Évaluation des interrelations entre la qualité du sommeil, la douleur et l'analgésie

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Postoperative analgesic effect, of preoperatively administered dexamethasone, after operative fixation of fractured neck of femur: randomised, double blinded controlled study.

Background: Fractured neck of femur is a common cause of hospital admission in the elderly and usually requires operative fixation. In a variety of clinical settings, preoperative glucocorticoid administration has improved analgesia and decreased opioid consumption. Our objective was to define the postoperative analgesic efficacy of single dose of dexamethasone administered preoperatively in patients undergoing operative fixation of fractured neck of femur. Methods: Institutional ethical approval was granted and written informed consent was obtained from each patient. Patients awaiting for surgery at Cork University Hospital were recruited between July 2009 and August 2012. Participating patients, scheduled for surgery were randomly allocated to one of two groups (Dexamethasone or Placebo). Patients in the dexamethasone group received a single dose of intravenous dexamethasone 0.1 mg kg -1 immediately preoperatively. Patients in the placebo group received the same volume of normal saline. Patients underwent operative fixation of fractured neck of femur using standardised spinal anaesthesia and surgical techniques. The primary outcome was pain scores at rest 6 h after the surgery. Results: Thirty seven patients were recruited and data from thirty patients were analysed. The groups were similar in terms of patient characteristics. Pain scores at rest 6 h after the surgery (the principal outcome) were lesser in the dexamethasone group compared with the placebo group [0.8(1.3) vs. 3.9(2.9), mean(SD) p = 0.0004]. Cumulative morphine consumption 24 h after the surgery was also lesser in the dexamethasone group [7.7(8.3) vs. 15.1(9.4), mean(SD) mg, p = 0.04]. Conclusions: A single dose of intravenous dexamethasone 0.1 mg kg -1 administered before operative fixation of fractured neck of femur improve significantly the early postoperative analgesia. Trial registration: ClinicalTrials.gov identifier: NCT01550146, date of registration: 07/03/2012

Influence de l'inflammation sur le métabolisme catalysé par les cytochromes P450 chez le rat : approches in vitro et implications sur la pharmacocinétique d'agonistes delta

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Évaluation des interrelations entre la qualité du sommeil, la douleur et l'analgésie

