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Aspirin and Topical Pain Relief Products Revisited

Non-steroid anti-inflammatory drugs (NSAID) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), and acetaminophen (Tylenol) are powerful over the counter drugs. These drugs primarily work by inhibiting the body’s ability to synthesize prostaglandins. Prostaglandins are a family of hormone-like chemicals that are derived from polyunsaturated fatty acids, such as arachidonic acid (concentrated in butter, lard, animal fat, organ meats, egg yolk) and linoleic acid (concentrated in soy, corn, cottonseed, and safflower oils). The common mechanism of action for all NSAID drugs is the inhibition of the enzyme cyclooxygenase (COX). COX is necessary for the formation of prostaglandins. There are two COX enzymes, COX-1, a so-called housekeeping enzyme that is active all the time, and COX-2, which is involved in making prostaglandins important in the induction of inflammation, pain and fever.

Most NSAIDs inhibit both COX-1 and COX-2 enzymes. COX-1 is always active to some extent. COX-2 is only induced during an inflammatory response. Obviously it would be advantageous to have drugs that only inhibited the COX-2 enzyme. Two COX-2 inhibitors have been approved, Celebrex and Vioxx, and extensively marketed as treatments for rheumatoid arthritis, osteoarthritis and acute pain. COX-2 drugs are very expensive. Celebrex wholesales for $2.80 a pill, while Motrin (ibuprofen) can be purchased retail for less than 10 cents a pill. The only benefit of using Celebrex over ibuprofen, aspirin, etc. is that it does not inhibit COX-1 in the stomach thereby inducing gastric inflammation. If NSAID drugs are injected under the skin, they do not cause stomach upset.

It is possible to introduce NSAID and other drugs into the body using topical gels. When 600 mg ibuprofen is taken orally, it is completely cleared from the body in 24 hours (as determined by urine analysis). If ibuprofen is topically introduced, 99.5 % of the drug is still in the body after 24 hours. When a drug enters the body through the skin (without breaking the skin), it enters the lymph before it ever enters the blood. The lymph is actually the fluid that bathes each and every cell in the body. As blood moves through the arteries, and veins the liquid portion of the blood diffuses through the endothelial cells lining the blood vessels and enters the tissue spaces. The lymph fluid transports oxygen, glucose, hormones, amino acids and other nutrients to the tissues. Eventually, the lymph fluid is collected in special lymphatic ducts and returned to the blood. When a molecule is injected into the blood, it is rapidly cleared from the blood by the kidneys or it is degraded in the blood by various enzymes. If the molecule is taken up into the blood from the intestines (as when the molecule is consumed as a food or supplement) the “first pass phenomenon” through the liver results in much of the product being chemically modified and returned to the intestines for disposal as excrement. The cells lining the intestinal wall also rapidly return molecules to the lumen (interior) of the intestines after they are absorbed. In the final analysis, it is difficult to “force” the body to take up medicinal compounds when they are introduced via the oral route. If they are injected, the kidneys clear small compounds from the blood rapidly. There is a better method of introducing medicinal compounds into the body.

Aspirin is a powerful drug, but its half life in the blood is only about two hours. In order to reduce inflammation and pain in the joints, for example, it would be necessary to increase the level of aspirin in the blood to about 5mM. This really isn’t possible. Most studies agree that blood concentrations of aspirin rarely rise above 2mM when orally consumed. Enteric formulations of aspirin and other NSAID (or gel caps) simply slow the release of aspirin into the cells lining the stomach. Most NSAID drugs are poorly soluble in water at neutral pH. The pH of the blood is 7.4. Aspirin and other NSAID drugs are soluble in stomach acid when the pH is about 2. At this pH, these drugs rapidly enter the cells lining the stomach and induce gastritis or inflammation. Herein lies the problem. NSAID drugs are anti-inflammatory but they have to pass through the stomach lining in order to enter the blood. In their passage from the stomach lining to the blood, they inhibit the COX-1 enzyme that maintains the integrity of the stomach lining. In short, these anti-inflammatory agents initiate an inflammatory response in their effort to reach the blood. It sounds like a contradiction in terms, but the problems created by the oral ingestion of NSAID drugs can be quite serious. Stomach cells are very sensitive to very low concentrations of aspirin (one inhibitor of the COX-1 enzyme). In order to inhibit the COX-2 enzyme and other pro-inflammatory mediators, the level of aspirin would have to increase over 20 fold from the level found to induce gastritis. It is obvious that the oral delivery of these drugs is far from medically optimal. Specific COX-2 inhibitors are a step in the right direction, but they are very expensive, and require a prescription. We have adopted a different approach to the control of inflammation and pain that involves the topical introduction of natural molecules, such as the flavonoids found in fruit and vegetables, directly into the body at sites of inflammation and pain.

