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Clinical pharmacology: traditional NSAIDs and selective COX-2 inhibitors
Published in Pamela E Macintyre, Suellen M Walker, David J Rowbotham, Clinical Pain Management, 2008
Stephen F Jones, Aidan M O’Donnell
Lumiracoxib is an arylacetic acid derivative with a structure very similar to that of diclofenac and lacks the sulfur-containing group of the other coxibs. It binds to the COX-2 enzyme at a different site and displays very high COX-2 selectivity.102 Lumiracoxib has fewer gastrointestinal side effects than diclofenac, although its kinetics are similar. It has a rapid onset of activity and good analgesic properties. A large randomized controlled study of lumiracoxib versus ibuprofen and naproxen showed a three- to four-fold reduction in ulcer complications in the lumiracoxib group when compared with either of the other NSAIDs, without an increase in cardiovascular events. 2.6 percent of patients developed an increase in liver enzymes, although this proportion is lower than with diclofenac.33 However, lumiracoxib has recently been withdrawn because of suspected adverse liver reactions.
The use of NSAIDs and paracetamol (acetaminophen) in chronic pain
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
NSAIDs tend to be plasma protein bound with low volumes of distribution and hepatically metabolized. Mild elevations in liver enzymes are common, with the elderly being at greatest risk. NSAIDs have been implicated in reports of liver injury, though the precise risk is unknown. In a systematic review of the published literature of population-based epidemiological studies reporting the incidence or comparative risk of NSAIDs for liver injury resulting in clinically significant events, defined as hospitalization or death, Rubenstein and Laine67 concluded that there is the possibility of a small increase in the risk of clinically relevant hepatotoxicity with NSAID use. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with any NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within four to six weeks of stopping the causative drug. However, some patients may develop acute liver failure. Lumiracoxib, a COX-2 inhibitor, has been reported to cause elevated liver enzymes and there have been case reports of severe hepatic reactions including liver failure and death.68 In November 2007 lumiracoxib was withdrawn from the UK.
Clinical pharmacology and therapeutics: nonopioids
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
Rofecoxib carries a dose-related cardiovascular risk.264[III] Despite Merck’s continued insistence that risk only increases after 18 months of use,267, 268, 269 substantial evidence indicates that it is elevated early on.262, 264, 270, 271, 272 Meta-analysis of epidemiological studies,264[III] and of RCTs,273[I] found no increased cardiovascular risk from celecoxib, in contrast to Kearney’s review of RCTs,265[I] which found celecoxib to be as risky as rofecoxib. However, more recent trial and survey results showed an increased risk274, 275[III] especially in the presence of previous myocardial infarction.276, 277 [III] Despite an early negative meta-analysis,278 valdecoxib was withdrawn in 2005 due to severe dermatological reactions, but also after the FDA had expressed disquiet about early toxicity,279 a lack of adequate cardiovascular safety data, and a lack of demonstrated advantages over other NSAIDs. A recent survey ascribed it the highest risk of myocardial infarction,275[III] (rofecoxib surprisingly came out as the lowest risk). Data for etoricoxib are limited but suggest moderate thrombogenicity.280[I] The TARGET study suggests that lumiracoxib carries similar risks to naproxen or ibuprofen, irrespective of aspirin use.281[II] A trade-sponsored metaanalysis confirms low risk,282[I] but powerful data are still scarce.
Pharmacological considerations when treating hypertensive patients for osteoarthritis
Published in Expert Opinion on Pharmacotherapy, 2022
Christopher R Piszczatoski, Steven M Smith
Oral non-steroidal anti-inflammatory drugs (NSAIDs) are considered first-line therapy for treatment of OA pain. NSAIDs are thought to produce their analgesic effect primarily by inhibiting the cyclooxygenase-2 enzyme (COX-2), resulting in decreased production of prostaglandins involved in pain and inflammation. Regardless of COX-2 isoform selectivity, the analgesic and anti-inflammatory activities of all oral NSAIDs are considered similar at equipotent dosages. Nevertheless, there does appear to be variability across NSAIDs in terms of risk of drug-induced adverse events, including effects on BP. For example, recent studies indicate essentially no meaningful change from baseline in 24-hour ambulatory systolic BP observed in celecoxib-treated patients compared to a 2–4 mmHg increase from baseline in ibuprofen- or naproxen-treated patients [6]. The COX-2 inhibitors valdecoxib and lumiracoxib appear to have similar negligible effects on BP, whereas rofecoxib and etoricoxib have been associated with greater incidence of hypertension compared with nonselective NSAIDs and placebo [7]. The antihypertensive regimen may also factor into decisions regarding oral NSAID therapy. Prostaglandin inhibition and sodium retentive effects caused by NSAIDs may blunt the effects some antihypertensives, particularly diuretics and renin-angiotensin-aldosterone system inhibitors [8], and oral NSAIDs may be less ideal in patients requiring these agents. Conversely, calcium channel blocker efficacy is not substantively affected and such combinations (CCB + NSAID) have recently come to market [8].
Lowering side effects of NSAID usage in osteoarthritis: recent attempts at minimizing dosage
Published in Expert Opinion on Pharmacotherapy, 2018
Kevin H. Maniar, Ian A. Jones, Rayudu Gopalakrishna, C. Thomas Vangsness
After the discovery of the COX-2 isoenzyme, considerable effort was directed towards producing NSAIDs that preferentially targeted COX-2. By targeting COX-2, this new generation of NSAIDs was expected to have the therapeutic effects of nonselective NSAIDs and limited gastrointestinal side effects. A number of selective COX-2-NSAIDs were approved by the US FDA in the late 1990s and early 2000s, including rofecoxib, valdecoxib, and celecoxib [30–32]. Sales and popularity of these drugs initially spiked [30]; however, the VIGOR study, a 2000 study comparing rofecoxib and naproxen, raised questions about the safety of these drugs. The VIGOR study found an increased incidence of myocardial infarction in patients taking rofecoxib compared to those taking naproxen [33]. These side effects disproportionately affected patients that were at a high risk of cardiovascular events – a group that may have benefited from the cardioprotective effects of aspirin. Thus, the difference in risk was initially attributed to an aspirin-like cardioprotective effect of naproxen rather than a side effect of rofecoxib use. However, further studies indicated that rofecoxib was directly related to an increased cardiovascular risk [25,32], and in 2004, rofecoxib was voluntarily withdrawn from the marketplace. Likewise, in 2005, the US FDA requested valdecoxib also be removed because it increased the risk of both cardiovascular and serious dermatologic side effects [30,31]. Other selective COX-2 inhibitors, etoricoxib and lumiracoxib, were subsequently rejected by the US FDA [34,35].
Cardiovascular safety of non-steroidal anti-inflammatory drugs revisited
Published in Postgraduate Medicine, 2018
Chris Walker, Luigi M. Biasucci
The manufacturers of lumiracoxib and etoricoxib broadly adopted this advice when designing later trials of their medicines. In the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), comparisons between a supratherapeutic dose of lumiracoxib (400 mg/day) and the maximum licensed doses of ibuprofen and naproxen yielded no significant differences in the APTC composite endpoint over the year-long study in more than 18,000 patients (Table 6) [96]. The APTC event rates were generally low, with 59 events (0.65%) reported with lumiracoxib compared with 50 events (0.55%) with the combined traditional NSAIDs [96]. Pairwise analysis of the different treatment arms also highlighted no differences (19 events with lumiracoxib vs. 23 with ibuprofen; 40 events with lumiracoxib vs. 27 events with naproxen) [96].