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Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain M Anesthesiology 2005; 102:822–31 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery Raymond S. Sinatra, M.D., Ph.D.,* Jonathan S. Jahr, M.D.,† Lowell W. Reynolds, M.D.,‡ Eugene R. Viscusi, M.D.,§ Scott B. Groudine, M.D.,ʈ Catherine Payen-Champenois, M.D.# Background: Intravenous acetaminophen injection (parac- patients treated with intravenous acetaminophen, propaceta- etamol) is marketed in Europe for the management of acute mol, and placebo, respectively. pain. A repeated-dose, randomized, double-blind, placebo-con- Conclusion: Intravenous acetaminophen, 1 g, administered Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 trolled, three–parallel group study was performed to evaluate over a 24-h period in patients with moderate to severe pain after the analgesic efficacy and safety of intravenous acetaminophen orthopedic surgery provided rapid and effective analgesia and as compared with its prodrug (propacetamol) and placebo. was well tolerated. Propacetamol has been available in many European countries for more than 20 yr. Methods: After orthopedic surgery, patients reporting mod- EFFECTIVE pain management is an important compo- erate to severe pain received either 1 g intravenous acetamino- nent of postsurgical care. Many patients, however, con- phen, 2 g propacetamol, or placebo at 6-h intervals over 24 h. tinue to experience inadequate pain relief.1 Despite im- Patients were allowed “rescue” intravenous patient-controlled provements in analgesic delivery, including patient- analgesia morphine. Pain intensity, pain relief, and morphine use were measured at selected intervals. Safety was monitored controlled analgesia (PCA) and sustained-release opioids, through adverse event reporting, clinical examination, and lab- several recent surveys have found that up to 80% of oratory testing. patients report moderate to severe pain after surgery.2–4 Results: One hundred fifty-one patients (intravenous acet- The ideal postoperative analgesic treatment should pro- aminophen: 49; propacetamol: 50; placebo: 52) received at least vide rapid and effective pain relief, have a low incidence one dose of study medication. The intravenous acetaminophen and propacetamol groups differed significantly from the pla- of adverse effects, and have minimal impact on major cebo group regarding pain relief from 15 min to6h(P < 0.05) organ systems or no significant interaction with other and median time to morphine rescue (intravenous acetamino- pharmacologic agents. phen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous Opioids remain the agents of choice for severe pain; acetaminophen and propacetamol significantly reduced mor- however, this class of analgesics is associated with dose- phine consumption over the 24-h period: The total morphine doses received over 24 h were 38.3 ؎ 35.1 mg for intravenous dependent adverse effects and negative postoperative 5,6 acetaminophen, 40.8 ؎ 30.2 mg for propacetamol, and 57. 4 ؎ outcomes. Nonopioid analgesics are commonly used mg for placebo, corresponding to decreases of ؊33% alone or as adjuncts to opioid-based analgesia to treat 52.3 ؊ (19 mg) and 29% (17 mg) for intravenous acetaminophen and moderate to severe pain. Perioperative administration of propacetamol, respectively. Drug-related adverse events were reported in 8.2%, 50% (most of them local), and 17.3% of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) has been advocated to provide “multimodal” or “balanced” analgesia that decreases opioid dose re- quirements and may reduce associated adverse events This article is featured in “This Month in Anesthesiology.” while reducing postsurgical pain intensity.5–9 ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. Acetaminophen has a well-established safety and anal- gesic profile. It has few contraindications and lacks sig- * Professor of Anesthesiology, Department of Anesthesiology, Yale University nificant drug interactions. Hepatic toxicity is relatively School of Medicine. † Professor of Anesthesiology, David Geffen School of rare but can occur with acetaminophen overdose. Its Medicine, UCLA. Charles R. Drew University of Medicine and Science. ‡ Asso- ciate Professor of Anesthesiology, Loma Linda University School of Medicine. possible potentialization by chronic alcoholism remains § Associate Professor of Anesthesiology, Jefferson Medical College of Thomas controversial.10–12 Jefferson University. ʈ Associate Professor of Anesthesiology, Albany Medical College. # Project Leader, Medical Department, Bristol-Myers Squibb Company. Until recently, there has not been an intravenous