The threats involved in the long‐term opioid treatment of chronic non‐cancer pain (CNCP) have increased notably. Strategies to identify at‐risk patients are important because there is no clear ...evidence showing which screening or deprescription programmes are appropriate. Our aim was to evaluate the evidence provided by pharmacogenetics applied to predict an analgesic toxicity profile in prescription opioid use disorder (POUD) patients participating in an opioid deprescription programme. Pharmacogenetic markers were analysed in an observational, prospective deprescription programme for POUD patients (n = 88) treated for CNCP. It consisted of monitoring visits (baseline, follow‐up and final), opioid rotation or discontinuation and the recording of adverse events and suspected adverse drug reactions (ADRs). Variants in OPRM1 (A118G), ABCB1 (C3435T), COMT (G472A), OPRD1 (T921C) and ARRB2 (C8622T) genes were tested by real‐time PCR. Ethics committee approved the study. Wild‐type OPRM1‐AA genotype carriers reported a significantly higher number of adverse events than OPRM1‐AG/GG (median p25‐75, 7 5‐11 vs 5 3‐9), particularly gastrointestinal system events (90% vs 63%) such as nausea (33% vs 0%). Suspected ADRs (affecting 17% of the patients) were three times higher in males than in females (30% vs 11%). The deprescription programme was effective and safe, and it achieved a significant progressive reduction in the morphine equivalent daily dose, strong opioids and other analgesics' use, without causing any changes in pain intensity or opiate abstinence syndrome. OPRM1 gene polymorphisms could identify the risk of gastrointestinal adverse events in POUD patients. Deprescription programmes including pharmacogenetic analysis should be considered during the follow‐up of this population.
Screening for opioid use disorder should be considered in chronic non‐cancer pain (CNCP) patients with long‐term use of opioids. The aim of our study was to assess the effectiveness of an ...individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid‐dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real‐time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118‐AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid‐dependent patients, with good conversion to buprenorphine that was more pronounced in 118‐AA OPRM1 patients.
Screening for opioid use disorder should be considered in patients with long‐term use of opioids. This study assessed the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence in chronic non‐cancer pain (CNCP) patients that included screening of pharmacogenetic markers to help predict response to the ITP.
Liver cirrhosis is the end stage of many different chronic liver diseases and is becoming an important cause of mortality and morbidity across the world. In theory, the numerous physiopathological ...changes suffered by these patients warrant relevant pharmacokinetic changes in most drugs. However, the influence of these changes on the efficacy and toxicity responses of patients with cirrhosis have been evaluated by few clinical trials and observational studies. As a consequence, therapeutic decisions in these patients are usually complex and subject to uncertainties. In this article, we review the regulatory guidelines to study responses to drugs according to pharmacokinetic variability and the published information that is useful for guiding the dosage adjustment of frequently used drugs in patients with cirrhosis (antivirals, antibiotics, analgesics, etc.) to obtain the best risk-benefit ratio.
Abstract Background/Aims: Morphine has been contraindicated for pain treatment in acute pancreatitis because of its presumed opioid-induced sphincter of Oddi dysfunction. However, scientific evidence ...supporting a deleterious influence on the clinical course is absent. This pilot study was undertaken to evaluate the efficacy and adverse events of metamizole versus morphine in acute pancreatitis. Methods: 16 patients with acute pancreatitis were randomized to receive 10 mg/ 4 h s.c. (n = 8) morphine or 2 g/8 h i.v. (n = 8) metamizole. Pain scores were recorded every 4 h during 48 h after admission by a Visual Analogue Scale. Pethidine was additionally administered as a rescue therapy. Results: 75% of patients achieved pain relief in the metamizole group versus 37.5% in the morphine group within 24 h of hospitalization (6/8 vs. 3/8; p: n.s.).The mean time to achieve pain relief was shorter in the metamizole group (10 ± 6.6 vs. 17 ± 18.3 h; p: n.s.). At the end of the study, 75% of patients achieved pain relief in the metamizole group versus 50% in the morphine group. Three patients in each group needed pethidine: 2 out of 3 achieved pain control in the metamizole group vs. 0 out of 3 in the morphine group. Conclusions: Intravenous metamizole shows a non-significant association with a quicker pain relief than morphine s.c. in acute pancreatitis. A larger randomized controlled trial should be desirable to confirm this result.
How can we treat patients with reduced morphine doses without loosing the pain killing effect or morphine antinociceptive effects (MAE)? To address this question, we hypothesized that serotonin ...(5-HT2) receptor antagonism could enhance MAE mediated by kappa-opioid receptors. We pretreated mice with ketanserin, a 5-HT2 receptor antagonist, and measured the morphine dose required to observe analgesia. The morphine dose effective in 50% of animals (ED
50) was reduced from 4.7 to 1.3
mg/kg, and the morphine dose effective in 100% of animals (ED
max) from 13.7 to 2.5
mg/kg. Ketanserin has a similar enhancer effect when morphine, which has a dual role via mu and kappa receptors, was substituted by the antinociceptive spiradoline, a selective κ-opioid agonist. At a morphine dose of 3.5
mg/kg, 30% of the mice showed antinociceptive behaviour, rising to 100% when ketanserin was co-administered and then reduced to 20% in the presence of nor-binaltorphimine, a kappa-opioid receptor antagonist. Our data strongly suggests a serotonergic inhibition of the kappa-opioid component of MAE and the possibility that this serotonergic inhibition could be reversed through 5-HT2 receptor antagonism.
