NSAIDs: Balancing the Risks and Benefits

Abstract and Introduction

Abstract

In July 2015, the FDA updated the label warnings on nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) as a result of findings presented at the joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee in February 2014. These warnings reflect new data that show NSAIDs have a higher risk of cardiovascular toxicity than previously suspected. Pharmacists need to weigh the risks and benefits of NSAID use with regard to the safety issues and the clinical implications of the newest FDA label changes to optimize patient care.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used drug classes in the world.^[1] It is estimated that more than 30 million people use these medications on a daily basis, and they account for 60% of the analgesic market in the United States.^[2] There are approximately 20 different OTC and prescription NSAIDs available in the U.S. (Table 1).^[1,3] NSAIDs are used for the treatment of fever, acute or chronic pain, and inflammation caused by a variety of conditions.

The mechanism of action of NSAIDs involves inhibition of cyclooxygenase-1 (COX-1) and/or COX-2 enzymes. COX-1 catalyzes the production of prostaglandins involved in various physiological functions (i.e., maintenance of renal function, mucosal protection in the gastrointestinal [GI] tract, platelet activation). COX-2 is expressed as part of the inflammatory response, resulting in vasodilation, platelet inhibition, and inhibition of smooth cell proliferation. The inhibition of COX-2 by NSAIDs plays a role in mediating pain, fever, and inflammation.^[2,4] Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes. Inhibition of COX-1 results in an increased risk of GI bleeding.

COX-2 selective NSAIDs were developed to maintain analgesia efficacy while minimizing the GI effects associated with COX-1 inhibition.^[4] Despite the potential GI benefit, COX-2 selective NSAIDs are presumed to have a higher risk of cardiovascular (CV) events.^[5] In 2004, a prospective analysis was performed to evaluate adverse drug reactions as a cause of hospital admission in patients >16 years of age.^[6] NSAIDs accounted for 29% of the cases leading to hospital admission. The adverse events observed included GI bleeds, peptic ulceration, hemorrhagic cerebrovascular accidents, and renal impairment.^[6] Although NSAIDs are effective, widespread use presents risks that can increase with long-term use and higher doses. In response to these risks, the FDA recently updated previous warnings regarding NSAID use.

Table 1. Common Oral NSAIDs
Generic	Brand	Max Daily Dose
OTC
Ibuprofen	Advil, Motrin	1,200 mg
Naproxen	Aleve	1,500 mg
Prescription
Celecoxib	Celebrex	400 mg
Diclofenac	Voltaren	200 mg
Diflunisal	N/A	1,500 mg
Etodolac	N/A	1,000 mg
Flurbiprofen	Ansaid	300 mg
Ibuprofen	N/A	3,200 mg
Indomethacin	Indocin	200 mg
Ketoprofen	N/A	300 mg
Ketorolac	Toradol	40 mg (max 5 days of total treatment)
Meloxicam	Mobic	15 mg
Nabumetone	N/A	2,000 mg
Naproxen	Naprosyn	1,500 mg
Oxaprozin	Daypro	1,800 mg
Piroxicam	Feldene	20 mg
Sulindac	Clinoril	400 mg

max: maximum; N/A: not applicable; NSAID: nonsteroidal anti-inflammatory drug. Source: References 7, 22.

Table 2. Risk of GI Toxicity
High Risk
History of a previously complicated ulcer, especially recently
Multiple (>2) risk factors
Moderate Risk (1–2 risk factors)
Age >65 y
High-dose NSAID therapy
A previous history of an uncomplicated ulcer
Concurrent use of aspirin (including low-dose), corticosteroids, or anticoagulants
Low Risk
No risk factors