INTRODUÇÃO:Pacientes em ventilação mecânica (VM) são freqüentemente submetidos ao uso prolongado e/ou a doses elevadas de opióides, que durante a retirada podem causar abstinência dificultando o desmame da VM. Objetivo: testar a hipótese de que a introdução da metadona enteral na fase de desmame da sedação e analgesia em pacientes adultos graves sob VM diminui o tempo de desmame da VM. MÉTODOS: Estudo prospectivo, randomizado, controlado e duplo-cego, realizado entre abril de 2005 e outubro de 2009, em quatro Unidades de Terapia Intensiva (UTIs) de adultos de Joinville, SC. Foram randomizados 75 pacientes que apresentavam critérios para desmame da VM e estavam em uso de fentanil por mais de cinco dias consecutivos ou infusão ³ 5 g/kg/h por 12 horas. Os pacientes foram randomizados em dois grupos: Grupo Metadona (GM) e Grupo Controle (GC). Nas primeiras 24 horas após a inclusão os dois grupos receberam 80% da dose original do fentanil. Ao GM administrou-se metadona via enteral (10 mg cada 6 horas), e ao GC administrou-se placebo via enteral. Após as primeiras 24 horas acrescentou-se infusão intravenosa de solução salina (placebo) no GM, enquanto o GC recebeu infusão de solução intravenosa de fentanil. Em ambos os grupos, a solução venosa foi reduzida em 20% a cada 24 horas. Episódios de intolerância à retirada de opióide foram medicados com suplementação de opióide. Os grupos foram comparados entre si avaliando-se o tempo de desmame da VM, tempo de VM, permanência na UTI e permanência hospitalar. RESULTADOS: Dos 75 pacientes randomizados, sete foram excluídos e 68 foram analisados: 37 no GM e 31 no GC. Entre o início do desmame e a extubação, observou-se maior probabilidade de antecipação da extubação no GM, porém a diferença não foi significativa (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analisando-se o intervalo entre a randomização e o quinto dia do desmame da VM, a probabilidade de sucesso de desmame foi significativamente maior no GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Dentre os 54 pacientes que completaram o desmame da VM (29 do GM e 25 do GC), o tempo de desmame da VM foi significativamente menor no GM (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). Não houve diferença entre os grupos com relação ao tempo de VM, permanência na UTI e permanência hospitalar. CONCLUSÃO: a introdução da metadona enteral na fase de desmame da sedação e analgesia de pacientes adultos graves sob VM resultou na diminuição do tempo de desmame da VM / INTRODUCTION: Patients on mechanical ventilation (MV) are often subjected to prolonged use and / or high doses of opioids, which when removed can cause withdrawal syndrome and to difficult weaning from MV. Objective: to test the hypothesis that the introduction of enteral methadone in weaning from sedation and analgesia in critically ill adult patients on MV decreases the time of weaning from MV. METHODS: Prospective, randomized, controlled, double-blind trial, conducted between April 2005 and October 2009 in ICUs of four hospitals in Joinville, SC. We randomized 75 patients who met the criteria for weaning from MV and were using fentanyl for more than 5 consecutive days or infusion ³ 5 g/ kg / h for 12 hours. Patients were randomized into two groups: Methadone group (MG) and Control Group (CG). At first 24 hours both groups received 80% of the original dose of fentanyl and received, additionally, enteral methadone (10mg qid) or enteral placebo. After the first 24 hours, MG: received enteral methadone (10mg qid) and intravenous placebo. CG received enteral placebo and intravenous fentanyl. In both groups, the blinded intravenous solutions were reduced by 20% of the original dose, every 24 hours. Episodes of intolerance opioid withdrawal were treated with supplemental opioid. The groups were compared by evaluating the time of weaning from MV, duration of MV, ICU and hospital stay.RESULTS: Of 75 randomized patients, 7 were excluded and 68 were analyzed: 37 at MG and 31 in CG. Between the beggining of weaning and extubation, there was a greater probability of anticipation of extubation in the MG, but the difference was not significant. (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analyzing