Opioid induced hyperalgesia : interest of parasympathetic tone monitoring in humans and study of molecular mechanisms of desensitization and tolerance in vitro and in mice

L’utilisation des opioïdes est à l’origine de phénomènes de tolérance et d’hyperalgésie induite (HIO) aussi bien chez l’animal qu’en utilisation clinique. Ces phénomènes surviennent avec tous les opioïdes de manière dose-dépendante. Les mécanismes qui les sous-tendent sont complexes et imparfaitement connus. Le rémifentanil et le sufentanil sont les opioïdes les plus utilisés en France en anesthésie-réanimation. Leur utilisation s’accompagne d’une HIO qui majore la douleur postopératoire et peut être responsable de la persistance de la douleur à long terme. La perception des stimuli nociceptifs chez un patient sous anesthésie générale n’est pas aisée et repose encore sur des signes cliniques indirects d’activation du système sympathique. Ces signes peu sensibles et peu spécifiques conduisent à sous doser ou sur-doser les patients en opioïdes. Récemment, un nouvel outil de monitorage de la nociception est apparu, l’analgesia nociception index (ANI). L’ANI reflète le tonus parasympathique et de ce fait permettrait aux anesthésistes de mieux adapter le dosage des opioïdes. Dans cette thèse, nous avons d’abord évalué la sensibilité et la spécificité de l’ANI à détecter les stimuli nociceptifs, puis montré qu’elles étaient supérieures à celles des signes cliniques, et supérieures à d’autres indices de monitorage proposés. Ensuite nous avons validé la capacité de l’ANI à guider l’analgésie peropératoire du rémifentanil dans différentes situations.Sur le plan expérimental, nous avons exploré, après une exposition courte ou prolongée à différentes doses de rémifentanil et de sufentanil, les mécanismes associés à l’hyperalgésie thermique in vivo, chez la souris, et ex vivo, sur la voie des MAP kinases ERK1/2 et sur le trafic membranaire des récepteurs opioïdes de type µ (MOR) dans différentes cultures cellulaires. Chez la souris, nous avons mis en évidence une hyperalgésie précoce au saut sur plaque chaude, après exposition aux doses les plus élevées de rémifentanil, mais pas avec le sufentanil. De plus, nous n’avons pas observé d’HIO sur le léchage des pattes.Sur les cultures cellulaires, le rémifentanil comme le sufentanil activent la voie des MAPK ERK1/2 lors d’une exposition courte, avec apparition d’une désensibilisation lorsque l’exposition se prolonge. Le rémifentanil comme le sufentanil induisent une internalisation précoce et progressive des récepteurs MOR.The use of opioids is associated with tolerance and induced hyperalgesia (OIH). Tolerance and OIH occur with all opioids and have been demonstrated both, in animals and in humans and are likely to be dose-dependent. The underlying mechanisms are complex and partially known. Remifentanil and sufentanil are the most used opioids in France in anesthesia and intensive care. Their use is associated with OIH that increases postoperative pain and may be responsible for persistent pain. In anesthetized patients, nociceptive stimuli are still detected according to clinical signs of sympathetic activation. These signs lack sensitivity and specificity and lead to underdosing or overdosing opioids. Recently, the analgesia nociception index (ANI), has been proposed as surrogate marker of nociception. The ANI reflects the parasympathetic tone and thus may allow anesthetists to better adapt the opioid dosage. In this thesis, we first evaluated the sensitivity and specificity of ANI to detect nociceptive stimuli, and showed that it better detects them than do clinical signs or than other currently available monitoring tools. Subsequently, we validated the ability of the ANI to adequately guide the intraoperative dosing of remifentanil in different clinical setting.After acute and sustained exposure to different doses of remifentanil and sufentanil we investigated, in vivo, the mechanisms associated with thermal hyperalgesia in mice, and ex vivo, the effect on the MAP kinase ERK1/2 pathway and the μ-type opioid receptor (MOR) membrane trafficking in human neuroblastoma and embryonic kidney cell cultures. In mice, high-dose remifentanil induced early hyperalgesia assessed by the jumping latency in a hot-plate test, but not the sufentanil. We did not observe OIH for the hind paw licking test. On cell cultures, after short exposure, both remifentanil and sufentanil produced activation of the MAP kinase ERK1/2 pathway, and rapid desensitization and internalization of the MOR

