No description available.

Agonistas colinérgicos (neostigmina), administrados por via espinhal, potencializam a analgesia dos opióides por aumentar a concentração de acetilcolina no líquido cérebro-espinhal. O objetivo deste trabalho foi verificar a duração e a eficácia analgésica, assim como a ocorrência de efeitos adversos, da neostigmina e morfina, isoladas ou associadas, administradas por via peridural em cães submetidos à cirurgia ortopédica nos membros pélvicos. Foram utilizados 30 cães de diferentes raças, machos ou fêmeas, de comportamento dócil submetidos à cirurgia ortopédica. Os cães foram prémedicados com meperidina (4 mg/kg IM); após 30 minutos, indução anestésica com propofol (5 mg/kg) e manutenção da anestesia com isofluorano. Após estabilização da anestesia, um cateter peridural era introduzido e a anestesia peridural foi realizada com lidocaína 2% (5 mg/kg). No final da cirurgia, os animais eram distribuídos aleatoriamente em 3 grupos de 10 e recebiam tratamento analgésico pelo cateter peridural como segue: grupo MOR, 0,1 mg/kg de morfina; grupo NEO, 5 µg/kg de neostigmina; e grupo MOR+NEO, associação de 0,1 mg/kg de morfina e 5 µg/kg de neostigmina. Soluções ajustadas com solução NaCl 0,9% até um volume total de 0,4 ml/kg, sendo o estudo caracterizado como prospectivo, clínico, tipo cego. Variáveis paramétricas mensuradas: frequência cardíaca (FC), frequência respiratória (f), temperatura retal (T°C) e as pressões arteriais sistólica, média e diastólica (PAS, PAM e PAD). Analgesia pós-operatória verificada por meio da escala analógica visual (EAV) e escala numérica descritiva (END). Tempos de avaliação: 1, 2, 3, 4, 6, 8, 12, 16 e 24 horas após o final da cirurgia. Caso o animal recebesse nota maior ou igual a quatro para EAV ou END, era realizado resgate analgésico com morfina 0,2 mg/kg (IV), morfina 0,1 mg/kg (peridural) mais meloxican 0,2 mg/kg (IV). Não houve diferenças significativas entre os grupos quanto aos valores demográficos e às variáveis paramétricas. Realizou-se resgate analgésico em 7 animais do grupo NEO, 4 do grupo MOR e 2 do grupo MOR+NEO. O grupo MOR+NEO apresentou menores valores nos escores de dor (EAV) no tempo 1 h em relação ao grupo NEO e no tempo 4 h em relação ao grupo MOR. Quanto aos efeitos adversos, não houve diferenças entre os grupos. A neostigmina como agente isolado não foi eficaz para o tratamento da dor pósoperatória, e a associação de morfina e neostigmina apresentou benefícios sem aumentar a incidência dos efeitos adversos comumente observados quando comparado ao uso isolado da morfina. / The epidural administration of cholinesterase inhibitor drug (nesotigmine) improves morphine analgesia for increased acetylcholine concentration in the cerebrospinal fluid. The aim of this study was to evaluate the possible analgesic effects of neostigmine and the possible potentiation of morphine analgesia in dogs undergoing orthopaedic pelvic limb surgery. Thirty healthy dogs, males or females, from several breeds were selected. They were sedated with meperidine (4 mg/kg IM). 30 minutes later, anestesia was induced with propofol (5 mg/kg IV) and anesthesia was maintained with isoflurane. An epidural catheter was inserted and local anaesthesia was performed with lidocaine 2% (5 mg/kg). At the end of surgical operation, the animals were randomly distributed into three groups of 10 animals each and received the analgesic treatment via epidural catheter using a factorial design: MOR group received 0.1 mg/kg morphine, while NEO group received 5 µg/kg neostigmine and MOR+NEO group received the combination of 0.1 mg/kg of morphine plus 5 µg/kg of neostigmine. In all cases, drug administration was completed with 0.4 ml of 0,9% NaCl. The study was characterized as a prospective, double-blind, randomized clinical trial. Parametric variables measured were heart rate (HR), respiratory rate (f), rectal temperature (T °C) and noninvasive estimation of systolic, diastolic and mean blood pressure (SBP, DBP, and MAP). Postoperative analgesia was evaluated on a visual analogue scale (VAS) and a descriptive numerical scale (DNS) at 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after the end of the surgery. When the VAS and DNS were equal or greater than four, postoperative analgesia was supplied with morphine 0.2 mg/kg (IV), morphine 0.1 mg/kg (epidural) plus meloxicam 0.2 mg/kg (IV). There were no statistically significant differences in demographic and parametric variables between the groups. Supplemental analgesia were administered in 7 animals of NEO group, 4 animals of MOR group and 2 animals of MOR+NEO group. Animals of MOR+NEO group showed lower values in pain scores (VAS) than animals of NEO group at time 1 hour and animals of MOR group at time 4 hours. The incidence of side effects was similar between the three treatment groups. In short, neostigmine alone was not effective in treatment postoperative pain in dogs undergoing orthopaedic surgery. The analgesics effects of neostigmine plus morphine showed benefits without increasing the incidence of adverses events commonly observed when compared to the use of morphine alone.

