**2. NSAIDs**

Nonsteroidal anti-inflammatory drugs (NSAIDs) were first introduced in the 1960s and are the most prescribed medication class in the world. The United States issues more than 100 million prescriptions annually [3] with approximately 20% of its citizens using NSAIDs on a frequent monthly basis at some point during their lifetime [4].

NSAIDs are a diverse group of compounds with varying chemical structures that possess anti-inflammatory, antipyretic, and analgesic properties [5]. They represent a class of drugs with a primary mechanism of action that involves inhibition of the pro-inflammatory cyclooxygenase (COX) enzymes. This includes both nonselective COX inhibitors (COX-1 and COX-2) including aspirin, indomethacin, and ibuprofen as well as the newer selective COX-2 inhibitors such as celecoxib. NSAIDs have an established short-term efficacy in the treatment of osteoarthritis (OA) and associated chronic low back pain as well as an opioid sparing effect when combined with most chronic pain management regimens [6, 7]. Despite the well-documented efficacy of NSAIDs, there are serious side effects associated with routine use that include gastrointestinal irritation (gastritis and ulceration of the stomach and small

intestine), cardiovascular events (myocardial infarction, hypertension exacerbation) and renal toxicity (acute renal failure, electrolyte and fluid abnormalities).
