Musculoskeletal injuries are one of the most common, if not the most common, condition we see in podiatric sports medicine practices. While the injuries can be acute or chronic, there are multiple treatment modalities podiatrists can use to resolve the condition and return the athlete to sport. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common prescribed medications and are a cornerstone in the treatment of musculoskeletal pain management. They are well known for their analgesic, anti-inflammatory and antipyretic properties, but they also known for adverse effects, specifically cardiovascular risk and gastrointestinal toxicity.
Topical NSAIDs emerged to limit systemic exposure and adverse effects. One can apply topical NSAIDs locally to the injured tissue, producing high enough concentrations without producing high systemic levels associated with common adverse effects. Topical NSAIDs differ from transdermal dosage forms that deliver high levels of the drug into the circulation with the goal of achieving the same systemic levels as the oral form. Given the reduced risk of topical NSAIDs as opposed to oral NSAIDs, is there a place for them in our treatment armamentarium?
Understanding The Pharmacology Of Topical NSAIDs
The main mechanism of NSAIDs is the reduction of prostaglandins by inhibiting the cyclooxygenase (COX) enzyme at the site of pain and inflammation.1 Cyclooxygenase exist as two isoenzymes (COX-1 and COX-2) and in different tissues. COX-2 functions more in pathological conditions such as inflammation.
To be effective, topical NSAIDs must penetrate the skin and either enter the circulation or be absorbed by the underlying tissues. The critical facet with topical NSAIDs is the ability of the active drug to penetrate the skin in high enough amounts to achieve the desired effect. The skin layers the drug must pass through to reach its site of action in soft tissue, bone or the systemic circulation are the stratum corneum, epidermis, basal membrane and the dermis.2 While the stratum corneum is largely lipophilic and the epidermis is largely hydrophilic, drugs that are both hydrophilic and hydrophobic demonstrate better penetration.
The absorption and penetration of topical NSAIDs are also affected by the dosage form (gel, solution, patch), salts of the same molecule, carrier-mediated transport and penetration enhancement methods (either chemical or physical). Seth’s study compared two topical gels of diclofenac.3 Diclofenac incorporated into an aqueous alcohol gel produced a mean increase of 53.8 percent in plasma area under the concentration time curve and an increase of 106 percent in the maximum plasma concentration. In another study comparing a diclofenac patch versus a gel, the bioavailability was about 30 percent less with a patch than with a gel.4
What The Literature Reveals About NSAIDs And Lower Extremity Injuries
Podiatrists can use NSAIDs to treat acute injuries and chronic overuse syndromes, postoperatively, and during rehabilitation with the benefits of controlling pain, decreasing inflammation, and allowing an earlier return to activity.
Most clinicians see ankle sprains on a regular basis and often prescribe a NSAID. Dreiser and co-workers compared a 40 mg patch of flurbiprofen versus a placebo patch over seven days in a randomized, double-blind study of 131 ankle sprains.5 Researchers measured efficacy via the visual analogue scale (VAS) and physician assessment. At day seven, they noted a statistical difference between the flurbiprofen and placebo in regard to spontaneous pain and edema.
Diebschlag and colleagues compared ketorolac gel versus placebo gel and etofenamate gel in 37 patients with ankle sprains over 14 days.6 All had relief at seven and 14 days, but there was significant improvement in pain after four days with the ketorolac gel, specifically when it came to pain on movement and night pain. There was no difference in ankle swelling.
Russell compared piroxicam gel to a placebo in 200 patients with acute soft tissue injures (Achilles versus supraspinatus tendonitis and ankle versus acromioclavicular sprains).7 They found that piroxicam was more effective for relief of pain, tenderness and range of motion, but this was only true in the tendonitis group and not the sprain group.
In a meta-analysis of 26 double-blind, placebo-controlled trials consisting of 2,853 patients, topical NSAIDs were significantly better in 19 of 26 of the trials with ketoprofen being the most effective.8 In their study of 101 patients with minor sports injuries, Jenoure and colleagues found a 61 percent reduction in pain on pressure and a 60 percent reduction in spontaneous pain after two weeks of treatment with topical diclofenac.9 Limiting absorption should produce fewer systemic adverse effects with the absorption of a diclofenac patch having fewer adverse effects than other forms of the drug.10 Researchers found that topical ketoprofen was useful for acute tendonitis injuries over seven days of treatment.11
What You Should Know About Adverse Reactions
The incidence of adverse reactions with topical NSAIDs is low, thus making them a safe alternative.
The most common adverse reaction is a cutaneous reaction occurring in 1 to 2 percent of patients with erythema, pruritus, irritation, a sensation of heat or burning, and contact dermatitis being the most common.12,13 The studies comparing oral versus topical NSAIDs concluded that topical NSAIDs demonstrated a decreased incidence of adverse events.14
Topical NSAIDs have been in use in Europe for over 30 years but are in use sparingly in the United States. The evidence supports that topical NSAIDs are effective and safe, and should have a place in treatment regimens for sports-related injuries. There remains a lack of evidence as to which penetration enhancement method provides the best results. There is also a paucity of head-to-head studies of various topical NSAIDs.
Currently, there are three approved topical NSAIDs available in the United States. They include diclofenac epolamine topical patch 1.3%; (Flector Patch, Pfizer); diclofenac sodium gel 1% (Voltaren Gel, Endo Pharmaceuticals/Novartis Pharmaceuticals); and diclofenac sodium topical solution 1.5% (Pennsaid, Covidien).
Dr. Yakel is a Fellow of the American College of Foot and Ankle Surgeons, and is board certified by the American Board of Podiatric Surgery. He is an Associate of the American Academy of Podiatric Sports Medicine. Dr. Yakel is in private practice in Longmont, Colo.
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3. Seth BL. Comparative pharmacokinetics and bioavailability study of percutaneous absorption of diclofenac from two topical formulations containing drug as a solution gel or as an emulsion gel. Arzneimittelforschung. 1992;42(2):120-2.
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