NSAIDs, or nonsteroidal anti-inflammatory drugs, are a class of medications that reduce pain, inflammation, and fever. The most familiar ones are ibuprofen (Advil, Motrin), naproxen (Aleve), and aspirin. But the NSAID family is much larger than those three drugstore staples, spanning dozens of prescription and over-the-counter options in oral, topical, and injectable forms.
How NSAIDs Work
All NSAIDs share the same basic mechanism: they block enzymes called COX-1 and COX-2, which your body uses to produce chemicals that trigger pain, swelling, and fever. By physically preventing these enzymes from doing their job, NSAIDs interrupt the inflammatory process at its source. That makes them fundamentally different from acetaminophen (Tylenol), which reduces pain and fever but does little for inflammation.
The distinction between COX-1 and COX-2 matters because it explains most of NSAIDs’ side effects. COX-1 helps maintain the protective lining of your stomach and supports normal kidney function. COX-2 is mainly active during inflammation. Older NSAIDs like ibuprofen and aspirin block both enzymes indiscriminately, which is why stomach irritation is such a common side effect. Newer prescription NSAIDs called COX-2 inhibitors (coxibs) were designed to target only the inflammation-related enzyme, sparing the stomach lining.
Over-the-Counter NSAIDs
Three NSAIDs are widely available without a prescription:
- Ibuprofen (Advil, Motrin): the most commonly used NSAID, effective for headaches, muscle pain, menstrual cramps, and mild arthritis pain.
- Naproxen sodium (Aleve): lasts longer than ibuprofen, so you take it less often. A single dose can provide relief for up to 12 hours.
- Aspirin (Bayer, Bufferin): the oldest NSAID, also used at low doses to reduce the risk of blood clots and heart attacks. Unlike other NSAIDs, aspirin permanently disables the COX enzyme in platelets, which is why it has unique blood-thinning properties.
These are available in standard strengths at pharmacies and grocery stores. Higher-dose versions of ibuprofen and naproxen exist but require a prescription.
Prescription NSAIDs
When over-the-counter options aren’t strong enough, or when a condition requires longer-term management, doctors prescribe from a wider range of NSAIDs. Some of the most commonly prescribed include:
- Celecoxib (Celebrex): a COX-2 selective inhibitor, often chosen for people with arthritis who need daily pain relief but are at higher risk for stomach problems.
- Meloxicam (Mobic): another COX-2 preferential NSAID, frequently prescribed for osteoarthritis and rheumatoid arthritis. Taken once daily.
- Diclofenac (Voltaren): available in oral tablets, topical gels, and patches. The topical gel version has moved to over-the-counter status in many countries.
- Indomethacin (Indocin): a potent NSAID often used for gout flares and certain types of inflammatory arthritis.
- Ketorolac (Toradol): one of the strongest NSAIDs available, typically used short-term for acute pain after surgery or injury.
- Mefenamic acid (Ponstel): commonly prescribed for menstrual pain.
- Piroxicam (Feldene): a long-acting NSAID used for arthritis, taken once daily.
Prescription NSAIDs are used to relieve pain from headaches, dental procedures, menstrual cramps, muscle injuries, post-surgical recovery, arthritis, and certain autoimmune conditions.
Topical NSAIDs
Not all NSAIDs come in pill form. Topical versions are applied directly to the skin over a painful joint or muscle. Diclofenac gel is the most widely available topical NSAID, sold under brand names like Voltaren and Pennsaid. Because the medication is absorbed through the skin at the site of pain, much less of it enters the bloodstream compared to a pill. This makes topical NSAIDs a practical option for localized joint pain, particularly in the knees and hands, when you want to minimize the systemic side effects that come with oral versions.
Cardiovascular and Heart Risks
The FDA requires all prescription NSAIDs to carry a boxed warning about cardiovascular risk. NSAIDs increase the chance of serious events including heart attack, stroke, heart failure, and atrial fibrillation. This risk can begin in the first weeks of treatment and climbs with higher doses and longer use.
For people without existing heart disease, the absolute risk is small: roughly one to two extra cardiovascular events per 1,000 people taking NSAIDs. Over a short course of less than a month, the likelihood is extremely low. But for people who already have cardiovascular disease, or who take high doses over long periods, the concern is more significant. The increased risk has been observed with both traditional NSAIDs and COX-2 selective inhibitors.
Stomach and Digestive Risks
NSAIDs can cause inflammation, bleeding, ulceration, and even perforation anywhere along the digestive tract, from the esophagus to the large intestine. These events can happen at any point during treatment, with or without warning symptoms. About 1% of people who take NSAIDs for three to six months develop a serious upper GI event such as an ulcer or significant bleeding. That figure rises to 2 to 4% after a year of use. Only one in five people who develop a serious upper GI complication had any warning symptoms beforehand.
Older adults and anyone with a history of peptic ulcers or GI bleeding face the highest risk. This is one reason doctors sometimes prescribe COX-2 selective NSAIDs like celecoxib for patients who need long-term anti-inflammatory treatment, since these drugs are gentler on the stomach lining.
Who Should Avoid NSAIDs
Certain medical conditions make NSAIDs risky enough that they should be avoided entirely. The National Kidney Foundation recommends that people with chronic kidney disease avoid NSAIDs, particularly if their kidney filtration rate (eGFR) falls below 60. NSAIDs reduce blood flow to the kidneys and can accelerate kidney damage in people whose kidneys are already compromised.
NSAIDs should also be avoided by people with liver disease, heart disease, heart failure, or uncontrolled high blood pressure. If you take blood pressure medications, particularly ACE inhibitors, ARBs, or diuretics, adding an NSAID can blunt their effectiveness and further strain the kidneys. Aspirin is sometimes an exception to these rules because of its unique role in preventing blood clots, but that’s a decision made on an individual basis.
NSAIDs vs. Other Pain Relievers
The most common source of confusion is the difference between NSAIDs and acetaminophen (Tylenol). Acetaminophen relieves pain and reduces fever but is not an anti-inflammatory. It works through a different pathway in the brain and carries virtually no risk to the stomach or cardiovascular system. On the other hand, it can cause serious liver damage at high doses or when combined with alcohol.
Because NSAIDs and acetaminophen work differently, they can sometimes be alternated or combined for pain that doesn’t respond well to either one alone. They are not interchangeable, though. For conditions driven by inflammation, such as arthritis, tendinitis, or a sprained ankle, NSAIDs are generally more effective because they target the underlying swelling, not just the pain signal.