DISPATCHING PAIN
Transdermal NSAID delivery offers equivalent efficacy sans gastric side effects
Nonsteroidal antiinflammatory drugs (NSAIDs) have been historically effective and widely prescribed for the treatment of osteoarthritic pain and inflammation. They attenuate the inflammatory reactions that cause joint swelling and pain by inhibiting the cyclooxygenase enzyme that converts arachidonic acid to prostaglandin, a major inflammatory mediator in arthritis. Another mechanism suggests that the benefits of NSAIDs on rheumatoid arthritis may also be caused by significant reduction in free radical formation.
Needless to say, most patients with inflammatory joint disorders benefit from the liberal use of NSAIDs when administered in sufficient doses. The therapeutic efficacy, however, would come at a price. "Cytoprotection" describes the protective effect of the prostaglandins against gastric ulcers in animals at low doses, and inhibit gastric-acid secretion at higher doses. With chronic NSAID use, prostaglandin depletion becomes manifest with gastric injury.
NSAIDs are associated with serious gastrointestinal complications such as ulcerations, perforations, and hemorrhage. Chronic users are at least thrice at greater risk for complications than nonusers. At the usual dosage, the main adverse effect is gastric upset (intolerance). The gastritis that occurs may be because of irritation of the gastric mucosa by the undissolved tablet, absorption in the stomach by nonionized salicylates, or inhibition of protective prostaglandins. Experimental and epidemiological studies document an increased incidence of gastric and duodenal ulcers with heavy NSAID use. Upper gastrointestinal bleeding would also be closely associated with erosive gastritis.
Patching up the wound
Piroxicam belongs to a newer class of NSAIDs called oxicam, which are highly effective for chronic disease because of its long half-life (45 hours), permitting once-daily dosing. Oral piroxicam therefore enhances compliance among patients with osteoarthritis, ankylosing spondylitis, or rheumatoid arthritis. It is rapidly absorbed in the stomach and reaches 80 percent of peak plasma concentration in an hour. However, 20 percent of patients still encounter gastrointestinal symptoms. Other systemic reactions include dizziness, tinnitus, headache, and rash.
In an attempt to lessen the side effects associated with piroxicam's systemic absorption, the Life Science Research Center of SK Chemicals came up with a technology that lessens piroxicam's absorption into the bloodstream--represented in the Macroxam patch's four layers.
The controlled-release layer ensures continuous delivery of piroxicam's antiinflammatory action for up to three days. The drug-penetration-enhancer layer ensures direct delivery of the drug deep into the inflamed area, resulting in a piroxicam-plasma concentration of only 0.11±3.72 mg/ml, which is 50 times lower than the 5.69±2.26 mg/ml of orally administered piroxicam. The two other layers are the piroxicam layer and the adhesive layer. The special adhesive formulation allows the underlying skin to breathe. The patch sticks in place even when the user is exercising, sweating, or bathing.
Macroxam patch delivers piroxicam directly into the area of inflammation for 48 to 72 hours without systemic side effects. The new route effectively avoids the gastrointestinal tract and the side effects that go with taking the drug orally, providing sustained release of the drug into the synovial fluid.
Dr. Won H. Jung of the Samsung Medical Center in Korea noted in their study (Kor J Clin Pharmacol Ther, 1998) that there is no statistical difference in the synovial-fluid concentration of the drug between patch and oral routes. But plasma distribution is 50-times lower with transdermal administration than when piroxicam is taken orally. Won said this suggests that "the transdermal patch would be expected to produce equivalent therapeutic effects while reducing systemic side effects."
By lowering the levels of the drug that circulates in the blood, Macroxam may serve to lessen a variety of systemic side effects. Actual results of a piroxicam phase-III trial in patients with osteoarthritis indicate that systemic side effects--especially gastric ulcer-were not observed, save for mild skin irritation (Jeoung YP et al., 1998).
A double-blind, placebo-controlled trial led by Dr. Chang Wan Han (Journal of the Korean Rheumatism Association, May 1998) showed that patients with rheumatoid arthritis who used Macroxam patch experienced a statistically significant reduction in pain measured by visual analogue scale (from 54.6 ±-5.9 mm at baseline to 48.2 ±-5.7 mm after two weeks of treatment, p = 0.03).
Although mild gastrointestinal disturbances and local side effects such as pruritus and erythema were noted, there was no significant difference compared with placebo.
"The study confirms that piroxicam patch is effective in the relief of knee-joint pain in patients with rheumatoid arthritis with…mild gastrointestinal and local adverse events," Chang concluded.
R. Badillo II, MD
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