Issued also as Thesis (Ph. D.)--Catholic University of America. / Bibliography: p. 57-63.

Agonistas colinérgicos (neostigmina), administrados por via espinhal, potencializam a analgesia dos opióides por aumentar a concentração de acetilcolina no líquido cérebro-espinhal. O objetivo deste trabalho foi verificar a duração e a eficácia analgésica, assim como a ocorrência de efeitos adversos, da neostigmina e morfina, isoladas ou associadas, administradas por via peridural em cães submetidos à cirurgia ortopédica nos membros pélvicos. Foram utilizados 30 cães de diferentes raças, machos ou fêmeas, de comportamento dócil submetidos à cirurgia ortopédica. Os cães foram prémedicados com meperidina (4 mg/kg IM); após 30 minutos, indução anestésica com propofol (5 mg/kg) e manutenção da anestesia com isofluorano. Após estabilização da anestesia, um cateter peridural era introduzido e a anestesia peridural foi realizada com lidocaína 2% (5 mg/kg). No final da cirurgia, os animais eram distribuídos aleatoriamente em 3 grupos de 10 e recebiam tratamento analgésico pelo cateter peridural como segue: grupo MOR, 0,1 mg/kg de morfina; grupo NEO, 5 µg/kg de neostigmina; e grupo MOR+NEO, associação de 0,1 mg/kg de morfina e 5 µg/kg de neostigmina. Soluções ajustadas com solução NaCl 0,9% até um volume total de 0,4 ml/kg, sendo o estudo caracterizado como prospectivo, clínico, tipo cego. Variáveis paramétricas mensuradas: frequência cardíaca (FC), frequência respiratória (f), temperatura retal (T°C) e as pressões arteriais sistólica, média e diastólica (PAS, PAM e PAD). Analgesia pós-operatória verificada por meio da escala analógica visual (EAV) e escala numérica descritiva (END). Tempos de avaliação: 1, 2, 3, 4, 6, 8, 12, 16 e 24 horas após o final da cirurgia. Caso o animal recebesse nota maior ou igual a quatro para EAV ou END, era realizado resgate analgésico com morfina 0,2 mg/kg (IV), morfina 0,1 mg/kg (peridural) mais meloxican 0,2 mg/kg (IV). Não houve diferenças significativas entre os grupos quanto aos valores demográficos e às variáveis paramétricas. Realizou-se resgate analgésico em 7 animais do grupo NEO, 4 do grupo MOR e 2 do grupo MOR+NEO. O grupo MOR+NEO apresentou menores valores nos escores de dor (EAV) no tempo 1 h em relação ao grupo NEO e no tempo 4 h em relação ao grupo MOR. Quanto aos efeitos adversos, não houve diferenças entre os grupos. A neostigmina como agente isolado não foi eficaz para o tratamento da dor pósoperatória, e a associação de morfina e neostigmina apresentou benefícios sem aumentar a incidência dos efeitos adversos comumente observados quando comparado ao uso isolado da morfina. / The epidural administration of cholinesterase inhibitor drug (nesotigmine) improves morphine analgesia for increased acetylcholine concentration in the cerebrospinal fluid. The aim of this study was to evaluate the possible analgesic effects of neostigmine and the possible potentiation of morphine analgesia in dogs undergoing orthopaedic pelvic limb surgery. Thirty healthy dogs, males or females, from several breeds were selected. They were sedated with meperidine (4 mg/kg IM). 30 minutes later, anestesia was induced with propofol (5 mg/kg IV) and anesthesia was maintained with isoflurane. An epidural catheter was inserted and local anaesthesia was performed with lidocaine 2% (5 mg/kg). At the end of surgical operation, the animals were randomly distributed into three groups of 10 animals each and received the analgesic treatment via epidural catheter using a factorial design: MOR group received 0.1 mg/kg morphine, while NEO group received 5 µg/kg neostigmine and MOR+NEO group received the combination of 0.1 mg/kg of morphine plus 5 µg/kg of neostigmine. In all cases, drug administration was completed with 0.4 ml of 0,9% NaCl. The study was characterized as a prospective, double-blind, randomized clinical trial. Parametric variables measured were heart rate (HR), respiratory