M.Tech.

Breast cancer is the most common cancer among Canadian women. Chronic neuropathic pain post breast surgery (PPBS), also known as chronic post mastectomy/lumpectomy pain syndrome, is a poorly understood complication posing a significant clinical challenge with major negative impact on patients' quality of life. This study aims to: 1) provide a preliminary determination of the prevalence rate of women who suffer from PPBS; and 2) explore potential risk factors associated with women developing PPBS. This pilot study used a prospective, longitudinal, quantitative survey design, with a demographic questionnaire and the Brief Pain Inventory. Seventeen women were recruited at a breast health clinic in Western Canada; 23.5% developed PPBS. Younger age (≤50 years), more invasive surgery, acute post-operative pain, and less analgesic use at the acute post-operative period, were more commonly found in the women who developed PPBS. Future research is required to confirm the significance of these potential risk factors.

Breast cancer is the most common cancer among Canadian women. Chronic neuropathic pain post breast surgery (PPBS), also known as chronic post mastectomy/lumpectomy pain syndrome, is a poorly understood complication posing a significant clinical challenge with major negative impact on patients' quality of life. This study aims to: 1) provide a preliminary determination of the prevalence rate of women who suffer from PPBS; and 2) explore potential risk factors associated with women developing PPBS. This pilot study used a prospective, longitudinal, quantitative survey design, with a demographic questionnaire and the Brief Pain Inventory. Seventeen women were recruited at a breast health clinic in Western Canada; 23.5% developed PPBS. Younger age (≤50 years), more invasive surgery, acute post-operative pain, and less analgesic use at the acute post-operative period, were more commonly found in the women who developed PPBS. Future research is required to confirm the significance of these potential risk factors.

Patellofemoral pain syndrome (PFPS) is one of the most common, but least understood, knee disorders. Fulkerson (1997) believes that pathology may result from an excessive valgus force being applied to the patella. Researchers have historically examined quadriceps strength and neuromuscular activity and knee kinematics. However, results from these works have not provided conclusive answers. Powers (2003) has theorized that other structures can influence knee function, and researchers have shown that PFPS subjects can exhibit hip weakness and demonstrate altered hip kinematics during functional activities. Although they provide preliminary evidence regarding hip influences, investigations that simultaneously examine hip and knee function in PFPS subjects are needed. The primary purpose of this study was to determine functional performance, strength, neuromuscular activity (amplitudes and onset timing differences), and kinematics of the hip and knee for people diagnosed with PFPS. Eighteen females diagnosed with PFPS and 18 asymptomatic female controls participated. Subjects initially completed a 10-cm visual analog scale. Next, they completed two functional performance tests and underwent a strength assessment for the hip abductors, hip external rotators, and knee extensors. Surface electromyography (EMG) electrodes and reflective markers were donned in order to collect EMG and kinematic data during a stair-stepping task. For this purpose, subjects ascended and descended two 20-cm high steps at a standardized rate. Seven PFPS and seven control subjects were retested five to seven days later to establish measurement reliability. A repeated measures analysis of variance was used to determine group differences. Correlation coefficients were calculated to identify associations between pain and dependent measures; intraclass correlation coefficients were calculated to determine measurement reliability for both control and PFPS subjects. Results from this study showed group differences for functional performance, strength, and EMG amplitudes but none for onset timing differences or kinematics. A strong association was found between pain and hip external rotator strength and EMG amplitudes during stair-stepping. Most tests provided reliable measures with repeat testing. PFPS subjects demonstrated quadriceps dysfunction but even greater hip weakness that was correlated more with pain. Contemporary rehabilitation has focused on quadriceps strengthening; however, results from this study support the importance of the hip.