acet- Received from the Department of Anesthesiology, Yale University School of aminophen solution available because it is poorly soluble Medicine, New Haven, Connecticut; Departments of Anesthesiology and Pain in water and not stable in solution. As a result, propac- Medicine, University of California-Davis, Sacramento, California; Loma Linda University School of Medicine, Loma Linda, California; Jefferson Medical College etamol, an intravenous, water-soluble prodrug of acet- of Thomas Jefferson University, Philadelphia, Pennsylvania; Albany Medical Col- aminophen with a well-established analgesic efficacy and lege, Albany, New York; and the Medical Department, Bristol-Myers Squibb Company, Rueil-Malmaison, France. Submitted for publication May 26, 2004. safety profile, has been widely prescribed in Europe for Accepted for publication October 22, 2004. Supported by Bristol-Myers Squibb the management of acute pain for the past 20 yr. It is not Company, Rueil-Malmaison, France. available in the United States. Address correspondence to Dr. Sinatra: Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, TMP-3 New Haven, Connecticut Propacetamol is rapidly hydrolyzed to acetaminophen 06520-8051. Address electronic mail to: [email protected]. Individual in the blood by the enzymatic action of esterases. Hy- article reprints may be purchased through the Journal Web site, www.anesthesiology.org. drolysis of 2 g propacetamol yields 1 g intravenous Anesthesiology, V 102, No 4, Apr 2005 822 IV ACETAMINOPHEN FOR ORTHOPEDIC SURGICAL PAIN 823 acetaminophen.13 In clinical trials conducted in patients cluded if they had received NSAIDs within 8 h, any with moderate to severe pain after orthopedic and gy- analgesic drug within 12 h, or corticosteroids within 7 necologic surgery, the analgesic efficacy of propaceta- days before administration of study medication. mol was similar to that of NSAID comparators.14–16 The study was conducted in accordance with Good While providing fast and significant pain relief as well as Clinical Practice and the Declaration of Helsinki and was a significant morphine-sparing effect,17–19 it is not asso- approved by an institutional review board for each clin- ciated with the increased incidence of nausea, vomiting, ical center. All participating patients provided written and respiratory depression observed with opioids or the informed consent. deleterious gastrointestinal, hematologic, and renal ef- fects associated with NSAIDs and cyclooxygenase Study Design (COX)-2 inhibitors.20 Lack of inhibition of COX-1 periph- This was a repeated-dose, randomized, double-blind, erally by paracetamol may explain its favorable safety placebo-controlled, three–parallel group study compar- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/102/4/822/358715/0000542-200504000-00019.pdf by guest on 02 October 2021 effect.21 However, propacetamol has some drawbacks: It ing intravenous acetaminophen and propacetamol to must be reconstituted into a solution, and rare cases of placebo and was conducted in seven centers in the contact dermatitis have been reported in healthcare pro- United States (see appendix). Patients were enrolled fessionals handling the drug.22 In addition, propaceta- from September 1999 to June 2000. mol can be associated with pain at the intravenous in- Propacetamol was chosen as a comparator because it jection site or along the vein being infused. is the only injectable, prodrug form of acetaminophen A ready-to-use formulation of intravenous acetamino- commercially available and because, having been widely phen has recently been developed that does not require prescribed for many years in Europe, its analgesic effi- reconstitution and is not associated with contact derma- cacy and safety profile have been well characterized. titis or pain at the injection site. In the clinical develop- The dose of 2 g propacetamol was chosen because it ment program, 1 g intravenous acetaminophen has been releases 1 g intravenous acetaminophen. found to be bioequivalent to 2 g propacetamol.23 More- During the screening visit scheduled within 21 days over, clinical studies have shown that intravenous acet- before the administration of study drug, informed con- aminophen offers improved local safety at infusion sites, sent and medical history were obtained, physical exam- compared with propacetamol.23 ination and laboratory testing were performed, and train- The aim of this study was to evaluate the analgesic ing on the use of the intravenous PCA device and pain efficacy and safety of a single dose and repeated doses of scales was provided. 1 g intravenous acetaminophen in comparison
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