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

In vitro studies of drug transformations: application to forensic toxicology

The forensic toxicologist faces challenges in the detection of drugs and poisons in biological samples due to transformations which occur both during life and after death. For example, changes can result from drug metabolism during life or from the use of formalin solution for post mortem embalming purposes. The former requires the identification of drug metabolites and the latter the identification of chemical reaction products in order to know which substances had been administered. The work described in this thesis was aimed at providing ways of tackling these challenges and was divided into two parts. Part 1 investigated the use of in vitro drug metabolism by human liver microsomes (HLM) to obtain information on drug metabolites and Part 2 investigated the chemical reactions of drugs and a carbamate pesticide with formalin solution and formalin-blood. The initial aim of part I was to develop an in vitro metabolism method using HLM, based on a literature review of previous studies of this type. MDMA was chosen as a model compound to develop the HLM method because its metabolism was known and standards of its metabolites were commercially available. In addition, a sensitive and selective method was developed for the identification and quantitation of hydrophilic phase I drug metabolites using LC/MS/MS with a conventional reverse-phase (C18) column. In order to obtain suitable retention factors for polar drug metabolites on this column, acetyl derivatives were evaluated for converting the metabolites to more lipophilic compounds and an optimal separation system was developed. Acetate derivatives were found to be stable in the HPLC mobile phase and to provide good chromatographic separation of the target analytes. In vitro metabolism of MDMA and, subsequently, of other drugs involved incubation of 4 µg drug substance in pH 7.4 buffer with an NADPH generating system (NGS) at 37oC for 90 min with addition of more NGS after 30 min. The reaction was stopped at 90 min by the addition of acetonitrile before extraction of the metabolites. Acetate derivatives of MDMA metabolites were identified by LC/MS/MS using multiple reaction monitoring (MRM). Three phase I metabolites (both major and minor metabolites) of MDMA were detected in HLM samples. 3,4-dihydroxy-methamphetamine and 4-hydroxy-3-methoxymethamphetamine were found to be major metabolites of MDMA whereas 3,4-methylenedioxyamphetamine was found to be a minor metabolite. Subsequently, ten MDMA positive urines were analysed to compare the metabolite patterns with those produced by HLM. An LC/MS method for MDMA and its metabolites in urine samples was developed and validated. The method demonstrated good linearity, accuracy and precision and insignificant matrix effects, with limits of quantitation of 0.025 µg/ml. Moreover, derivatives of MDMA and its metabolites were quantified in all 10 positive human urine samples. The urine metabolite pattern was found to be similar to that from HLM. The second aim of Part 1 was to use the HLM system to study the metabolism of some new psychoactive substances, whose misuse worldwide has necessitated the development of analytical methods for these drugs in biological specimens. Methylone and butylone were selected as representative cathinones and para-methoxyamphetamine (PMA) was chosen as a representative ring-substituted amphetamine, because of the involvement of these drugs in recent drug-related deaths, because of a relative lack of information on their metabolism, and because reference standards of their metabolites were not commercially available. An LC/MS/MS method for the analysis of methylone, butylone, PMA and their metabolites was developed. Three phase I metabolites of methylone and butylone were detected in HLM samples. Ketone reduction to β-OH metabolites and demethylenation to dihydroxy-metabolites were found to be major phase I metabolic pathways of butylone and methylone whereas N-demethylation to nor-methylone and nor-butylone were found to be minor pathways. Also, demethylation to para-hydroxyamphetamine was found to be a major phase I metabolic pathway of PMA whereas β-hydroxylation to β-OH-PMA was found to be a minor pathway. Formaldehyde is used for embalming, to reduce decomposition and preserve cadavers, especially in tropical countries such as Thailand. Drugs present in the body can be exposed to formaldehyde resulting in decreasing concentrations of the original compounds and production of new substances. The aim of part II of the study was to evaluate the in vitro reactions of formaldehyde with selected drug groups including amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (alprazolam and diazepam), opiates (morphine, hydromorphone, codeine and hydrocodone) and with a carbamate insecticide (carbosulfan). The study would identify degradation products to serve as markers for the parent compounds when these were no longer detectable. Drugs standards were spiked in 10% formalin solution and 10% formalin blood. Water and whole blood without formalin were used for controls. Samples were analysed by LC/MS/MS at different times from the start, over periods of up to 30 days. Amphetamine, methamphetamine and MDMA were found to rapidly convert to methamphetamine, DMA and MDDMA respectively, in both formalin solution and formalin blood, confirming the Eschweiler-Clarke reaction between amine-containing compounds and formaldehyde. Alprazolam was found to be unstable whereas diazepam was found to be stable in both formalin solution and water. Both were found to hydrolyse in formalin solution and to give open-ring alprazolam and open-ring diazepam. Other alprazolam conversion products attached to paraformaldehyde were detected in both formalin solution and formalin blood. Morphine and codeine were found to be more stable than hydromorphone and hydrocodone in formalin solution. Conversion products of hydromorphone and hydrocodone attached to paraformaldehyde were tentatively identified in formalin solution. Moreover, hydrocodone and hydromorphone rapidly decreased within 24 h in formalin blood and could not be detected after 7 days. Carbosulfan was found to be unstable in formalin solution and was rapidly hydrolysed within 24 h, whereas in water it was stable up to 48 h. Carbofuran was the major degradation product, plus smaller amounts of other products, 3-ketocarbofuran and 3-hydrocarbofuran. By contrast, carbosulfan slowly hydrolysed in formalin-blood and was still detected after 15 days. It was concluded that HLM provide a useful tool for human drug metabolism studies when ethical considerations preclude their controlled administration to humans. The use of chemical derivatisation for hydrophilic compounds such as polar drug metabolites for analysis by LC/MS/MS with a conventional C18 column is effective and inexpensive, and suitable for routine use in the identification and quantitation of drugs and their metabolites. The detection of parent drugs and their metabolites or conversion and decomposition products is potentially very useful for the interpretation of cases in forensic toxicology, especially when the original compounds cannot be observed.

Fatal methadone intoxication in an infant listed as a homicide.

