Paracetamol: Update on its Analgesic Mechanism of Action

Paracetamol is the most widely used over-the-counter medication in the world. The mechanism of action of its analgesic effect was often considered as based on the mobilization of the cyclooxygenases and more recently on serotonergic pathways. A new metabolic pathway involving the generation of an active metabolite, AM404 (N-(4-Hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), in the brain by the fatty acid amide hydrolase (FAAH) enzyme, was recently identified. This chapter describes experimental data that have shown the involvement of this metabolic pathway in the analgesic action of paracetamol and its relationship with the cyclooxygenase and serotonergic systems. It also explains how new targets and systems, such as the cannabinoid and vanilloid systems and the calcium channel receptor Cav3.2, play a role in the action of paracetamol. Finally, it suggests how research on the mechanism of the clinically relevant effects of this long-established analgesic could lead to new therapeutic pain strategies

Fibrose et insuffisance cardiaque

No abstract availableCe travail de thèse avait pour objectif d'évaluer l'intérêt des peptides collagéniques sanguins dans différentes populations à haut risque de développer une insuffisance cardiaque (patients présentant une obésité abdominale ou en post-infarctus du myocarde) ou déjà symptomatiques (post-infarctus du myocarde). En effet la fibrose myocardique est un élément essentiel de l'évolution péjorative de l'insuffisance cardiaque.Ces travaux ont permis de montrer la pertinence clinique des dosages sanguins des peptides collagéniques tout au long du processus de l'insuffisance cardiaque : du stade asymptomatique aux stades symptomatiques. Nous avons mis en évidence, à travers l'expression des peptides collagéniques que : 1/ des patients asymptomatiques ayant une obésité abdominale présentent un remodelage cardiaque précoce tant structurel que fonctionnel (augmentation de la masse ventriculaire gauche, dysfonction diastolique associée au PIIINP) : R2C2 Study. 2/ le ratio PIIINP/ICTP ≤ 1, mesuré 1 mois après un infarctus, est indépendamment associé à la survenue d'un remodelage ventriculaire gauche à un an et améliore la prédiction de survenue d'évènements cardiovasculaires (décès cardiovasculaires et hospitalisation pour décompensation cardiaque) à 3 ans : REVE-2 study. 3/ les antagonistes des récepteurs aux minéralocorticoïdes (éplérénone), traitement anti-fibrotique par excellence, sont efficaces et sûrs (hyperkaliémie et insuffisance rénale) chez des patients à haut risque de remodelage et de complications: EMPHASIS-HF study. Ce travail doit conduire à la validation dans d'autres populations du rôle prépondérant de la fibrose mais surtout au bénéfice thérapeutique des classes anti-fibrotiques dans l'insuffisance cardiaque

Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain

International audienceGlutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling. While the role of group I and II mGluRs is now well established, little is known about the part played by group III mGluRs in pain. In this work, we studied comparatively the involvement of spinal group III mGluR in modulation of acute, inflammatory and neuropathic pain. While intrathecal injection of ACPT-I, a selective group III mGluR agonist, failed to induce any change in vocalization thresholds of healthy animals submitted to mechanical or thermal stimuli, it dose-dependently inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with different animal models of inflammatory (carrageenan-treated and monoarthritic rats) or neuropathic pain (mononeuropathic and vincristine-treated rats). Similar effects were also observed following intrathecal injection of PHCCC, a positive allosteric modulator of mGlu4. Antihyperalgesia induced by ACPT-I was blocked either by LY341495, a nonselective antagonist of mGluR, by MAP4, a selective group III antagonist. This study provide new evidences supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. It more particularly highlights the specific involvement of mGlu4 in this process and may be a useful therapeutic approach to chronic pain treatment

Validation of an educational booklet targeted to patients candidate for total knee arthroplasty

SummaryBackgroundKnee osteoarthritis is a highly prevalent condition and the leading reason for total knee arthroplasty (TKA). No consensus exists about the optimal content of preoperative patient information and, to the best of our knowledge, no validated information document is available. Our objective here was to obtain validation by healthcare professionals and patients of an educational booklet for patients awaiting TKA.Materials and methodsThe booklet was developed and validated in six phases: systematic literature review, drafting of the first version, critical revision by a panel of experts, modification of the booklet, validation by a multidisciplinary panel of experts, and validation by two groups of patients, one composed of patients awaiting TKA and the other of patients in the immediate post-TKA period. We assessed the impact of the booklet based on knowledge and belief scores before and 2 days after receiving the booklet.ResultsCritical revision of the first draft led to changes to meet the concerns voiced by the experts. Knowledge improved only in the patient group given the booklet preoperatively (from 6/10 to 9/10, P=0.005). The booklet did not modify beliefs in either patient group.DiscussionWe used a rigorous methodology to develop and validate the contents of an educational booklet. Receiving this document before TKA resulted in improved patient knowledge but had no impact on beliefs.Level of evidenceLevel IV

Echocardiographic diastolic function evolution in patients with an anterior Q-wave myocardial infarction: insights from the REVE-2 study.

