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Management of osteoarthritis with the COX-2 selective inhibitor meloxicam

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Management of osteoarthritis with the COX-2 selective inhibitor meloxicam

  1. 1. Management of osteoarthritis with the COX-2 selective inhibitor meloxicam [EXCERPT] Copyright © by Lorena Tonarelli, M.Sc. 2014 Prostanoids are generated intracellularly by the action of the cyclooxygenase (COX) enzymes COX-1 and COX-2 on arachidonic acid, an unsaturated fatty acid stored in the cell membrane. Arachidonic acid is first released by phospholipases in the intracellular space, where it is converted to prostaglandin H2 (PGH2) by the cyclooxygenases and, subsequently, metabolized to prostanoids by tissue-specific synthases. (Funk 2001; Gryglewski 2008; Smyth 2009) Currently available non-steroidal anti-inflammatory drugs (NSAIDs) include traditional NSAIDs and selective NSAIDs. Traditional NSAIDs are non-selective COX inhibitors; they halt the formation of both COX-1 and COX-2 dependent prostanoids; diclofenac, ibuprofen and naproxen are among the most commonly used of these agents. Selective NSAIDs predominantly prevent either COX-1 or COX-2 dependent prostanoids formation; meloxicam and celecoxib are selective COX-2 inhibitors. (Rao 2008; Smyth 2009) The variation in COX selectivity results in differences, between selective and traditional NSAIDs, in terms of safety profile. COX-2 dependent prostanoids are primarily involved in pathophysiological processes like inflammation, fever and pain; COX-1 dependent prostanoids mainly serve physiological functions like gastrointestinal (GI) cytoprotection, platelet aggregation and vascular tone regulation. (Rao 2008; Smyth 2009) Therefore, although all NSAIDs have anti-inflammatory, antipyretic and analgesic benefits, non-selective and COX-1 selective ones carry a greater risk for serious gastrointestinal adverse events, including ulceration, bleeding and perforation, compared with COX-2 selective inhibitors. (Rao 2008; Smyth 2009) The improved gastrointestinal safety of the latter has been confirmed in large randomized trials, (Bombardier 2000; Schnitzer 2004) but comes at the price of an increased risk for cardiovascular complications (e.g., myocardial infarction, stroke and thrombosis) compared with traditional NSAIDs. (Grosser 2006;Capone 2010) However, a recent meta-analysis of randomized trials concluded that the vascular risks of high-dose diclofenac, and possibly ibuprofen, are similar to those of selective COX-2 inhibitors. (CNT Collaboration 2013) 1
  2. 2. Multiple challenges Clearly, when considering treatment with a COX-2 selective NSAID such as meloxicam, physicians face a considerable challenge, because they need to minimize the risk of adverse events and, at the same time, ensure that their patients gain maximum benefit from the treatment. The challenge is greater when treating older osteoarthritis (OA) patients, who are inherently at risk of both cardiovascular and gastrointestinal complications. (van Leerdam 2003; Thomopoulos 2004) Since the latter are the most common complications associated with oral NSAIDs treatment, preventing gastrointestinal bleeding, ulcers and perforation is the main goal. (Lazzaroni 2009) Randomized studies suggest that meloxicam carries a lower risk of GI adverse events than traditional NSAIDs such as diclofenac and piroxicam when administered in 7.5 to 15 mg daily doses and for a limited amount of time – one month for meloxicam 7.5 mg daily, and up to two months for meloxicam 15 mg daily. (Lund 1998; Shoenfeld 1999 cited by Degner et al. 2001; Yocum 2000; Chen 2011) The problem is that the majority of osteoarthritis patients need treatment for considerably longer periods. Furthermore, some patients do not respond to treatment with meloxicam and continue to experience pain. (Park 2011) Work conducted by Park et al. (2011) suggests that both issues could be addressed by administering meloxicam in combination with analgesics that have a different mechanism of action. In one randomized trial, knee OA patients with unresolved pain received meloxicam (7.5 or 15 mg daily) in combination with tramadol/APAP (tramadol 37.5 mg/acetaminophen 325 mg) for four weeks. Pain decreased significantly in 67.8 percent of patients (p<0.0005), and the improvement was maintained for another eight weeks, during which patients received meloxicam or tramadol/APAP alone. Side effects were mild and well tolerated for both combination and mono therapy. However, these results may not apply to all older knee osteoarthritis patients, such as those on certain antidepressants or with dementia, as these were excluded from the study. (Park 2011) The management of older OA patients is further complicated by the presence of additional risk factors for gastrointestinal complications, such as prior GI history, active ulcers, Helicobacter pylori infection, a diagnosis of Alzheimer’s disease, and the concomitant use of other medications, including diuretics, corticosteroids and low-dose aspirin. (Pilotto 2006; Chen2008; Venerito 2010; Wu 2011) 2

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