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No. of bitstreams: 4 Carta de encaminhamento para Autodepósito.pdf: 331385 bytes, checksum: 531c27ef5d65302d431d11bc3a7d8924 (MD5) Ata da Defesa Pública.pdf: 879468 bytes, checksum: 070af76dbbeb551e87bd807f93302c3a (MD5) Projeto Final_Christiane.pdf: 5105546 bytes, checksum: 7e363fd433154b9aacfad042f4d44b0e (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-09-21 / BACKGROUND. Untreated pain leads to postoperative complications that prolong hospital stay. The association of analgesic drugs with different mechanisms of action, such as clonidine, allows the use of smaller doses of medication for better control of pain. OBJECTIVES. This dissertation aims to evaluate the use of multimodal analgesia in the control of postoperative pain in patients submitted to videolaparoscopic cholecystectomy (VLC); to compare the analgesic activities of intrathecal and intravenous clonidine for postoperative analgesia; to analyze the need for analgesic drugs in the immediate postoperative (tramadol / morphine) and to identify possible complications. METHOD. A prospective, randomized clinical trial was conducted with patients divided into three blocks, with 20 patients each one: Group I (n = 20) control, submitted to standard anesthesia; Group II (n = 20) intrathecal clonidine, submitted to standard anesthesia associated with the use of intrathecal clonidine; Group III (n = 20) intravenous clonidine, submitted to standard anesthesia associated with the use of intravenous clonidine. RESULTS. The pain scores between the groups did not present significant differences, but a greater analgesic need was observed in the control group (p = 0.005), as well as a higher incidence of nausea and vomiting (p = 0.240), probably due to side effects of morphine as rescue medication. Groups II and III presented a significant reduction of heart rate (p ˂ 0.001), but without clinical repercussion. CONCLUSIONS. In patients undergoing VLC there is evidence that the perioperative administration of alpha 2-agonists preserves hemodynamic stability, decreases opioid consumption and the incidence of nausea and vomiting in the postoperative. / JUSTIFICATIVA. A dor não tratada leva a complicações pós-operatórias que prolongam o tempo de internação hospitalar. A associação de fármacos analgésicos com diferentes mecanismos de ação, como a clonidina, permite usar doses menores de medicamentos para melhor controle da dor. OBJETIVOS. Esta dissertação tem por objetivo avaliar o emprego de analgesia multimodal no controle da dor pós-operatória de pacientes submetidos à colecistectomia por videolaparoscopia (CVLP); comparar as atividades analgésicas da clonidina intratecal e endovenosa para analgesia pós-operatória; analisar a necessidade de drogas analgésicas no pós-operatório imediato (tramadol/morfina) e identificar possíveis complicações. MÉTODO. Foi realizado um estudo de ensaio clínico prospectivo, experimental e randômico, com os pacientes divididos em 03 blocos, com 20 pacientes cada: Grupo I (n=20) controle, submetido à anestesia padrão; Grupo II (n=20) clonidina intratecal, submetido à anestesia padrão associada ao uso de clonidina intratecal; Grupo III (n=20) clonidina endovenosa, submetido à anestesia padrão associada ao uso de clonidina endovenosa. RESULTADOS. Os escores de dor entre os grupos não apresentaram valores com diferenças significativas, porém foi observada maior necessidade analgésica do uso da morfina no grupo controle (p = 0,005), assim como maior incidência de náuseas e vômitos (p=0,240), provavelmente devido aos efeitos colaterais da morfina como medicação de resgate. Os grupos II e III apresentaram uma redução significativa da frequência cardíaca (p ˂0,001), porém sem repercussão clínica. CONCLUSÕES. Nos pacientes submetidos à CVLP há evidências de que a administração perioperatória de alfa 2-agonistas preserva a estabilidade hemodinâmica, diminui o consumo de opióides e a incidência de náuseas e vômitos no pós-operatório.

