127 Impact of CYP2D6, CYP3A4, and CYP2C9 pharmacogenomic profile on pain relief and adverse events in Canadian children treated with oxycodone and ibuprofen

Primary Subject area Clinical Pharmacology and Toxicology Background Genomic variation impacts drug pharmacokinetics for commonly used children’s pain medications such as oxycodone and ibuprofen. In order to personalize and best treat children’s pain, how cytochrome enzyme polymorphisms for CYP2D6, CYP3A4, and CYP2C9 impact clinical effectiveness and safety for oxycodone and ibuprofen were studied. Objectives Primary objectives were to evaluate if allelic variations of CYP2D6, CYP2C9, and CYP3A4 would a) alter clinical effectiveness of ibuprofen and oxycodone for pain relief, and b) impact the occurrence of adverse events. Secondary objectives were to determine the degree to which these genetic and other clinical factors influence analgesic effectiveness and safety. Design/Methods This prospective, observational cohort included children aged 4-16 years who were seen in a pediatric emergency department (between June 2010 - July 2014) with an acute fracture and used ibuprofen OR oxycodone for at-home pain management. Saliva samples were obtained prior to discharge, and daily telephone follow-up collected self-reported pain scores, medication use, adverse events, and functional limitations for 3 days. Genotyping identified allelic variants of CYP2D6, CYP3A4, and CYP2C9. Pain was measured using the Faces Pain Scale-Revised. CYP2D6 metabolic phenotypes were determined based on identified variants. Regression analyses were employed to determine relationships between clinical and genomic patient characteristics, pain relief, and adverse events. Results We included 210 children (n=140 ibuprofen, n=70 oxycodone); mean age was 11.1 (±3.5) years, 66.2% were male, and 79.5% self-identified as Caucasian. The median pain reduction in the ibuprofen group was 4 (±2.0) and 4 (±3.5) in the oxycodone group on Day 1 (p = 0.69). Adverse events were experienced by 53.2% of the ibuprofen group and 78.3% of the oxycodone group (p < 0.001). CYP2D6 Intermediate Metabolizers had significantly less pain relief using oxycodone than Extensive Metabolizers (p = 0.04). CYP3A4 variants did not significantly impact pain relief or adverse events. Those with the decreased functioning CYP2C9*2 allele experienced less adverse events compared to the normal functioning allele CYP2C9*1 (p = 0.003) when using ibuprofen. Males (p = 0.035) and all children using non-pharmacological pain strategies (p = 0.02) experienced less pain relief with oxycodone. Conclusion A better understanding of pharmacogenomic variation could help personalize medication choice. Sex and non-pharmacologic pain management impact pain relief with oxycodone, warranting further study to better understand their relationship with opioid pain relief in children.

Comparison of intravenous ibuprofen and intravenous ketorolac effectivity for non-specific acute musculoskeletal pain

Acute musculoskeletal pain is an illness of muscle, bone, joint, and muscle tissue that is caused by an injury or inflammation. Ibuprofen and Ketorolac are Non-Steroid Anti-Inflammatory Drugs or NSAID that are usually used for non-specific acute musculoskeletal pain. The purpose of the study is to compare the pain relief of non-specific acute musculoskeletal pain between intravenous Ibuprofen and intravenous Ketorolac therapy. This study uses a quasi-experimental, non-randomized, non-equivalent, active comparator, open-label study. The total sample for this study is 60 subjects, divided into two groups (n-30), subjects are required by using purposive sampling. Pain measured by Numeric Pain Scale. The mean baseline of the pain intensity were 63.33 ± 8.841 for the Ibuprofen group and 59.33 ± 12.847 for the Ketorolac group. There was not any differences between both of group (p = 0.107) after the medication were given all measurement shows significant differences between two groups (p = <0.05) that Ibuprofen group shows better results. Intravenous Ibuprofen has better effectivity rather than intravenous Ketorolac as a treatment of non-specific acute musculoskeletal pain.

Longer-Term Omega-3 LCPUFA More Effective Adjunct Therapy for Tuberculosis Than Ibuprofen in a C3HeB/FeJ Tuberculosis Mouse Model

Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.

Effect of Local Dexamethasone on Pain, Swelling, and Trismus After Extraction of Impacted Mesioangular Third Molar