the interval between randomization and the fifth day of weaning from MV, the probability of successful weaning was significantly higher in GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Within the 54 patients who completed the weaning from MV (29 on the MG and 25 on the CG), weaning time from MV was significantly less in the MG (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). There was no difference between the two groups with respect the duration of MV, length of ICU stay and hospital stay. CONCLUSÃO: the introduction of enteral methadone in weaning from sedation and analgesia of critically ill adult patients on MV decreased the time of weaning from MV

Introdução: pacientes submetidos a procedimentos cirúrgicos ainda comumente referem dor pós-operatória moderada ou intensa. Com o aumento da prevalência de obesidade em todo o mundo, existe uma demanda crescente de procedimentos cirúrgicos nesse subtipo de população, relacionados ao controle da própria obesidade ou não. O uso de metadona como adjuvante analgésico no intraoperatório tem sido estudado nos últimos anos, mas não há estudo envolvendo essa população específica. O objetivo deste ensaio clínico foi avaliar o uso da metadona endovenosa como opioide no intraoperatório para controle da dor pós-operatória em obesos submetidos a cirurgia bariátrica. Métodos: pacientes admitidos no hospital com programação de cirurgia bariátrica foram distribuídos entre dois grupos. Ambos foram submetidos a uma anestesia geral padronizada e receberam Fentanil (grupo F) ou metadona (grupo M) durante a indução e manutenção anestésica. O desfecho primário foi o consumo de morfina nas primeiras 72 horas após a cirurgia. Nas primeiras 48 horas o consumo de opioide era quantificado por meio de um dispositivo de analgesia controlada pelo paciente, enquanto entre 48 h e 72 h foram prescritos bolus de morfina conforme necessidade. Como desfechos secundários foram avaliados os escores de dor ao repouso e ao esforço de tosse, efeitos adversos relacionados ao uso de opioides e grau de satisfação do paciente com a analgesia até 72 h no pós-operatório. Os pacientes também foram avaliados três meses após a cirurgia quanto à presença de dor, disestesia e parestesia na cicatriz operatória. Resultados: o consumo de morfina no pós-operatório foi menor em pacientes do grupo M nos períodos de avaliação pós-operatórios de 2 horas (diferença média [DM] 6,4 mg; intervalo de confiança [IC] 95% entre 3,1 e 9,6; p < 0,001); entre 2 e 6 horas (DM 11,4 mg; IC95% 6,5 a 16,2; p < 0,001); entre 6 e 24 horas (DM 10,4 mg; IC95% 5,0 a 15,7; p < 0,001) e entre 24 e 48 horas (DM 14,5 mg; IC95% 3,9 a 25,1; p=0,01). Pacientes do grupo M também referiram menores escores de dor até 24 horas de pós-operatório, houve menor incidência de náusea e vômito e maior satisfação com a analgesia. Na avaliação três meses após a cirurgia, menos pacientes do grupo M apresentaram dor evocada na cicatriz cirúrgica se comparados aos do grupo F. / Introduction: patients undergoing surgical procedures still commonly report moderate to severe postoperative pain. With the increasing prevalence of obesity worldwide, there is a growing demand for surgical procedures in this population, whether related to obesity or not. The use of methadone as an adjuvant analgesic in the intraoperative period has been studied in recent years, but there is no research involving this specific population. The aim of this clinical trial was to evaluate the use of intraoperative intravenous methadone for the control of postoperative pain in morbidly obese patients submitted to bariatric surgery. Methods: patients with a body mass index of 35 Kg.m-2 or greater who were admitted to the hospital for bariatric surgery were divided into two groups. Both underwent standardized general anesthesia and received Fentanyl (group F) or methadone (M group) during anesthetic induction and maintenance. The primary endpoint was morphine consumption within the first 72 hours after surgery. In the first 48 h postoperatively, opioid use was measured using a patient-controlled analgesia device, and between 48 h and 72 h opioid boluses were prescribed as needed. Secondary outcomes were