Prevention of post-mastectomy neuropathic pain with memantine: study protocol for a randomized controlled trial

International audienceBackground: N-methyl-D-aspartate receptor antagonists are potential therapies for neuropathic pain, and memantine has a good tolerance profile. A preclinical study recently reported that presurgery memantine may prevent neuropathic pain development and cognition dysfunction. Considering the high prevalence of breast cancer and of post-mastectomy neuropathic pain, a clinical trial is carried out to evaluate if memantine may prevent neuropathic pain development and maintain cognitive function and quality of life in cancer patients. Methods/Design: A randomized clinical trial (NCT01536314) includes 40 women with breast cancer undergoing mastectomy at the Oncology Hospital, Clermont-Ferrand, France. Memantine (5 to 20 mg/day; n = 20) or placebo (n = 20) is administered for 4 weeks starting 2 weeks before surgery. Intensity of pain, cognitive function, quality of life and of sleep, anxiety and depression are evaluated with questionnaires. The primary endpoint is pain intensity on a 0 to 10) numerical scale at 3 months post-mastectomy. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α = 0.05. Discussion: The hypothesis of this translational approach is to confirm in patients the beneficial prophylactic effect of memantine observed in animals. Such a protective action of memantine against neuropathic pain and cognitive dysfunction would greatly improve the quality of life of cancer patients. Trial registration: ClinicalTrials.gov: NCT01536314 on 16 February 201

The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

International audienceBackground: Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.Methods and results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain

Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids

Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (+/- SEM) age 74 +/- 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation

Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: an fMRI study

IntroductionThis randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored.MethodsThe study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28.ResultsBased on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) −0.46 (−0.91; −0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042].ConclusionSupplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus

Circulating human serum metabolites derived from the intake of a saffron extract (Safr’Inside™) protect neurons from oxidative stress: Consideration for depressive disorders

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr’Inside™ ) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron’s metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression

<p>Ketamine and depression: a narrative review</p>

International audienceInflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15–45 mg of TNBS) in 30 rats, whereas the control rats ( n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity ( P = 0.03), 2) an increased colon weight-to-length ratio ( P = 0.01), 3) higher inflammatory and fibrosis scores ( P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production ( P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae. NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management

Les antalgiques et la personne âgée (du mécanisme d'action à la dispensation)

En France, la population des plus de 65 ans augmente et ceci s'accentuera dans les prochaines années. De nombreuses prescriptions médicales comportent des antalgiques car la douleur est une composante importante chez le sujet âgé ce qui est corrélé à la consommation d'antalgiques. Cette thèse de pharmacie a pour but d'une part de revoir la littérature sur les antalgiques de manière générale et aussi les points pertinents de la consommation d'antalgiques chez les personnes âgées. D'autre part, une enquête effectuée sur un mois en pharmacie d'officine d'une ville de plus de 12 000 habitants a permis de montrer le risque potentiel d'interactions médicamenteuses et de proposer des conseils et des alternatives que le pharmacien pourra utiliser au quotidien à l'officine.CLERMONT FD-BCIU-Santé (631132104) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Recherche d'une interaction pharmacodynamique entre le paracétamol et le tropisétron chez des patients en postopératoire

L'objectif de notre étude est de confirmer en période postopératoire d'une chirurgie légère de l'oreille, l'interaction pharmacodynamique entre le paracétamol et le tropisétron se traduisant par une diminution de l'effet analgésique du paracétamol. Il s'agit d'une étude monocentrique, randomisée, contrôlée et réalisée en double aveugle avec accord du CPP Sud-Est VI. Après recueil de leur consentement éclairé, quarante patients caucasiens devant bénéficier d'une chirurgie pour otospongiose ou cholestéatome ont été inclus dans l'étude de juin 2008 à juin 2009 dans le service d'oto-rhino-laryngologie du CHU de Clermont-Ferrand. Le critère de jugement principal est l'échelle numérique simple utilisée pour la cotation de la douleur. Le score de douleur est recueilli toutes les 30 minutes pendant les 4 heures suivant le réveil du patient. Les 2 groupes sont homogènes en terme de données démographiques et opératoires. La moyenne des sommes des scores d'évaluation numérique (SUMNS) est 39% plus élevée dans le groupe tropisétron (8,72 +- 10,14) par rapport au groupe placebo (6,25 +- 7,04). Cependant, il n'y a pas de différence statistiquement significative entre les 2 groupes (p=0,759). Cette étude ne permet donc pas de démontrer une inhibition de l'effet antalgique du paracétamol par le tropisétron. Une étude complémentaire prenant en compte les limites de notre essai est probablement souhaitable pour valider l'hypothèse d'une interaction pharmacodynamique entre le paracétamol et le tropisétron.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Kétamine et douleur chronique : une revue narrative de son efficacité et sécurité

International audienc