A exposição de animais a situações ameaçadoras de natureza inata ou aprendida resulta em exibição de um repertório de comportamentos defensivos espécie-específicos, alterações autonômicas e em inibição da dor, sendo esse conjunto de reações de alta relevância para a sobrevivência de uma espécie. Considerando este contexto, um importante componente da resposta do organismo a situações de emergência é a redução da capacidade de perceber a dor. O processamento de estímulos nociceptivos pode ser modulado no prosencéfalo, na medula espinal, no tronco encefálico e no diencéfalo, por mecanismos envolvendo diferentes neurotransmissores e neuromoduladores. Nos últimos anos, evidências têm demonstrado que o monóxido de carbono (CO), produzido a partir da enzima heme-oxigenase estimula a formação de guanosina 3, 5- monofosfato cíclico (GMPc), participando como neuromodulador de vários processos fisiológicos. Dentro deste contexto, mostrou-se que a via HO-CO-GMPc está envolvida na modulação periférica e espinal da dor inflamatória, bem como na modulação do estresse, porém não há conhecimento da participação desta via na modulação de estímulo doloroso agudo, bem como da antinocicepção induzida pelo estresse. Assim, este trabalho teve como objetivo avaliar o envolvimento da via HO-CO-GMPc na nocicepção e na antinocicepção induzida pelo estresse agudo em ratos, avaliada pelo índice de analgesia no teste de retirada da cauda (IARC). Nossos resultados demonstraram que a ativação da via HO-CO-GMPc por meio da administração ICV de heme-lisinato (substrato) tem efeito antinociceptivo, sendo este efeito dependente da atividade GMPc, desde que o pré-tratamento com inibidor da guanilase ciclase solúvel (GCs), ODQ, bloqueou o aumento do IARC. Ainda, esta modulação ocorre de maneira fásica e não tônica, pois o tratamento isolado ICV com o inibidor da HO, ZnDBPG ou com o inibidor da GCs, ODQ, não alterou o IARC. A antinocicepção induzida pelo estresse agudo (restrição física por 120 min) não é dependente da via HO-CO-GMPc, desde que o tratamento com o ZnDBPG, nem com o heme-lisinato alteraram o IARC. No entanto, esta antinocicepção é dependente da atividade do GMPc, pois o pré-tratamento com ODQ bloqueou o aumento do IARC. / The exposure of animals to threatening situations of innate or learned nature results in exhibition of a repertoire of species-specific defensive behaviors, autonomic alterations and pain inhibition. This group of reactions has high relevance for the survival of species. In this context, an important component of the response of the organism in the emergency situations is the reduction of the capacity to perceive pain. The processing of nociceptive stimulus can be modulated in forebrain, in spinal, and in midbrain, for mechanisms involving different neurotransmitters and neuromodulators. Recently, evidence has demonstrated that carbon monoxide gas (CO), produced from the enzyme heme oxygenase (HO), stimulate the formation of 3\', 5\' - cyclic guanosine monophosphate (cGMP), and this molecule has participated as neuromodulator in some physiological processes. In this way, it has shown that the HO-CO-cGMP pathway is involved in the peripheral and spinal modulation of inflammatory pain, as well as in the modulation of the stress. However, the involvement of this pathway in the modulation of acute painful stimulus, as well as in the antinociception induced by stress isn´t clarified. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in nociception and in antinociception induced by acute stress in rats, by means the of analgesia index in the tail flick test (AITF). Our results demonstrated that the activation of the HO-CO-cGMP pathway by means of heme-lysinate ICV administration has antinociceptive effect. Again, the increase of the AITF was dependent of the cGMP activity, since that the pretreatment with inhibitor of soluble guanylase cyclase (sGC), ODQ, blocked the antinociceptive effect. This modulation occurs in fasic and not tonic manner, because per se ICV treatment with inhibitor of the HO, ZnDBPG or with inhibitor of the sGC, ODQ did not modify the AITF. The antinociception induced by acute stress (physical restriction during 120 min) is not dependent of the HO-CO-cGMP pathway, since that neither the treatment with the ZnDBPG, nor with the heme-lysinate had modified the AITF. However, this antinociception is dependent of the activity of the cGMP, because the pretreatment with ODQ blocked the increase of the AITF induced by acute stress.

