Mike A. Royal

Plasma and Cerebrospinal Fluid Pharmacokinetic Parameters after Single-Dose Administration of Intravenous, Oral or Rectal Acetaminophen

Background:  This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen.

Safety of Multiple-Dose Intravenous Acetaminophen in Adult Inpatients

BACKGROUND Intravenous (IV) acetaminophen provides rapid and effective analgesia in the postoperative and inpatient settings. The utility and efficacy of acetaminophen is well established; however, due to chronic excessive dosing of over-the-counter acetaminophen products and prescription opioid combination products resulting in the potential for hepatic toxicity, concerns remain about acetaminophen safety. In order to evaluate the safety of IV acetaminophen 1,000mg q6h or 650mg q4h with repeated dosing for 5 days, a randomized, open-label study assessed the safety and tolerability of repeated doses used to treat acute pain or fever in 213 adult inpatients was conducted. METHODS Subjects were randomized (3:3:1) to receive IV acetaminophen (1,000mg q6h or 650mg q4h) or standard-of-care treatment for pain or fever. Safety was assessed according to spontaneous reports of adverse events (AEs) and clinically meaningful changes from baseline laboratory parameters. RESULTS Overall, IV acetaminophen was shown to be safe and well tolerated in adult inpatients when given as repeated doses for up to 5 days. Owing to the comorbidities in the study population, the frequency of AEs reported was high. However, the majority of treatment-emergent adverse events (TEAEs) were unrelated to treatment, and only 8% of the study population withdrew because of TEAEs. No major hepatic issues associated with IV acetaminophen warranted concern, and most hepatic events were likely related to underlying medical conditions or recent trauma/surgery. CONCLUSIONS Consistent with the tolerability and safety results, both treatment groups (1,000mg q6h and 650mg q4h) demonstrated statistically significantly better ratings for the Subject Global Evaluations for the level of satisfaction with side effects related to study treatments as compared with the control group. The findings from this trial support the use of IV acetaminophen as a safe therapy in adult patients.

A review of the literature on the effects of acetaminophen on pregnancy outcome

Acetaminophen is commonly used during pregnancy. Experimental animal studies do not suggest increased malformations after therapeutic use of single-ingredient acetaminophen during pregnancy. Cohort studies in humans in which exposure is prospectively ascertained show no detectable increase in congenital malformation risk associated with single-ingredient acetaminophen use during pregnancy. A case-control study identified an association between acetaminophen use during pregnancy and risk of gastroschisis in the offspring, but the study was limited by recall bias, unblinded interviewers, possible misclassification of gastroschisis, confounding by indication, difficulty in separating out the effects of combination products, and possible selection bias. Two case-control studies failed to identify a statistically significant association between acetaminophen use during pregnancy and gastroschisis. No other malformation has been shown to be causally associated with single-ingredient acetaminophen. A reported association between pre-eclampsia, preterm birth, and acetaminophen may be explained by reverse causation. Concerns expressed about childhood asthma and prenatal acetaminophen use has been addressed in a separate review. The use of single-ingredient acetaminophen during pregnancy can be justified based on outcome data. Data on the effects of acetaminophen cannot necessarily be extended to acetaminophen combination products.

Childhood asthma and use during pregnancy of acetaminophen. A critical review

The possible association between acetaminophen use during pregnancy and childhood asthma has been a subject of interest based on the theory that acetaminophen metabolism may deplete glutathione in the developing lung, leading to oxidative damage and inflammation. Epidemiology studies from eight centers have reported conflicting results. In some cases, end points of these studies have included wheezing in very young children, which is a poor predictor of asthma. Other study problems have included the common use of acetaminophen as the analgesic and antipyretic of choice during pregnancy. Because acetaminophen use may be a marker for infectious or inflammatory disorders, the results of the epidemiology studies may be influenced by confounding by indication. A placebo-controlled randomized trial of acetaminophen use during pregnancy would be helpful in resolving the question of whether acetaminophen use causes childhood asthma. At present, the evidence is inconclusive that any such association is causal.

A randomized study of the efficacy and safety of intravenous acetaminophen vs. Intravenous placebo for the treatment of fever

This randomized, double‐blind, placebo‐controlled study evaluated the antipyretic effect and safety of intravenous (i.v.) acetaminophen using an endotoxin‐induced fever model. Subjects exhibiting sufficient fever response following administration of reference standard endotoxin (RSE) were randomly assigned to receive i.v. acetaminophen 1,000 mg (n = 31) or matching placebo (n = 29). The primary efficacy end point was the weighted sum of temperature differences from baseline through 6 h. Relative to placebo, i.v. acetaminophen administration produced a rapid decrease in temperature that persisted throughout the 6‐h study period. The primary end point favored i.v. acetaminophen over placebo (P < 0.001). Temperature differences from baseline reached statistical significance at T30 min after endotoxin administration (15 min after completing the study medication infusion). Acetaminophen administered i.v. was well tolerated, and the frequency of adverse events was comparable to that after administration of i.v. placebo. This study shows that i.v. acetaminophen in a single 1,000‐mg dose is safe and effective in reducing fever.

IV acetaminophen: Efficacy of a single dose for postoperative pain after hip arthroplasty: subset data analysis of 2 unpublished randomized clinical trials.

Inadequate control of postoperative pain after orthopedic procedures may trigger complications that increase morbidity. Multimodal analgesia is used to manage pain effectively after surgical procedures and reduce the need for rescue analgesia. Intravenous (IV) acetaminophen (OFIRMEV; Cadence Pharmaceuticals, Inc.), an analgesic that has been studied and used in the multimodal management of acute pain after major orthopedic procedures, combines the safety seen with oral and rectal formulations with a preferred route of administration. Two double-blind, randomized, placebo-controlled clinical trials were conducted (total 130 patients) to determine the efficacy and safety of single-dose IV acetaminophen in patients following total hip arthroplasty. Although both studies were stopped prematurely, overlap in patient populations, study design, and methodologies in the single-dose phase of these studies allowed for analysis of their results to be presented concurrently. Both trials demonstrated IV acetaminophen having greater efficacy than placebo in terms of primary endpoints [pain intensity differences from T0.5 to T3 (P < 0.05 in both studies)]. The use of IV acetaminophen also reduced the need for rescue opioid consumption, with patients receiving IV acetaminophen consuming, on average, less than half the amount of rescue medication as those receiving placebo. IV acetaminophen was effective in treating moderate-to-severe pain after total hip arthroplasty and reduced the need for rescue opioid consumption.

Safety and efficacy of intravenous acetaminophen in the elderly after major orthopedic surgery: subset data analysis from 3, randomized, placebo-controlled trials.

As the number of patients aged 65 years and older increases, joint replacement has become a frequent procedure after progressive osteoarthritis or fractures. Although hip and knee arthroplasty has become a relatively commonplace procedure in this age-group, the advanced age in patients undergoing these procedures often is associated with comorbidities and potential complications that can present challenges and limit analgesic choices. This subset analysis is designed to determine the efficacy and safety of intravenous (IV) acetaminophen in the elderly subpopulation from 3 placebo-controlled studies conducted to document the safety and efficacy of IV acetaminophen. A total of 231 patients were enrolled in the 3 trials, and of these, a total of 107 patients (46%) were aged 65 years or older. Across the studies, safety and efficacy were well documented in the elderly subpopulation and were comparable with the subpopulation younger than 65 years. A review of the literature similarly demonstrates the efficacy and safety of IV acetaminophen used for postoperative analgesia after joint replacement.