rate (f), rectal temperature (T °C) and noninvasive estimation of systolic, diastolic and mean blood pressure (SBP, DBP, and MAP). Postoperative analgesia was evaluated on a visual analogue scale (VAS) and a descriptive numerical scale (DNS) at 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after the end of the surgery. When the VAS and DNS were equal or greater than four, postoperative analgesia was supplied with morphine 0.2 mg/kg (IV), morphine 0.1 mg/kg (epidural) plus meloxicam 0.2 mg/kg (IV). There were no statistically significant differences in demographic and parametric variables between the groups. Supplemental analgesia were administered in 7 animals of NEO group, 4 animals of MOR group and 2 animals of MOR+NEO group. Animals of MOR+NEO group showed lower values in pain scores (VAS) than animals of NEO group at time 1 hour and animals of MOR group at time 4 hours. The incidence of side effects was similar between the three treatment groups. In short, neostigmine alone was not effective in treatment postoperative pain in dogs undergoing orthopaedic surgery. The analgesics effects of neostigmine plus morphine showed benefits without increasing the incidence of adverses events commonly observed when compared to the use of morphine alone.

No description available.

No description available.

La douleur post-opératoire chez les patients constitue un défi thérapeutique important pour les cliniciens. Le traitement de la douleur post-opératoire n’est pas accessoire ni optionnel, puisqu’il permet de donner un congé de l’hôpital plus rapide aux patients et ainsi, il contribue à des économies importantes pour notre système de santé. Parmi les approches thérapeutiques utilisées pour la prise en charge de la douleur post-opératoire, cette thèse s’intéresse particulièrement aux blocs de nerfs périphériques par les anesthésiques locaux et à l’administration de la néostigmine par voie épidurale. Ces médicaments sont utilisés en clinique sans avoir préalablement établi, en se basant sur leur propriétés pharmacocinétiques et pharmacodynamiques spécifiques, leurs doses optimales. Ces doses devraient également tenir en considération les particularités anatomiques du site d’injection par rapport au site d’action. Cette thèse inclut des études exploratoires qui ont contribué à caractériser la pharmacocinétique de la ropivacaïne et de la bupivacaïne ainsi que la pharmacocinétique et la pharmacodynamie de la néostigmine. La première étude portait sur seize patients subissant une chirurgie orthopédique avec un bloc combiné des nerfs fémoral et sciatique par la ropivacaïne (n=8) ou la bupivacaïne (n=8). C’était la première étude qui a inclu des temps d’échantillons pharmacocinétiques allant jusqu’à 32 h après le bloc et ces résultats ont démontré une variabilité interindividuelle considérable. La modélisation par approche de population a aidé à expliquer les sources de la variabilité et démontré que l’absorption systémique des anesthésiques locaux était très lente. De plus, les concentrations plasmatiques demeuraient mesurables, et dans certains cas présentaient un plateau, 32 h après le bloc. Dans les prochaines études, un échantillonnage allant jusqu’à 4 ou 5 jours sera nécessaire afin d’atteindre la fin de l’absorption. La deuxième étude a établi le développement d’un modèle animal en étudiant la pharmacocinétique de la ropivacaïne après administration intraveineuse ainsi que son degré de liaison aux protéines plasmatiques chez le lapin (n=6). Les résultats ont démontré que, chez le lapin la ropivacaïne est beaucoup moins liée aux protéines plasmatiques comparativement à l’humain. Ce résultat important sera utile pour planifier les prochaines études précliniques. La troisième étude a exploré, pour la première fois, la pharmacocinétique et la pharmacodynamie de la néostigmine administrée par voie épidurale et a essayé de caractériser la courbe dose-réponse en utilisant