Opioid Prescribing and Monitoring - (Second Edition)
Primary Care Models for Pain Management

Effective Alternative Treatments and How to Assess Whether They’re Working

Page 1 of 3

The recent emphasis on decreasing the use of opioid analgesics has contributed to an unfortunate side effect: many patients are struggling to receive adequate pain management. This unintended consequence can profoundly affect the quality of life and function of millions of patients. In this chapter, the authors review some effective opioid alternatives that may help providers manage their patients’ chronic pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of medications within the available pain pharmacotherapy arsenal. Other alternatives, such as acetaminophen and topical medications, can be highly effective in sparing opioids or in targeting localized pain generators.


NSAIDs encompass a class of medications available over the counter (OTC) or via prescription that are widely used to treat inflammation, pain, and fever. The modern age of NSAID agents began in 1965 with the approval of indomethacin, the first non-aspirin NSAID.1 While still demonstrating considerable gastrointestinal (GI) upset, indomethacin showed enormous improvement over aspirin in reducing “pill burden” and acid load, and in increasing overall tolerability.

In 1971, British pharmacologist Sir John Vane described inhibition of prostaglandin synthesis as the mechanism of action for aspirin and NSAIDs, and he won the Nobel Prize in 1982 for his work.2 Prostaglandins help regulate a variety of physiological functions, including inflammation, pain, fever, platelet aggregation, mucosal protection in the GI tract, and renal function.3,4 NSAIDs inhibit biosynthesis of prostaglandins by preventing the substrate arachidonic acid from binding to the active site of cyclooxygenase (COX) enzymes.5

The 2 known isoforms of the COX enzyme, COX-1 and COX-2, each have distinct physiological roles. COX-1 is constitutively expressed in nearly all cells; it regulates function in the GI tract, kidneys, and platelets. COX-1 produces vasoactive substances such as thromboxane and prostacyclin in equal amounts, thereby maintaining a balance.6 COX-2 is expressed in the brain, kidneys, and blood vessels—the areas most susceptible to thrombotic events. Expression of COX-2 can be induced by cytokine release due to injury or inflammation.7-11

Vane’s discovery sparked an NSAID research renaissance that yielded
15 new agents from 1976 to 1991. While more than 25 NSAIDs are now available, physicians should recognize that they belong to different pharmacologic classes with distinct properties (Figure 1, page 60). Each agent also has unique features such as varying levels of selectivity, efficacy, and toxicity.


Both aspirin and NSAIDs bind to the same COX-1 enzyme and can increase bleeding risk; the profound difference is how they bind and how long their effects last. NSAIDs bind reversibly to COX-1 enzymes and inhibit platelet function for the duration of binding, which is usually shorter than their duration of action. This means that NSAIDs must be taken consistently to increase the risk of bleeding. Approximately 5 half-lives (usually 1 to 4 days depending on the specific NSAID) are sufficient to completely clear the medication from the body and eliminate any associated bleeding risk. Aspirin, however, binds irreversibly to COX-1 enzymes. Since platelets are anucleated, they do not recover and remain inhibited for their entire life cycle (7 to 10 days).12 Therefore, the bleeding risk of aspirin, even at low doses, is profoundly higher than that of any other NSAID.

Despite these differences, patients are often asked to stop taking NSAIDs 7 to 10 days before a procedure or surgery, resulting in unnecessary discomfort and decreased ability to function. Patients who require aspirin for its cardio-protective effects should be counseled to take it at least 30 minutes prior to non-aspirin NSAIDs to receive the intended benefits.12

Many clinicians assume aspirin and NSAIDs are the same. This conflation can lead to inappropriate use and avoidable suffering. Aspirin is rarely used as an anti-inflammatory in modern medicine because very high doses (≥ 3 g/day) are required for efficacy but are generally not well tolerated.13,14 Instead, aspirin is primarily used as a cardioprotective antiplatelet agent, for which it is highly effective at even low doses (≤ 81 mg/day).12

Adverse Effects and FDA Warnings

Although the potential adverse effects of NSAIDs have been extensively studied and reported on over the past 20 years (see below), widespread confusion still exists about their risks and benefits.

In 2005, the US Food and Drug Administration (FDA) released a boxed warning for all NSAIDs that stated, “NSAIDs are associated with an increased risk of adverse cardiovascular [CV] thrombotic events including myocardial infarction and stroke; and NSAIDs may increase risk of GI irritation, inflammation, ulceration, bleeding, and perforation. These events may occur at any time during therapy and without warning.”15

In July 2015, the FDA strengthened the warnings for CV events with NSAIDs as a class effect.16 Every new NSAID approved over the past 20 years has attempted to improve the safety of these medications by lowering their GI or CV risk profile. The preferred hypothesis for many NSAID side effects is an imbalance between prostacyclin and thromboxane.6,17

Gastrointestinal Adverse Effects

Because COX-1 inhibition directly affects platelet aggregation, the degree to which an NSAID inhibits COX-1 plays an integral role in determining a patient’s bleeding risk.6,12 Strong COX-1 inhibitors, with > 50x selectivity (eg, indomethacin, tolmetin, piroxicam, and sulindac), are associated with more GI ulcers and bleeding.7,18 In 2010, an estimated 7,215 deaths were attributed to GI bleeds, one-third of which were blamed on NSAID use.19 Assessing the true GI risk of NSAIDs is difficult because they are commonly used inappropriately and/or in combination therapy. An estimated 12% of the general population uses NSAIDs regularly (at least 3 times per week for more than 3 months). A separate survey found that roughly 40% of respondents use both prescription and OTC NSAIDS, and that 29% believe OTC NSAIDs are safer than prescription NSAIDs.3,5,20 These NSAID usage patterns and perceptions are important because nearly 30% of GI bleeds are associated with aspirin use alone. The risk of bleeding can increase significantly for the estimated 16% of the population using NSAIDs and aspirin together.21 Clinicians should counsel patients to avoid concomitant use of prescription and OTC NSAIDs/aspirin, and should provide strategies for GI protection, if appropriate. At higher doses, all NSAIDs lose selectivity as they significantly inhibit both COX-1 and COX-2 and dramatically increase the risk of adverse effects, as demonstrated in the study that prompted the FDA’s 2015 NSAID class warnings on CV risk (Figure 2, page 62).22

Last updated on: September 13, 2017
Continue Reading:
Buprenorphine and Surgery: What’s the Protocol?
close X