International audienceBackground: Myocardial fibrosis plays a key role in the development of adverse left ventricular remodeling after myocardial infarction (MI). This study aimed to determine whether the circulating levels of BNP, collagen peptides, and galectin-3 are associated with diastolic function evolution (both deterioration and improvement) at 1-year after an anterior MI.Methods: The REVE-2 is a prospective multicenter study including 246 patients with a first anterior Q-wave MI. Echocardiographic assessment was performed at hospital discharge and ±1-year after MI. BNP, Galectin-3 and collagen peptides were measured ±1-month after MI. Left ventricular diastolic dysfunction (DD) was defined according to the presence of at least 2 criteria of echocardiographic parameters: septal e’6 mg/l (Odds Ratio, OR=5.29; 95%CI=1.05-26.66; p=0.044), Galectin-3>13 μg/l (OR=5.99; 95%CI=1.18-30.45; p=0.031), and BNP>82 ng/l (OR=10.25; 95%CI=2.36-44.50; p=0.002) quantified at 1-month post-MI were independently associated with 1-year DD. Follow-up of the 137 patients with DD at baseline among the 159 patients showed that 36 patients (26%) had a normalized diastolic function at 1-year post-MI. Patients with a BNP>82 ng/l were less likely to improve diastolic function (OR=0.06; 95%CI=0.01-0.28; p=0.0003).Conclusions. The present study suggests that circulating levels of PIIINP, Galectin-3 and BNP may be independently associated with new-onset DD in post-MI patients

Chronic Pain Opioid-Maintained Patients Receive Less Analgesic Opioid Prescriptions

Treating pain and opioid use disorder represents a clinical challenge. While most studies that have assessed opioid analgesic use in opioid substitution treatment (OST) patients primarily address opioid analgesic misuse (1, 2), only few studies focused on OST patients assessed the prescription of analgesic opioids for chronic pain. We sought to compare the prevalence of analgesic opioid prescription (AOP) in two groups of chronic non-cancer pain (CNCP) patients: OST patients vs. the general population. This was a population-based cross-sectional study based on the French national healthcare claims database SNIIRAM (Système National d'Informations Inter-Régimes de l'Assurance Maladie) covering over 66 million people (98.8% of the French population). Overall, 67,173 participants ≥15 years old undergoing continuous OST in 2015 (“OST patients” group) were included and age- and gender-matched by means of a 1:1 ratio with 67,173 patients without OST (“control” group). In each group, patients with cancer conditions were excluded and those having received opioid and non-opioid analgesics for at least 3 months were identified (CNCP patients). Compared to control patients, CNCP OST patients received less AOP (47.8 vs. 68.0%, p < 0.0001) and more often non-opioid prescription (52.2 vs. 32.0%, p < 0.0001). In multivariate analysis, CNCP OST patients were 2.7 times less likely to be prescribed analgesic opioids (adjusted odds ratio [OR] = 2.7 [2.42–3.01], p < 0.0001) than control patients. AOP correlated in CNCP OST patients with: age ≤ 40 years old, female gender, low-income status, methadone-maintained treatment, mental health disorder, hepatitis C virus (HCV) infection, and alcohol abuse disorder. Opioid analgesics were less often prescribed in CNCP OST patients. AOP prevalence was 2.7-fold lower than in the general population. Chronic pain management in OST patients needs to be reinforced through additional physician training and a multidisciplinary approach

Anti-nociceptive effect of Faecalibacterium prausnitzii in non-inflammatory IBS-like models

International audienceVisceral pain and intestinal dysbiosis are associated with Irritable Bowel Syndrome (IBS), a common functional gastrointestinal disorder without available efficient therapies. In this study, a decrease of Faecalibacterium prausnitzii presence has been observed in an IBS-like rodent model induced by a neonatal maternal separation (NMS) stress. Moreover, it was investigated whether F. prausnitzii may have an impact on colonic sensitivity. The A2-165 reference strain, but not its supernatant, significantly decreased colonic hypersensitivity induced by either NMS in mice or partial restraint stress in rats. This effect was associated with a reinforcement of intestinal epithelial barrier. Thus, F. prausnitzii exhibits anti-nociceptive properties, indicating its potential to treat abdominal pain in IBS patients