Combining Paracetamol (Acetaminophen) with …

1 Pain MedicineSection Editor:Spencer S. LiuCombining Paracetamol ( acetaminophen ) withNonsteroidal Antiinflammatory Drugs: A QualitativeSystematic Review of Analgesic Efficacy for AcutePostoperative PainCliff K. S. Ong, PhD,* Robin A. Seymour, PhD, Phillip Lirk, MD, and Alan F. Merry, MBChB, FANZCA, FPMANZCA, FRCA BACKGROUND:There has been a trend over recent years for Combining a nonsteroidalantiinflammatory drug (NSAID) with Paracetamol ( acetaminophen ) for pain management. How-ever, therapeutic superiority of the combination of Paracetamol and an NSAID over either drugalone remains controversial.

2 We evaluated the efficacy of the combination of Paracetamol and anNSAID versus either drug alone in various acute pain :A systematic literature search of Medline, Embase, Cumulative Index to Nursing andAllied Health Literature, and PubMed covering the period from January 1988 to June 2009 wasperformed to identify randomized controlled trials in humans that specifically comparedcombinations of Paracetamol with various NSAIDs versus at least 1 of these constituent studies were stratified into 2 groups: Paracetamol /NSAID combinations versusparacetamol or NSAIDs.

3 We analyzed pain intensity scores and supplemental analgesicrequirements as primary outcome measures. In addition, each study was graded for quality usinga validated :Twenty-one human studies enrolling 1909 patients were analyzed. The NSAIDs usedwere ibuprofen (n 6), diclofenac (n 8), ketoprofen (n 3), ketorolac (n 1), aspirin(n 1), tenoxicam (n 1), and rofecoxib (n 1). The combination of Paracetamol and NSAIDwas more effective than Paracetamol or NSAID alone in 85% and 64% ofrelevant studies,respectively.

4 The pain intensity and analgesic supplementation was and lesser, respectively, in the positive studies for the combination versus Paracetamol group, and lesser, respectively, in the positive studies for the combinationversus the NSAID group. No statistical difference in median quality scores was found betweenexperimental :Current evidence suggests that a combination of Paracetamol and an NSAID mayoffer superior analgesia compared with either drug alone. (Anesth Analg 2010;110:1170 9)Different classes of analgesics exert their effectsthrough different mechanisms.

5 Their side effects( , respiratory depression with opioids or enter-opathy with nonsteroidal antiinflammatory drugs [NSAIDs])tend to bedifferent and may be dose related. A combi-nation of analgesics from different classes may provideadditive analgesic effects with fewer side effects thanwhen a single therapeutic drug is used. There has been atrend over recent years for Combining NSAIDs withparacetamol ( acetaminophen ) for the management ofacute postoperative pain,1,2but the therapeutic superior-ity of the combination over either drug alone ,4In 2002, Hyllested et thatparacetamol/NSAID combinations showed superiorpain relief over Paracetamol alone in 5 of 7 studies, butover an NSAID alone in only 2 of 4 studies, whereasR msing et an advantage for such combina-tions over Paracetamol alone in 6 of 9 studies but over anNSAID alone in only 2 of 6 studies.

6 These authors notedthat relevant studies were sparse. We have updated thesereviews to include randomized controlled trials (RCTs)published since then with the aim of evaluating whetherparacetamol/NSAID combinations provide superior ef-ficacy in the treatment of acute postoperative pain toeither drug IN HUMAN CLINICAL STUDIES FOR THEUSE OF Paracetamol /NSAID COMBINATIONSWe aimed to determine whether Paracetamol /NSAID com-binations provide superior efficacy in the treatment ofacute postoperative pain to either drug the *Department of Oral & Maxillofacial Surgery, Faculty of Dentistry,National University of Singapore.

7 Republic of Singapore; School of DentalStudies, University of Newcastle Upon Tyne, UK; Department ofAnesthesiology and Critical Care Medicine, Innsbruck Medical Univer-sity, Innsbruck, Austria; and Department of Anaesthesiology, Univer-sity of Auckland, Auckland, New for publication November 12, by a grant from AFT Pharmaceuticals Ltd, level 2, 9 Anzac St.,Takapuna, Auckland 0622, New Zealand (to CKSO).Address correspondence and reprint requests to Cliff K. S. Ong, DDS, 435 Orchard Rd., Suite 11-02, Wisma Atria, Zip 238877, Republic of e-mail to 2010 International Anesthesia Research SocietyDOI: 2010 Volume 110 Number 4 METHODSA broad free-text search restricted to RCTs in English wasundertaken in Medline, Embase, Cumulative Index to Nurs-ing and Allied Health Literature, and PubMed, from January1988 to June 2009.

8 The full reports were retrieved for double-blind RCTs comparing Paracetamol /NSAID combinationswith 1 or both of their constituent drugs for pain of the search terms including Paracetamol /NSAID scombination, acetaminophen , combination analgesics, acute postoperative pain, and ibuprofen/ Paracetamol orindividual drug names were entered as major subject head-ings. Reference lists of retrieved publications were checked foradditional criteria were (1) comparison of a Paracetamol /NSAID combination with analgesics other than paraceta-mol or NSAIDs, (2) other pain models, , chronic pain,and (3) retrospective, nonrandomized, or nonblinded retrieved reports were stratified according to theNSAID in the combination, the mode of administration(oral, IM, IV, rectal)

9 , and the surgical procedures possible, data on the following outcome mea-sures were extracted from the retrieved publications in theform of mean/median and assessed for reported differ-ences between the combination and constituent druggroups:1. Pain intensity in the form of pain scores, , post-operative visual analog scale (VAS) Supplemental postoperative analgesic requirements, , opioid cases in which results of trials were reported only ingraphical form, the means andsds were estimated fromthese graphs.

10 The difference in analgesic response amongthe study groups, , % difference in pain intensity and %difference in analgesic supplementation, was extractedfrom the studies or calculated from the studies wheneverpossible. The mean/sdof the difference in analgesic re-sponse of all the positive studies was study was graded for quality, using the validatedscale of Jadad et al.,6on the extent to which its design, datacollection, and statistical analysis minimized or avoidedbias as follows:1. Randomization: If the reports were described as ran-domized, 1 point was given.