Hyperalgésie induite par les opioïdes : intérêt du monitorage du tonus parasympathique chez l'homme et étude des mécanismes moléculaires de désensibilisation et de tolérance in vitro et chez la souris

The use of opioids is associated with tolerance and induced hyperalgesia (OIH). Tolerance and OIH occur with all opioids and have been demonstrated both, in animals and in humans and are likely to be dose-dependent. The underlying mechanisms are complex and partially known. Remifentanil and sufentanil are the most used opioids in France in anesthesia and intensive care. Their use is associated with OIH that increases postoperative pain and may be responsible for persistent pain. In anesthetized patients, nociceptive stimuli are still detected according to clinical signs of sympathetic activation. These signs lack sensitivity and specificity and lead to underdosing or overdosing opioids. Recently, the analgesia nociception index (ANI), has been proposed as surrogate marker of nociception. The ANI reflects the parasympathetic tone and thus may allow anesthetists to better adapt the opioid dosage. In this thesis, we first evaluated the sensitivity and specificity of ANI to detect nociceptive stimuli, and showed that it better detects them than do clinical signs or than other currently available monitoring tools. Subsequently, we validated the ability of the ANI to adequately guide the intraoperative dosing of remifentanil in different clinical setting.After acute and sustained exposure to different doses of remifentanil and sufentanil we investigated, in vivo, the mechanisms associated with thermal hyperalgesia in mice, and ex vivo, the effect on the MAP kinase ERK1/2 pathway and the μ-type opioid receptor (MOR) membrane trafficking in human neuroblastoma and embryonic kidney cell cultures. In mice, high-dose remifentanil induced early hyperalgesia assessed by the jumping latency in a hot-plate test, but not the sufentanil. We did not observe OIH for the hind paw licking test. On cell cultures, after short exposure, both remifentanil and sufentanil produced activation of the MAP kinase ERK1/2 pathway, and rapid desensitization and internalization of the MOR.L’utilisation des opioïdes est à l’origine de phénomènes de tolérance et d’hyperalgésie induite (HIO) aussi bien chez l’animal qu’en utilisation clinique. Ces phénomènes surviennent avec tous les opioïdes de manière dose-dépendante. Les mécanismes qui les sous-tendent sont complexes et imparfaitement connus. Le rémifentanil et le sufentanil sont les opioïdes les plus utilisés en France en anesthésie-réanimation. Leur utilisation s’accompagne d’une HIO qui majore la douleur postopératoire et peut être responsable de la persistance de la douleur à long terme. La perception des stimuli nociceptifs chez un patient sous anesthésie générale n’est pas aisée et repose encore sur des signes cliniques indirects d’activation du système sympathique. Ces signes peu sensibles et peu spécifiques conduisent à sous doser ou sur-doser les patients en opioïdes. Récemment, un nouvel outil de monitorage de la nociception est apparu, l’analgesia nociception index (ANI). L’ANI reflète le tonus parasympathique et de ce fait permettrait aux anesthésistes de mieux adapter le dosage des opioïdes. Dans cette thèse, nous avons d’abord évalué la sensibilité et la spécificité de l’ANI à détecter les stimuli nociceptifs, puis montré qu’elles étaient supérieures à celles des signes cliniques, et supérieures à d’autres indices de monitorage proposés. Ensuite nous avons validé la capacité de l’ANI à guider l’analgésie peropératoire du rémifentanil dans différentes situations.Sur le plan expérimental, nous avons exploré, après une exposition courte ou prolongée à différentes doses de rémifentanil et de sufentanil, les mécanismes associés à l’hyperalgésie thermique in vivo, chez la souris, et ex vivo, sur la voie des MAP kinases ERK1/2 et sur le trafic membranaire des récepteurs opioïdes de type µ (MOR) dans différentes cultures cellulaires. Chez la souris, nous avons mis en évidence une hyperalgésie précoce au saut sur plaque chaude, après exposition aux doses les plus élevées de rémifentanil, mais pas avec le sufentanil. De plus, nous n’avons pas observé d’HIO sur le léchage des pattes.Sur les cultures cellulaires, le rémifentanil comme le sufentanil activent la voie des MAPK ERK1/2 lors d’une exposition courte, avec apparition d’une désensibilisation lorsque l’exposition se prolonge. Le rémifentanil comme le sufentanil induisent une internalisation précoce et progressive des récepteurs MOR