Background: Pain and inflammation are common problems after the third molar surgery. The purpose of this study was to compare the effect of ibuprofen and intra-muscular injection or the intra-socket placement of dexamethasone on pain, swelling, and trismus after the extraction of impacted third molar. Methods: In this triple-blind randomized clinical trial study, 72 eligible patients were randomly divided into four groups of 18 subjects. The groups received dexamethasone powder (4 mg) inside the alveolar socket immediately before flap suturing, injection in the masseter muscle (4 mg/1 mL) immediately after the suture, the ibuprofen tablet from an hour before the surgery (400 mg every 6 hours for 1 day), and placebo. Three parameters of pain severity, swelling, and trismus were evaluated on the second and seventh days after the surgery. Data were analyzed using SPSS 17. Qualitative and quantitative data were expressed as a percentage and mean ± standard deviation, respectively. Chi-square, one-way analysis of variance (ANOVA) and, if necessary, the least significant difference tests were used for inter-group comparison. The findings were significant at P<0.05 Results: Dexamethasone groups had significantly lower pain severity (second and seventh days), swelling (second day), and maximum mouth opening (MMO, alveolar socket: second and seventh days, masseter: second day) in comparison to the other groups (P<0.05). The ibuprofen group had significantly lower levels of pain (second and 7th days) and swelling (second day) in comparison to the control group (P<0.05). There was no significant difference between dexamethasone groups in any measurement for pain, swelling, and MMO. Conclusions: The findings of this study suggest that the intra-oral administration of dexamethasone may have a better effect on pain, swelling, and trismus compared to ibuprofen and has no placebo effect.

The Effect of Single or Multiple Doses of Grapefruit Juice on the Analgesic Effect of Ibuprofen in Mice

Grapefruit juice (GFJ) is a rich source of nutritional compounds but has been shown to alter the concentrations of several clinically useful drugs. Ibuprofen is a commonly used over-the counter-drug. Aim: This study aims to examine the effect of a single or multiple dose of GFJ on the analgesic effect of ibuprofen. Methodology: CD1 male mice were randomly distributed into four equal groups (n=9, each). The first group served as a control, the second group was given ibuprofen (100 mg/Kg) by oral gavage, the third group was given a single dose of GFJ (10 mg/Kg) by oral gavage followed by ibuprofen, and the fourth group was given a single dose of GFJ for five days and on the fifth day was given ibuprofen. The analgesic effect was tested using two methods with different mechanisms: thermal (hot plate) and chemical (acetic acid-induced abdominal constriction) pharmacologic stimuli models. Results: Both GFJ dosing regimen significantly increased the duration of abdominal constriction test when compared with ibuprofen group and did not exert any significant effect on the hot plate effect. This suggest that GFJ may affect the peripherally modulated analgesic effect of ibuprofen. Conclusion: The observed effect of GFJ on ibuprofen analgesic effect warrants further studies on their impact and clinical significance on humans.

Paracetamol vs Ibuprofen in Hemodynamically Significant Patent Ductus Arteriosus (HsPDA) in Preterms: A Randomized Controlled Trial

Background and Objective: Hemodynamically significant patent ductus arteriosus (HsPDA) is a common cause of morbidity in preterm infants. Indomethacin and Ibuprofen, which are cyclo-oxygenase (COX) 1, 2 inhibitors are commonly used drugs for closure of HsPDA. As, Ibuprofen has several contraindications, we designed study using oral paracetamol (a peroxidase inhibitor) and compared with oral ibuprofen, for efficacy and safety in relation to closure of HsPDA in preterm infants. Methods: 140 preterm infants (gestational age less than 32 weeks) with HsPDA (confirmed by 2D Echo) were randomly assigned in two groups and received first course of either oral paracetamol (70) or ibuprofen (70). The need for a second course was determined by 2D Echo evaluation. Parameters studied were rate of ductal closure, any adverse effects and discharge rate. Results: Both groups were similar in term of ductal closure after first course (p=0.46) and second course (p=0.59). However, 22 from Ibuprofen group and only 2 from PCM group developed adverse effects (p<0.001). From paracetamol group 58 were discharged, and 12 died; while from ibuprofen group 46 discharged, 24 died (p=0.03). Conclusion: Paracetamol for HsPDA in preterm neonates was associated with good efficacy and better safety; and less deaths, as compared to ibuprofen.

P6591Arrhythmogenic effects of non-steroidal anti-inflammatory drugs (NSAID)

Background Clinical and experimental data suggest potential deleterious effects of non-steroidal anti-inflammatory drugs (NSAID) in cardiac disease. The aim of the present study was to characterize potential direct arrhythmogenic effects of ibuprofen or indometacin on cardiac electrophysiology. Methods and results In 13 isolated rabbit hearts, indometacin was administered in increasing concentrations (10, 30 and 50μM) after obtaining baseline data. In further 13 hearts, ibuprofen was infused (10, 30 and 50μM). Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant decrease of QT-interval in indometacin- (50μM: −60ms, p<0.05) and ibuprofen-treated hearts (50μM: −81ms, p<0.01). This was accompanied by a similar decrease of action potential duration (APD). Effective refractory period (ERP) was also reduced by indometacin (−24ms, p<0.05) and ibuprofen (−22ms, p<0.05) while spatial dispersion of repolarisation remained stable with both drugs. Programmed ventricular stimulation and burst stimulation were employed for provocation of ventricular arrhythmias. In the indomethacin group 7 episodes of ventricular arrhythmias were inducible at baseline. The incidence was increased to 22 (10μM), 37 (30μM) and 51 (50μM) with higher concentrations of indometacin. In the ibuprofen group 15 episodes were inducible at baseline. After infusion of 10μM ibuprofen, also 15 episodes of ventricular arrhythmias occurred while 34 episodes were inducible with 30μM ibuprofen. Conclusion Infusion of the NSAID ibuprofen and indometacin resulted in a significant abbreviation of myocardial repolarization and a shortening of ventricular refractory periods. This resulted in an enhanced inducibility of ventricular arrhythmias and may contribute to the proposed deleterious effects of NSAID in the presence of cardiac disease.

