Showing papers by "Michael J. Rieder published in 2014"

Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

Abstract: OBJECTIVE To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. RESULTS Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. SIGNIFICANCE This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial

Abstract: Background: Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain. Methods: We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale — Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose. Results: We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre–post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) –0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI –0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ –0.1 [95% CI –0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI –0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points ( p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p Interpretation: We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective for outpatient pain management in children with uncomplicated fractures. Trial registration: ClinicalTrials.gov, no. NCT01690780.

Opioid Analgesia for Acute Abdominal Pain in Children: A Systematic Review and Meta‐analysis

Abstract: Objectives There are long-held concerns that analgesia in patients with acute abdominal pain may obscure the physical examination and lead to missing a diagnosis of appendicitis. Despite evidence to the contrary, analgesia continues to be underutilized and suboptimally dosed in children with acute abdominal pain. The objective of this systematic review and meta-analysis was to determine if opioids provide analgesia without an increase in side effects and appendicitis-related complications. Methods Trials were identified through electronic searches of MEDLINE (1946–2013), EMBASE (1980–2013), Cochrane Central Register of Controlled Trials (2013), CINAHL (1981–2013), and Google Scholar (2013). All randomized controlled trials (RCTs) of children aged 0–18 years with acute abdominal pain that compared any opioid analgesic to placebo were included. The methodologic qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration's Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system, respectively. Results Six RCTs met inclusion criteria, and each compared a single-dose parenteral opioid to a placebo, providing data on 342 children aged 5 to 18 years. The pooled mean pre/post difference in self-reported pain scores was 19.61 mm (95% confidence interval [CI] = –1.16 to 40.37 mm) lower in those receiving opioid analgesia. There was no significant increase in the risk of perforation or abscess associated with opioids in cases of appendicitis (relative risk [RR] = 1.03, 95% CI = 0.55 to 1.93). The risk of side effects was significantly greater in patients who received opioids (RR = 6.06, 95% CI = 1.10 to 33.49). Subtherapeutic dosing of opioids was detected in all six trials. Conclusions The use of opioids in undifferentiated acute abdominal pain in children is associated with no difference in pain scores and an increased risk of mild side effects. However, there is no increased risk of perforation or abscess. The overall quality of evidence is low, suggesting the need for larger, high-quality trials that are powered to detect both serious complications of appendicitis and determine the most efficacious opioid dosing for children.

Pharmacogenomics in children.

Abstract: Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision making process for children, notably in areas such as childhood cancer where the benefits and risks of therapy are considerable.

Measuring oral bioavailability of tacrolimus.

Abstract: In this issue of Pediatric Transplantation, Jacobo-Cabral et al. from Mexico City describe their work comparing the systemic bioavailability of two formulations of tacrolimus – the original Prograf (Astellas Pharma US, Northbrook, IL, USA) – and a Mexican non-innovator formulation, Limustin (1). They conclude that their data prove inferiority of the local Mexican product, as use of this drug results in lower systemic exposure. For a drug such as tacrolimus, which exhibits a narrow therapeutic range, suboptimal bioavailability may lead to serious consequences and even transplant failure (2). Previous studies have shown that impaired bioavailability may raise the risk of therapeutic failure (3). This is potentially an important finding that could directly impact patient care. However, before one accepts the authors’ conclusions, the sampling strategy used by the investigators must be examined carefully. For the benefit of readers unfamiliar with bioavailability studies, we will first briefly review the standard approach. To ensure that a generic compound is similar to the original compound in the systemic levels it produces, measurement of levels over time (so-called the area under the concentration–time curve, or AUC) needs to be within 20% of each other. In other words, the generic product can achieve anywhere between 80–120% of the AUC produced by the original drug. In a typical bioavailability study, the systemic exposure of formulation A and B has to be compared when the subjects serve as their own controls (3). This means that the same subject receives drug A and drug B. By so doing, one eliminates intersubject variability in absorption, distribution, and elimination of drug. Moreover, the subjects have to be randomized to receive first drug A or drug B, and after a washout period to receive the other formulation. These steps aim to ensure that there is no “order effect,” for example, if the first drug given induces the metabolism of the second formulation. None of these conditions were met in the study by Cabral et al. Each formulation was studied in a different group of children, and as the authors pointed out, the two groups differed in age, which may affect drug absorption. Moreover, the two groups differed in height, weight, and proportions of genetic polymorphism relevant to tacrolimus metabolism, all of which may affect the area under the concentration–time curve through differences in clearance rate. Furthermore, while Prograf was studied in 23 children, Limustin was studied in only nine, which increases the chance of error. The authors document that despite relatively similar dose per kg, the AUC and peak levels of tacrolimus achieved by Limustin were only half of what was achieved with Prograf. However, there is a major issue with this result: If this is correct, then the trough steady state levels with Limustin should have been half of the level with Prograf, as steady state trough levels are dependent on the AUC. So how then is it that the steady state trough levels were similar when the two formulations are compared? The answer to this enigma possibly lies in the dissolution data. Limustin dissolves more slowly than Prograf, resulting in a lower AUC over the sampling frame reported in this study, but possibly by the time of the next trough, the drug had the chance to dissolve fully and be absorbed, resulting in an equivalent steady state trough concentration. That is not to say that this study is unimportant, far from it. This study raises a very important question for all of us sharing the common goal of better therapy for children with renal disease. The claim that Limustin has inferior bioavailability is too serious to be determined based on the sampling strategy used in this study. Rather, bioequivalence should be carried out appropriately with children serving as their own controls, or if this cannot be carried out, then one should study this issue in adults where it is