Flavonoids are nature’s answer to synthetic anti-inflammatory agents. They are very potent anti-inflammatory agents, but they apparently do not directly inhibit the COX-1 enzyme. They do inhibit the COX-2 enzyme and a host of additional pro-inflammatory enzymes and hormones. In fact, flavonoids in general are much more anti-inflammatory than pharmacological doses of NSAIDs (in some case they are 100 times more anti-inflammatory). The ingestion of flavonoids in food or in supplement form does not cause gastric inflammation. Flavonoids are found in virtually all vegetables and fruits. Although there are 4000 different types of flavonoids, one flavonoid is worthy of special mention. There must be 500 to 1000 scientific articles written in the last 30 years on the biochemistry of quercetin. It is an amazing molecule, but bioavailability, or the uptake of quercetin into the blood, is a problem. Quercetin is completely insoluble in water. It is very soluble in alcohol, however, and it readily crosses the skin when the alcohol extract is mixed with certain oils and chemical enhancers. Yellow onions contain the highest concentration of quercetin of any vegetable or fruit. When adults are fed large amounts of onions, only a small amount of quercetin can be found in the blood, approximately 2microM. This concentration is too small to be anti-inflammatory. Remember, most scientific studies are done in a tissue culture dish or in mice. The quercetin doses scientists use cannot be reached in the human body by the oral ingestion of food or most supplements (unless you are ingesting gram quantities of quercetin supplements). I have found that quercetin and many other natural and synthetic molecules can be rapidly carried across the skin at sites of inflammation and pain. This method allows relatively low amounts of flavonoids, aspirin, whatever, to act as site-specific anti-inflammatory/anti-pain agents.

To date, we have made lotions that contain aspirin, ibuprofen, naproxen and various natural compounds such as quercetin and applied them to the skin of people suffering from chronic lower back and neck pain, rotator cuff inflammation, Achilles tendon inflammation, and elbow and foot gout. In each case, the inflammation/pain was either completely eliminated or greatly reduced. This anecdotal evidence is even more significant when you consider that we are applying very low doses to the affected areas. If we add menthol or another vasodilator to the formula, the medicinal compounds enter the body even faster. It is virtually impossible to develop a contact or delayed hypersensitivity reaction to the ingredients in the lotion. Quercetin is quite immunosuppressive, which is exactly what you would expect from a powerful anti-inflammatory agent.

86 million people suffer from chronic pain in the US. Although these lotions were not designed to be treatments for rheumatoid arthritis, they can be reformulated to treat malignant inflammatory diseases as well. FDA approval is not required for a topical pain relief product that is herbal (it is a supplement topically applied), but treating arthritis would require a clinical trial. This should not be difficult since all the ingredients are natural and completely safe. We can manufacture aspirin, ibuprofen, naproxen and acetaminophen creams that are 100s if not thousands of times more powerful than the oral formulation. Medicinal creams can place the NSAIDs directly over the areas of inflammation, such as elbow, knee, lower back, neck, etc. Pain relief products, such as Aspercream, do not actually contain aspirin. Aspirin will not cross the skin without substantial help. These OTC products all contain methyl salicylate or another salicylate, plus menthol, wintergreen, or capsaicin, the “heat” in chili powder. All these products have to be constantly reapplied and produce only a temporary relief of pain. Our products produce a profound, long lasting relief of pain. A formal, FDA approved clinical trial will not be difficult to design and conduct. These NSAIDs are already approved by the FDA as OTC anti-inflammatory products. We are simply reformulating them into products that are both safer (no gastric discomfort) and more efficacious.

Copyright © 2002, Stephen Martin, Ph.D
Chief Scientist, Grouppe Kurosawa
All Rights Reserved
http://grouppekurosawa.com
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He used to have the actual formula for making topical pain relievers on the web site. Now they can be found in a book. Available at amazon.com -- just search under Stephen Martin's name. Dear Steve died recently -- a great loss to to those who believe in alternative therapies.

When ibuprofen came out in gelcaps, it made the making of the topical much easier -- IIRC, just open a gel cap, squeeze out the gel, mix with a little DMSO cream (from health food store) and apply topically. One application was supposed to last for days. I might try this. Or just buy topical ketoprofen at amazon.