The Bank of Syria and Lebanon, lever of development or instrument of French imperialism? (1919-1945)

La Banque de Syrie et du Liban a été créée le 2 janvier 1919 par la Banque Impériale ottomane. Étant une banque commerciale, elle s’est vue attribuer, suite à la signature de la Convention du 23 janvier 1924 avec les États du Levant, le privilège de l’émission de la nouvelle livre libano-syrienne. Cette monnaie est rattachée directement au Franc français afin de faciliter le fonctionnement administratif de la France au Levant et le commerce avec la Métropole. Forte de cette position, la Banque n’a pas hésité d’exercer parallèlement son activité de banque commerciale et en tirer profit. Son activité principale est axée vers le crédit et les avances aux États du Levant et aux particuliers. En plus d’être l’agent financier des États du Levant, elle a été connue aussi pour être une banque de dépôt. Sa position d’une banque émettrice du billet local a inspiré confiance à la population locale pour y venir déposer leurs économies. Sa connaissance du territoire a poussé les capitaux français à s’allier avec elle pour l’exécution de leurs investissements au Levant. Tout au long de son existence, la BSL sera un acteur incontournable de la place financière en Orient. Son histoire est considérée comme indissociable de l’histoire économique du Levant et de la France.The Bank of Syria and Lebanon was created on January 2, 1919 by the Imperial Ottoman Bank. Being a commercial bank, it has been attributed, following the signature of the Convention of January 23, 1924 with the States of the Levant, the privilege of the issue of the new Lebanese-Syrian bank-note. This currency is directly attached to the French Franc to facilitate the administrative operation of France in the Levant and trade with the Metropolis. In this position, the Bank has not hesitated to simultaneously carry out its commercial banking activity and profit from it. Its main activity is focused on credit and advances to the Levant States and individuals. In addition to being the financial agent of the Levant States, it has also been known to be a deposit bank. Its position as a bank issuing the local bank-note has inspired confidence to the local population to come and deposit their savings. Its knowledge of the territory has pushed French capital to ally with it for the execution of their investments in the Levant. Throughout its existence, BSL will be a key player in the financial market in the East. Its history is considered inseparable from the economic history of the Levant and France

L'analgesia nociceptive index en chirurgie bariatrique (une analyse de la consommation de rémifentanil, à posteriori et en double aveugle)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

A targeted remifentanil administration protocol based on the analgesia nociception index during vascular surgery

International audienc

Does preoperative B-type natriuretic peptide better predict adverse outcome and prolonged length of stay than the standard European System for Cardiac Operative Risk Evaluation after cardiac surgery?

OBJECTIVES: Although B-type natriuretic peptide (BNP) strongly predicts cardiac morbidity and mortality, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) has a modest predictive value to identify a composite operative risk after cardiac surgery. The authors tested the hypothesis that a single preoperative BNP measurement would be superior to standard EuroSCORE in predicting composite adverse outcomes after cardiac surgery. DESIGN: A prospective observational study. SETTING: A teaching university hospital. PARTICIPANTS: Two hundred eight adult patients. INTERVENTIONS: Conventional cardiac surgery with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: The preoperative additive EuroSCORE and BNP measurement were performed in all patients. Postoperative nonfatal major adverse cardiac events (malignant ventricular arrhythmia, myocardial infarction, and cardiac dysfunction), all-cause mortality, and prolonged lengths of stay were chosen as study endpoints. Predictive abilities of both EuroSCORE and BNP were assessed using logistic regression and compared with receiver operating characteristic (ROC) curves. Thirty-six (17%, 95% confidence interval [CI], 12%-22%) patients experienced 49 events over the study period. The areas under the ROC curves assessing the utility of EuroSCORE and BNP in predicting adverse outcome and prolonged in-hospital stay were 0.59 (95% CI, 0.48-0.69) versus 0.76 (95% CI, 0.68-0.85; p < 0.001) and 0.65 (95% CI, 0.57-0.74) versus 0.71 (95% CI, 0.63-0.80; p = 0.147), respectively. Using logistic regression, BNP considered as a dichotomized variable was the only independent predictor of adverse cardiac outcome (adjusted odds ratio = 10.7; 95% CI, 4.1-27.8; p < 0.001). CONCLUSIONS: Preoperative BNP measurement is a strong, independent, and more accurate predictor of adverse outcome than EuroSCORE in patients undergoing cardiac surgery. BNP could be considered as a simple and objective tool for the detection of high-risk patients after cardiac surgery

