Diclofenac In Children Research Articles

Proteomics‐informed physiologically‐based pharmacokinetic (PBPK) modeling revealed differential effects of UGT2B17 variability on the pharmacokinetics of diclofenac following intravenous and oral administration

Uridine 5′‐diphospho‐glucuronosyltransferase 2B17 (UGT2B17) demonstrates dramatic inter‐individual variability (>3000‐fold) in the activity and expression in humans, which is associated with age, sex, genotype, and ethnicity.1We recently found that diclofenac is a UGT2B17 substrate, however, the quantitative contribution of UGT2B17 in the metabolism and pharmacokinetics (PK) of diclofenac is not well studied. Moreover, we hypothesized that the higher intestinal abundance of UGT2B17 could further amplify the magnitude and variability in its in vivo PK. We first investigated diclofenac glucuronide (DG) formation kinetics in human liver microsomes (HLM) and human intestinal microsomes (HIM) that were isolated from human donors containing the deletion genotype and the highest‐expressor of UGT2B17 in our tissue bank. Diclofenac showed 4‐ and 16‐fold difference in maximum DG formation rate (Vmax) in UGT2B17 highest‐expressor versus deletion in HLM and HIM, respectively (Fig. 1). Proteomics‐informed PBPK modeling2 estimated the quantitative contribution (fm) of UGT2B17 in the intestinal and hepatic glucuronidation of diclofenac, which revealed fm of 0.77, 0.24, and 0.0 in the highest, average, and null UGT2B17 expressors, respectively. Interestingly, intestinal fm of UGT2B17 was 0.94, 0.90, and 0.0 in the highest, average, and null expressors, respectively. The organ‐specific changes in the fm were also substantiated by the predicted fraction gut escaped (fg), which was primarily associated with UGT2B17 abundance in the enterocytes. A PBPK model was first developed and validated in the UGT2B17 average expressor and then extended to other populations utilizing UGT2B17 abundance data. Predicted plasma levels (AUC) of diclofenac were 20 % and 100 % higher following an IV dose (50 mg) in UGT2B17 deletion versus the average and the highest expressor subjects, respectively. Similalry, after 50 mg oral dose, ~2‐fold and 8.5‐fold higher AUC was observed in UGT2B17 deletion as compared to that in the average and the highest UGT2B17 expressors, respectively. Sex differences in UGT2B17 abundance explained ~2‐fold higher diclofenac AUC in females after oral administration. In summary, the unique intestinal abundance and the highly prevalent gene deletion of UGT2B17 could likely contribute to the variable bioavailability of its substrate drugs. Similarly, poor metabolism of diclofenac in children and in UGT2B17 deletion subjects could predispose these patients to high GI discomfort.References Bhatt et al., Drug Metab. Dispos. (2018). Parvez Md M et al., Drug Metab. Dispos.(2021).

Intravenous Acetaminophen vs Intravenous Diclofenac Sodium in Management of Skeletal Vaso-occlusive Crisis Among Children with Homozygous Sickle Cell Disease: A Randomized Controlled Trial

To compare the efficacy of intravenous acetaminophen and intravenous diclofenac sodium in the management of skeletal vaso-occlusive crisis among children with sickle cell disease. Single blind randomized controlled trial. Tertiary care hospital. 104 children with sickle cell disease and skeletal vaso-occlusive crisis. Intravenous acetaminophen at 10mg/kg/dose 8 hourly and intravenous diclofenac sodium at 1mg/kg/dose 8 hourly in 1:1 ratio. Reduction in pain score (50%), number of doses needed to relieve pain after 24 hours of drug administration and decrease in pain score at 1 hour. A 50% reduction in pain score was seen in 35 (77.3%) and 10 (21.7%) children among acetaminophen and diclofenac sodium groups respectively (RR, 95% CI 3.6; 2.02-6.33, P< 0.001). The mean (SD) fall in pain score at 1 hour was significantly higher among intervention arm as compared to control arm [1.51 (0.5) and 1.06 (0.5); P<0.001]. Eight (17.4%) patients developed local phlebitis at the site of infusion among diclofenac group. Intravenous acetaminophen is a better alternative to intravenous diclofenac in children with skeletal vaso-occlusive crisis.

