Valdecoxib: A Review of its Use in the Management of Osteoarthritis, Rheumatoid Arthritis, Dysmenorrhoea and Acute Pain.

摘要

AbstractValdecoxib is an orally administered, highly selective cyclo-oxygenase (COX)-2 inhibitor with anti-inflammatory and analgesic properties.In well designed trials, valdecoxib demonstrated efficacy versus placebo in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenorrhoea and postoperative pain. Initial results in patients with migraine headache were promising. The efficacy of valdecoxib appears dose dependent up to 40 mg/day.Valdecoxib 10 mg/day was as effective as naproxen and rofecoxib in improving signs and symptoms of OA. The American College of Rheumatology 20% response rate was similar in recipients of valdecoxib, naproxen and diclofenac in patients with RA. In patients with dysmenorrhoea, valdecoxib 20 or 40mg up to twice daily provided as effective pain relief as naproxen sodium 550mg twice daily.In acute post-surgical pain, single-dose valdecoxib 40mg had a rapid onset of action, provided similar analgesia to oxycodone 10mg plus paracetamol (acetaminophen) 1000mg and provided a longer time to rescue medication than rofecoxib or oxycodone/paracetamol after oral surgery. Pre-emptive administration of valdecoxib 10-80mg was particularly effective in dental pain. Valdecoxib had opioid-sparing effects after hip or knee arthroplasty and reduced pain after laparoscopic cholecystectomy.Valdecoxib is generally well tolerated. The incidence of gastroduodenal ulcers was generally lower than with nonselective NSAIDs (i.e. NSAIDs not specifically developed as selective COX-2 inhibitors). With concomitant aspirin, the ulcer rate in valdecoxib recipients increased significantly, but was still lower than that in recipients of aspirin plus nonselective NSAIDs.In conclusion, valdecoxib, a COX-2-selective inhibitor, is as efficacious in pain relief as nonselective NSAIDs, with better gastrointestinal tolerability. It was as effective in RA, OA and primary dysmenorrhoea (the approved indications) as nonselective NSAIDs and as effective as rofecoxib in RA flare. In acute post-surgical pain, valdecoxib provided similar pain relief to oxycodone/paracetamol, had a long duration of action, a rapid onset of analgesia and was opioid-sparing. Valdecoxib provides a valuable alternative in the treatment of chronic arthritis pain and acute pain.Pharmacodynamic PropertiesValdecoxib (a 'coxib') is a highly selective inhibitor of cyclo-oxygenase (COX)-2 with anti-inflammatory and analgesic properties. This selectivity is the likely mechanism conferring the better gastrointestinal (GI) tolerability profile of coxibs relative to NSAIDs not specifically developed as selective COX-2 inhibitors (referred to here as nonselective NSAIDs). In an in vitro study, the valdecoxib concentration required to inhibit 50% of enzyme activity was 0.005 micromol/L for COX-2, but was 140 micromol/L for COX-1. Binding of valdecoxib to COX-2 is reversible and inhibited by nonselective NSAIDs. An in vitro study found valdecoxib only weakly antagonised the anti-platelet effect of aspirin.Pharmacokinetic PropertiesIn healthy male volunteers, valdecoxib 10 mg/day was rapidly absorbed, reaching a steady-state mean maximum plasma concentration (C(max)) of 161 ng/mL after a mean 2.25 hours (t(max)). A single dose of valdecoxib 50mg reached a mean C(max) of 1040 ng/mL at a t(max) of 1.7 hours. Absorption may be delayed by up to 2 hours by food. The elimination half-life of valdecoxib was approximate, equals 7-8 hours; this increased in elderly patients, with overall exposure to valdecoxib increasing by 30-40%. In patients with moderate hepatic impairment, exposure to valdecoxib is increased by 130%. Valdecoxib is extensively metabolised via cytochrome P450 (CYP) isoenzymes, especially CYP3A4 and CYP2C9, and interacts with some drugs metabolised by CYP isoenzymes (e.g. fluconazole, dextromethorphan and omeprazole). Excretion is mainly renal (76% of a radiolabelled valdecoxib dose) and metabolites are mostly excreted via the kidney.In healthy voluntee