We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on ...Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioequivalence study. Significant increases were found in
CYP2C9*3 alleles vs. *1 and *2 in AUC
0–∞ (median (min–max)): 256 (230–516) vs. 150 (100–268) and 169 (124–197)
μg
h/mL (
p
<
0.01) and half-life time (
t1/2) 102 (79–36) vs. 56 (45–94) and 64 (60–80)
h (
p
<
0.01). Non-significant differences were observed in
C
max 1.9 (1.8–2.9) vs. 2.4 (1.7–3.4), 2.5 (1.6–2.9)
μg/mL or in according to CYP2C8 alleles presence.
CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioequivalence studies (AUC
0–∞,
t1/2) may be influenced by the presence of
CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile.
Aliment Pharmacol Ther 31, 1337–1345
Summary
Background Drug‐induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) ...elevations in clinical trials and published case reports.
Aim To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting.
Methods Hepatotoxic drugs were identified from product labelling and classified in high‐medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (ID) and placebo (IC) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE.
Results The median IC was 10/1000. The high‐medium‐risk drugs’ median ID was significantly higher compared with low‐risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi‐squared test, absolute difference and odds ratio comparing ID and IC identified 35%, 51% and 77% of high‐medium‐risk drugs respectively. Less number of case reports were associated with low‐ than high‐medium‐risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (ID vs. IC) was the strongest predictor of published DILI case reports.
Conclusion A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.
Summary
Aim : To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis.
Methods : Oral acetaminophen (1000 mg) was administered to seven ...healthy subjects and 14 patients with cirrhosis (nine Child‐Pugh A or B and five Child‐Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC.
Results : Patients showed a higher mean area under the curve concentration‐time (67.4 ± 22.4 mg h/L vs. 38.8 ± 4.3 mg h/L; P = 0.01), a lower clearance (166.7 ± 85.0 mL/min vs. 367.8 ± 62.5 mL/min; P = 0.01) and higher elimination half‐life (3.8 ± 1.1 h vs. 2.0 ± 0.4 h; P = 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage.
Conclusions : Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.
Background The aim of this study was to determine compliance with published good practice guidelines for gender and clinical trials using etoricoxib. The rationale for choosing etoricoxib was that it ...is widely used by women and there is evidence of potential interaction with contraceptives and hormone replacement therapy as highlighted in the product characteristics. Methods The study reviewed 58 etoricoxib published trials (54 papers) to determine if they met the gender recommendations of the Guidelines of Food and Drug Administration (1993) and the Sex, Gender and Pain Special Interest Group Consensus Working Group Report (2007). Results Women formed 70% of a total of 49 835 subjects included in the etoricoxib trials, but only 31% of the subjects were in Phase I. About 85.7% of trials did not show sex-stratified data. About 90.6 and 93.3% did not provide efficacy and adverse effects data by sex, respectively. There is scarce information about the influence of issues that specifically affect women. Discussion Women are under-represented in the published etoricoxib trials, specifically, in Phase I. Sex-stratified data on efficacy and adverse effects are scarce in etoricoxib trials. Together with the lack of data on women-specific issues, this suggests that etoricoxib may pose the same potential problems for women as other cyclooxygenase-2 inhibitors.
Resumen: Los estudiantes de medicina necesitan adquirir una serie de conocimientos, habilidades y actitudes que les capaciten para el desempeño de la medicina. La facultad de Medicina de la ...Universidad Miguel Hernández de Elche incluyó en su plan de estudios del Grado en Medicina 4 asignaturas denominadas «talleres integrados» en las que se desarrollan diversas actividades docentes para integrar conocimientos y habilidades clínicas de varias disciplinas y fomentar la adquisición de competencias transversales. En este artículo describimos la organización y métodos didácticos empleados en la asignatura «Talleres integrados II» como un elemento de reflexión para compartir la experiencia con la comunidad educativa en medicina. Esta asignatura integra las siguientes materias: bases generales de la cirugía, farmacología clínica, patología general, inmunología y alergia, dermatología, epidemiología y demografía sanitaria, microbiología, obstetricia y oftalmología. Es una asignatura con 4,5 créditos prácticos y utiliza elementos docentes como práctica hospitalaria guiada por objetivos, participación de alumnos y talleres prácticos, simulación, prueba evaluación de competencias objetiva estructurada, y presentación clínica en formato Pecha Kucha, lo que potencia la integración de conocimientos y el aprendizaje activo con adquisición de competencias y habilidades prácticas muy pertinentes para el futuro médico. Abstract: Medical students need to acquire a range of knowledge, skills, and attitudes that will prepare them for medical clinical practice. The School of Medicine of Miguel Hernández University (Elche, Spain) includes, in its Medical Degree curriculum, 4 subjects called “Talleres integrados” (Integrated Workshops-II). Diverse teaching activities are developed to integrate knowledge and clinical skills of several disciplines, and to promote the acquisition of transversal skills. A description is presented of the organisation and didactic methods used in the Integrated Workshops-II subject as an element for reflection and to share the experience with the educational community in medicine. This subject integrates the following: general bases of surgery, clinical pharmacology, general pathology, immunology and allergy, dermatology, epidemiology and health demography, microbiology, obstetrics and ophthalmology. It is a subject with 4.5 practical credits and uses teaching elements such as hospital practice guided by objectives, student participation and practical workshops, simulation, objective structured clinical examination (OSCE), and presentation of cases in Pecha Kucha format, all of which enhances the integration of knowledge and active learning with acquisition of skills and practical skills very pertinent for the future doctor. Palabras clave: Talleres integrados, Enseñanza, Medicina, Competencias, Evolución Clínica Objetiva Estructurada, Portafolio, Keywords: Integrated workshops, Teaching, Medicine, Competencies, Objective Structured Clinical Examination, Portfolio
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