Voluntary methadone administration for the purpose of sedation eventually resulting in the infant's death is extremely infrequent, though it has been observed. In this report, we describe an autopsy case pertaining to a 32-month-old infant who was repeatedly exposed to methadone by his parents. Autopsy revealed a coarctation of the aorta with a focal stenosis located at the junction of the distal aortic arch and the descending aorta. Left ventricular hypertrophy was also observed. Both these findings were considered to not have played a role in the child's death. Methadone was detected in the femoral blood (0.633 mg/l), urine (5.25 mg/l), bile (2.64 mg/l), and gastric contents (1.08 mg). A segmental hair analysis showed the presence of methadone and morphine in both the proximal and distal portion of the lock. Methadone was also detected in nail samples. A segmental hair analysis performed on the younger brother of the deceased revealed the presence of methadone and morphine in both the proximal and distal segments, as well as the presence of 6-monoacetylmorphine exclusively in the distal portion. Though the parents denied any involvement in methadone administration or exposure for the purpose of sedation, the manner of death was listed as homicide. The case emphasizes the usefulness of hair analysis to identify threatening situations for the children of drug-dependent parents and possibly support measures by the authorities to recognize and intervene in these potentially fatal situations.

Refolding of omega conotoxin peptide derived from marine snail, Conus magus, to evaluate its analgesic effects

Oxidative refolding is one of the key challenges hampering the development of peptide based compounds as therapeutics. The correct refolding for three disulfide peptide like w-Conotoxi n MVIIA is difficult and crucial for biological activity. This work advanced knowledge of chemical and biological for improve oxidative refolding of synthetic w-Conotoxi n MVIIA in base of Conus magus venom. The present study aimed to set up an appropriate and effective protocols for refolding of disulfide-rich w-Conotoxin MVIIA. In this study, the crude peptide was protected with Acm group, according to the right amino acid sequences (Synthesized by Australian Company). The crude peptide was purified by H PLC. To prepare the peptide to refolding, innovative deprotection applied molar ratio (AMR) method was performed based on mercury. Accuracy of deprotection was approved by reverse phase chromatography. The deprotected target peptide (omega-conotoxin) was determined by SDS-PAGE. Then the Oxidative refolding of target peptide was performed in six protocol based on Guanidinium chloride and oxidized and reduced Glutathione. Analgesic effect of refolded peptide was surveyed with formalin test in mice Balb/c. Non neurotoxic effects of target peptides were survey with ICV injection in mice model (C57/BL6). The innovative deprotection protocol performed based on the best ratio of mercury/2-mercaptoethanol adjusted to 1mg/10p1 in 90 minute. The results showed the yield and purity of omega-conotoxin MVIIA as 93 and 95%, respectively. Refolding of 40 mg omega Conotoxin with GSSG and GSH on ratio of 10:1 and 20 mM ammonium acetate showed the best analgesic effect compared with the other methods. The result showed 95.5% yield and 98% purity of omega-conotoxin MVIIA in this refolding method. Related refolding method reduced 85% pain in experimented mice using 7 ng of the peptide. That was 71.5 fold stronger than morphine and 2 times than standard Prialt®. And it was not neurotoxic in mice. In this study, refolding method for omega-conotoxin MVIIA was optimized in the fourth factor including: reducing the time, amount and number of reagent and increase the efficiency. We introduced new method for deprotection of omega-conotoxin MVIIA. Effective, economic and applied refolding and deprotecti on method was performed in this research may al so be applied to similar omega conotoxin peptides.

A review of patients with advanced cervical cancer presenting to palliative care services at Queen Elizabeth Central Hospital in Blantyre, Malawi

