PharmacotherapyOriginal researchA Randomized, Double-Blind, Placebo-Controlled, Multicenter, Repeat-Dose Study of Two Intravenous Acetaminophen Dosing Regimens for the Treatment of Pain After Abdominal Laparoscopic Surgery
Introduction
Pain relief (PR) in the postoperative setting is of particular importance to patients undergoing surgery. Although highly effective in the treatment of acute pain, opioid use is associated with dose-dependent risks including nausea, vomiting, constipation, urinary retention, sedation, and respiratory depression.1 Evidence suggests that a multimodal approach to postoperative analgesia, including analgesics with different mechanisms of action and regional anesthesia techniques, can reduce opioid consumption, minimize adverse events (AEs), improve PR and patient satisfaction, facilitate earlier recovery, and reduce costs of hospitalization.2, 3
In the United States, there are a number of nonopioid oral analgesics that, either alone or in combination with opioids, are approved and frequently used for acute pain treatment.4 Nonopioid analgesics include acetaminophen, aspirin, NSAIDs, and selective cyclooxygenase-2 inhibitors; commonly used opioids include hydrocodone and oxycodone.5 When oral administration is not feasible, there are only 2 approved intravenous nonopioid analgesics available for use in the United States for inpatient multimodal pain management: ketorolac and ibuprofen, both of which are NSAIDs.6, 7 Unfortunately, intravenous NSAIDs may cause AEs, such as bleeding and renal toxicity, that may limit their use in the perioperative setting.
Intravenous acetaminophen is approved for the short-term treatment of acute pain and fever in >60 countries outside the United States. In countries where it has been approved, intravenous acetaminophen is considered a valuable component of a multimodal analgesic approach.8 In the United States, intravenous acetaminophen was approved by the US Food and Drug Administration (FDA) in November 2010 for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. Its safety profile is supported by >7 years of clinical postmarketing safety experience outside the United States and >60 years of clinical experience with oral and rectal acetaminophen.
Laparoscopic surgery has become an increasingly common way to perform procedures that were previously done with an open incision. The laparoscopic approach is typically associated with reduced length of stay and less severe pain.9 Because of these characteristics, it was considered an appropriate surgical model for use in the present study of intravenous acetaminophen, which was designed and accepted as 1 of 2 pivotal trials in the new drug application in support of intravenous acetaminophen for an acute pain indication, and in support of an alternative dosing regimen of 650 mg q4h in addition to the 1000 mg q6h regimen approved throughout Europe. The study evaluated the analgesic efficacy and safety of repeated doses of these 2 dosing regimens compared with placebo over 24 hours in subjects with moderate to severe pain after abdominal laparoscopic surgery.
Section snippets
Subject Selection and Study Design
This randomized, double-blind, placebo-controlled, parallel-group study was conducted at 17 sites across the United States with subject enrollment from November 2007 (first subject in) to September 2008 (last subject out). The protocol and the informed-consent form were approved by the central institutional review board (Western Institutional Review Board, Olympia, Washington), site-specific institutional review boards operating in compliance with current local regulations and the International
Subject Disposition, Demographics, and Clinical Characteristics
A total of 349 subjects were screened before their planned elective laparoscopic surgeries. In all, 106 subjects were determined to be ineligible, including 1 subject who was enrolled in error; therefore, although 243 subjects were deemed eligible postoperatively, 244 subjects were randomized (ITT population) (Figure 1). All 244 randomized subjects received ≥1 full dose of study medication and were included in the safety population. One subject randomized to receive IV acetaminophen 1000 mg q6h
Discussion
The data from this study suggest that IV acetaminophen 1000 mg q6h and 650 mg q4h were both efficacious, compared with placebo, for the treatment of moderate to severe postoperative pain after abdominal laparoscopic surgery procedures. Intravenous acetaminophen was well tolerated with a safety profile that did not differ significantly from that of placebo. The main efficacy outcome measure, sum of PI differences (based on VAS score) from 0 to 24 hours, significantly favored both dosing regimens
Conclusions
In this study, 2 dosing regimens of intravenous acetaminophen (1000 mg q6h and 650 mg q4h) were associated with analgesic efficacy that was statistically significant compared with placebo in adults with pain on the day after abdominal laparoscopic surgery procedures. Both regimens were well tolerated, with a safety profile that did not differ significantly from that of placebo.
Acknowledgments
This study was designed, conducted, and analyzed by its sponsor, Cadence Pharmaceuticals, Inc. Dr. Royal was the medical monitor for the study.
The authors would like to acknowledge the investigators for their participation in and conduct of this clinical trial: Vaibhav Anvekar, MD; Keith Aqua, MD; Keith Candiotti, MD; Gene F. Coppa, MD; Laurence Ferber, MD; Michael E. Goldberg, MD; Craig T. Hartrick, MD; William B. King, MD; Arthur Levine, MD; Henry Lujan, MD; Timothy I. Melson, MD; and Sonia
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