pain at rest and while coughing, adverse effects related to the use of opioids and degree of patient satisfaction with analgesia until 72 h postoperatively. Patients were also evaluated three months after surgery for the presence of pain, dysesthesia and paraesthesia at the surgical site. Results: postoperative morphine consumption was lower in patients in the M group in the postoperative evaluation periods of 2 hours (mean difference [MD] 6.4 mg, 95% confidence interval [CI] between 3.1 and 9.6, p < 0.001); between 2 and 6 hours (MD 11.4 mg, 95% CI 6.5 to 16.2, p < 0.001); between 6 and 24 hours (MD 10.4 mg, 95% CI 5.0 to 15.7, p < 0.001) and between 24 and 48 hours (MD 14.5 mg, CI 95% 3.9 to 25.1, p = 0.01). Patients in the M group also reported lower pain scores up to 24 hours after surgery, there was a lower incidence of nausea and vomiting and greater satisfaction with analgesia. At the three months after the surgery evaluation, less patients in the M group presented evoked pain in the surgical scar compared to those in the F group. Conclusion: the intraoperative use of intravenous methadone for morbidly obese patients submitted to bariatric surgeries may reduce postoperative opioid use and reduce the intensity of postoperative pain safely when compared to fentanyl

It is well established that methadone maintenance (MM) reduces but does not eliminate the self-administration of other illicit drugs. For those on MM, there is considerable variation in consumption patterns, route of heroin administration, additional non-opioid substances routinely administered and the clinical disorders associated with these patterns of use. While there is a large literature base documenting these phenomena, studies have been almost exclusively descriptive in nature, with little attempt to develop a theoretical model in which to understand such use. In the following thesis, a model proposed by Gray was tested, the Reinforcement Sensitivity Theory (RST). This biopsychosocial model broadly describes two action tendencies; approach (Behavioural Activation System) and avoidance or withdrawal (Flight Fight Freeze System and the Behavioural Inhibition System). The model proposes that a heightened sensitivity to punishment underlies anxiety disorders. Conversely, a heightened sensitivity to rewarding stimuli may predispose some individuals to engage in highly rewarding behaviour and is associated with conduct disorder and antisocial personality disorder. According to the Joint Subsystems Hypothesis, these personality styles are mutually dependent, whereby BIS and BAS interact to influence reward mediated and punishment mediated behaviours. Based on Gray's model, this thesis tests whether opiate dependent individuals with heightened sensitivity to punishment are more likely to use anxiolytic drugs (such as benzodiazepines), and individuals with heightened reward sensitivity will show a preference for substances that have high reward potential (such as stimulants). At time one, the participant sample (N= 120) comprised 71 males (59%) and 49 females who were opioid dependent and recruitment took place over an eight-month period in two city opioid replacement clinics. A range of measures was administered to assess substance use, mood, anxiety and the personality dimensions of reward sensitivity and punishment sensitivity, with substance use again measured at three months. Results of the first study suggested that a large proportion of the variance was accounted for by personality within the models. A total of 98 participants (81%) participated in the 12-week follow-up study. Sensitivity to punishment and reward significantly predicted drug preference. Although psychopathology symptoms were not able to moderate the relationship between personality and drug use, anxiety symptoms negatively mediated the relationship between punishment sensitivity and anxiolytic use, whereby the relationship became non-significant. In contrast, sensitivity to reward remained the strongest predictor of amphetamine use over antisocial characteristics. Individual differences were not able to predict treatment retention nor susceptibility to relapse during a 12-week initiation to a MM programme.