Introduction: Complex regional pain syndrome (CRPS) is a form of neuropathic pain that sometimes develops after trauma or surgery. While diagnostic criteria have been debated, there is agreement participation in rehabilitation should be the primary management. However, there are gaps in the evidence guiding assessment and treatment choices for individuals with CRPS. The purpose of this thesis was to advance the rehabilitation of CRPS by 1) ongoing development and refinement of evaluations for the specific symptoms of CRPS, and 2) to investigate effectiveness of a new treatment (somatosensory rehabilitation) posited to address allodynia associated with CRPS. Methods: We conducted a series of 4 studies addressing various aspects of CRPS assessment and the somatosensory rehabilitation method: a) a cognitive debriefing study for content validation of the Patient-Reported Hamilton Inventory for CRPS; b) English translation and cultural validation of the Radboud Evaluation of Sensitivity; c) a retrospective cohort study of the effectiveness of somatosensory rehabilitation for allodynia in the upper limb; and d) a pilot study of the somatosensory rehabilitation method to consider the measurement properties of the embedded evaluation tools of allodynography and the rainbow pain scale, and to provide estimates for future controlled trials of effectiveness. Results: The cognitive debriefing study identified potentially problematic items, and constructs which needed enhancement in future versions of the PR-HICRPS assessment. The second paper reported the translation and cultural validation of the RES-E, finding support for test-retest reliability, internal consistency, and preliminary evidence for construct validity and reproducibility. The third paper presented preliminary evidence of a strong effect size for the SRM in an uncontrolled consecutive cohort. Finally, the fourth paper provides an interm analysis of the psychometric properties of allodynography and the rainbow pain scale, and estimates large sample sizes will be required for future trials. Discussion and Conclusion: None of the assessment tools described herein is ready for unrestricted use in clinical practice or research. Although the effect size estimates for somatosensory rehabilitation from the retrospective cohort are encouraging, the incomplete pilot data suggests large, multi-site trials and careful selection of the primary outcome measures will be required for future, rigorous trials of this method. / Dissertation / Doctor of Philosophy (PhD) / Complex regional pain syndrome (CRPS) is a painful collection of symptoms that can develop after trauma. Why it happens is not well understood, but most scientists and health care providers agree that rehabilitation should be the primary focus for managing the painful consequences of this condition. There is a need for simple and accurate ways to assess CRPS, as well as to treat it. Better assessment will support treatment that is more targeted to the symptoms of the individual. One of the very challenging symptoms experienced by persons with CRPS is painful sensitivity of the skin, also known as allodynia. This thesis describes the development and testing of several new patient-reported assessments for CRPS and allodynia, as well as two studies on a new method of treatment for allodynia.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Die Dysregulation von Neurotransmittersystemen spielt eine wesentliche Rolle für die Pathophysiologie des Bladder Pain Syndrom/Interstitielle Zystitis (BPS/IC). Diese Arbeit beschäftigt sich daher mit der veränderten Expression muskarinerger (M2, M3) und purinerger (P2X1, P2X2, P2X3) Rezeptoren auf Urothelzellen und suburothelialen Myofibroblasten der Harnblasenwand im Rahmen BPS/IC. Dazu wurde eine Gruppe von Patientinnen mit Verdacht auf BPS/IC (n=17) einer Kontrollgruppe (n=7) gegenübergestellt. Die Gewebeproben der Patientengruppe sind im Zuge der Basisdiagnostik (transurethrales Harnblasenmapping) bei klinischem Verdacht auf das Vorliegen eines BPS/IC entnommen worden. Das Gewebe der Kontrollgruppe entstammt makroskopisch unauffälligen Bereichen von Harnblasen, welche im Rahmen einer radikalen Zystektomie oder einer lateral erweiterten endopelvinen Resektion (LEER-OP) entnommen worden sind. Die semi-quantitative Analyse der Rezeptorexpression erfolgte mittels indirekter Immunfluoreszenz, die Auswertung erfolgte mittels konfokaler Laserscanningmikroskopie. Die Ergebnisse der Patientengruppe wurden mit denen der Kontrollgruppe verglichen. Im Rahmen dessen wurde auch ein individuelles Rezeptorprofil für jeden Patienten erstellt. Es zeigte sich eine Hochregulation von M2R, M3R und P2X1R auf Urothelzellen sowie eine Hochregulation von M2R, M3R, P2X1R und P2X2R auf suburothelialen Myofibroblasten in der BPS/IC-Gruppe im Vergleich zur Kontrollgruppe. Des Weiteren zeigten sich individuelle Unterschiede in den Rezeptorprofilen der Patienten. Die Ergebnisse werden vor dem Hintergrund einer möglichen Beteiligung der Regulation von muskarinergen und purinergen Rezeptoren an der Pathophysiologie des BPS/IC diskutiert. Ferner werden diagnostische und therapeutische Möglichkeiten einer erweiterten Mollekulardiagnostik diskutiert.

