Orientador: Norma Sueli Pinheiro Módolo / Resumo: Justificativa: a obesidade é uma doença crônica caracterizada por acúmulo excessivo de gordura corporal. Devido aos riscos associados, é considerada um grande problema de saúde pública nos países desenvolvidos. A cirurgia bariátrica (gastroplastia aberta) tem sido usada como uma estratégia importante para tratar esta condição nos países em desenvolvimento, especialmente quando associada a outras comorbidades. A qualidade de recuperação, no entanto, tem sido uma preocupação frequente no manejo pós-operatório desses pacientes. A pregabalina é um análogo estrutural do neurotransmissor ácido gama-aminobutírico (GABA) que se liga à subunidade alfa-2 do canal de cálcio voltagem dependente, bloqueando o desenvolvimento da hiperalgesia e a sensibilização central à dor. Objetivo: o objetivo principal da pesquisa foi avaliar o efeito da pregabalina perioperatória versus placebo na qualidade de recuperação pós-operatória em pacientes submetidos à cirurgia bariátrica. Métodos: trata-se de estudo prospectivo, randomizado, controlado com placebo, duplo cego. Após a aprovação do Comitê de Ética, setenta pacientes submetidos à gastroplastia abdominal foram randomizados para receber pregabalina, grupo 1 (75 mg por via oral 1 hora antes da cirurgia) ou uma pílula de placebo idêntica, grupo 2. O desfecho primário foi a avaliação da qualidade da recuperação (questionário QoR-40) em 24 horas. Os resultados secundários incluíram o consumo de opioides e os escores de dor pós-operatória. Um valor de... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: obesity is a chronic disease characterized by excessive accumulation of body fat. Due to the associated risks, it has been considered a major public health problem in developed countries. Bariatric surgery (open gastroplasty) has been used as an important strategy to treat this condition in developing countries, especially when associated with other comorbidities. The quality of recovery, however, has been a frequent concern in the postoperative management of these patients. Pregabalin is a structural analogue of the gamma-aminobutyric acid neurotransmitter (GABA) that binds to the alpha-2-subunit of the voltage-dependent calcium channel, blocking the development of hyperalgesia and central pain sensitization. Objective: the main objective of the current investigation was to evaluate the effect of perioperative pregabalin versus placebo on postoperative quality of recovery in patients undergoing bariatric surgery. Methods: the study was a prospective, randomized, placebo-controlled, double-blinded trial. After ethics committee approval, seventy patients undergoing abdominal gastroplasty were randomized to receive pregabalin, group 1 (75 mg orally 1 hour before surgery) or an identical placebo pill, group 2. The primary outcome was the quality of recovery-40 score at 24 hours. Secondary outcomes included opioid consumption and postoperative pain scores. A P value <0.05 was used to reject type I error. Results: seventy patients were randomized and 60 subjects comple... (Complete abstract click electronic access below) / Doutor

Acute and chronic pain conditions cause significant patient distress, interference with daily activities, and increased health care costs. It is important to evaluate analgesic interventions to improve pain relief, function, quality of life, and also to prevent persisting pain after surgery. This thesis is a combination of studies evaluating analgesic interventions in the setting of acute surgical pain; prevention of persistent post-surgical pain; and chronic low back pain. In part 1, we report our comparison of morphine and hydromorphone in 402 ambulatory surgery patients, for their ability to achieve satisfactory analgesia with minimal emesis using a design of multicentre randomized controlled trial. We observed no differences in their analgesic potential and common side effects and note that appearance of side effects is likely to be idiosyncratic. In part 2, we report our 2×2 factorial feasibility trial to prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, comparing N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. As our feasibility outcomes were not met, we suggest appropriate considerations for protocol changes before embarking on a definitive larger trial. In part 3, we report on our systematic review and meta-analysis assessing the effectiveness and safety of gabapentinoids (gabapentin and pregabalin) in adult patients with chronic low back pain. We observed that the existing evidence is small and there is minimal improvement in pain and other outcomes with potential for adverse events. We suggest that the use of gabapentinoids for chronic low back pain merits caution and there is need for large high-quality trials. / Thesis / Doctor of Philosophy (PhD) / It is important to evaluate analgesic interventions to decrease pain, improve function, and lessen health care costs. In a randomized controlled trial of day surgery patients, we demonstrate that there are no differences between morphine and hydromorphone in achieving pain relief and common side effects. To prevent persistent post-surgical pain in patients having elective video-assisted thoracic surgery lobectomies, we performed a 2×2 factorial, feasibility randomized controlled trial, to compare N-methyl-D-aspartate antagonists versus placebo, and intravenous steroids versus placebo. We observe that appropriate protocol changes must be made before embarking on a larger trial. Finally, we report our systematic review and meta-analysis on the use of gabapentinoids in adult patients with chronic low back pain and observe that the existing evidence is small and not supportive, and the use of gabapentinoids for chronic low back pain merits caution.