Durante muitos anos a sedação consciente com a mistura de oxigênio e óxido nitroso foi utilizada por cirurgiões-dentistas em vários países do mundo. Já no Brasil, essa utilização só foi regulamentada com a edição da resolução do Conselho Federal de Odontologia CFO 51/04 (CFO, 2004b). Como todo instrumento de regulamentação, este também deve ser analisado para que possa ser melhor entendido. Assim, o presente estudo teceu comentários acerca dos aspectos integrantes de tal resolução, procurando destacar a importância e a relevância de cada um deles. Tal avaliação reveste-se de grande importância, pois a organização dos cursos que habilitarão os cirurgiões-dentistas a aplicar a sedação consciente com a mistura de oxigênio e óxido nitroso terá que cumprir os requerimentos presentes na citada resolução. Ressalte-se que não se pretendeu esgotar o assunto, até mesmo porque isso seria impossível, mas suscitar o interesse dos pesquisadores no desenvolvimento de investigações mais aprofundadas sobre a matéria. / For many years the conscious sedation with nitrous oxide and oxygen has been used in various countries in the world. This usage in Brazil has only been regulated with the present Resolução do Conselho Federal de Odontologia CFO 51/04. As any other regulating instrument, this also needs analysis for its complete understanding. In this study every aspect of the Conselho´s Resolution were analyzed, trying to underline their importance and relevance of each one of them. This evaluation becomes of great importance because it is based on its requirements that the courses for the habilitation of dentists who intend to use the technique of conscious sedation with nitrous oxide and oxygen will be developed and ruled. This study intends to be one of the tools that will be used to fully understand this resolution.

Orientador: Cláudia Herrera Tambeli / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T16:27:32Z (GMT). No. of bitstreams: 1 Favaro-Moreira_NadiaCristina_D.pdf: 14440949 bytes, checksum: 19ac7e9f7196c13dfd756bd4150b1456 (MD5) Previous issue date: 2014 / Resumo: Disfunção temporomandibular (DTM) é um termo coletivo que abrange uma série de problemas clínicos que envolvem os músculos mastigatórios e a articulação temporomandibular (ATM) e está comumente associada à inflamação. Apesar de medicamentos anti-inflamatórios não esteróides (AINEs) serem frequentemente utilizados no controle de dor inflamatória, sabe-se que a dor inflamatória possui um componente simpático que pode predominar em casos menos responsivos a tratamentos com AINEs. Portanto, os objetivos deste estudo foram: (i) avaliar se os hormônios gonadais modulam a resposta antinociceptiva ao bloqueio dos ?-adrenoreceptores (ARs) na ATM de ratos, (ii) avaliar se um e três dias de tratamento com o ?-bloqueador não seletivo para AR ?1 e ?2 nadolol reduzem a dor em pacientes com DTM significativamente mais do que o placebo, (iii) avaliar se as mulheres experimentam relativamente maior benefício com o tratamento com nadolol que os homens dependendo do seu estado hormonal, e (iv ) comparar o efeito do nadolol com o efeito do ibuprofeno. O primeiro objetivo foi desenvolvido em ratos machos e fêmeas, intactos ou gonadectomizados (com ou sem reposição hormonal) através da coadministração de formalina e antagonista específico para AR ?1 , ?2 e ?3 na região da ATM. O comportamento nocieptive foi quantificado e utilizado para a análise estatística. Para o segundo objetivo Nadolol (40 mg/dia), ibuprofeno (400 mg/dia) ou placebo foi administrado em 27 mulheres que não usam contraceptivo oral (CO), 28 mulheres usando CO e 29 homens, que estavam de acordo com os Critérios Diagnósticos para Pesquisa (Research Diagnostic Chriteria) para DTM. Eles completaram um estudo cruzado, aleatorizado, duplo-cego e com controle placebo. As mulheres participaram durante três meses (durante a fase menstrual e durante a fase peri-ovulatória em mulheres que não usam CO, e durante a fase menstrual e durante a fase de uso do CO em mulheres usando CO), em um total de 6 etapas de análise ( 2 por mês), e homens participaram durante um mês com três etapas de análise com um período de 6 dias entre cada etapa. Cada etapa consistiu de uma avaliação de basal e duas avaliações durante o tratamento, uma no primeiro e o outra no terceiro dia de tratamento. A dor foi avaliada por meio da utilização da escala visual analógica (VAS) e as comparações foram feitas através do pré-tratamento (basal), o primeiro e o terceiro dia de intervenção (pós-tratamento). O bloqueio dos ARs ? reduz significativamente a nocicepção da ATM em ratos machos e fêmeas, mas as fêmeas são mais sensíveis. Os hormônios gonadais reduziram a resposta ao bloqueio de ARs ? na ATM de machos e fêmeas. No estudo em humanos um e três dias de tratamento com nadolol ou ibuprofeno produz uma analgesia em mulheres e homens