Die Dysregulation von Neurotransmittersystemen spielt eine wesentliche Rolle für die Pathophysiologie des Bladder Pain Syndrom/Interstitielle Zystitis (BPS/IC). Diese Arbeit beschäftigt sich daher mit der veränderten Expression muskarinerger (M2, M3) und purinerger (P2X1, P2X2, P2X3) Rezeptoren auf Urothelzellen und suburothelialen Myofibroblasten der Harnblasenwand im Rahmen BPS/IC. Dazu wurde eine Gruppe von Patientinnen mit Verdacht auf BPS/IC (n=17) einer Kontrollgruppe (n=7) gegenübergestellt. Die Gewebeproben der Patientengruppe sind im Zuge der Basisdiagnostik (transurethrales Harnblasenmapping) bei klinischem Verdacht auf das Vorliegen eines BPS/IC entnommen worden. Das Gewebe der Kontrollgruppe entstammt makroskopisch unauffälligen Bereichen von Harnblasen, welche im Rahmen einer radikalen Zystektomie oder einer lateral erweiterten endopelvinen Resektion (LEER-OP) entnommen worden sind. Die semi-quantitative Analyse der Rezeptorexpression erfolgte mittels indirekter Immunfluoreszenz, die Auswertung erfolgte mittels konfokaler Laserscanningmikroskopie. Die Ergebnisse der Patientengruppe wurden mit denen der Kontrollgruppe verglichen. Im Rahmen dessen wurde auch ein individuelles Rezeptorprofil für jeden Patienten erstellt. Es zeigte sich eine Hochregulation von M2R, M3R und P2X1R auf Urothelzellen sowie eine Hochregulation von M2R, M3R, P2X1R und P2X2R auf suburothelialen Myofibroblasten in der BPS/IC-Gruppe im Vergleich zur Kontrollgruppe. Des Weiteren zeigten sich individuelle Unterschiede in den Rezeptorprofilen der Patienten. Die Ergebnisse werden vor dem Hintergrund einer möglichen Beteiligung der Regulation von muskarinergen und purinergen Rezeptoren an der Pathophysiologie des BPS/IC diskutiert. Ferner werden diagnostische und therapeutische Möglichkeiten einer erweiterten Mollekulardiagnostik diskutiert.

The aim of this thesis is to investigate the prevalence and management of bladder pain syndrome (BPS) amongst women with chronic pelvic pain (CPP) through a series of systematic reviews, a structured survey and primary study. It has been acknowledged that the diagnosis and management of BPS is a contentious subject. The mean prevalence of BPS in women with CPP is 61%. I initially carried out a patient and clinician survey to understand how BPS was being managed in the UK. I found wide variation in diagnostic methods and treatments of BPS used by clinicians and experienced by patients with no obvious consensus. Since we know the predominant complaint in these patients is pain (bladder or pelvic) I used patients with pelvic pain as my cohort. Cystoscopy is no longer used as a diagnostic test for BPS. It is possible to diagnose BPS through a consensus expert panel using symptom-based criteria. This method of deriving a reference standard is demonstrated in the primary study, since no gold standard diagnostic test exists for BPS. A case-control feasibility study was undertaken to investigate the accuracy of a group of urinary symptoms to diagnose BPS. While, neither index test of bladder filling pain or bladder wall tenderness can sensitively diagnose BPS alone, the symptoms of bladder filling pain, urinary frequency, pain on urination and pain on full bladder are a good predictor of the condition. A systematic review assessing the reporting outcomes identified five measures that should be included in studies; pain, urinary symptoms, general 8 wellbeing, quality of life and bladder capacity. Of the 19 treatments used for BPS, the level and strength of evidence ratings overestimated quality compared to the GRADE ratings. BPS can be diagnosed symptomatically but there is variable reporting of outcome measures and poor evidence for treatment effectiveness.

Introduction. Inflammatory bowel disease (IBD) is a condition affecting more than 3 million people in Europe and the USA combined. Patients report pain as one of the most severe and debilitating symptoms leading to a lower quality of life. Current analgesics lack efficacy for the treatment of visceral pain or produce unacceptable side effect profiles. New targets are needed. Aims and methods. The aim of this thesis was to examine the activation of primary visceral afferents in C57BL/6 mice in response to biopsy supernatants from paediatric patients with IBD (Crohn's disease and ulcerative colitis) and functional abdominal pain syndrome (FAPS). By comparing the expression of pro-inflammatory and pro-nociceptive mediators in these biopsy samples with patient pain scores and afferent nerve recording activation, we identified putative mediators likely to be responsible for causing pain. The ability of inflammatory mediators to drive visceral nociception was then examined by their exogenous application in recordings of mouse and human visceral nociceptor activity. Results. Nerve activation increased significantly in response to biopsy supernatants from FAPS, CD, and UC patients, when compared to controls. Supernatant IL-8, TNFα, IL-6 and IL-1β, levels were increased in IBD samples compared with control patients. Analysis of mRNA expression also showed high levels of pro-inflammatory cytokines and raised MMP-1, MMP-3, MMP-9, MMP-12, and MMP-19 in IBD samples. The expression of MMP-12 in biopsy samples from Crohn's patients significantly correlated with afferent firing suggesting a causative role. This was confirmed by exogenously application of MMP-12 stimulated afferent firing and sensitised responses to mechanical stimulation and inflammatory mediators. UC samples showed TIMP-1 as an effective inhibitor of afferent firing. Conclusion. Data from this study demonstrates that the bowel of patients with IBD and FAP releases pro-nociceptive mediators which stimulate visceral afferents. MMP's play an important role in the afferent activation mediated by IBD samples suggesting that exploiting the endogenous inhibitor TIMP-1 could be a key target for future therapeutic strategies.