Pain Management After Surgical Tonsillectomy: Is There a Favorable Analgesic?

The aim of this study was to examine how ibuprofen and paracetamol prevent pain after cold-steel extracapsular tonsillectomy in children. Also, we examined the relation between age, gender, nausea, postoperative bleeding, antibiotic use, type of diet, and postoperative pain intensity and the type of administered analgesic. A prospective study was conducted on 147 children (95 males and 52 females, aged 7-17 years) who underwent tonsillectomy in the Clinical-Hospital Center “Dragiša Mišović” from January 1 to June 30, 2016. The degree of pain was measured using a visual analog scale (VAS). We did not observe any significant differences in postoperative nausea, hospitalization rate postoperative bleeding, and antibiotic use between the paracetamol and ibuprofen groups. A test of within-patient effects showed that VAS scores changed significantly during the postoperative follow-up period ( P = .00), but there were no significant differences between the groups ( P = .778). After 12 hours, 29.3% of the patients on paracetamol and 21.8% on ibuprofen were transferred to a soft diet; after 24 hours, 84.8% of the paracetamol group and 85.5% of the ibuprofen group were on a soft diet (χ2test, P < .05). There was a statistically significant correlation between VAS scores measured 4 hours after the surgery and the time of transference to the soft diet (Spearman ρ test, P < .001). The transfer to soft and normal diets was not significantly different between the 2 groups as assessed by the VAS scores (Pearson χ2test, P = .565).There is still no consensus on the most effective postoperative pain-control regiment after tonsillectomy. This study showed that satisfactory pain management was achieved equally with both paracetamol and ibuprofen.

Risk of acute exacerbation between acetaminophen and ibuprofen in children with asthma

Background Antipyretics are widely prescribed in pediatric practice. Some reports have mentioned that acetaminophen and non-steroid anti-inflammatory drugs may negatively affect asthma control by causing asthma exacerbation (AE). However, many confounding factors can also influence the risks. We assessed the impact of using acetaminophen or ibuprofen on AE in asthmatic children, especially those with strong risk factors. Methods We used the 2010 Taiwan National Health Insurance Research Database and identified 983 children with persistent asthma aged 1–5 years old; among them, 591 used acetaminophen alone and 392 used ibuprofen alone in 2010. Then, we analyzed the risk of AE over 52 weeks in the patients with and without severe AE in the previous year. Results The ibuprofen group had a higher risk of an emergency room (ER) visit or hospitalization for AE (odds ratio (OR) = 2.10, 95% confidence interval (CI) [1.17–3.76], P = 0.01). Among asthmatic children who had severe AE in the previous year, the risk of AE was higher in the ibuprofen group than in the acetaminophen group (OR = 3.28, 95% CI [1.30–8.29], P = 0.01), where as among those who did not, the risks of AE were similar between the acetaminophen and ibuprofen groups (OR = 1.52, 95% CI [0.71–3.25], P = 0.28). Conclusions Among young asthmatic children, use of ibuprofen was associated with a higher risk of AE than acetaminophen, if they had severe AE with ER visit or hospitalization in the previous year. Pediatricians should use antipyretics among children with asthma after a full evaluation of the risk.

The Control Of Postoperative Pain Following Oral Surgical Procedures By Ibuprofen Or Acetaminophen

Aim: The aim of this study was to compare the effects of anti-inflammatory (ibuprofen, 600 mg) and analgesic (Acetaminophen, 750 mg) drugs on postoperative pain. Material and methods: Patients with indications for surgery were selected, and a total of 57 patients, 20 male (35.1%) and 37 female (64.9%) were included in the study. Of these, 26 patients were placed in the acetaminophen group, and 31 were placed in the ibuprofen group. The average age of the patients was 30 years. The following types of surgeries were included in the evaluation: clinical crown lengthening, gingivectomy, pre-prosthetic surgery, labial frenum and frenum lingual. The surgeries were performed by students in a postgraduate training program in periodontics. Subsequent surgery, postoperative period orientations were provided by the researcher, and the medication to be prescribed was selected at random allocation. Both medications were administered for 48-h periods. A visual analogue scale with values ranging from 0 to 10, where 0 represented no pain and 10 represented maximum pain, was provided to the patients, and the patients were asked to rate their pain using this scale each time they took the medication. At the time of the follow-up visit, the patient data were given to the researcher and subsequently tabulated and applied to the statistical analysis (Mann-Whitney, p<0.05). Results: The results showed no significant difference in pain between medications (p>0.05). Conclusions: There was no difference in postoperative periodontal surgery pain after the use of anti-inflammatory or analgesic drugs.