significativamente maior que placebo, mas as mulheres são mais sensíveis independente do estado hormonal. Em resumo, estes dados demonstram que os hormonios sexuais podem modular o efeito analgésico de bloqueadores de ARs ? dependendo dos níveis séricos dos hormonios gonadais, do subtipo de ARs ? ativado e da dose de droga administrada. A maior eficácia no tratamento da dor em mulheres é clinicamente relevante uma vez que a DTM é mais prevalente e mais severa em mulheres do que em homens / Abstract: Temporomandibular disorder (TMD) is a collective term embracing a number of clinical problems that involve the masticatory muscles, and the temporomandibular joint (TMJ), commonly associated with inflammation. Despite anti-inflammatory drugs (NSAIDs) are frequently used in the control of inflammatory pain, it is well known that inflammatory pain has a sympathetic component that might predominate in the cases less responsive to NSAIDs treatments. Therefore, the aims of this study were: (i) to evaluate whether gonadal hormones modulate the antinociceptive responsiveness to the blockade of ?-adrenoreceptors (ARs) in the TMJ of rats, (ii) to evaluate whether one and three days of treatment with the nonselective ?1 and ?2-AR antagonist nadolol would reduce clinical pain symptoms in TMD patients significantly more than placebo, (iii) to evaluate whether women would experience relatively greater benefit from nadolol than men depending on their hormonal status, and (iv) compared the effect of nadolol with the effect of ibuprofen. The first aim was developed in male and female rats, intact or gonadectomized (with or without hormone replacement), by coadministration of formalin and specific antagonist for ?1, ?2 and ?3-ARs in the TMJ region. The nocieptive behavior was quantified and used for estatistical analysis. For the second aim Nadolol (40 mg/day), ibuprofen (400 mg/day) or placebo was administrated in 27 women not using oral contraceptive (OC), 28 women using OC, and 29 men which met the Research Diagnostic Criteria for TMD. They completed a randomized, crossover, double¿blind, placebo controlled study. Women participated for three months (during menstrual phase and during peri-ovulatory phase in women not using OC, and during menstrual phase and during OC using phase in women using OC) in a total of 6 stages of analysis (2 per month), and men participated for one month whith three stages of analysis and 6 days of wash out. Each stage consisted of a baseline evaluation and two evaluations during treatment, one on the first and the other on the third day of treatment. Clinical pain ratings were obtained by Visual Analog Scale (VAS) and comparisons were made across the pre-treatment (baseline), the first and the third day of intervention (post-treatment). Blockade of ?-ARs significantly reduce the TMJ nociception in male and female rats, but females are more responsive. The gonadal hormones reduce the responsiveness to the blockade of ?-ARs in the TMJ of males and females rats. In the human study one and three days of treatment with nadolol or ibuprofen produces analgesia in TMD women and men significantly more than placebo, but women are more responsive independent of their hormonal status. In summary, these data demonstrate that gonadal hormones can modulate the analgesic effect of ?-ARs blockers depending on the gonadal hormones serum levels, on the ?-ARs activated subtype and on the dose of drug administered. The greater treatment efficacy in women is of clinical relevance since TMD is more prevalent and severe in women than in men / Doutorado / Fisiologia Oral / Doutora em Odontologia

Orientador: Guilherme Antonio Moreira de Barros / Resumo: A Síndrome Dolorosa Miofascial (SDM) é considerada um importante problema de saúde pública, podendo, muitas vezes, ser incapacitante e de difícil tratamento. Considerando que, atualmente, o tratamento da SDM é pouco eficaz para o controle da dor, verificamos a necessidade do estudo de novas técnicas e da comparação com as técnicas já existentes. O presente estudo teve como objetivo comparar técnicas de eletroestimulação intramuscular com a técnica de agulhamento seco para o tratamento dessa enfermidade musculoesquelética. Foram estudados 90 pacientes divididos em três grupos. O primeiro grupo foi tratado com agulhamento seco em pontos de gatilhos (PGs), o segundo grupo com eletroestimulação intramuscular de PGs e o terceiro grupo foi tratado com eletroestimulação de pontos motores (PMs) pertencentes ao músculo acometido e/ou o nervo responsável pela inervação desse músculo. O músculo utilizado foi a porção superior do trapézio que é inervado pelo nervo acessório espinal. Foram realizadas sete sessões de tratamento em cada grupo e todos foram avaliados antes e após o término do mesmo. Não houve diferença estatisticamente significativa nos escores de dor da Escala Verbal