trois doses différentes : 0.5, 1 et 1.5 mg. Bien que les concentrations de la néostigmine dans le liquide céphalo-rachidien fussent très variables une relation inverse entre la consommation de mépéridine et la dose de néostigmine a été démontrée. La dose de 1.5 mg a donné une meilleure réponse pharmacodynamique sur la douleur, mais elle a été considérée comme dangereuse puisqu’elle a résulté en deux cas d’hypertension. Nous avons conclu que des doses plus faibles que 1.5 mg devront être utilisées lors de l’utilisation de la néostigmine par voie épidurale. En conclusion, les études rapportées dans cette thèse ont exploré les propriétés pharmacocinétiques et/ou pharmacodynamiques de certains médicaments utilisés pour le traitement de la douleur post-opératoire. Ceci mènera au but ultime qui est la meilleure prise en charge de la douleur post-opératoire chez les patients. / Post-operative pain in surgical patients remains a challenging problem for the clinicians. The treatment of post-operative pain is no longer an accessory or nice to have, since it can significantly shorten hospital stays and lead to important savings for our health system. Amongst the therapeutic approaches used in the management of post-operative pain, we will focus on peripheral nerve blocks with local anesthetics and epidural neostigmine. These drugs are currently used in the clinic, without the prior characterization of an optimal dose that took into consideration their specific pharmacokinetic and pharmacodynamic properties. Optimal doses will need to consider the specific regional anatomy of the site of drug administration with respect to the site of action. This thesis included exploratory studies that helped to characterize the pharmacokinetics of ropivacaine and bupivacaine as well as the pharmacokinetics and pharmacodynamics of neostigmine. The first study included sixteen patients undergoing orthopedic surgeries with a combined femoral and sciatic nerve blocks technique using ropivacaine (n=8) or bupivacaine (n=8). The study was the first to include pharmacokinetic sampling up to 32 h after the block and results have shown that large between subject variability was present. Population modeling helped to explain and separate the various sources of variability and showed that systemic absorption was very slow. In addition, plasma concentrations were still measurable, and in some cases, plateaued at 32 h after the block. Future studies should extend sampling times to 4 or 5 days after the block in order to wait for the completion of the absorption. The second study attempted to establish an animal model by studying the intravenous pharmacokinetics and protein binding of ropivacaine in the rabbit (n=6). Results have shown that ropivacaine is much less bound to plasma protein in rabbits as compared to humans. This important information will be useful in future preclinical and clinical research. The third study explored, for the first time, the pharmacokinetics and the pharmacodynamics of epidural neostigmine (n=15) and attempted to characterize the dose effect relationship by testing the following doses: 0.5, 1 and 1.5 mg. Although the CSF pharmacokinetics of neostigmine were variable, a relationship between dose and meperidine consumption could be shown. The dose of 1.5 mg resulted in a better pharmacodynamic response on pain but it was deemed unsafe since it led to hypertension in two patients. We conclude that doses below 1.5 mg should be used for an epidural block with neostigmine. In conclusion, this research work investigated the pharmacokinetic and/or the pharmacodynamic characteristics of some drugs used for the treatment of post-operative pain. The gathered information will be essential to be able to reliably characterize the pharmacokinetic-pharmacodynamic relationships. This will help in achieving the ultimate goal which is a better management of post operative pain in surgical patients.