<p>Methadone Maintenance treatment of compulsive opioid addiction was started by the study of Dole and Nyswander (1965) and has subsequently been replicated in programs throughout the world. Methadone treatment has become the most effective modality for the treatment of chronic heroin addiction. </p><p>In 1966 a Swedish National methadone maintenance program was opened at the Psychiatric Research Center, Ulleråker hospital at Uppsala.</p><p>The aim of this thesis was to study the outcome of methadone treatment along various lines:</p><p>• An open randomised controlled study comparing the efficacy of methadone treatment and drug free treatment in 34 heroin addicts, 20-24 years of age. </p><p>• Before/after comparisons of rehabilitation among 345 heroin addicts admitted during the 23 years when this was a centralised National program.</p><p>• Retention in treatment.</p><p><b>Study subjects, methods and treatment goals: </b>Subjects underwent an admission procedure when background data was collected through hospital records, and personal interviews. Therapeutic efforts focused on vocational rehabilitation, i.e. a return to full-time work or studies, hoping to make patients abandon their drug addict’s life-style and make them socially accepted and self-supporting. </p><p><b>Results: </b>Thirty-four heroin addicts with a history of 4-8 years of heroin use were randomly assigned either to methadone treatment (17) or an untreated control group (17). The controls could not apply for methadone treatment until two years later. Outcome after six years observation showed that 81% became free of drug abuse, while the corresponding figure for the controls was only 1/17 (6%). The mean yearly death rate for the controls was 7.2%. Likewise, among the total material of 345 heroin addicts, 70-80% of the patients became engaged in work or studies, a significant increase compared with the situation before treatment (1.7%). The program was an effective reducer of illicit heroin use and criminality among its patients and prevented the occurrence of HIV infection among patients in long-term methadone treatment. The average one-year retention during 1967-1989 was 90% and cumulative retention showed that 29% were still in treatment 10 years after admission.</p><p><b>Conclusion: </b>The present results emphasise the importance of vocational rehabilitation and support in a treatment strategy based on long-term maintenance therapy.</p>

Methadone Maintenance treatment of compulsive opioid addiction was started by the study of Dole and Nyswander (1965) and has subsequently been replicated in programs throughout the world. Methadone treatment has become the most effective modality for the treatment of chronic heroin addiction. In 1966 a Swedish National methadone maintenance program was opened at the Psychiatric Research Center, Ulleråker hospital at Uppsala. The aim of this thesis was to study the outcome of methadone treatment along various lines: • An open randomised controlled study comparing the efficacy of methadone treatment and drug free treatment in 34 heroin addicts, 20-24 years of age. • Before/after comparisons of rehabilitation among 345 heroin addicts admitted during the 23 years when this was a centralised National program. • Retention in treatment. <b>Study subjects, methods and treatment goals: </b>Subjects underwent an admission procedure when background data was collected through hospital records, and personal interviews. Therapeutic efforts focused on vocational rehabilitation, i.e. a return to full-time work or studies, hoping to make patients abandon their drug addict’s life-style and make them socially accepted and self-supporting. <b>Results: </b>Thirty-four heroin addicts with a history of 4-8 years of heroin use were randomly assigned either to methadone treatment (17) or an untreated control group (17). The controls could not apply for methadone treatment until two years later. Outcome after six years observation showed that 81% became free of drug abuse, while the corresponding figure for the controls was only 1/17 (6%). The mean yearly death rate for the controls was 7.2%. Likewise, among the total material of 345 heroin addicts, 70-80% of the patients became engaged in work or studies, a significant increase compared with the situation before treatment (1.7%). The program was an effective reducer of illicit heroin use and criminality among its patients and prevented the occurrence of HIV infection among patients in long-term methadone treatment. The average one-year retention during 1967-1989 was 90% and cumulative retention showed that 29% were still in treatment 10 years after admission. <b>Conclusion: </b>The present results emphasise the importance of vocational rehabilitation and support in a treatment strategy based on long-term maintenance therapy.