Comparing the Efficacy of Postoperative Diclofenac Suppository with Intramuscular Diclofenac in Children under going Inguinal Hernia Surgery

Objective: To compare the analgesic effect of postoperative Diclofenac suppository with intramuscular Diclofenac in children undergoing inguinal hernia surgery. Methodology: This study was held in Paeds Surgery Department, Nishtar Hospital Multan, Bahawal Victoria hospital Bahawalpur. from August 2018 to March 2019. Total no. of 160 patients were divided into two groups, one receiving diclofenac suppository group DS and the other which was group DI received intramuscular diclofenac injection. Numerical variables like age and weight were analyzed statistically by taking their mean and standard deviation while the outcome variable i.e. severity of pain was assessed through facial expressions as no pain, mild, moderate and severe pain in frequency percentage at 0, 2 and 4 hours interval. Results: Total 160 patients were divided into 2 groups equally, 80 in each (DS &amp; DI). There was no significant difference in the efficacy of diclofenac suppository and diclofenac intramuscular when calculated at 0, 2 and 4 hours interval. When Chi-Square was applied to determine the association, it was observed that pain severity was significantly associated with age. But the association of pain severity with weight and with time intervals in two groups was not statistically significant. Conclusion: From this study we conclude that there is no significant difference between the postoperative analgesic effect of either suppository or intramuscular diclofenac but suppository route has an advantage over intramuscular in that it is easier and safer, less prone to injury, easy to administer and has longer duration of action, especially preferable in pediatric patients. Keywords: Children, diclofenac Sodium, inguinal Hernia, intramuscular, suppository DOI: 10.7176/JMPB/65-05 Publication date: April 30 th 2020

Diclofenac pharmacokinetic meta‐analysis and dose recommendations for surgical pain in children aged 1–12 years

Diclofenac is an effective, opiate-sparing analgesic for acute pain in children, which is commonly used in pediatric surgical units. Recently, a Cochrane review concluded the major knowledge gap in diclofenac use is dosing information. A pharmacokinetic meta-analysis has been undertaken with the aim of recommending a dose for children aged 1-12 years. Studies containing diclofenac pharmacokinetic data were identified during a Cochrane systematic review, and authors were asked to provide raw data. A pooled population analysis was undertaken in NONMEM to define the pharmacokinetics of intravenous, oral, and rectal diclofenac in children. Simulations were performed to recommend a dose yielding an equivalent area under diclofenac concentration-time curve (AUC) to a 50-mg dispersible tablet in adults. Data from 111 children aged 1-14 years consisting of 375 samples following intravenous, oral suspension, and suppositories were used. Adult dispersible tablet and suspension data were added to provide a reference AUC and support the absorption modeling, respectively. A three-compartment model described disposition, a dual-absorption compartment model was used for suspension and dispersible tablet data, and single-absorption compartment model for suppositories. The estimate of clearance was 16.5 l·h(-1) ·70 kg(-1) and bioavailabilities were 0.36, 0.63, and 0.35 for suspension, suppository, and dispersible tablets, respectively. Single doses of 0.3 mg·kg(-1) for intravenous, 0.5 mg·kg(-1) for suppositories, and 1 mg·kg(-1) for oral diclofenac in children aged 1-12 years are recommended as they yield a similar AUC to 50 mg in adults.

Prospective observational study of adverse drug reactions to diclofenac in children.

The aim of this study was to investigate the type of common (occurring in >1% of patients) adverse reactions caused by diclofenac when given to children for acute pain. A prospective observational study was undertaken on paediatric surgical patents aged < or =12 years at Great Ormond Street and University College London Hospitals. All adverse events were recorded, and causality assessment used to judge the likelihood of them being due to diclofenac. Prospective recruitment meant not all patients were prescribed diclofenac, allowing an analysis of utilization. Causality of all serious adverse events was reviewed by an expert panel. Children prescribed diclofenac were significantly older, and stayed in hospital for shorter periods than those who were not. Diclofenac was not avoided in asthmatic patients. Data on 380 children showed they suffer similar types of nonserious adverse reactions to adults. The incidence (95% confidence interval) of rash was 0.8% (0.016, 2.3); minor central nervous system disturbance 0.5% (0.06, 1.9); rectal irritation with suppositories 0.3% (0.009, 1.9); and diarrhoea 0.3% (0.007, 1.5). No serious adverse event was judged to be caused by diclofenac, meaning the incidence of serious adverse reactions to diclofenac in children is <0.8%. Children given diclofenac for acute pain appeared to suffer similar types of adverse reactions to adults; the incidence of serious adverse reaction is <0.8%.

Diclofenac readily penetrates the cerebrospinal fluid in children

Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans. Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg(-1), sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h. The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children. A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg(-1). Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection. In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 microg l(-1). At 5.5 h the CSF concentration was 0.1 microg l(-1), and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 microg l(-1) (range 70-272 microg l(-1)). No serious or unexpected adverse effects were reported. Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

Prospective randomised controlled trial comparing rectal versus oral paracetamol and diclofenac in children following appendicectomy

Summary The analgesic efficacy and pharmakokinetics of paracetamol and diclofenac are similar. We have studied the pain reported by patients and the acceptability of the modes of analgesia of 31 paediatric patients undergoing appendicectomy. No significant difference in pain scores or need for rescue analgesia was found. The oral route was preferred.

