Topical NSAIDs: Old Wine in a New Bottle

Over the past decade, NSAIDs have been on a roller-coaster ride almost as wild as that now being experienced by this country’s housing and financial markets. The selective COX-2 inhibitors-first celecoxib (Celebrex) and then rofecoxib (Vioxx) and valdecoxib (Bextra)-promised to revolutionize the treatment of pain. Despite the absence of any proof that these agents were more effective than the older nonselective NSAIDs, both physicians and patients rapidly became enamored of them. The downfall of the COX-2 inhibitors came suddenly when Vioxx and then Bextra were withdrawn from the market, the former because of a reported increased risk of myocardial infarction and stroke, the latter because of an association with Stevens-Johnson syndrome. Celebrex remains available, but physicians are now much more cautious about prescribing it.

Since the demise of Vioxx and Bextra, no new NSAIDs have become available in the United States. However, 2 products that use new formulations of an older NSAID have recently appeared. Diclofenac has been on the market for years in an oral form. It is now available in 2 topical preparations-diclofenac epolamine topical patch, 1.3% (Flector Patch)¹ and diclofenac sodium topical gel, 1% (Voltaren Gel).²

Although the diclofenac patch appears to be the first NSAID available in the US in this form, NSAIDs have been available in ointments for years in over-the-counter (OTC) preparations and in prescription formulations prepared by pharmacists for the specific needs of individual patients.³ Despite their widespread availability, however, topical NSAIDs have been infrequently recommended by physicians. There appear to be 2 major reasons for this-one commercial and one clinical:

• Unlike the diclofenac patch and gel, older topical NSAIDs have received little publicity. Consequently, physicians are less likely to be aware of them and their potential benefits.

• Topical NSAIDs clearly offer more pain relief than placebo,⁴ but whether they are as effective as oral NSAIDs, especially for chronic pain, remains the subject of debate. This issue is particularly relevant to diclofenac gel, which is FDA-approved for chronic osteoarthritis. The diclofenac patch is approved for acute pain from minor strains, sprains, and contusions.

An example of the debate over efficacy can be found in 2 studies published in the British Medical Journal.^4,5 A 2004 meta-analysis of published studies on topical NSAIDs found that these agents were beneficial for osteoarthritis pain only for a brief period and that after 2 weeks of use they did not appear to be any more effective than placebo.⁵ In contrast, a more recent study found that even after a year’s use, topical ibuprofen provided those with knee pain from osteoarthritis efficacy similar to that attained with oral NSAIDs.⁴

The obvious advantage of topical NSAIDs is that they reduce the risk of systemic side effects that can range from mild GI distress to potentially life-threatening GI bleeding. As with any topical analgesic (patch and gel), the most common adverse effect is skin irritation at the application site.^1,2 The prescribing information for both the patch and the gel indicates that there is a possibility of systemic effects. Also, both formulations carry the black box warning (now required by the FDA for all NSAIDs) about the potential for adverse cardiovascular and GI events. However, based on the pharmacokinetics of these drugs, the risk of such effects appears to be slight. A study of the diclofenac patch found that at steady state, the systemic exposure to the drug from the patch was less than 1% of that from oral diclofenac.⁶

One of the problems clinicians face in determining the safety of these medications is that the studies of potential side effects have generally been performed on patients without pre-existing risk factors. Thus, there is little information about the use of either the diclofenac patch or gel for patients with medical histories that would contraindicate the use of oral NSAIDs (eg, those with a history of peptic ulcer disease or who are taking an anticoagulant). Oral NSAIDs can reduce renal excretion of lithium. As far as I am aware, there is as yet no information on the effect of topical NSAIDs on lithium excretion.

What is the place of the new diclofenac preparations in the hierarchy of analgesic medications? For patients without contraindications to oral NSAIDs, use of the Flector Patch or Voltaren Gel is probably an unnecessary expense. In those for whom oral NSAIDs are contraindicated or who have difficulty tolerating their side effects, acetaminophen (Tylenol) is an acceptable alternative if the patient has no hepatic disease or is not at high risk for hepatic problems. The analgesic effects of acetaminophen are often downplayed, but they are frequently equal to those of NSAIDs.⁷ Even in disorders such as osteoarthritis in which the pain may at least be partly related to an inflammatory mechanism, acetaminophen can often provide marked analgesia similar to that of NSAIDs. Obviously, topical analgesics are of little benefit for patients whose pain is not localized.

As far as I am aware, no studies have yet compared the diclofenac patch or gel with other topical analgesics-most notably capsaicin, which is available in multiple OTC preparations, and the lidocaine patch 5% (Lidoderm), which is FDA-approved for postherpetic neuralgia pain but has been shown to be beneficial for other localized pains. Thus, it is difficult to offer any research-based advice on which medication is likely to be most effective apart from the general guidance offered by the FDA-approved indications.

I have found the lidocaine patch to be effective for a wide range of both acute and chronic localized pain conditions. None of the patients for whom I have prescribed it have experienced any systemic adverse effects related to its use. When the lidocaine patch has provided insufficient relief, I have considered capsaicin. However, intolerance to the burning sensation that frequently accompanies use of capsaicin is a common problem, especially when the higher, more effective concentrations of this drug are used. In this situation, I would prescribe either the diclofenac patch or gel.

As physicians gain experience with these newer medications, we should have a better sense of which of the various topical analgesics is most likely to work for the individual patient.

References:

References

1. Flector Patch prescribing information.

http://www. flectorpatch.com/

. Accessed September 3, 2008.
2. Voltaren Gel prescribing information.

http://www. voltarengel.com

. Accessed September 3, 2008.
3. McCleane G. Topical analgesics. Med Clin North Am. 2007;91:125-139.
4. Underwood M, Ashby D, Cross P, et al. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study. BMJ. 2008;336:138-142.
5. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ. 2004;329:324.
6. Rusca A, Mautone G, Sun S, et al. Comparison of plasma pharmacokinetics of FLECTOR Patch (diclofenac epolamine topical patch) and oral Voltaren (diclofenac sodium enteric-coated tablets) in healthy volunteers. Presented at: the 27th Annual Scientific Meeting of the American Pain Society; May 2008; Tampa, FL.
7. America Pain Society. Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. Glenview, IL: American Pain Society; 2002.