Background: In many countries, buprenorphine and methadone are licensed for the maintenance treatment (MT) of opioid dependence. Despite many short-term studies, little is known about the long-term (12-month) effects of these treatments in different settings, i.e. primary care-based (PMC) and specialized substitution centers (SSCs). Objectives: To describe over a period of 12 months: (1) mortality, retention and abstinence rates; (2) changes in concomitant drug use, somatic and mental health; and (3) to explore differences between different types of provider settings. Methods: 12-Month prospective-longitudinal naturalistic study with four waves of assessment in a prevalence sample of N= 2694 maintenance patients, recruited from a nationally representative sample of N= 223 substitution physicians. Results: The 12-month retention rate was 75%; the mortality rate 1.1%. 4.1% of patients became “abstinent” during follow-up. 7% were referred to drug-free addiction treatment. Concomitant drug use decreased and somatic health status improved. No significant improvements were observed for mental health and quality of life. When controlling for initial severity, small PMC settings revealed better retention, abstinence and concomitant drug use rates. Conclusion: The study underlines the overall 12-month effectiveness of various forms of agonist MT. Findings reveal relatively high retention rates, low mortality rates, and improvements in most 12-month outcome domains, except for mental health and quality of life. PMC settings appear to be a good additional option to improve access to MTs.

This study reports the investigation of hyperbaric opioids and 10% glucose studied in a experimental in vitro model of a subarachnoid space and the in vivo subarachnoid administration of hyperbaric opioids and 10% glucose in horses. The first in vitro phase was done with a translucid poly vinil chloride (PVC) model filled with horse cerebral spinal fluid and injected with hyperbaric opioids and 10% glucose tinted with methylene blue. The objective was to evaluate the physic behavior of the substances within the model. In the second in vivo phase, the hyperbaric opioids (morphine, methadone and buprenorphine) were subarachnoidally administered in six adult horses through a subarachnoid catheter. Cardiopulmonary effects, behavior and pain threshold to noxious electrical stimulation on the perineal, lumbar, sacral and thoracic dermatomes was evaluated. Theresults demonstrated that the model was able to indicate the more appropriate opioids to be used subarachnoidally, and that segmental analgesia was considered intense with hyperbaric morphine and hyperbaric methadone, and moderate with hyperbaric buprenorphine, with minimal effects on cardiorespiratory function, without ataxia or CNS excitation. / Este trabalho apresenta a investigação da utilização de soluções hiperbáricas de opióides e glicose a 10% em um modelo experimental in vitro do espaço subaracnóide, bem como o estudo in vivo da administração de opióides hiperbáricos e glicose a 10% pela via subaracnóide em cavalos. A primeira fase in vitro , constou da utilização de um modelo confeccionado em PVC (policloreto de vinila) transparente, preenchido com líquido cérebro espinhal eqüino, onde foram injetados os agentes opióides hiperbáricos e glicose a 10% marcados com azul de metileno, com o objetivo de avaliar o comportamento físico de distribuição das substâncias no modelo. Na segunda fase in vivo , os opióides hiperbáricos (morfina, buprenorfina e metadona) e glicose a 10% (grupo controle) foram administrados pela via subaracnóide em seis cavalos adultos por meio de um cateter. Avaliaram-se efeitos cardiorrespiratórios, comportamentais e limiar doloroso por estimulação elétrica dos dermátomos perineal, sacral, lombar e torácico. Os resultados mostraram que o modelo proposto serviu como base para a escolha dos agentes utilizados pela via subaracnóide. Houve produção de analgesia segmentar considerada intensa com a morfina hiperbárica e a metadona hiperbárica, e analgesia moderada com a buprenorfina hiperbárica, com mínimos efeitos sobre as funções cardiorrespiratórias, sem ocorrência de ataxia ou excitação do SNC.

