In the early nineties cannabinoid receptors, the main target for Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana were identified. Shortly after their endogenous ligands, N-arachidonoylethanolamine (anandamide, AEA) and 2-diacylglycerol (2-AG) were characterized. The enzymes primarily responsible for catalysing the degradation of AEA and 2-AG are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) respectively. AEA is a member of the N-acylethanolamine (NAE) class of lipids, which depending on the acyl chain length and number of double bonds can act as ligands for a variety of biological targets. Exogenous cannabinoids have long been reported to have analgesic effects, however the clinical usefulness of such substances is limited by their psychoactive effects. Inhibition of endocannabinoid degradation would mean enhancing the therapeutic effects without producing these unwanted side effects. In order to succeed in developing such compounds the pharmacology of the enzymes responsible for the degradation of endocannabinoids has to be thoroughly understood. When the preclinical part of this thesis was planned, FAAH had been well characterized whereas little was known as to the pharmacology of MGL. A series of compounds were tested in this first study aiming to find MGL-selective compounds. Although no compounds showed selectivity for MGL over FAAH, several interesting agents affecting both enzymes were identified. In order to increase the knowledge concerning which patient group would benefit from such treatment strategies it is important to investigate in which pain states the endocannabinoids/NAEs are altered. Thus the general aim of the clinical part of this thesis was to investigate the levels of endocannabinoids/NAEs in the interstitium of the trapezius muscle in women suffering from chronic neck/shoulder pain (CNSP) and chronic wide spread pain (CWP) and in healthy pain-free controls. Furthermore for the CNSP the effect of training, which is a commonly recommended treatment for these patients, on the levels of endocannabinoids/NAEs was also investigated. Microdialysis technique in the trapezius muscle was used for sampling and masspectrometry was used for analysing. Two NAEs, N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA), could be repeatedly measured. The levels of these two lipids were significantly higher in CNSP compared to CON. The result showed also that PEA and SEA mobilize differently in CWP compared to both CNSP and CON. Taken together the results presented in thesis represent an early characterization of the pharmacology of MGL and provides novel information on NAEs in chronic muscle pain.

Background: Previous research states that chronic widespread pain (CWP) has a negative impact on health status and daily life activities. Risk factors for developing CWP are, e.g. female sex, other chronic diseases, smoking, inactivity, sleeping problems and obesity. The average prevalence of CWP is 9.6-15% in the general population. The results vary regarding sex differences in prevalence, pain experience, impact on daily life, work, and health status. Therefore, the overall aim was to investigate CWP’s impact on health status and long-term lifestyle predictors for better health when having CWP. Method: The study is a general population cohort study including 975 participants (442 men, 533 women) at the age of 35-54 years with a 12- and 21-year follow-up. CWP was defined according to the American College of Rheumatology’s (ACR) definition stating pain must be present for at least three months, below and above the waist, on both sides of the body, and the axial skeleton to be classified as widespread. Using a pain mannequin and additional questions the individuals were sorted in three different pain groups: no chronic pain (NCP), chronic regional pain (CRP), and CWP. The questionnaire included questions about lifestyles factors (personal support, friendship circuit, smoking, alcohol intake, physical activity and sleeping habits) and SF-36 measuring health status. Differences in health status were analysed by independent samples t-test and health predictors by logistic regression analysis. The results were further analysed using Tengland’s two-dimensional health theory and the relational gender theory. Results: The prevalence of CWP was higher among women during all time points, but health status was statistically significant reduced for both