Nonopioid analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs), as well as acetaminophen. Examples of NSAIDs include ibuprofen, naproxen, celecoxib, and aspirin. They each work via slightly different mechanisms, but in general inhibit cyclooxygenase (COX), an enzyme involved in the conversion of arachidonic acid to prostaglandins, which are mediators of inflammation, fever, and pain.4, 5 The mechanism by which acetaminophen provides pain relief is less clear, but there is some evidence suggesting it involves the inhibition of prostaglandin synthesis in the central nervous system.4, 6
NSAIDs act peripherally, meaning they help with pain by reducing inflammation at the site where it is occurring. Alternatively, acetaminophen acts centrally by blocking the transmission of pain signaling within the central nervous system. Due to these differing mechanisms of action, taking NSAIDs and acetaminophen in combination has been shown to be highly effective in reducing mild to moderate pain, as the pain is being blocked at both ends of the nociceptive pathway.7
Acetaminophen and some NSAIDs (aspirin, ibuprofen, and naproxen sodium) are available to patients over-the-counter (OTC) in standard doses (e.g., 200 mg ibuprofen; 325 or 500 mg acetaminophen), but higher doses of these medications can be prescribed to patients. In 2020, the U.S. Food and Drug Administration approved an OTC fixed-dose combination product containing ibuprofen plus acetaminophen; each 2-caplet dose contains 250 mg ibuprofen and 500 mg acetaminophen.8 There are also several other NSAIDs only available with a prescription, such as celecoxib, ketoprofen, and diclofenac.7
Although effective in relieving acute pain, use of NSAIDs, especially long-term use, can be accompanied by adverse effects. Because prostaglandins have a role in gastrointestinal (GI) mucosal protection and also play an essential role in renal perfusion, by blocking prostaglandin synthesis, NSAIDs can cause GI and renal adverse effects. The most common adverse effect with NSAID use is GI toxicity, which can result in symptoms such as nausea, heartburn, abdominal pain, and bleeding. Additionally, NSAIDs may increase the risk of serious cardiovascular events and nephrotoxicity.4, 9 All prescription NSAIDs must display a black box warning that cardiovascular thrombotic events as well as gastrointestinal risks are possible when using the medication.4
Acetaminophen use has been associated with liver toxicity as well as other less serious adverse effects such as headache, agitation, and GI symptoms.4 Prescription acetaminophen must display a black box warning about hepatotoxicity, as taking over 4,000 mg per day has been associated with acute liver failure.4 Patients may be at risk of exceeding this 4,000 mg limit with OTC drugs, as there are many OTC combination drugs that contain acetaminophen as an active ingredient (i.e., cold and flu medications), and patients may unknowingly take more than one acetaminophen-containing drug at once.10 When NSAIDs are taken in combination with acetaminophen, there is little indication that adverse effects are any greater than those experienced with each drug individually.7