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Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

ABSTRACT: Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ? 50 kg receiving 1000 mg every 6 hours.

SUBMITTER: Hammer GB

PROVIDER: S-EPMC6973014 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Hammer Gregory B GB Maxwell Lynne G LG Taicher Brad M BM Visoiu Mihaela M Cooper David S DS Szmuk Peter P Pheng Leng Hong LH Gosselin Nathalie H NH Lu Jia J Devarakonda Krishna K

Journal of clinical pharmacology 20190825 1

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and inf ...[more]

PMID: 31448420

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Project description:Importance:Intravenous acetaminophen is a commonly prescribed analgesic for the prevention and treatment of postsurgical pain. Its efficacy in the context of endoscopic sinus surgery (ESS) has yielded mixed results. Objective:To compare the efficacy of perioperative intravenous acetaminophen (IVAPAP) with that of placebo in improving early postoperative pain after endoscopic sinus surgery (ESS). Design, Setting, and Participants:A prospective, randomized clinical trial including 62 patients undergoing ESS for chronic rhinosinusitis in a single tertiary referral hospital. Interventions:Participants were randomized to receive 1 g of IVAPAP or 100 mL of placebo consisting of saline infusions immediately before the start of surgery and 4 hours after the initial dose. Main Outcomes and Measures:The primary outcome was postoperative pain measured by visual analog scale (VAS) scores up to 24 hours after surgery by blinded observers. Secondary endpoints included postoperative opioid (intravenous and oral) use and adverse events in the 24-hour postoperative period. Results:Of the 62 enrolled adult participants, 60 were randomized (31 to IVAPAP intervention and 29 to placebo). The mean (SD) age of participants was 53.7 (14.7) years and 35 (58%) of the participants were men and 25 (42%) were women. Within the first hour, mean pain scores were reduced in the IVAPAP group compared with the control group, reaching a maximum difference of 7.7 mm on a VAS scale favoring the treatment group with a true difference possibly as high as 22 mm, and the data are compatible with a clinically meaningful difference. At 12- and 24-hours, average pain scores were less in the placebo group and the data are compatible with a clinically meaningful difference of 5.8 (-5.2 to 16.8) and 8.2 (-1.9 to 18.4), respectively, favoring the placebo group. However, at all time points the CIs included the null value and were wide, thus preventing definitive conclusions. Inspection of the secondary outcomes favored IVAPAP, but the wide range of the CIs and inclusion of the null value prevent definitive conclusions. Conclusions and Relevance:The results of this study are inconclusive. The data suggest that perioperative intravenous acetaminophen may reduce immediate postoperative pain and opioid requirements compared with placebo and these differences could be clinically meaningful. Unfortunately, the imprecision of the estimates prevents definitive conclusion. Use of IVAPAP does not seem to increase adverse events. Trial Registration:clinicaltrials.gov Identifier: NCT01608308.

Project description:OBJECTIVES:Older adults are at risk for undertreatment of pain. We examined intravenous (IV) acetaminophen as an analgesic adjunct to IV opioids in the care of older emergency department (ED) patients with acute severe pain. METHODS:This was a randomized clinical trial conducted in two EDs in the Bronx, New York. Eligible adults aged 65 years and older with acute severe pain were randomized to 0.5 mg of IV hydromorphone and 1 g of IV acetaminophen or 0.5 mg of IV hydromorphone and 100 mL of normal saline placebo. The primary outcome was the between group difference in improvement of numerical rating scale (NRS) pain scores at 60 minutes. Secondary outcomes were the between-group differences in the proportion of patients who chose to forgo additional pain medications at 60 minutes; the proportion who developed side effects; the proportion who required rescue analgesia; and between-group differences in NRS pain scores at 5, 15, 30, and 45 minutes. RESULTS:Eighty-one patients were allocated to each arm. Eighty patients in the IV acetaminophen arm and 79 patients in the placebo arm had sufficient data for analysis. At 60 minutes, patients in the hydromorphone + IV acetaminophen group improved by 5.7 NRS units while those in the hydromorphone + placebo group improved by 5.2 NRS units, for a difference of 0.6 NRS units (95% confidence interval [CI] = -0.4 to 1.5). A total of 28.7% of patients in the hydromorphone + IV acetaminophen group wanted more analgesia at 60 minutes versus 29.1% in the hydromorphone + placebo group, for a difference of -0.4% (95% CI = -14.3% to 13.5%). These differences were neither clinically nor statistically significant. Safety profiles were similar in both groups. CONCLUSION:In this randomized clinical trial, the addition of IV acetaminophen to IV hydromorphone as an adjunctive analgesic for acute, severe, pain in older adults provided neither clinically nor statistically superior pain relief when compared to hydromorphone alone within the first hour of treatment.

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Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Publications

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

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