Background Cervical cancer is the commonest cancer affecting women in Malawi, which has the highest rate of this disease in the world. Most cases are diagnosed at an advanced stage. Aim To describe the symptom burden, palliative care interventions, and outcomes of cervical cancer patients who entered care at Tiyanjane Clinic in Blantyre, Malawi, between January and December 2012. Methods We reviewed the case files of 72 patients presenting to our hospital-based palliative care service over one year. Results The mean age was 49.5 years. Twenty-six patients (36%) were HIVpositive and the majority of these (n = 22; 85%) were on antiretroviral medication at presentation to palliative care. Pain (n = 66; 92%), vaginal discharge (n = 44; 61%), and unpleasant odour (n = 37; 51%) were commonly reported. Over a third of patients (n = 26; 36%) reported pain in two or more sites. Fourteen patients (19%) reported vaginal bleeding. Spousal breakdown (through widowhood or divorce) was noted in over half (n = 41; 57%) of all cases. Pain relief was provided to 69 (96%) of the patients (morphine to 40 patients; 56%). Common interventions provided included metronidazole tablets (used vaginally), sanitary items, and counselling. At the end of the study period, 18 patients (25%) were still under the care of palliative services. Conclusions Access to medications such as morphine, metronidazole and tranexamic acid can improve quality of life, even when radiotherapy is limited. Health care teams require necessary skills and training, including how to perform a comprehensive assessment, with an emphasis on the provision of psychosexual counselling, to assist with the complexity of symptoms occurring in this vulnerable group.

Comparison of the eficacy and safety of 4 mg of ondansetron vs. 4 mg of nalbuphine for the treatment of neuraxial morphineinduced pruritus

Objective: To compare the eficacy and safety of 4 mg of ondansetron vs. 4 mg of nalbuphine for the treatment of neuraxial morphine-induced pruritus, in patients at the “Dr. José Eleuterio González” University Hospital from September 2012 to August 2013. Material and methods: A controlled, prospective, randomized study of 28 patients (14 per group) receiving neuraxial morphine analgesia was conducted, which was registered and approved by the ethics Committee of the Institution and patients agreed to participate in the study under informed consent. The results were segmented and contrasted (according to drug) by hypothesis testing; the association was determined by X2 with a 95% conidence interval (CI). Results: Pruritus was effectively resolved in both groups and no signiicant difference was found in the rest of the variables. An increase in the visual analogue scale (eVA) was observed at 6 and 12 hours for the ondansetron group, which was statistically signiicant (p≤0.05), however both groups had an eVA of less than 3. Conclusions: When comparing the eficacy and safety of ondansetron 4 mg vs. nalbuphine 4 mg for the treatment of neuraxial morphine induced pruritus, the only signiicant difference found was the mean eVA at 6 and 12 hours, favoring the ondansetron group. However, both groups scored less than 3 on the eVA. Therefore, we consider that both treatments are effective and safe in the treatment of pruritus caused by neuraxial morphine.

Manejo del dolor postoperatorio con morfina en anestesia espinal en cirugía gineco-obstétrica de la Fundación Pablo Jaramillo Crespo

Objetivo: Evaluar la eficacia del tratamiento del dolor postoperatorio con el uso de la morfina en anestesia conductiva en pacientes con cirugía ginecológica, obstétrica. Fundación Pablo Jaramillo Crespo; septiembre- diciembre de 2011. Métodos: Estudio observacional, analítico, prospectivo y cuantitativo. Se incluyeron, con la clasificación de la Sociedad Americana de Anestesiología (ASA) I y II a 231 pacientes, entre 15 y 65 años, hospitalizadas en la Fundación Pablo Jaramillo Crespo, por cirugía ginecológica-obstétrica, realizadas desde septiembre a diciembre de 2011. Se administraron dosis de morfina: 2 mg para epidural y 0,2 mg para anestesia raquídea. El dolor fue evaluado a las 12 y 24 horas, con la escala visual analógica de la intensidad del dolor (EVA). Resultados: La morfina utilizada no tuvo preservantes; se observó que la anestesia raquídea muestra una ligera ventaja a la epidural, con mejor tolerancia al dolor a las 12 y 24 horas (p<0.05) No hubo relación entre la etiología de las cirugías ginecológicas y obstétricas con el dolor a las 12 y 24 horas (p>0.05). En 25.78 % de los casos, la analgesia de la morfina, por administración raquídea, se complementó con el uso de ketorolaco por vía intravenosa. Un 49.2% de las pacientes no mostró efectos secundarios; de estos, los más observados fueron: el prurito (13.14 %), retención urinaria (11.3%), náuseas (9.8%) y vómitos (6.9%). Conclusión: el uso de morfina en dosis: 2 mg para epidural y 0.2 mg para anestesia raquídea, proporciona una favorable recuperación del dolor en las pacientes con cirugía ginecológica y obstétrica. Los efectos secundarios provocados por su administración pueden manejarse de manera eficiente sin alterar la recuperación postoperatoria