Le syndrome douloureux régional complexe (SDRC) est un trouble neurologique qui se caractérise par des douleurs intenses, des troubles vasomoteurs, sudomoteurs, moteurs et trophiques, accompagnés d’un œdème au niveau du membre affecté. Malgré la présence de peu de données en faveur, à cause de l’absence d’un traitement clé du SDRC, le blocage sympathique a été utilisé depuis de nombreuses années pour traiter ce syndrome. Objectif Le but principal de ce projet est d’étudier l’effet antalgique de la néostigmine utilisée comme adjuvant à la bupivacaïne lors d’un bloc stellaire dans le traitement du syndrome douloureux régional complexe du membre supérieur. Méthodes Il s’agit d’une étude pilote, randomisée en double insu. L’intensité de la douleur a été évaluée en utilisant l’échelle numérique. La force de préhension aux deux mains a été estimée par dynamométrie de Jamar. La dextérité fine des doigts a été mesurée par le « Purdue Pegboard Test ». L’œdème au niveau de la main a été déterminé par la volumétrie. Le questionnaire « SF-36 » a été utilisé afin de déterminer l’homogénéité des échantillons. Résultats Notre étude a eu des difficultés à établir l’efficacité de la thérapie par bloc stellaire dans le traitement du syndrome douloureux régional complexe. Conclusion Notre recherche n’a pu prouver l’hypothèse que le traitement de la douleur dans le SDRC du membre supérieur par un bloc stellaire est plus efficace quand l’action de l’anesthésique local est potentialisée par l’ajout de la néostigmine. / Complex regional pain syndrome (CRPS) is a neurological disorder characterized by severe pain, vasomotor, sudomotor, motor and trophic changes, accompanied by a swelling in the affected limb. Despite the limited data on his efficiency, in the absence of a definite curative treatment of the CRPS, sympathetic blocks have been used for years to treat the syndrome. Objective The main purpose of this project was to investigate the analgesic effect of neostigmine used as an adjuvant to the local anaesthetic bupivacaine in stellate ganglion blockade, in treating CRPS of the upper limb. Methods This was a pilot, randomized, double-blind study. The intensity of the pain was evaluated using a numeric scale. Grip strength in both hands was estimated by Jamar dynamometry. Fine finger dexterity was measured by the "Purdue Pegboard Test." The swelling in the hand was determined by volumetry. The questionnaire "SF-36" was used to determine the homogeneity of the samples in terms of quality of life assessment. Results Our study had difficulties in establishing the efficiency of stellate ganglion blockade in the treatment of complex regional pain syndrome. Conclusion This research project has not been able to prove that the pain treatment in upper limb CRPS by means of stellate ganglion blockade is more effective when the action of the local anesthetic is potentiated by the addition of neostigmine.

La douleur post-opératoire chez les patients constitue un défi thérapeutique important pour les cliniciens. Le traitement de la douleur post-opératoire n’est pas accessoire ni optionnel, puisqu’il permet de donner un congé de l’hôpital plus rapide aux patients et ainsi, il contribue à des économies importantes pour notre système de santé. Parmi les approches thérapeutiques utilisées pour la prise en charge de la douleur post-opératoire, cette thèse s’intéresse particulièrement aux blocs de nerfs périphériques par les anesthésiques locaux et à l’administration de la néostigmine par voie épidurale. Ces médicaments sont utilisés en clinique sans avoir préalablement établi, en se basant sur leur propriétés pharmacocinétiques et pharmacodynamiques spécifiques, leurs doses optimales. Ces doses devraient également tenir en considération les particularités anatomiques du site d’injection par rapport au site d’action. Cette thèse inclut des études exploratoires qui ont contribué à caractériser la pharmacocinétique de la ropivacaïne et de la bupivacaïne ainsi que la pharmacocinétique et la pharmacodynamie de la néostigmine. La première étude portait sur seize patients subissant une chirurgie orthopédique avec un bloc combiné des nerfs fémoral et sciatique par la ropivacaïne (n=8) ou la bupivacaïne (n=8). C’était la première étude qui a inclu des temps d’échantillons pharmacocinétiques allant jusqu’à 32 h après le bloc et ces résultats ont démontré une variabilité interindividuelle considérable. La modélisation par approche de population a aidé à expliquer les sources de la variabilité et démontré que l’absorption systémique des anesthésiques locaux était très lente. De plus, les concentrations plasmatiques demeuraient mesurables, et dans certains cas présentaient un plateau, 32 h après le bloc. Dans les