Numérica (EVN) entre os grupos estudados, apesar de todas as intervenções terem se mostrado eficazes para o tratamento da dor miofascial do músculo trapézio. / Abstract: Myofascial Pain Syndrome (SDM) is considered an important public health problem and can often be disabling and difficult to treat. Considering that, currently, the treatment of SDM is not very effective for pain control, we verified the need to study new techniques and to compare them with existing techniques. The present study aimed to compare intramuscular electrostimulation techniques with the dry needling technique for the treatment of this musculoskeletal disease. Ninety patients were studied, divided into three groups. The first group was treated with dry needles at trigger points (PGs), the second group with intramuscular electrostimulation of PGs and the third group was treated with electrostimulation of motor points (PMs) belonging to the affected muscle and / or the nerve responsible for innervation of that muscle. The muscle used was the upper portion of the trapezius, which is innervated by the spinal accessory nerve. Seven treatment sessions were carried out in each group and all were evaluated before and after the end of the same. There was no statistically significant difference in pain scores on the Numerical Verbal Scale (EVN) between the groups studied, although all interventions have been shown to be effective for the treatment of trapezius muscle myofascial pain. / Doutor

Nyfödda barn som är kroniskt eller tillfälligt sjuka upplever multipla invasiva och vävnadsskadande procedurer på akutmottagningar och intensivvårdsavdelningar. Smärtsamma procedurer är en risk för hjärnskador hos den nyfödde. Den här litteraturstudien hade som syfte att beskriva den smärtlindrande effekten av sockerlösning i samband med smärtsamma procedurer hos nyfödda samt att beskriva möjliga komplement till administrering av sockerlösning. Vidare var syftet att beskriva de valda artiklarnas design. Artiklarna hämtades från databasen PubMed genom sökord i olika kombinationer. Undersökningsgruppen var tillfälligt sjuka samt friska nyfödda barn. Artiklarna bearbetades noggrant genom att läsas igenom med fokus på resultatdelen. Resultatet av de granskade artiklarna visar att sockerlösningen har en god effekt på smärta hos nyfödda när den jämförs med placebo eller sterilt vatten. I studier som jämfört sockerlösningen med metoder som att den nyfödda fick suga, fick värme eller hud mot hud så har sockerlösningen en sämre effekt på smärta hos nyfödda. Ett resultat talade helt emot att använda sig av sockerlösning till nyfödda i smärtlindrande syfte. Komplement till sockerlösning i smärtlindrande syfte, som t ex att den nyfödda fick värme, hud mot hud eller fick suga tillsammans med sockerlösning gav bättre effekter än att ge endast sockerlösning. Resultatet visade även att bröstmjölk (inte genom amning) har en sämre effekt jämfört med sockerlösning avseende smärta, men när den nyfödda fick amma visades det motsatta. Författarens tredje frågeställning beskriver ett resultat där de flesta studier har en liknande design, dock ser strukturen för hur man presenterat sin design olika ut mellan de olika studierna. / Newborn babies who are chronically or temporarily ill are experiencing multiple invasive and noxious procedures in emergency rooms and intensive care units. Painful procedures are a risk of brain damage in newborn. This literature review aims to describe the analgesic effect of the sugar solution during painful procedures in neonates and to describe possible complement to the administration of sugar solution. A further aim was to describe the selected articles design. Studies retrieved from the database PubMed by keywords in various combinations. The study group was temporarily ill and healthy babies. Articles were processed carefully by being read with a focus on results section. The results of the reviewed articles show that the sugar solution has a good effect on pain in newborns when compared with placebo or sterile water. In studies that compared the sugar solution with methods that newborn babies were sucking, got heat or skin to skin so the sugar has a worse effect on pain in neonates. One result speaks totally against the use of sugar solution to newborn for pain-relieving. Complement to the sugar solution in purpose of pain relief, such as the newborn got warmth, skin to skin or got sucking in combination with sugar solution provides better effects than giving only the sugar solution. A result also show that breast milk (not through breastfeeding) has a worse effect than sugar solution in pain, but when the newborn babies were breast-feeds the opposite was shown. The author`s third question describes a performance were most studies has a similar design, but the structure of how it has been presented differs between the different studies.

