Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess antipyretic, analgesic and anti-inflammatory effects. They are frequently used in children and have numerous therapeutic indications, the most common ones being fever, postoperative pain and inflammatory disorders, such as juvenile idiopathic arthritis (JIA) and Kawasaki disease. Their major mechanism of action is through inhibition of prostaglandin biosynthesis by blockade of cyclo-oxygenase (COX). The disposition of most NSAIDs has been mainly studied in infants > or = 2 years of age. Compared with adults, the volume of distribution and clearance of NSAIDs such as diclofenac, ibuprofen (infants aged between 3 months and 2.5 years), ketorolac and nimesulide were increased in children. The elimination half-life was similar in children to that in adults. These pharmacokinetic differences might be clinically significant with the need for higher loading and/or maintenance doses in children. Ibuprofen, acetylsalicylic acid (ASA) and acetaminophen are the most frequently used agents for fever reduction in children. Over the past 20 years, because of the association between ASA use and Reye's syndrome, most of the interest has been directed toward ibuprofen and acetaminophen. In view of its comparable antipyretic efficacy, but superior tolerability profile, acetaminophen, when used appropriately with age-adapted formulations, should remain the first-line therapy in the treatment of childhood fever. At the moment, there is no scientific evidence to recommend simultaneous use of these two antipyretic drugs. Most NSAIDs provide mild to moderate analgesia, with the exception of ketorolac which has a strong analgesic activity. The analgesic efficacy of ketorolac, ketoprofen, diclofenac and ibuprofen in the treatment of postoperative pain has been mainly studied following a single dose, in children of > or = 1 year of age undergoing minor surgeries. In this setting, when used either alone or in adjunct to caudal or epidural anaesthesia, they were associated with an opioid-sparing effect and were well tolerated. With the exception of ketorolac use in children undergoing tonsillectomy, where controversy exists regarding the risk of postoperative haemorrhage, NSAIDs have not been associated with an increased risk of perioperative bleeding. NSAIDs are the first-line therapy in JIA. They appear to be equally effective and tolerated, with the exception of ASA which is associated with more adverse effects. ASA has been used for many years in the treatment of Kawasaki disease and is part of the standard modality of treatment in combination with intravenous gammaglobulins. More recently, lung inflammation associated with cystic fibrosis (CF) has become a new target for NSAIDs. Despite promising preliminary results with ibuprofen, numerous questions need to be answered before this new strategy becomes part of the conventional treatment of patients with CF. In summary, NSAIDs are effective in reducing fever, alleviating pain and reducing inflammation in children, with a good tolerance profile. Pharmacokinetic studies are needed to characterise the disposition of NSAIDs in very young infants in order to use them rationally. To date, no studies have been published on the disposition, tolerability and efficacy of specific COX-2 inhibitors in children. Further clinical experience with these agents in adults is warranted before undergoing trials with specific COX-2 inhibitors in children.