NSAID Pharmacology

NSAIDs alleviate pain, inflammation and fever, by inhibiting the formation of prostanoids, which reduce the threshold to stimulation of peripheral nociceptors, increase the excitability of spinal sensory neurons and stimulate thermo sensitive neurons in the preoptic area of the brain (1). The major NSAID side effects are caused by coincident inhibition of cytoprotective and homeostatic prostanoids. Thus, despite their efficacy in the relief of pain and inflammation, NSAIDs may be associated with gastrointestinal complications, including serious bleeds. COX-2 selective pdNSAIDs, have been shown to reduce the incidence of these bleeding events, but are more likely to cause serious cardiovascular events than nonselective drugs (2). All NSAIDs have been reported to elevate blood pressure and/or cause salt retention and edema, although they do so to variable degrees amongst individuals, if at all.

1. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J Lipid Res. 2009;50 Suppl:S423-8. PMCID: PMC2674745
2. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116(1):4-15. PMCID: PMC1323269

Why NSAIDs?

We have chosen to focus on efficacy and cardiovascular risk from NSAIDs for several reasons.

• Pain is the nation’s leading cause of disability - about 1 in 5 US adults suffer from intermittent or chronic pain - and NSAIDs are amongst the most commonly prescribed drugs. More than 20 members of the class are on the US market today in a total of almost 1000 brands, doses and dosage forms. There is no controlled evidence as to whether there are differences in efficacy amongst these compounds and if there are differences in efficacy, why?
• Aside from their value in the relief of pain and inflammation, NSAIDs have been associated with the risk of gastrointestinal bleeds and cardiovascular events, such as myocardial infarction, stroke and heart failure. Although relatively rare, both gastrointestinal (GI) and especially cardiovascular (CV) adverse events on NSAIDs may be fatal (1-2). Placebo controlled trials demonstrated that NSAIDs purposefully designed (pd) to inhibit specifically cyclooxygenase (COX)-2, such as rofecoxib (Vioxx ®), celecoxib (Celebrex ®) and valdecoxib (Bextra ®) conferred a CV hazard and accounted for many thousands of excess deaths (3). However, many of the commonly used traditional (t)NSAIDs also inhibit COX-2 with specificity. Although more than 100,000 patients have been included in randomized controlled trials (RCTs) of NSAIDs, we still do not know the NSAID of choice – even in terms of average safety and efficacy – for patients with concurrent arthritis and cardiovascular disease.
• While both the efficacy and risk of NSAIDs are mechanistically explicable in terms of COX inhibition (3), many other unknown factors must contribute to whether either benefit or risk or both occur in an individual patient.
• Antecedent experience (3) affirms the utility of model systems (fish, mice, hamsters, dogs) at least in the prediction and mechanistic elucidation of CV risk.
• Alternative analgesic medication classes are few and associated with distinct and serious risk profiles of their own (e.g. opioids).
• We have focused on pain and CV risk as quantitative surrogates of efficacy (e.g. fMRI and analog scales) and CV risk (e.g. blood pressure) which are readily tractable.
   

1. Bombardier C. An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol. 2002;89(6A):3D-9D.
2. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: A randomized controlled trial. Lancet. 2004;364(9435):665-74.
3. Grosser T, Yu Y, Fitzgerald GA. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med. 2010;61:17-33.