Covalent Protein Adduction by Drugs of Abuse

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

Sucrose Bingeing Reduces the Reward Value of Sucrose

Binge eating occurs primarily on highly palatable food (PF) suggesting that the reward value of food has an important role in this behaviour. Bingeing also leads to reward dysfunction in rats and humans. The rewarding effect of binge eating may involve opioid mechanisms as opioid antagonists reduce PF consumption in animals that binge eat and binge eating produces neuroadaptations of opioid receptors in rodents. We tested this hypothesis by using the conditioned place preference (CPP) paradigm. First we established a sucrose CPP in male and female Long-Evans rats (n=8 for each group) using 1%, 5%, 15%, or 30% sucrose solution. Next, rats underwent the sucrose bingeing model in which separate groups of rats (n=8 for each group) received 12hr and 24hr access to 10% sucrose solution and chow, 12hr access to 0.1% saccharin solution and chow, or 12hr access to chow only every day for 28 days. Immediately following these sessions, rats were conditioned and tested in the CPP paradigm using a 15% sucrose solution. Finally, we examined whether the sucrose bingeing model altered morphine reward in female rats. Rats (n=8 for each group) received 12hr and 24hr access to 10% sucrose solution and chow every day for 28 days. Immediately following this access period, rats were conditioned to morphine (6mL/kg) or saline solution in the CPP paradigm and tested for a CPP. In all experiments, rats drank more sucrose solution than water during conditioning sessions. Male rats did not develop a CPP to any concentration of sucrose solution and females developed a CPP to 15% sucrose solution only. Following the sucrose bingeing protocol, sucrose CPP was attenuated in male rats that binged on sucrose and in all female rats. Sucrose bingeing in females did not affect the development of a CPP to morphine. These results suggest that sucrose consumption and sucrose CPP are measures of different psychological components of reward. Furthermore, sucrose bingeing reduces the rewarding effect of sucrose, but not morphine, suggesting that opioid reward is still intact.

An examination of verbal descriptors of cancer-induced bone pain and neuropathic cancer pain

Aims: The aim of the thesis was to identify verbal descriptors of cancer induced bone pain (CIBP) and neuropathic cancer pain (NCP). An examination of the verbal descriptors associated with these two pain syndromes further considered the relationship between common verbal descriptors, cancer type, performance status and analgesia. Methods: The project was conducted in two phases; Phase one was a systematic review of the literature to examine current evidence of verbal descriptors in CIBP and NCP. Phase two utilised secondary data analysis methodology. Data from 120 patients with confirmed CIBP and 61 patients with confirmed NCP were deemed eligible for entry into a de novo database for secondary analysis. Key descriptive data were considered such as gender, ECOG and pain scores to characterise the patient population. Verbal descriptors of CIBP and NCP were considered in detail across the secondary de novo database. Results: Gender was not identified as a diagnostic characteristic of CIBP and NCP with similar distribution across prevalence of pain reporting and also pain severity. Patients with breast (n=52,43.3%), prostate (n=35,29.2%) and lung (n=14,11.7%) cancer were found to be at an increased risk of CIBP. Those with NCP more was found more commonly among patients with breast cancer (n=21,34.4%). Patients with CIBP were found to have an ECOG performance of 1 (n=49, 40.8%) or 2 (n=43, 35.8%) which was lower than those with NCP with an ECOG of 0 (n=32, 52.5%) or 2 (n=18, 29.5%). Comparisons were made across analgesia and treatment options for CIBP and NCP. Patients with CIBP received a greater variety of treatment options including bisphosphonates and radiotherapy while patients with NCP were more commonly treated with analgesia alone. Patients with CIBP and NCP were taking strong opioids, however those with NCP (n=45, 73.8%) were more likely to utilise strong opioids than those with CIBP (n=61, 50.8%). It was noted that those with NCP required a daily morphine equivalence of almost 50% higher than those with CIBP. Average consumption of opioids was 155.6mg, for patients with NCP, compared to 76mg in patients with CIBP. Common verbal descriptors of CIBP and NCP were identified. The most common verbal descriptors for CIBP were aching, gnawing and throbbing and the most common verbal descriptors of NCP were aching, tender and sharp. Of the most common 6 descriptors for CIBP and NCP only one descriptor was unique to each pain type, gnawing for CIBP and stabbing for NCP. Conclusions: Patients with CIBP and NCP use similar verbal descriptors to characterise their pain with gnawing being unique to CIBP and stabbing being unique to NCP in the data considered within project. Further research is required to explore verbal descriptors which are both common and unique to CIBP and NCP. Further exploration of verbal descriptors would assist development of a comprehensive pain assessment tool which would enhance pain assessment for nurses, clinicians and patients.