French guidelines for the diagnosis and management of migraine in adults and children

BackgroundThe French Recommendations for Clinical Practice: Diagnosis and Therapy of Migraine are guidelines concerning the overall management of patients with migraine, including diagnostic and therapeutic strategies and assessment of disability. ObjectiveThis article summarizes the guidelines as they apply to adults and children, and proposes future direction for steps toward optimal treatment of migraine in patients in France. MethodsThe recommendations were categorized into 3 levels of proof (A—C) according to the National Agency for Accreditation and Evaluation in Health (ANAES) methodology and were based on a professional consensus reached among members of the Working Group and the Guidelines Review Group of the ANAES. ResultsThe International Headache Society diagnostic criteria for migraine should be used in routine clinical practice. Recommended agents for the treatment of migraine in adults include nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) monotherapy or in combination with metoclopramide, acetaminophen monotherapy, triptans, ergotamine tartrate, and dihydroergotamine mesylate. Patients should use the medication as early as possible after the onset of migraine headache. For migraine prophylaxis in adults, the following can be used: propranolol, metoprolol, oxetorone, or amitriptyline as first-line treatment, and pizotifen, flunarizine, valproate sodium, or topiramate as second-line treatment. Migraine in children can be distinguished from that in adults by shorter duration (2–48 hours in children aged <15 years), more frequent bilateral localization, frequent predominant gastrointestinal disturbances, and frequent pallor hailing the onset of the attack. The following drugs are recommended in children and adolescents: ibuprofen in children aged >6 months, diclofenac in children weighing >16 kg, naproxen in children aged >6 years or weighing >25 kg, ASA alone or in combination with metoclopramide, acetaminophen alone or in combination with metoclopramide, and ergotamine tartrate in children aged >10 years. ConclusionsThese guidelines are intended to help general practitioners to manage migraine patients according to the rules of evidence-based medicine.

Diclofenac and metabolite pharmacokinetics in children.

Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children. Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability. Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26. The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1) 70 kg(-1)). The rectum is a suitable route for administration of diclofenac in children 2-8 year of age and was associated with a higher relative bioavailabilty than enteric-coated tablets and an earlier maximum concentration (50 vs. 108 min). This pharmacokinetic profile renders diclofenac suppository a suitable formulation for short duration surgery.

Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine

We studied 80 children, aged 5-13 yr, who received PCA with morphine after appendicectomy using a standardized tracheal general anaesthetic. All patients received morphine 0.1 mg kg-1 before surgical incision and all had wound infiltration with bupivacaine 1 mg kg-1 at the end of surgery. Patients were allocated randomly to receive postoperative analgesia with PCA morphine alone, morphine plus diclofenac 1 mg kg-1, morphine plus paracetamol 15-20 mg kg-1 or morphine plus a combination of both diclofenac and paracetamol. Cumulative morphine consumption was significantly reduced by concurrent administration of diclofenac but no additive effect of paracetamol was demonstrable with the doses used in the study. Analgesia, as assessed by movement pain scoring, was significantly improved by the addition of diclofenac despite lower morphine consumption. Adverse effects and duration of PCA were comparable in the four groups.

Postoperative pain in children.

An audit project was designed to assess and improve the provision of postoperative analgesia in a children's hospital. Pain assessment for all children and analgesia standards for our institution were introduced prior to data collection. Data were collected on consecutive samples of 316 and 325 children undergoing surgery as inpatients during 10-week periods. Change was initiated between the two periods in response to our findings; our action plan involved education, changes to documentation, the widespread use of diclofenac in children over 2 years of age and recommendations for the prescription of analgesia. The initial prescription of analgesia increased from 95% to 98% (p = 0.019), administration of analgesia to children experiencing bad or severe pain increased from 57% to 71% (p = 0.032) and the number of children experiencing severe pain reduced from 17% to 11% (p = 0.050). Application of audit, by a clinical nurse specialist, enabled us to achieve and demonstrate improvements in the prescription, administration and effectiveness of postoperative analgesia.

The effect of a combination of rectal diclofenac and caudal bupivacaine on postoperative analgesia in children

Both caudal anaesthesia and non-steroidal anti-inflammatory drugs have been used in the management of postoperative pain in children. The aim of the present study was to evaluate the combination of caudal analgesia and rectally administered diclofenac in the treatment of pain following minor surgery in children. Thirty-nine, ASA grade 1 or 2, children undergoing inguinal or penoscrotal surgery were randomly assigned to receive either a caudal block using 0.125% bupivacaine with adrenaline or a similar caudal block in combination with rectally administered diclofenac 1 mg.kg-1. Children given a caudal block alone were more likely to need analgesia in the first 24 h postoperatively. It would appear that the combination of a caudal block and rectal diclofenac in children undergoing minor lower abdominal surgery reduces the need for subsequent analgesia.