prochaines études, un échantillonnage allant jusqu’à 4 ou 5 jours sera nécessaire afin d’atteindre la fin de l’absorption. La deuxième étude a établi le développement d’un modèle animal en étudiant la pharmacocinétique de la ropivacaïne après administration intraveineuse ainsi que son degré de liaison aux protéines plasmatiques chez le lapin (n=6). Les résultats ont démontré que, chez le lapin la ropivacaïne est beaucoup moins liée aux protéines plasmatiques comparativement à l’humain. Ce résultat important sera utile pour planifier les prochaines études précliniques. La troisième étude a exploré, pour la première fois, la pharmacocinétique et la pharmacodynamie de la néostigmine administrée par voie épidurale et a essayé de caractériser la courbe dose-réponse en utilisant trois doses différentes : 0.5, 1 et 1.5 mg. Bien que les concentrations de la néostigmine dans le liquide céphalo-rachidien fussent très variables une relation inverse entre la consommation de mépéridine et la dose de néostigmine a été démontrée. La dose de 1.5 mg a donné une meilleure réponse pharmacodynamique sur la douleur, mais elle a été considérée comme dangereuse puisqu’elle a résulté en deux cas d’hypertension. Nous avons conclu que des doses plus faibles que 1.5 mg devront être utilisées lors de l’utilisation de la néostigmine par voie épidurale. En conclusion, les études rapportées dans cette thèse ont exploré les propriétés pharmacocinétiques et/ou pharmacodynamiques de certains médicaments utilisés pour le traitement de la douleur post-opératoire. Ceci mènera au but ultime qui est la meilleure prise en charge de la douleur post-opératoire chez les patients. / Post-operative pain in surgical patients remains a challenging problem for the clinicians. The treatment of post-operative pain is no longer an accessory or nice to have, since it can significantly shorten hospital stays and lead to important savings for our health system. Amongst the therapeutic approaches used in the management of post-operative pain, we will focus on peripheral nerve blocks with local anesthetics and epidural neostigmine. These drugs are currently used in the clinic, without the prior characterization of an optimal dose that took into consideration their specific pharmacokinetic and pharmacodynamic properties. Optimal doses will need to consider the specific regional anatomy of the site of drug administration with respect to the site of action. This thesis included exploratory studies that helped to characterize the pharmacokinetics of ropivacaine and bupivacaine as well as the pharmacokinetics and pharmacodynamics of neostigmine. The first study included sixteen patients undergoing orthopedic surgeries with a combined femoral and sciatic nerve blocks technique using ropivacaine (n=8) or bupivacaine (n=8). The study was the first to include pharmacokinetic sampling up to 32 h after the block and results have shown that large between subject variability was present. Population modeling helped to explain and separate the various sources of variability and showed that systemic absorption was very slow. In addition, plasma concentrations were still measurable, and in some cases, plateaued at 32 h after the block. Future studies should extend sampling times to 4 or 5 days after the block in order to wait for the completion of the absorption. The second study attempted to establish an animal model by studying the intravenous pharmacokinetics and protein binding of ropivacaine in the rabbit (n=6). Results have shown that ropivacaine is much less bound to plasma protein in rabbits as compared to humans. This important information will be useful in future preclinical and clinical research. The third study explored, for the first time, the pharmacokinetics and the pharmacodynamics of epidural neostigmine (n=15) and attempted to characterize the dose effect relationship by testing the following doses: 0.5, 1 and 1.5 mg. Although the CSF pharmacokinetics of neostigmine were variable, a relationship between dose and meperidine consumption could be shown. The dose of 1.5 mg resulted in a better pharmacodynamic response on pain but it was deemed unsafe since it led to hypertension in two patients. We conclude that doses below 1.5 mg should be used for an epidural block with neostigmine. In conclusion, this research work investigated the pharmacokinetic and/or the pharmacodynamic characteristics of some drugs used for the treatment of post-operative pain. The gathered information will be essential to be able to reliably characterize the pharmacokinetic-pharmacodynamic relationships. This will help in achieving the ultimate goal which is a better management of post operative pain in surgical patients.

No description available.