An investigation into the suitability of time-of-flight mass spectrometry in forensic toxicology

Liquid chromatography coupled with mass spectrometry is one of the most powerful tools in the toxicologist’s arsenal to detect a wide variety of compounds from many different matrices. However, the huge number of potentially abused substances and new substances especially designed as intoxicants poses a problem in a forensic toxicology setting. Most methods are targeted and designed to cover a very specific drug or group of drugs while many other substances remain undetected. High resolution mass spectrometry, more specifically time-of-flight mass spectrometry, represents an extremely powerful tool in analysing a multitude of compounds not only simultaneously but also retroactively. The data obtained through the time-of-flight instrument contains all compounds made available from sample extraction and chromatography, which can be processed at a later time with an improved library to detect previously unrecognised compounds without having to analyse the respective sample again. The aim of this project was to determine the utility and limitations of time-of-flight mass spectrometry as a general and easily expandable screening method. The resolution of time-of-flight mass spectrometry allows for the separation of compounds with the same nominal mass but distinct exact masses without the need to separate them chromatographically. To simulate the wide variety of potentially encountered drugs in such a general screening method, seven drugs (morphine, cocaine, zolpidem, diazepam, amphetamine, MDEA and THC) were chosen to represent this variety in terms of mass, properties and functional groups. Consequently, several liquid-liquid and solid phase extractions were applied to urine samples to determine the most general suitable and unspecific extraction. Chromatography was optimised by investigating the parameters pH, concentration, organic solvent and gradient of the mobile phase to improve data obtained by the time-of-flight instrument. The resulting method was validated as a qualitative confirmation/identification method. Data processing was automated using the software TargetAnalysis, which provides excellent analyte recognition according to retention time, exact mass and isotope pattern. The recognition of isotope patterns allows excellent recognition of analytes even in interference rich mass spectra and proved to be a good positive indicator. Finally, the validated method was applied to samples received from the A& E Department of Glasgow Royal Infirmary in suspected drug abuse cases and samples received from the Scottish Prison Service, which we received from their own prevalence study targeting drugs of abuse in the prison population. The obtained data was processed with a library established in the course of this work.

Ketamina para el tratamiento de la hiperalgesia causada por remifentanil en cirugía: revisión sistemática de literatura

La hiperalgesia secundaria a la administración de remifentanil se ha documentado tanto en estudios animales como en estudios experimentales en humanos y ha aumentado su incidencia dado su uso cada vez más frecuente para el mantenimiento durante diferentes procedimientos anestésicos, anestesia general balanceada, anestesia total intravenosa y sedaciones. La hiperalgesia secundaria al uso de remifentanil es un proceso pro-nociceptivo relacionado pero que difiere de la tolerancia aguda, en el que los neurotransmisores excitatorios de N- metil D aspartato (NMDA) juegan un rol central. Por tanto la ketamina se ha utilizado en diferentes dosis para la prevención de dicha hiperalgesia sin que se haya establecido su efectividad para la prevención y tratamiento de esta condición. Se encontraron 8 estudios publicados en los últimos 10 años que proponen a la ketamina como una estrategia útil y efectiva el tratamiento de la hiperalgesia inducida por el uso de remifentanil. Los resultados demuestran que la ketamina es un tratamiento costo efectivo para el tratamiento de la hiperalgesia en diferentes poblaciones sometidas a diversos procedimientos quirúrgicos y anestésicos que incluyan la administración de remifentanil tanto en la inducción como en el mantenimiento anestésico sin generar efectos secundarios adicionales, así como que logra disminuir el consumo de opioides y la EVA en el posoperatorio.