Made available in DSpace on 2015-03-26T13:47:13Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1145808 bytes, checksum: b5728162a868498b33d833fb18168ba3 (MD5) Previous issue date: 2013-02-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This study aimed to evaluate and compare the analgesic effect of opioids morphine and methadone by intramuscular and epidural, with or without the association of lidocaine, seeking to identify if the route of administration as well as the addition of epidural local anesthetic, can interfere with analgesia and sedation without postoperative cardiovascular and respiratory changes. Thirty female dogs with indication for unilateral radical mastectomy were anesthetized with isoflurane and propofol. The animals were randomly assigned to six treatment: methadone (0.5 mg.kg-1) or morphine (0.5 mg.kg-1) intramuscular (MET-IM and MORF-IM, respectively), methadone (0.3 mg.kg-1) or morphine (0,1 mg.kg-1) epidural (MET-EP and MORF-EP, respectively), methadone (0.3 mg.kg-1) or morphine (0.1 mg.kg-1) combined with lidocaine epidural (METL and MORFL, respectively), The volumes administered epidural and intramuscular were adjusted to 0.2 mL.kg-1 with the use of 0.9% NaCl solution or lidocaine, when this group was present. Equal volume of saline was administered in the opposite route of administration of drugs for blinded evaluation of treatments used. We evaluated the cardiovascular and respiratory parameters during the pre-and intraoperative. The evaluation of pain and post-operative sedation was performed for 24 hours. The supplemental analgesia was administered whenever the pain score was equal or higher 13 points (total 27 points) according to the University of Melbourne Scale of Pain (UMPS). The group MET-IM had lower mean FC in M6, as well as the group METL had lower SBP in M3, M4 and M5. The group MORF-EP showed higher sedation score in MP4. The MORF-IM group had higher pain scores in MP0, MP1, MP2, MP12 and MP24 and the group MORF-IM and METL in MP4 and MET-EP in MP6 and MP8. Methadone promoted greater cardiovascular depression than morphine however, neither of treatments tested has altered respiratory function. Both groups of the morphine and methadone produced postoperative sedation of mild to moderate. Morphine intramuscular results in inadequate postoperative analgesia compared to epidural administration with or without lidocaine, and also when compared with methadone intramuscular and epidural. Methadone epidural no produced better analgesia when compared to intramuscular administration. The epidural morphine, with or without lidocaine and the methadone combined with lidocaine produced effective analgesia without the need for supplemental analgesia for 24 hours. / Objetivou-se neste estudo comparar os efeitos analgésicos da morfina e metadona, procurando identificar se a via de administração, bem como se a adição do anestésico local pela via epidural, podem interferir na analgesia e sedação pós-operatória de cadelas submetidas à mastectomia. Trinta cadelas com indicação de mastectomia radical unilateral foram anestesiadas com propofol e isofluorano. Os animais receberam aleatoriamente metadona (0,5 mg.kg-1) ou morfina (0,5 mg.kg-1) intramuscular (grupo MET-IM e MORFIM, respectivamente); metadona (0,3 mg.kg-1) ou morfina (0,1 mg.kg-1) epidural (grupo MET-EP e MORF-EP, respectivamente); metadona (0,3mg.kg-1) ou morfina (0,1 mg.kg-1) associada à lidocaína epidural (grupo METL e MORFL, respectivamente). Os volumes injetados pelas vias epidural e intramuscular foram ajustadas para 0,2 ml.kg-1 com o emprego de solução de NaCl 0,9% ou lidocaína 2%, quando esta estava presente no grupo. Foram avaliados os parâmetros cardiovasculares e respiratórios durante o período pré e transoperatório. A avaliação da dor e sedação pós-operatória foi realizada durante 24 horas. A suplementação analgésica foi administrada sempre que o escore de dor fosse igual ou superior a 13 pontos (total de 27 pontos) de acordo com a Escala de dor da Universidade de Melbourne (EDUM). O grupo MET-IM apresentou menores médias de FC em M6, assim como o grupo METL apresentou menores médias de PAS em M3, M4 e M5. O grupo MORF-EP apresentou maior escore de sedação em MP4. O grupo MORF-IM apresentou maiores escores de dor em MP0, MP1, MP2, MP12 e MP24 assim como o grupo MORF- IM e METL em MP4 e MET-EP em MP6 e MP8. A metadona intramuscular promoveu maior diminuição da frequência cardíaca que a morfina, no entanto, nenhum tratamento promoveu alteração na função respiratória. Tanto a morfina quanto a metadona promoveram sedação pós-operatória discreta à moderada. A morfina administrada por via intramuscular resulta em inadequada analgesia pós-operatória quando comparada a administração epidural, associada ou não à lidocaína, e também quando comparada à metadona por via intramuscular e epidural. A metadona por via epidural não promoveu melhor analgesia quando comparada a administração intramuscular. Tanto a morfina epidural, associada ou não à lidocaína quanto à metadona associada à lidocaína promoveram eficaz analgesia sem a necessidade de suplementação analgésica por 24 horas.