Local infiltration analgesia (LIA) is a new technique for postoperative pain management following knee arthroplasty. LIA involves a long-acting local anesthetic (ropivacaine), a non-steroid anti-inflammatory drug (ketorolac) and epinephrine infiltrated into the knee joint during surgery and injected postoperatively via a catheter. In the first two studies, LIA was compared with placebo in unicompartmental (I) and total (II) knee arthroplasty. Postoperative pain levels, morphine consumption and the incidence of side effects were lower in the LIA groups. In addition, we found a shorter length of hospital stay in the LIA group following unicompartmental knee arthroplasty compared with placebo (I), while the time to home readiness was shorter in the LIA group following total knee arthroplasty (II). In this study, we found that the unbound venous blood concentration of ropivacaine was below systemic toxic blood concentrations in a sub-group of patients. In the third study, LIA was compared with intrathecal morphine for postoperative pain relief following total knee arthroplasty (III). Pain scores and morphine consumption were lower, length of hospital stay was shorter and patient satisfaction was higher in the LIA group. In the final study, we investigated the effect of minimally invasive surgery (MIS) compared with conventional surgery in unicompartmental knee arthroplasty (IV). Both groups received LIA. We found no statistically significant differences in postoperative pain, morphine consumption, knee function, home readiness, hospital stay or patient satisfaction. In conclusion, LIA provided better postoperative pain relief and earlier mobilization than placebo, both in unicompartmental and total knee arthroplasty. When compared to intrathecal morphine, LIA also resulted in improved postoperative pain relief and earlier mobilization. Minimally invasive surgery did not improve outcomes after unicompartmental knee arthroplasty, when both groups received LIA.

Chronic neuropathic pain affects up to 8% of the United Kingdom population and is a difficult condition to manage. It is established and maintained through many mechanisms, including central sensitisation (CS) in the spinal cord and brainstem. Neuropathic pain manifests as spontaneous pain, sensory loss and evoked hypersensitivity. The development of novel treatments for neuropathic pain is challenging, in part due to inadequate experimental models of clinically relevant pain. The use of functional magnetic resonance imaging (fMRI) techniques for imaging acute and increasingly tonic states enables the assessment of the neural correlates of evoked hypersensitivity and persistent pain, with the goal of developing appropriate biomarkers to test new therapies. This thesis develops novel techniques for the assessment of ongoing pain states and their modulation by therapies. We first identified a suitable human experimental model of CS using topical capsaicin, and an fMRI pipeline for the investigation of supraspinal involvement in pain hypersensitivity. In a placebo-controlled study, we then demonstrated the improved sensitivity of fMRI above subjective reports in detecting the efficacy of a known analgesic as compared to an ineffective active compound in a small cohort. To translate this to the more clinically relevant symptom of spontaneous pain, we developed and validated the use of a multi-inversion time pseudo-continuous arterial spin labelling (ASL) imaging and analysis pipeline for the neural assessment of tonic states and the absolute quantification of cerebral blood flow (CBF). Current evidence from structural and functional studies suggests a direct role for the posterior insula cortex in the encoding of nociception and pain. Using the ASL pipeline, we found that only a CBF change in the posterior insula region was correlated with the changing perception of persistent capsaicin-induced pain, and in a separate experiment showed that suppression of CBF in this region by gabapentin was related to the drug's suppression of subjective pain perception. We also demonstrated in a cohort of phantom limb patients that pain relief resulting from transcranial direct current stimulation of the deprived sensorimotor cortex is neurally represented by a decrease in posterior insula CBF. In a separate study, we showed that baseline CBF in the periaqueductal grey can predict individuals who are most vulnerable to pain and hypersensitivity following the induction of capsaicin-related CS. Taken together, these findings suggest that fMRI can be used as a tool to assess the efficacy of established and novel analgesics, with the midbrain reticular formation and posterior insula cortex being prime candidates as biomarkers of CS mechanisms and persistent pain respectively. Relatedly, ASL-fMRI may also be an effective technique for evaluating individuals' susceptibility to pain following inflammation or injury.