women and men with CWP (p <0.001) showing no sex differences of clinical relevance. At the 12-year follow-up, 58% of the women and 53% of the men had persistent CWP (p <0.001). At the 21-year follow-up, 59% of the women and 29% of the men had persistent CWP (p <0.001). Health predictors for better health when having persistent CWP were male sex (OR 3.03-6.76), having social support (OR 9.27), no sleeping problems (OR 3.48-4.76), being a former smoker (OR 4.38-7.83) and a weekly intake of alcohol (OR 4.94). Conclusion: More women reported persistent CWP in a 12- and 21-year perspective than men, but when having CWP the health status was equally as bad among women and men. Modifiable health factors such as having no sleeping problems was strongly associated with better mental health, and personal support could be of importance for a better vitality. The higher prevalence reported among women and male sex as a health predictor seems to be influenced by the psychosocial mechanisms of gender. However, health status did not show any association with the relational gender theory. The results suggests, even though men have less prevalence of CWP the condition should be regarded as having the same impact for women and men in health care. Further research should continue studying persistent CWP and possible confounders to establish the sex and gender differences in the long-term perspective. / Bakgrund: Tidigare forskning visar att långvarig generell smärta (CWP) har en negativ påverkan på hälsostatus och dagliga aktiviteter. Riskfaktorer för att utveckla CWP är t.ex. kvinnligt kön, andra kroniska sjukdomar, rökning, inaktivitet, sömnproblem och övervikt. Den genomsnittliga prevalensen av CWP i den allmänna befolkningen är 9,6–15 %. Resultat på könsskillnader varierar gällande prevalens, upplevelse av smärta, påverkan på det dagliga livet, arbetslivet samt hälsostatus. Det övergripande syftet var därför att undersöka CWP:s påverkan på hälsostatus samt långsiktiga livsstilsfaktorer för en bättre hälsa för dem med CWP. Metod: Studien är en befolkningskohort med 975 deltagare (442 män, 533 kvinnor) i åldern 35–54 år med en 12- och 21-års uppföljning. CWP definierades enligt American College of Rheumatology (ACR) definition som säger att smärta ska vara närvarande i minst tre månader, under och över midjan, på båda sidorna av kroppen samt axialskelettet för att klassificeras som generell. Med hjälp av en ritad smärtfigur och ytterligare frågor sorterades deltagarna in i tre olika smärtgrupper: ingen långvarig smärta (NCP), långvarig regional smärta (CRP) och CWP. Frågeformuläret bestod av frågor om livsstilsfaktorer (personligt stöd, vänskapskrets, rökning, alkoholintag, fysisk aktivitet samt sovvanor) och SF-36 som mäter hälsostatus. Skillnader i hälsostatus analyserades genom ett oberoende t-test och hälsoprediktorer genom logistisk regressionsanalys. Resultatet analyserades ytterligare utifrån Tenglands två-dimensionella hälsoteori och den relativa genusteorin. Resultat: Prevalensen av CWP var högre bland kvinnor vid samtliga tidpunkter och hälsostatus var statistiskt signifikant lägre för både kvinnor och män med CWP (p < 0.001). Det fanns inga könsskillnader av klinisk relevans. Vid 12 års uppföljningen hade 58 % av kvinnorna och 53 % av männen långvarig CWP (p < 0.001). Vid 21 års uppföljningen hade 59 % av kvinnorna och 29 % av männen långvarig CWP (p < 0.001). Hälsoprediktorer för bättre hälsostatus för CWP-drabbade var manligt kön (OR 3,03–6,76), socialt stöd (OR 9,27), inga sömnproblem (3,48–4,76), före detta rökare (4,38–7,83) och att varje vecka dricka alkohol (OR 4,94). Slutsats: Fler kvinnor än män rapporterade långvarig CWP i ett 12- och 21-års perspektiv, men bland de som hade CWP var hälsostatusen lika dålig hos kvinnor och män. Att inte ha några sömnproblem var starkt förknippat med en bättre mental hälsa och personligt stöd kan vara av betydelse för en bättre vitalitet. Den högre prevalensen bland kvinnor samt manligt kön som hälsoprediktor verkar vara påverkade av de psykosociala mekanismerna för genus. Hälsostatus visade emellertid inte någon koppling till den relativa genusteorin. Resultet innebär att även om män har en lägre prevalens av CWP bör tillståndet betraktas detsamma för män som hos kvinnor i vården. Vidare forskning bör studera långvarig CWP och möjliga confounders för att faststlå köns- och genusskillnader i ett långsiktigt perspektiv.