INTRODUÇÃO:Pacientes em ventilação mecânica (VM) são freqüentemente submetidos ao uso prolongado e/ou a doses elevadas de opióides, que durante a retirada podem causar abstinência dificultando o desmame da VM. Objetivo: testar a hipótese de que a introdução da metadona enteral na fase de desmame da sedação e analgesia em pacientes adultos graves sob VM diminui o tempo de desmame da VM. MÉTODOS: Estudo prospectivo, randomizado, controlado e duplo-cego, realizado entre abril de 2005 e outubro de 2009, em quatro Unidades de Terapia Intensiva (UTIs) de adultos de Joinville, SC. Foram randomizados 75 pacientes que apresentavam critérios para desmame da VM e estavam em uso de fentanil por mais de cinco dias consecutivos ou infusão ³ 5 g/kg/h por 12 horas. Os pacientes foram randomizados em dois grupos: Grupo Metadona (GM) e Grupo Controle (GC). Nas primeiras 24 horas após a inclusão os dois grupos receberam 80% da dose original do fentanil. Ao GM administrou-se metadona via enteral (10 mg cada 6 horas), e ao GC administrou-se placebo via enteral. Após as primeiras 24 horas acrescentou-se infusão intravenosa de solução salina (placebo) no GM, enquanto o GC recebeu infusão de solução intravenosa de fentanil. Em ambos os grupos, a solução venosa foi reduzida em 20% a cada 24 horas. Episódios de intolerância à retirada de opióide foram medicados com suplementação de opióide. Os grupos foram comparados entre si avaliando-se o tempo de desmame da VM, tempo de VM, permanência na UTI e permanência hospitalar. RESULTADOS: Dos 75 pacientes randomizados, sete foram excluídos e 68 foram analisados: 37 no GM e 31 no GC. Entre o início do desmame e a extubação, observou-se maior probabilidade de antecipação da extubação no GM, porém a diferença não foi significativa (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analisando-se o intervalo entre a randomização e o quinto dia do desmame da VM, a probabilidade de sucesso de desmame foi significativamente maior no GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Dentre os 54 pacientes que completaram o desmame da VM (29 do GM e 25 do GC), o tempo de desmame da VM foi significativamente menor no GM (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). Não houve diferença entre os grupos com relação ao tempo de VM, permanência na UTI e permanência hospitalar. CONCLUSÃO: a introdução da metadona enteral na fase de desmame da sedação e analgesia de pacientes adultos graves sob VM resultou na diminuição do tempo de desmame da VM / INTRODUCTION: Patients on mechanical ventilation (MV) are often subjected to prolonged use and / or high doses of opioids, which when removed can cause withdrawal syndrome and to difficult weaning from MV. Objective: to test the hypothesis that the introduction of enteral methadone in weaning from sedation and analgesia in critically ill adult patients on MV decreases the time of weaning from MV. METHODS: Prospective, randomized, controlled, double-blind trial, conducted between April 2005 and October 2009 in ICUs of four hospitals in Joinville, SC. We randomized 75 patients who met the criteria for weaning from MV and were using fentanyl for more than 5 consecutive days or infusion ³ 5 g/ kg / h for 12 hours. Patients were randomized into two groups: Methadone group (MG) and Control Group (CG). At first 24 hours both groups received 80% of the original dose of fentanyl and received, additionally, enteral methadone (10mg qid) or enteral placebo. After the first 24 hours, MG: received enteral methadone (10mg qid) and intravenous placebo. CG received enteral placebo and intravenous fentanyl. In both groups, the blinded intravenous solutions were reduced by 20% of the original dose, every 24 hours. Episodes of intolerance opioid withdrawal were treated with supplemental opioid. The groups were compared by evaluating the time of weaning from MV, duration of MV, ICU and hospital stay.RESULTS: Of 75 randomized patients, 7 were