Nonsteroidal Anti-Inflammatory Drugs

Arjun Sharma, MD

Erielle Anne P. Espina, PharmD

Charity Hale, PharmD

FAST FACTS

Nonsteroidal anti-inflammatory drugs (NSAIDs) can be useful for acute and chronic inflammatory pain conditions as well as fever.
NSAIDs should be used at the lowest dose possible for the shortest time needed and evaluated frequently.
NSAIDs can cause significant gastrointestinal, cardiovascular, and renal side effects.
Some NSAIDs confer less risk than others, especially with regard to gastrointestinal (GI) and cardiovascular (CV) complications. However, all non-ASA NSAIDs increase the chance of myocardial infarction or cerebrovascular accident.

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used medications to help treat acute and chronic pain conditions. Although NSAIDs are very effective for many of our patients, they are not without risk. Use of NSAIDs can be associated with kidney damage, GI bleeding, and cardiovascular risk. Understanding such risks will allow the practitioner to decide whether it is appropriate to use NSAIDs, given a patient’s comorbid conditions. Likewise, the practitioner may consider options to mitigate some of the side effects of NSAIDs. For example, alternating daily between an NSAID and acetaminophen can decrease chronic exposure of NSAIDs, reduce the risk of GI bleed, prevent kidney damage, and provide satisfactory analgesia. Similar risk reduction strategies for the use of pain medications are further discussed in chapter 5 Rational Analgesic Poly Pharmacotherapy.

INDICATIONS AND MECHANISM OF ACTION

NSAIDs are indicated to treat fever and multiple types of pain including mild to moderate, acute, dental, musculoskeletal (e.g., sprains and strains), and inflammatory (e.g., bone pain, joint pain, ankylosing spondylitis, rheumatoid arthritis, and osteoarthritis), as well as dysmenorrhea.

Inflammatory prostaglandins are synthesized from arachidonic acid via the cyclooxygenase-2 (COX-2) pathway. These prostaglandins serve an important role in recruiting inflammatory cells, sensitizing pain receptors, and regulating hypothalamic temperature control. Nonselective agents and celecoxib inhibit the COX-2 pathway, decreasing inflammation, pain, and fever.¹ Because NSAIDs also reduce fever, it is important to understand that if treating a painful condition, an underlying infection may be masked particularly during the postsurgical period. Therefore, it is essential to integrate clinical acumen in determining appropriate use while accounting for temporal impact.

Cytoprotective prostaglandins are synthesized from arachidonic acid via the cyclooxygenase-1 (COX-1) pathway. These prostaglandins regulate renal blood flow, protect gastrointestinal mucosa, and aid in platelet activation and aggregation. Nonselective NSAIDs inhibit COX-1 enzymes potentially leading to renal dysfunction, GI complications, and cardiovascular events.² Unlike nonselective agents, celecoxib (a selective COX-2 inhibitor) does not affect platelet function.³

CONTRAINDICATIONS AND PRECAUTIONS

Cardiovascular Complications

NSAIDs increase the risk of cardiovascular thrombotic events, myocardial infarction, and stroke and are contraindicated following coronary artery bypass graft surgery per the Food and Drug Administration (FDA). These complications may occur early during NSAID therapy and increases with prolonged use. Although certain NSAIDs appear to confer lower overall CV risk than others, recent reviews have found that all NSAID therapies carry some risk, and in general, careful consideration should be given before recommending NSAIDs in patients with cardiovascular comorbities.⁴^,⁵

Furthermore, 20% to 25% of patients use both low-dose aspirin for secondary prevention and an additional NSAID for pain management. It appears that nonselective NSAIDs may impair the antiplatelet activities of aspirin. This interaction is more evident when nonselective agents are administered before the aspirin dose.⁶^,⁷ This is potentially due to the reversible binding properties of all NSAIDs apart from aspirin. With this being said, discontinuation of low-dose aspirin increases the risk of cardiovascular events more than 3-fold and by 90-fold in patients with intracoronary stents.⁷^,⁸^,⁹

GI Complications

More than 30 million people use NSAIDs every day, and over 40% of patients consume more than the recommended dose of over-the-counter (OTC) analgesics including NSAIDs and acetaminophen.⁷^,¹⁰^,¹¹^,¹² Endoscopic gastrointestinal (GI) lesions including hemorrhages, erosions, and ulcerations are seen in 30% to 50% of chronic NSAID users. Generally, these lesions have no clinical significance and are not symptomatic. It appears that the GI mucosa adapts to the presence of NSAIDs, and the lesions often reduce or disappear with chronic NSAID use.¹¹^,¹³^,¹⁴

Nearly 40% of NSAID users are symptomatic most frequently presenting as gastroesophageal reflux disease, heartburn, belching, epigastric discomfort, bloating, early satiety, and postprandial nausea.¹¹^,¹⁴ Serious complications including bleeding, perforation, and obstruction are seen in 1% to 2% of patients.¹¹ There are 7000 to 10,000 deaths associated with NSAID-induced GI complications each year.¹⁰^,¹⁵^,¹⁶^,¹⁷ These risks appear to be highest within the first month of therapy and remain elevated for up to 2 months after discontinuation.¹¹^,¹⁸

There are over 100,000 hospitalizations due to NSAID-induced GI complications each year.¹⁰^,¹⁵^,¹⁶^,¹⁷ Eighty-six percent of hospitalized patients with lower GI bleeds reported using NSAIDs or aspirin for a short duration, 7 days or less. Furthermore, the reported mortality rate due to bleeding associated with peptic ulcers is 5%.¹¹^,¹⁹^,²⁰^,²¹^,²²^,²³

NSAIDs increase the risk of developing peptic ulcers by 4 to 5 times.¹¹^,¹⁸^,²⁴^,²⁵ Additional risk factors that increase the likelihood of GI complications include age greater than 65 years, history of peptic ulcer disease or GI bleed, severe illness, concomitant therapy with more than one NSAID, antiplatelet agents, anticoagulants, corticosteroids, SSRIs (selective serotonin reuptake inhibitors), and SNRIs (selective norepinephrine reuptake inhibitors) as well as the synergistic combination of Helicobacter pylori and NSAIDs.¹¹^,²⁵^,²⁶

Ibuprofen may be a safer option because of lower doses needed to achieve adequate analgesia. Nonselective agents with a higher selectivity for COX-2 (nabumetone, meloxicam, and etodolac) also appear to cause less GI harm.¹⁵^,²⁷ On the other hand, agents with longer half-lives (ketorolac, piroxicam, and sulindac) provide longer exposure to the GI mucosa increasing the risk for complications.¹¹^,¹⁵^,²⁸

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