Übergewicht und Adipositas bei Kindern und Jugendlichen ist ein weit verbreitetes Problem der Bundesrepublik Deutschland. Auch der Anästhesist sieht sich im täglichen klinischen Alltag mit diesem Patientenkollektiv und den damit verbundenen pathophysiologischen und pharmakologischen Besonderheiten konfrontiert. In dieser Dissertation werden Anästhesieverfahren, intraoperative und postoperative Analgesie, sowie die Inzidenz von postoperativer Übelkeit und Erbrechen bei nicht-übergewichtigen und übergewichtigen Kindern und Jugendlichen erhoben und untersucht. Im Rahmen einer Observationsstudie wurden Daten zur Prämedikation, zu den Anästhesieverfahren, dem Einsatz von Muskelrelaxanzien, zu regional- und lokalanästhetischen Verfahren, zur PONV-Prophylaxe und Inzidenz von PONV sowie zum Analgetikabedarf intra- und postoperativ erfasst und anhand des BMI verglichen. Es konnte nachgewiesen werden, dass bei nicht-übergewichtigen Kindern und Jugendlichen signifikant häufiger eine volatile Einleitung durchgeführt wird als eine intravenöse (p < 0,05). Hinsichtlich der Dosierungen der verwendeten Medikamente ergab sich für die Prämedikation mit Midazolam eine geringere Dosierungen pro kg KG (p < 0,05); dies konnte auch für die intraoperative Analgesie mittels Metamizol i.v. und postoperativ für Paracetamol p.o. im übergewichtigen Patientenkollektiv aufgezeigt werden (p < 0,05). Übergewichtige erhalten signifikant häufiger ein Muskelrelaxanz als Nicht-übergewichtige (p < 0,05). Dabei wird bei Übergewichtigen Rocuronium signifikant häufiger als andere Muskelrelaxanzien angewandt, während bei nicht-übergewichtigen Kindern häufiger Cis-Atracurium (p < 0,05) Verwendung findet. Übergewichtige und adipöse Kinder und Jugendliche weisen keine erhöhte Inzidenz für PONV auf. Als Risikofaktor für das Auftreten von PONV, unabhängig vom Gewicht des Kindes, ist die Applikation von Piritramid, innerhalb der ersten 24 h postoperativ, zu werten (p < 0,05). Hinsichtlich der Art des operativen Eingriffes konnte die Adenotomie als signifikanter Risikofaktor für die Inzidenz von postoperativem Erbrechen, unabhängig vom Gewicht, nachgewiesen werden (p < 0,05). Die Ergebnisse werden innerhalb der Promotionsschrift aufgelistet und es werden Gründe für Unterschiede beim nicht-übergewichtigen vs. übergewichtigen Kind diskutiert

Ultra-low doses (ULD) of the opioid receptor antagonists, naloxone and naltrexone, augment the analgesic actions of morphine, block the induction of tolerance, and reverse established tolerance by an unknown mechanism. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Thus, this thesis investigated the inhibition of spinal gliosis as a mechanism by which ULD antagonists attenuate analgesic tolerance and opioid-induced hyperalgesia. Immune cell activation is implicated in the etiology of morphine tolerance and intrathecal catheterization, a technique commonly used to study the spinal effects of drugs, causes profound gliosis. Thus, the first study investigated the effects of catheter-induced gliosis on acute and chronic morphine analgesic tolerance. Catheterization-induced gliosis did not alter antinociceptive responses to acute intrathecal morphine; however, tolerance to chronic morphine was exacerbated in catheterized rats compared to sham and surgery-naïve controls. The potentiation of analgesic tolerance to chronic morphine by spinal gliosis provided evidence that glia modulate opioid analgesia; therefore, inhibition of opioid-induced activation of glia was explored