excluded and 68 were analyzed: 37 at MG and 31 in CG. Between the beggining of weaning and extubation, there was a greater probability of anticipation of extubation in the MG, but the difference was not significant. (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analyzing the interval between randomization and the fifth day of weaning from MV, the probability of successful weaning was significantly higher in GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Within the 54 patients who completed the weaning from MV (29 on the MG and 25 on the CG), weaning time from MV was significantly less in the MG (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). There was no difference between the two groups with respect the duration of MV, length of ICU stay and hospital stay. CONCLUSÃO: the introduction of enteral methadone in weaning from sedation and analgesia of critically ill adult patients on MV decreased the time of weaning from MV

Background: Negative outcomes from fetal exposure to maternal dug use include Neonatal Abstinence Syndrome (NAS) and altered development, the unpredictability of which suggests a biological element as yet not accounted for. The manner in which the human placenta protects the fetus from xenobiotics such as drugs of misuse is not completely characterised. However, Adenosine Triphosphate Binding Cassette (ABC) transporters in placentae have demonstrated their ability to efflux xenobiotics away from the fetal vascular compartment leading to lower concentrations than in the maternal compartment and some commonly used drugs have been shown to be substrates for these proteins, e.g. methadone. It is suggested that polymorphisms in the genes that encode these transporter proteins may alter their expression and/or function. Hypothesis- Polymorphisms (SNPs) in the ABC transporters ABCB1, ABCG2, ABCC1 and ABCC2 change protein expression and/or function leading to increased fetal exposure demonstrated by increased signs of NAS and/or altered development. Objectives: To determine if genotype alters protein expression and whether there is a relationship between the level of placental multidrug resistance protein P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Associated Proteins (MRP1 and MRP2) expression and neonatal and/or developmental outcomes. Methods: Drug using women were recruited. In the immediate postnatal period placental tissue, cord blood and maternal hair samples were taken. Hair was analysed to determine drug use in the preceding 3 months, immunoblotting determined the level of P-gp, BCRP, MRP1 and MRP2 protein expression. Sequenom MassExtend Array produced genotypes from DNA obtained from cord blood. Infants were assessed for NAS at birth, 3 days and 3 weeks. At 8 months and 1 year development was assessed using the Griffiths Mental Development Scales. Plink was used to determine statistically significant associations between genotype and outcome phenotypes. Results- The level of fetal drug exposure did not predict the need for pharmacological treatment for NAS. 32 polymorphisms with significant associations to outcome measures were identified: 4 SNPs significantly altered protein expression, (3 for P-gp and 1 for MRP1). 41 SNPs were associated with changes across 4 of the 5 GMDS subscales. Discussion: No clear relationship between MDRP protein expression and neonatal outcome was noted. However, fetal genotype did influence the expression of P-gp and MRP1 and genotype across all four proteins was associated with significant changes in the measures of infant development. This was a small study and as such generation of susceptible haplotypes was not possible. However the data generated do support the concept. Further larger and longer term prospective studies, building on the experience reported in this thesis, are necessary to generate more data in order to identify haplotypes leading to increased fetal susceptibility to drug exposure.