NSAIDs and Their Mechanism of Action
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), and acetaminophen (Tylenol) are powerful over-the-counter drugs. These medications inhibit the body’s production of prostaglandins—hormone-like chemicals derived from polyunsaturated fatty acids.
These fatty acids include arachidonic acid, found in butter, lard, animal fat, organ meats, and egg yolk, and linoleic acid, found in soy, corn, cottonseed, and safflower oils. The common target of all NSAIDs is the enzyme cyclooxygenase (COX), which is essential for prostaglandin formation.
There are two COX enzymes. COX-1 is always active and plays a protective role in the body, especially in the stomach. COX-2 is activated during inflammation and is responsible for pain and fever responses.
COX-2 Inhibitors: Targeted but Costly
Most NSAIDs inhibit both COX-1 and COX-2. While COX-1 has constant activity, COX-2 is only induced during an inflammatory response. Drugs that selectively block COX-2 are ideal for reducing pain and inflammation without irritating the stomach lining.
Celebrex and Vioxx are two such COX-2 inhibitors. They were widely promoted for conditions like rheumatoid arthritis, osteoarthritis, and acute pain. However, these drugs are expensive—Celebrex, for example, wholesales at $2.80 per pill, whereas generic ibuprofen can cost less than 10 cents.
The primary benefit of Celebrex is that it does not inhibit COX-1 in the stomach, reducing the risk of gastric inflammation. NSAIDs do not cause stomach upset when injected or introduced through the skin.
Topical Drug Delivery and Retention
NSAIDs and similar drugs can be administered through topical gels. When 600 mg of ibuprofen is taken orally, it is fully cleared from the body within 24 hours. In contrast, when introduced through the skin, 99.5% of the drug remains in the body after 24 hours.
Drugs that pass through the skin first enter the lymphatic system before reaching the bloodstream. Lymph fluid surrounds all body cells and delivers nutrients like oxygen, glucose, hormones, and amino acids. Eventually, lymph is collected and returned to the blood.
When a drug enters the blood directly—either by injection or through absorption in the intestines—it is rapidly cleared by the kidneys or broken down by enzymes. Oral supplements are further degraded by liver metabolism or expelled by the intestinal lining.
This makes it difficult to introduce many medicinal compounds effectively via oral routes. Injected drugs are quickly filtered out, which limits their impact. A more effective method involves delivering these compounds through the skin.
The Problem with Oral NSAIDs
Aspirin is a powerful drug, but its half-life in the bloodstream is only about two hours. To meaningfully reduce joint pain and inflammation, blood levels of aspirin would need to reach around 5 mM. This is difficult to achieve through oral dosing. Most studies report peak levels below 2 mM after oral administration.
Delayed-release versions of aspirin only slow its absorption in the stomach but do not address the root issue. NSAIDs are poorly water-soluble at the body’s natural pH of 7.4. They dissolve in the acidic environment of the stomach (pH ~2), where they can easily penetrate the stomach lining and trigger inflammation.
Ironically, in an effort to reduce inflammation, NSAIDs must pass through and irritate the stomach lining. This happens because they inhibit COX-1, which protects the stomach. Even small amounts of aspirin can trigger gastritis. Achieving effective COX-2 inhibition would require aspirin levels 20 times higher than those that induce stomach irritation.
Clearly, oral delivery of NSAIDs is not optimal. COX-2 inhibitors are better in theory, but they are costly and require prescriptions.
A Different Approach: Topical Flavonoids
An alternative approach involves delivering natural compounds like flavonoids directly through the skin at sites of inflammation and pain. Flavonoids are potent anti-inflammatory agents. Unlike NSAIDs, they do not block COX-1 but selectively inhibit COX-2 and other pro-inflammatory enzymes and hormones.
In fact, many flavonoids are significantly more effective than NSAIDs—some are 100 times more anti-inflammatory. They also do not cause gastric irritation when consumed in food or supplements.
Flavonoids are found in nearly all fruits and vegetables. Among them, quercetin stands out. With 500 to 1000 scientific papers dedicated to its study, it’s one of the best-understood flavonoids. However, quercetin has poor bioavailability—it does not dissolve in water and is poorly absorbed through the digestive tract.
Transdermal Quercetin and Its Benefits
Quercetin is soluble in alcohol and can easily cross the skin with certain oils and penetration enhancers. Yellow onions contain the highest levels of quercetin among common vegetables, yet even large dietary amounts result in only low blood levels—around 2 µM—far below the therapeutic threshold.
Most scientific research on quercetin is conducted in lab cultures or in animals. To achieve therapeutic effects in humans, much higher concentrations are needed—levels that are nearly impossible to achieve through oral intake alone.
Contrastingly, topical application allows quercetin and similar compounds to enter the body directly at targeted sites. This enables low doses to function effectively as localized anti-inflammatory and pain-relieving agents.
Real-World Results from Topical Applications
Lotions containing aspirin, ibuprofen, naproxen, and natural compounds like quercetin have been used on people with chronic pain. Conditions treated include lower back and neck pain, rotator cuff issues, Achilles tendon inflammation, and gout in the elbow or foot. In every case, pain and inflammation were either eliminated or significantly reduced.
This outcome is even more impressive, considering the low doses used. When menthol or another vasodilator is added, absorption improves further. These formulations are very unlikely to trigger allergic reactions. Quercetin itself is immunosuppressive, a typical feature of strong anti-inflammatory agents.
A Safer, More Effective Option
About 86 million Americans suffer from chronic pain. Although these lotions are not designed to treat rheumatoid arthritis, they could be reformulated. FDA approval is not required for herbal topical products marketed as supplements, but clinical trials would be needed to position them as treatments for diseases like arthritis.
This would be a manageable process, as the ingredients are natural and considered safe. Topical formulations of NSAIDs such as aspirin, ibuprofen, naproxen, and acetaminophen can be vastly more effective than oral versions.
Topical NSAIDs can be applied directly to inflamed areas—such as the elbow, knee, lower back, or neck—where they act locally. Over-the-counter creams like Aspercreme don’t actually contain aspirin. Instead, they use methyl salicylate or similar compounds, along with menthol or capsaicin. These ingredients provide short-lived pain relief and must be reapplied frequently.
By contrast, the topical formulations described here produce long-lasting and substantial pain relief. Given that the NSAIDs involved are already approved for over-the-counter use, a properly designed FDA trial would be relatively simple to conduct. Reformulating them into a safer and more effective topical version represents a logical and accessible next step in pain management.
Credited to: Stephen Martin, Ph.D
Chief Scientist, Grouppe Kurosawa
All Rights Reserved