Background People with rheumatic or neurologic conditions are commonly referred for occupational therapy because of decreased ability to perform ADL tasks. Upon referral, occupational therapists use a client-centred, occupationfocused approach when evaluating a person's perceived and observed quality of ADL task performance to clarify the nature and extent of the person’s problems, plan interventions and determine effectiveness of interventions. Evaluation of the extent of problems and change following intervention require the use of linear measures of ADL. The aim of this doctoral thesis was to develop and validate linear measures of perceived and observed quality of ADL task performance for occupational therapy clinical praxis and research. Methods To develop linear measures of observed quality of ADL task performance based on Rasch measurement methods, clients with ABI (n=70) were evaluated using a 3-category rating scale and the ADL Taxonomy. Similarly, to develop linear measures of perceived quality of ADL task performance women with rheumatic diseases (n=118) reported their ability on a questionnaire and in an interview based on the ADL Taxonomy and a 4- category rating scale. To further validate the ADL ability measures of the Assessment of Motor and Process Skills (AMPS) data were collected in two samples. In a sample of women with chronic widespread pain (CWP) or fibromyalgia (FM) (n=50) the ADL ability measures were validated with regard to discrimination, stability and sensitivity to changes. Discrimination was examined by comparing AMPS data from women with CWP/FM to those of healthy women. Stability and sensitivity to change were examined based on repeated AMPS observations pre and post intervention. In addition, sensitivity to change was examined in a sample of clients with ABI (n=36) using a pre- and post-test design. Finally, the validity of the AMPS ADL ability measures in relation to perceived ADL ability was examined in women with rheumatic diseases (n=118) and women with CWP/FM (n=50). Results Based on the results of the four studies in this thesis, we were able to conclude that it was possible to obtain linear measures of observed quality of ADL task performance based on a revised version of the ADL Taxonomy (ADL-O). It was also possible to obtain linear measures of perceived quality of ADL task performance based on revised versions of the ADL Taxonomy using the formats of questionnaires (ADL-Q) and interviews (ADL-I). Moreover, it was possible to establish further evidence of validity of the ADL ability measures of the AMPS. Thus, the AMPS ADL ability measures could discriminate between women with CWP/FM and healthy women. The ADL ability measures of remained stable when no intervention was provided and the ADL motor ability measures were sensitive to change among women with CWP/FM. Moreover, the ADL ability measures were sensitive to change among clients with low ADL ability following ABI. Finally, only low to moderate correlations were found between measures of perceived and observed ADL ability. Conclusions Rasch analyses of revised versions of the ADL Taxonomy suggest that the majority of the ADL tasks and rating scales focused on quality of ADL task performance can be used to obtain linear measures of quality of ADL task performance based on methods of questionnaire, interview or observation. Furthermore, the studies provided evidence of validity of the ADL ability measures of the AMPS in relation to discrimination, stability and sensitivity to change and relation to perceived ADL ability. The results may, therefore, enhance the use of ADL instruments that provide linear measures of perceived and observed quality of ADL task performance in occupational therapy clinical praxis and research.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Fibromyalgia (FM) is a syndrome characterized by chronic widespread musculoskeletal pain and hyperalgesia, especially in specific points called |tender points|. Furthermore, this syndrome is associated with psychosomatic disorders, such as chronic fatigue, depression, anxiety and sleep disorders. Interferential current (IFC) is a non-pharmacological and non-invasive treatment commonly used in promoting the symptomatic relief of pain. However, there is little evidence to support the effective use of IFC in patients with FM and little is known about the optimal parameters of stimulation by IFC. Thus, the present study had, as objective, to investigate the effects of different intensities of stimulation with IFC in pain relief and the other disorders present in individuals with FM. This study is a randomized, placebo-controlled and double-blind clinical trial. To assess the effects of IFC before and after treatment, the following outcomes were measured (with their respective instruments) in each session of application by IFC: pressure pain threshold (PPT: digital algometry), cutaneous sensory threshold (CST: von Frey filaments) and pain intensity at rest (11-point numeric rating scale). In addition, were also measured in the first and last day of treatment: impact of fibromyalgia (Fibromyalgia Impact Questionnaire), depression level (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), functional capacity (Sitting-Rising and Timed Up and Go tests), fear to move (Tampa Scale of Kinesiophobia), pain catastrophizing (Pain Catastrophizing Scale), characterization of pain (McGill Pain Questionnaire), quality of life (Short Form Health Survey 36), temporal summation (temporal summation test), conditioned pain modulation (conditioned pain modulation test) and fatigue intensity (11-point numeric rating scale). Twenty nine women with FM were recruited and allocated to three groups: Motor (n=10; IFC was applied at high intensity, with motor contraction), Sensory (n=10; high intensity, but without motor contraction) and placebo (n=9). Patients allocated into the motor and sensory groups were stimulated at an amplitude-modulated frequency of 100 Hz, for 30 minutes. In the placebo group, the current was released only in the first 40 seconds of stimulation. Ten treatment sessions were performed and the electrodes were applied to the paravertebral region. The t Student test, Wilcoxon and ANOVA for repeated measures were used to compare the results found, intra-group, before and after treatment. In women allocated to the motor group, there was a significant increase PPT, measured in the conditioned pain modulation test (p≤0.03), and significant reduction in amplification of pain intensity in temporal summation (p=0.03) after the end of treatment. None of the studied group showed significant change in the PPT and CST values in 18 tender points specific to FM, and pain intensity each treatment session with IFC (p>0.05). However, only the motor group had a significant reduction in the impact of the disease (p=0.01), depression (p=0.006), anxiety state (p=0.01), kinesiophobia (p=0.002), catastrophizing (p=0.008), pain rating index (p=0.04), fatigue (p=0.02) and number of tender points (p=0.04), and increased quality of life (p=0.006). Thus, the results, obtained in this study, provide strong evidence that the IFC, only when applied in high intensities of stimulation, is an effective treatment in reducing pain and psychosomatic disorders present in patients with FM / A fibromialgia (FM) é uma síndrome caracterizada por dor musculoesquelética crônica generalizada e hiperalgesia, principalmente em pontos específicos, chamados tender points . Além disso, essa síndrome está associada a alterações psicossomáticas, como fadiga crônica, depressão, ansiedade e distúrbios do sono. A corrente interferencial (CI) é um tratamento não-farmacológico e não-invasivo comumente utilizado na promoção do alívio sintomático da dor. Apesar disso, há pouca evidência que suporte o uso efetivo da CI em pacientes com FM e pouco se conhece sobre os parâmetros ideais de estimulação por meio da CI. Sendo assim, o presente estudo teve, como objetivo, investigar os efeitos de diferentes intensidades de estimulação com CI no alívio da dor, bem como das demais alterações presentes em indivíduos com FM. Este trabalho trata-se de um ensaio clínico randomizado, controlado por placebo e duplamente encoberto. Para avaliação dos efeitos da CI antes e após o tratamento, foram medidos os seguintes desfechos (com seus respectivos instrumentos) em cada sessão de aplicação da CI: limiar de dor por pressão (LDP: algometria digital), limiar sensitivo cutâneo (LSC: filamentos de von Frey) e intensidade de dor em repouso (Escala Numérica de 11 pontos). Além disso, foram também mensurados, no primeiro e no último dia de atendimento: impacto da fibromialgia (Questionário de Impacto da Fibromialgia), nível de depressão (Inventário de Depressão de Beck), ansiedade (Inventário de Ansiedade Traço-Estado), capacidade funcional (testes de Sentar e Levantar e Timed Up and Go), medo de movimentar-se (Escala de Cinesiofobia de Tampa), catastrofização da dor (Escala de Catastrofização da Dor), caracterização da dor (Questionário de Dor McGill), qualidade de vida (Short Form Health Survey 36), somação temporal (Teste de Somação Temporal), modulação condicionada da dor (Teste de Modulação Condicionada da Dor) e intensidade de fadiga (Escala Numérica de 11 pontos). Foram recrutadas 29 mulheres com FM, que foram alocadas em três grupos de estudo: Motor (n=10; a CI foi aplicada em alta intensidade, com contração motora), Sensorial (n=10; alta intensidade, porém sem contração motora) e Placebo (n=9). As pacientes alocadas nos grupos motor e sensorial foram estimuladas com uma frequência de amplitude modulada em 100 Hz, durante 30 minutos. Já no grupo placebo, a corrente foi liberada apenas nos primeiros 40 segundos de estimulação. Foram realizadas 10 sessões de tratamento e os eletrodos foram aplicados na região paravertebral. Os testes t de Student, Wilcoxon e ANOVA para medidas repetidas foram utilizados para comparação dos resultados encontrados, intra-grupo, antes e após o tratamento. Nas mulheres alocadas no grupo motor, foi observado aumento significativo do LDP, mensurado no teste de modulação condicionada da dor (p≤0,03), além de redução significativa na amplificação da intensidade de dor da somação temporal (p=0,03) após o término do tratamento. Nenhum dos grupos de estudo apresentou alteração significativa dos valores de LDP e LSC nos 18 tender points específicos para FM, e na intensidade de dor a cada sessão de tratamento com CI (p>0,05). No entanto, apenas o grupo motor apresentou redução significativa no impacto da doença (p=0,01), depressão (p=0,006), estado de ansiedade (p=0,01), cinesiofobia (p=0,002), catastrofização (p=0,008), índice de classificação da dor (p=0,04), fadiga (p=0,02) e quantidade de tender points (p=0,04), além do aumento da qualidade de vida (p=0,006). Dessa forma, os resultados encontrados, no presente estudo, fornecem fortes evidências de que a CI, apenas quando aplicada em altas intensidades de estimulação, é um tratamento eficaz na redução da dor e alterações psicossomáticas presentes em indivíduos com FM.