as a potential mechanism by which ULD antagonists prevent tolerance. The second series of experiments reported morphine-induced activation of spinal microglia and astrocytes was blocked by co-administering ULD naltrexone with morphine. These findings prompted us to elucidate the specific molecular target through which ULD antagonists attenuate opioid analgesia. Activation of glial Toll-like receptor 4 (TLR4) induces gliosis and may contribute to analgesic tolerance and/or morphine-induced hyperalgesia (MIH). Antagonism of TLR4 by the opioid receptor-inactive (+) stereoisomer of naloxone was identified as a potential mechanism by which ULD antagonists modulate opioid analgesia. Tolerance and MIH developed in mice expressing non-functional TLR4 and in wildtype controls. Analgesic tolerance was stereoselectively blocked by ULD (-)naloxone, whereas MIH was blocked by both naloxone enantiomers. Collectively, these studies demonstrate analgesic tolerance and MIH occur through distinct mechanisms. ULD naloxone attenuates analgesic tolerance likely via an opioid receptor-mediated mechanism that is TLR4-independent. ULD antagonists do not attenuate tolerance via inhibition of spinal gliosis as hypothesized. In contrast, ULD antagonists prevent MIH by inhibiting opioid-induced gliosis in an opioid receptor- and TLR4-independent manner. Immune cell activation is implicated in the etiology of morphine tolerance and intrathecal catheterization, a technique commonly used to study the spinal effects of drugs, causes profound gliosis. Thus, the first study investigated the effects of catheter-induced gliosis on acute and chronic morphine analgesic tolerance. Catheterization-induced gliosis did not alter antinociceptive responses to acute intrathecal morphine; however, tolerance to chronic morphine was exacerbated in catheterized rats compared to sham and surgery-naïve controls. The potentiation of analgesic tolerance to chronic morphine by spinal gliosis provided evidence that glia modulate opioid analgesia; therefore, inhibition of opioid-induced activation of glia was explored as a potential mechanism by which ULD antagonists prevent tolerance. The second series of experiments reported morphine-induced activation of spinal microglia and astrocytes was blocked by co-administering ULD naltrexone with morphine. These findings prompted us to elucidate the specific molecular target through which ULD antagonists attenuate opioid analgesia. Activation of glial Toll-like receptor 4 (TLR4) induces gliosis and may contribute to analgesic tolerance and/or morphine-induced hyperalgesia (MIH). Antagonism of TLR4 by the opioid receptor-inactive (+) stereoisomer of naloxone was identified as a potential mechanism by which ULD antagonists modulate opioid analgesia. Tolerance and MIH developed in mice expressing non-functional TLR4 and in wildtype controls. Analgesic tolerance was stereoselectively blocked by ULD (-)naloxone, whereas MIH was blocked by both naloxone enantiomers. Collectively, these studies demonstrate analgesic tolerance and MIH occur through distinct mechanisms. ULD naloxone attenuates analgesic tolerance likely via an opioid receptor-mediated mechanism that is TLR4-independent. ULD antagonists do not attenuate tolerance via inhibition of spinal gliosis as hypothesized. In contrast, ULD antagonists prevent MIH by inhibiting opioid-induced gliosis in an opioid receptor- and TLR4-independent manner. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-04-25 15:06:50.731