Metastatic bone cancers cause severe symptoms including pain that compromises patient functional status, quality of life, and survival. Current treatment strategies have limited efficacy and dose-limiting side effects. Cancer-induced bone pain (CIBP) is a unique pain state that shares features with but is distinct from the pathology of neuropathic and inflammatory pain. This dissertation investigates how CIBP is generated and maintained by the direct effects of cancer cells on their metastatic microenvironment and the peripheral nervous system, including unique signaling properties and gene expression changes. In particular, we found that genetic knockdown of the functional subunit xCT of the system xC- cystine/glutamate antiporter can reduce CIBP, further elucidating this as a therapeutic of interest. We found that the neuroprotective voltage-gated calcium channel inhibitors progesterone and pregabalin markedly reduce mechanical hypersensitivity and excitability in sensory neurons of the dorsal root ganglion (DRG) in male rat models of neuropathic pain, but that these effects and less pronounced in females. In cancer pain, these sex differences are reversed, with females but not males demonstrating a delay in time-to-onset of mechanical hypersensitivity. We also analyzed gene expression at the DRG by RNA-Sequencing of rat models of CIBP. Our findings uncovered differential gene expression between CIBP and sham controls and between ipsilateral and contralateral DRGs in CIBP model rats. These studies have identified several promising avenues for therapeutic research for CIBP. / Dissertation / Doctor of Philosophy (PhD) / The tools we have right now to manage severe and chronic pain are insufficient. Patients with advanced cancers including bone cancer can suffer from very severe pain. This pain is generated in a number of ways including by the tumour itself releasing chemicals that activate pain-sensing nerves, by the destruction of the bone in and around the tumour, and by the sensitization of the nervous system, which can make pain worse and longer lasting. We have taken three approaches to researching cancer pain and to investigating new treatments. We have found that by reducing the amount of glutamate that cancer cells can release into their environment, we can reduce cancer pain in mice. We also found that treating rats with pregabalin and progesterone can change nerve signaling and reduce neuropathic pain, but that this effect is most pronounced in male rats with neuopathic pain and smaller in female rats with neuropathic pain, and even smaller in rats with cancer pain. We also analyzed expression of all the protein-coding genes in dorsal root ganglia from rats with cancer pain and found that there are many differences from rats without pain. Some of these differences may be promising new research targets. Going forward this research has provided important evidence necessary for next steps to develop new therapies and research strategies for cancer pain.

La douleur neuropathique est due à une lésion ou une pathologie du système nerveux somatosensoriel. La prégabaline, un anticonvulsivant, et la duloxétine, un antidépresseur, sont des traitements de référence, efficaces chez un tiers des patients. Mieux comprendre leurs mécanismes d’action est crucial pour améliorer leur tolérance et leur efficacité. En utilisant un modèle murin de douleur neuropathique périphérique, nous montrons que : 1) la prégabaline, dont l’action est indépendante du système opioïdergique, agit sur la composante neuroimmunitaire périphérique de la douleur ; 2) la duloxétine agit via deux mécanismes indépendants, l’un central (contrôles descendants) pour un traitement aigu et l’autre périphérique (ganglion rachidien) pour un traitement chronique. Dans ce cas, l’analyse transcriptomique met en évidence une inhibition de l’inflammation neurogène. La comparaison des taux plasmatiques de duloxétine chez l’homme et chez la souris suggère une action périphérique chez l’homme. / Neuropathic pain is caused by a lesion or a disease of the somatosensory nervous system. Pregabalin, an anticonvulsant, and duloxetine, an antidepressant, are the standard treatments, effective in one-third of patients. A better understanding of their mechanisms of action is a crucial point to improve their tolerance and efficiency. By using a murine model of peripheral neuropathy, we have shown that : 1) pregabalin, whose effect is independent from the opioid system, acts on the peripheral neuroimmune component of pain ; 2) duloxetine acts via two independent mechanisms, one central (descending controls) for an acute treatment and the other peripheral (dorsal root ganglia) for a chronic treatment. In this case, transcriptomic analysis hightlights an inhibition of the neurogenic inflammation. Comparison of duloxetine plasmatic levels in humans and mice suggests a peripheral action in humans.

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.