The prognostic value of B-type natriuretic peptide after cardiac surgery: a comparative study between coronary artery bypass graft surgery and aortic valve replacement

OBJECTIVES: The influence of the cardiac surgical procedure on B-type natriuretic peptide (BNP) for the identification of high-risk patients has not been evaluated. This study aimed to compare the prognostic utility of pre- and postoperative BNP in predicting adverse long-term outcome after coronary artery bypass graft (CABG) surgery and aortic valve replacement (AVR). DESIGN: A retrospective study. SETTING: A university teaching hospital. PARTICIPANTS: One hundred eighty-nine patients. MEASUREMENTS AND MAIN RESULTS: Preoperative, early postoperative (24 hours), and late postoperative (day 5) BNP levels were measured. Major adverse cardiac events (MACEs) within 12 months after surgery were chosen as study endpoints. The predictive abilities of BNP measurements were compared using receiver operating characteristic (ROC) curves. Patients were stratified by CABG surgery (n = 100) and AVR (n = 89). Thirty-four (18%) patients experienced 44 MACEs over the study period. Preoperative BNP values were significantly different between groups. Postoperative BNP gradually increased by 431% on day 5 after CABG surgery and by 100% after AVR (both p < 0.001 v preoperative values). Pre- and early postoperative BNP values were accurate in predicting MACEs after AVR (areas under the ROC curves: 0.78 [95% confidence interval, 0.66-0.90] and 0.76 [95% confidence interval, 0.62-0.89], respectively) and inaccurate after CABG surgery (0.54 [95% confidence interval, 0.38-0.70] and 0.54 [95% confidence interval, 0.36-0.73], respectively). The late postoperative BNP value was of limited value. CONCLUSIONS: BNP measurements should take into account the type of cardiac surgery. Whatever the time of measurement, BNP accurately predicts long-term adverse outcome in valve surgery patients. A late postoperative BNP measurement is useless after cardiac surgery

Tolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain

International audienceBackground: Polyamines have been identified as pain agonists and interact with NMDA receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. Material and Methods: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 days before and 5 days after surgery). Pain (numerical scale at rest and motion), Quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured.Results: Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After seven days of the diet before surgery, a trend of decrease on pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS ≥ 4) at rest (P = 0.03). and on motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the post-operative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022). and on motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and on motion (P = 0.005) in group 1 compared to group 2.Conclusion: Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approache

Uncovering the role of urinary microbiota in urological tumors : a systematic review of literature

Purpose Urinary microbiota has been found to play a key role in numerous urological diseases. The aim of this systematic review is to depict the role of urinary microbiota in the pathogenesis, diagnosis, prognosis, and treatment of urological tumors, including bladder cancer (BCa), prostate cancer (PCa) and renal cell carcinoma (RCC). Methods A systematic PubMed and Scopus search was undergone from inception through June 2021 for studies investigating urinary microbiota alterations in urological tumors. Study selection followed the PRISMA statement. Phylum, family, genus and species of each bacterium in cancer patients and controls were recorded. Results Twenty-one studies with 1194 patients (748 cancer patients and 446 controls) were included in our final analysis. Certain bacterial phylum, family, genus, and species were more predominant in each of BCa, PCa and RCC patients compared to controls. Abundance and specificity of urinary microbiota were prognosticators for: (1) recurrence, distinguishing recurrent from non-recurrent BCa, (2) disease stage, distinguishing non-muscle invasive from muscle invasive BCa, and (3) disease grade, distinguishing high- vs. low-grade PCa and BCa. Dietary, environmental and geographic patterns influenced urinary microbiota. Urinary microbiota of benign prostatic hyperplasia was different from PCa. Conclusion Urological cancer patients have an altered urinary microbiota compared to controls. This may predict recurrence, disease stage and disease grade of these tumors. Further prospective studies are needed to depict a potential influence on therapeutic outcomes

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study

International audienceCytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping