small bias. When exploring sensitivity and specificity with psychophysical tests, the RC-CSI showed little clinical value over the original CSI. We therefore recommend that the original CSI should be used with individual clients as our preliminary findings suggest that there is no added benefit to using the RC- CSI. / Thesis / Master of Science Rehabilitation Science (MSc)

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system that has high association with chronic pain syndromes such as fibromyalgia, migraine disorders, and chronic abdominal pain in adolescents with the diagnosis. Many of these disorders are characterized as central sensitization disorders, or pathological pain memory mediated by neural plasticity. Ehlers Danlos Syndrome Type 3 (EDS-3), also called joint hypermobility syndrome (JHS) is a genetic disorder of the connective tissue that causes joint laxity and is also highly associated with chronic pain syndromes as well as POTS. Methods: This study proposed to characterize POTS as a disorder of central sensitization. The hypothesis, presented within the proposed theoretical model, demonstrates that JHS leads to chronic pain that results in central sensitization and autonomic nervous system dysfunction (POTS). Other factors that were evaluated were anxiety and function. A sample size of 40 adolescents between the ages of 12 and 19 years were recruited from the cardiology and pain clinics at Children’s National Medical Center. Analysis of data utilizing Wilcoxon, Chi square, Pearson correlation, and logistic regression tests were completed using SAS 9.3. Results: In comparison to those without POTS, there were no significant associations found between having the diagnosis of POTS and any other variable studied in the model. JHS had a stronger correlation with anxiety, central sensitization, both subjectively, and objectively with hyperalgesia on Aδ sensory nerve fiber when compared to those without JHS. Subjective central sensitization was highly correlated with anxiety, function, age, and female gender. Function and central sensitization had a significant association even when removing anxiety as a covariate. Conclusions: These findings suggest that joint hypermobility may be a factor that contributes to the development of central sensitization in individuals with chronic pain. Dysautonomia is likely not a disorder of central sensitization, but rather a variable related to joint hypermobility and chronic pain in ways yet to be discovered. As previously discussed in other literature, anxiety has strong associations with central sensitization and functional disability in chronic pain syndromes, and when treated effectively may increase function in those that suffer with these disorders.

Inflammatory and neuropathic pains arise in part from sensitization at nociceptive synapses in the spinal cord. Activity-dependent signaling cascades converge onto the tyrosine kinase Src, which participates in augmenting the function of N-methyl-D-aspartate receptors (NMDARs) and thus potentiates the nociceptive system. Src is capable of these effects because it is anchored to the NMDAR complex via an adaptor protein called NADH dehydrogenase subunit 2 (ND2). There is evidence that this interaction occurs between amino acids 40-49 of Src and amino acids 310-321 of ND2. I have determined that a peptide consisting of amino acids 310-321 of ND2, and affixed to the HIV Tat domain for cell permeability, is capable of alleviating tactile allodynia induced by Complete Freund's Adjuvant (CFA) in rats. Src40-49Tat was not effective in two models of inflammatory pain. This work further implicates the Src-ND2 interaction in pain hypersensitivity and suggests that Tat ND2 310-321 may alleviate it.

Inflammatory and neuropathic pains arise in part from sensitization at nociceptive synapses in the spinal cord. Activity-dependent signaling cascades converge onto the tyrosine kinase Src, which participates in augmenting the function of N-methyl-D-aspartate receptors (NMDARs) and thus potentiates the nociceptive system. Src is capable of these effects because it is anchored to the NMDAR complex via an adaptor protein called NADH dehydrogenase subunit 2 (ND2). There is evidence that this interaction occurs between amino acids 40-49 of Src and amino acids 310-321 of ND2. I have determined that a peptide consisting of amino acids 310-321 of ND2, and affixed to the HIV Tat domain for cell permeability, is capable of alleviating tactile allodynia induced by Complete Freund's Adjuvant (CFA) in rats. Src40-49Tat was not effective in two models of inflammatory pain. This work further implicates the Src-ND2 interaction in pain hypersensitivity and suggests that Tat ND2 310-321 may alleviate it.

This thesis is an investigation of the neurophysiologic mechanism, central sensitization, underlying pain and dysfunction in osteoarthritis. Central sensitization is an important mechanism in the pathophysiology of osteoarthritis but, to our knowledge, its influence on motoneurone excitability is unknown. Our primary hypothesis states that increasing central sensitization within a spinal segment will cause a greater increase in the excitability of motoneurones in subjects with osteoarthritis when compared to healthy controls. To test this hypothesis, we experimentally induced central sensitization in individuals and monitored the recruitment threshold force of the motor units in the first dorsal interosseous muscle using indwelling electromyography. Findings from this study suggest that central sensitization lowers the motor unit recruitment threshold in osteoarthritis compared to healthy individuals. Motoneurone excitability might be inhibited in healthy individuals with persistent sensitization as well. Thus, central sensitization is an important consideration in the biomechanical dysfunction seen in osteoarthritis. / Canadian Arthritis Network

OBJECTIVES: This study aims to explore the relationships between preoperative psychosocial factors in relation to postoperative chronic pelvic pain (CPP) in adolescents and young women with endometriosis, which is a significant public health concern. As a pilot sample, there is large need to present preliminary data exploring the biopsychosocial correlates and possible predictors of central sensitization and CPP, which remains non-existent in the realm of adolescents and young adults with CPP secondary to endometriosis. METHODS: Eligible candidates included patients 12-22 years old who were diagnosed with CPP after laparoscopic confirmation of endometriosis. 25 successfully enrolled subjects had pre-surgical information obtained from baseline surveys and underwent a postoperative sensory protocol to assess mechanical allodynia, pressure pain sensitivity, central sensitization, and a self-report measure of pain sensitivity. Correlation calculations were conducted between pre-surgical factors (pain intensity, pain catastrophizing (PCS), and quality-of-life (from SF-36)) and post-surgical factors (pain and sensitivity thresholds as measured by QST and the PSQ) in the subject population as a whole, and in two population subgroups: those exhibiting central sensitization and those who are not. One-way ANOVA calculations and one sample t-tests were conducted to compare differences between cohorts and between abdominal and control sites for various study parameters. RESULTS: 6 of 25 (24%) subjects experienced a wind-up phenomenon during the temporal summation for pain test, serving as a surrogate for central sensitization. The differences in study parameters that this group (+CS) exhibited in comparison to the –CS group, failed to reach significance in all study parameters. Both cohorts exhibited positive correlations between pre-operative disability due to bodily pain (SF-36) and sensitivity of the abdomen, as well as negative correlations between disability due to bodily pain and pressure pain thresholds of the abdomen. The +CS cohort also exhibited a negative correlation between disability due to bodily pain and pinprick pain scores, a positive correlation between role limitations due to physical health (SF-36) and sensitivity of the abdomen, and a positive correlation between pain catastrophizing and sensitivity of the abdomen. As a whole, the subject population had significantly higher levels of catastrophizing than published means. In all cohorts, pressure pain thresholds of the abdomen were significantly lower than the control values, and PSQ-minor scores were significantly higher than published means. CONCLUSIONS: Results suggest the importance of pre-operative pain and psychosocial functioning on pain outcomes, particularly when considering subjects presenting with central sensitization, in young women with CPP secondary to endometriosis. The results indicate the need for a larger sample as well as established control values to further explore the relationships between these variables.

OBJECTIVES: This study aims to better understand the relationship between psychosocial factors and the development of chronic pelvic pain (CPP) in cases of adolescent endometriosis, specifically mood disorders, pain catastrophizing and quality of life, and to detect the development of central sensitization within this population. METHODS: Eligible candidates were patients between 14 and 22 years old with confirmed diagnosis of endometriosis and chronic pelvic pain who were enrolled in the Women’s Health Study: From Adolescence to Adulthood through the Boston Center for Endometriosis (BCE) and Boston Children’s Hospital. The administration of quantitative sensory testing (QST) to assess mechanical touch perception, pressure pain sensitivity and temporal summation was performed on 48 subjects. Pre-surgical baseline surveys, which included pain catastrophizing and quality of life measures, were obtained from the BCE. Record of diagnosed mood disorder (anxiety/depression) was obtained through medical chart review. Pearson correlations between QST measures, pain catastrophizing, presence of mood disorders or central sensitization and pre-surgical pain scores were conducted. One-way ANOVA calculations, and one sample and paired t-tests were conducted to gain further understanding of these variables as they relate to groups within the cohort. RESULTS: Regarding QST measures, 23 subjects (47.9%) produced a wind-up phenomenon from temporal summation during QST administration, which serves as a surrogate for the presence of central sensitization (+CS). Pressure sensation and pain scores correlated at all test sites (lower and upper abdomen, as well as finger control site) and wind-up phenomenon correlated in the lower and upper abdomen throughout the cohort. For the presence of mood disorders, anxiety and depression were equally distributed across the +CS and –CS groups. Review of pre-surgical pain scores and pain catastrophizing (PCS) within the cohort had significant correlations between pre-surgical pain and PCS subsets of rumination and magnification. PCS total and subset scores also correlated to +CS. One-way ANOVA calculations showed the cohort as a whole presented with clinically significant helplessness. CONCLUSIONS: Results encourage further investigation of the relationship between endometriosis, comorbid conditions, environmental factors and the development of CPP within the adolescent population. More detailed data regarding mental health and documentation of condition progression, as well as establishment of health control values and sample growth are encouraged for the continued progress of this project. / 2020-07-03T00:00:00Z

Prior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.

Adverse childhood events have been identified as a risk factor for developing chronic pain conditions in adulthood. However, previous studies have inconsistently supported the link between adverse childhood events and hypersensitivity to laboratory-induced pain. Therefore, this study intended to investigate the effects of adverse childhood events on temporal summation of second pain (TSSP). A group of 38 healthy and pain-free college students participated in laboratory pain tests after being screened for childhood trauma history. Half of participants (47.5% female) were positive for childhood trauma and the other half (63.2% female) reported no adverse childhood event. The laboratory pain tests measured TSSP using 10 thermal pulses per trial over four consecutive trials. The trauma group showed a tendency of greater sensitization within TSSP trials and lack of habituation over repeated TSSP trials. In sum, adverse childhood events predisposed adults to enhanced TSSP, which is potentially linked to an increased likelihood to develop chronic pain problems.

Introduction: Chronic pain after whiplash trauma (chronic WAD) to the neck is still a common clinical problem in terms of pain management, rehabilitation and insurance claims. In contrast to the increased knowledge concerning mechanisms of chronic pain in general, no clinical guidelines exist concerning assessment, pain control and rehabilitation of patients with chronic WAD. Aim: The general aim of this thesis was to use experimental techniques to better understand the complex mechanisms underlying chronic pain after whiplash trauma. The specific aims of papers I and II were mainly to use analgesic drugs with different target mechanisms alone or in combinations to assess their effects on pain intensity (VAS). Experimental pain techniques were used in all studies to assess deep tissue sensitivity (electrical, mechanical and chemical stimuli). Paper IV aimed at assessing deep tissue sensitivity to mechanical and chemical stimulation. The aim in paper III was to investigate if biochemical changes in interstitial muscle tissue (trapezius muscle) could be detected in WAD patients. Materials and Methods: The thesis is based on three different groups of patients with chronic WAD. In paper III and IV two different groups of healthy controls also participated. All patients were initially assessed in the pain and rehabilitation centre. In paper I (30 patients) and II (20 patients) two different techniques of drug challenges were used. In paper I: morphine, ketamine and lidocaine were used as single drugs. In paper II: remifentanil, ketamine and placebo were used in combinations and together with experimental pain assessments. Microdialysis technique was used in paper III (22 patients from study IV and 20 controls). In paper IV (25 patients and 10 controls) a new quantitative method, computerized cuff pressure algometry, was used in combination with intramuscular saline. In all papers, experimental pain techniques for deep tissue assessment (except cutaneous electrical stimulation in paper I) were used in different combinations: intramuscular hypertonic saline infusion, intramuscular electrical stimulation and pressure algometry. Results and Conclusion: There are multiple mechanisms behind chronic whiplash-associated pain, opioid sensitive neurons, NMDA-receptors and even sodium channels might play a part. A significant share of the patients were pharmacological non-responders to analgesic drugs targeting the main afferent mechanisms involved in pain transmission, this implies activation of different pain processing mechanisms (i.e. enhanced facilitation or changes in the cortical and subcortical neuromatrix). Experimental pain assessments and drug challenges together indicate a state of central hyperexcitability. Ongoing peripheral nociception (paper III), central sensitization and dysregulation of pain from higher levels in the nervous system may interact. These findings are likely to be present early after a trauma, however it is not possible to say whether they are trauma-induced or actually represents pre-morbid variations. Clinical trials with early assessments of the somatosensory system (i.e., using experimental pain) and re-evaluations, early intervention (i.e. rehabilitation) and intensified pain management could give further knowledge.