I have a mental basket of drugs that I suspect may be placebos. In that basket were the topical versions of non-steroidal anti-inflammatory drugs (NSAIDs). When the first products were commercially marketed over a decade ago, I found the clinical evidence unconvincing, and I suspected that the modestly positive effects were probably due to simply rubbing the affected area, or possibly due to the effects of the cream or vehicle itself. Frankly, I didn’t think these products worked. So when I recently noticed a topical NSAID appear for sale as an over-the-counter treatment for muscle aches and pains (seemingly only in Canada, for now), I was confident it would make a good case study in bad science.

It’s not that I’m partial to the oral NSAIDs. Yes, they’re among the most versatile, and probably most well-loved drugs in our modern medicine cabinet. They offer good pain control, reduce inflammation and can eliminate fever. We start using it in our sick and feverish infants, through childhood and adulthood for the aches and pains of modern life, and into our later years for the treatment of degenerative disease like osteoarthritis, which affects pretty much everyone as we age. An astonishing 17 million Americans use NSAIDs on a daily basis, and this number is expected to grow as the population ages. In the running groups I frequent, ibuprofen has the affectionate nickname “Vitamin I”, where it’s perceived as an essential ingredient for dealing with the consequences of training.

But NSAIDs have a long list of side effects. Not only do they cause stomach ulcers and bleeding by damaging the gastrointestinal mucosa, there are heart risks, too. It was the arrival (and departure) of the drugs Bextra and Vioxx that led to documentation of the potential for cardiovascular toxicity. And now there’s data to suggest that these effects are not limited to the “COX-2″ drugs – almost all NSAIDs, including the old standbys we have used for years, seem capable of raising the risks of heart attacks and strokes.

So despite my initial skepticism, I took another look at the topical NSAIDs. The data were not what I expected.

The use of NSAIDs

ASA (acetylsalicylic acid, Aspirin) the prototypical NSAID, traces its origin back to willow bark, a natural source of salicylate. All NSAIDs work the same way, interrupting the production of inflammatory and pain-related hormones called prostaglandins. Since ASA’s introduction in 1897, more than two dozen chemically related drugs have come to market. They’re now among the commonly used drugs used worldwide, playing a crucial role in pain management. Given the ubiquity of acute pain conditions, as well as chronic conditions like osteoarthritis, it’s estimated that 1 in 20 physician visits are related to prescriptions for NSAIDs. In general, all NSAIDS have equivalent efficacy at the population level, though individual response, and side effects, can vary between drugs. The discovery of different forms of cyclooxygenase enzymes led to new drugs that targeted COX-2 (at sites of inflammation) rather than COX-1 (which is involved with the stomach mucosa. Inhibit COX-2 rather than COX-1, the thinking went, and you could get the antinflammatory action of a traditional NSAID without the gastrointestinal toxicity. However, as the COX-2 saga demonstrated, effects can include the creation of a significant prothrombic effect – with devastating consequences.

The Risks of NSAIDs

Prescription drugs can and do cause significant morbidity, leading to frequent hospital admissions. While we may think nothing of popping a few ibuprofen now and then, NSAIDs have been linked to about 30% of drug-related hospital admissions, and it’s estimated that 12,000-16,000 Americans die annually as a result of gastrointestinal bleeding caused by NSAIDs.

Stomach bleeding and ulcers are a consequence of an NSAID’s mechanism of action – their effect on prostaglandins. The lining of the gut is weakened, and stomach and duodenal ulcers result. Even very low doses of ASA have been documented to have measurable effects on the mucosal lining of the gastrointestinal tract. The risks of gastrointestinal toxicity are significantly increased in the elderly, in those on high doses of NSAIDs, and when combined with other drugs (e.g., steroids) that suppress normal stomach protection.

The cardiovascular risks of NSAIDs became well documented following the worldwide withdrawal of rofecoxib (Vioxx) and international examinations of the cardiovascular risks of the entire category of drugs. Data have now emerged to convincingly establish that most NSAIDs (except ASA) are associated with an increased risk of cardiovascular events. Chronic (routine) consumption of most drugs is linked to small but real increases in heart attacks and stroke. These effects may be a consequence of interference with the beneficial effects of ASA (Aspirin), direct negative cardiovascular effects, and exacerbations of fluid balance, leading to heart failure.

When it comes to cardiovascular risks, not all NSAIDs are the same. A recently published network meta-analysis summarizes the differences, and the overall risks. Both traditional NSAIDs, like naproxen, ibuprofen, and diclofenac, as well as the COX-2 selective NSAIDs, like celecoxib (Celebrex) and rofecoxib (Vioxx) were studied. Happily for those that use over-the-counter anti-inflammatories only occasionally: naproxen seems to be the safest among the NSAIDs, with little to no increase in risk, and ibuprofen’s elevated risk seems limited to regular doses of 1200mg per day or more. So for the individual consumer, when do the risks outweigh the benefits of NSAIDs? Ultimately this comes down to an individual consideration of reasons for use, risk factors, and expected benefits.

To be clear, the absolute cardiovascular risks of NSAIDs, on an individual level, are low, compared to the other side effects of NSAIDs. They seem to cause three or more excessive events like heart attacks and stroke events, per 1000 patients, per year. Compare this to the 20-40 per 1000 per year that may have a (sometimes fatal) stomach bleed, a risk that’s 4x that of non-users. Still, their risk profile suggests that a consideration of their risk and benefits is warranted, particularly when they’re being contemplated in people with preexisting cardiovascular disease. On balance, when treating short-term conditions, the incremental risk in patients without cardiovascular disease is probably very low. Still, it seems prudent to use safer alternatives first (when possible) and if using NSAIDs, considering the lowest possible dose for the shortest possible duration.

Topical NSAIDs: The evidence

Over the past two decades, evidence has emerged to demonstrate that topical versions of NSAIDs are well absorbed through the skin and reach therapeutic levels in synovial fluid; muscle, and fascia. With topical use, little drug actually circulates in the plasma, leading to levels that are a fraction of comparable oral doses. As adverse events from NSAIDs are largely dose-related, it’s expected (thought not as well documented) that serious side effects should be minimized.

For chronic conditions like osteoarthritis, the data are of fair quality and are persuasive. The National Institutes for Health and Clinical Excellence osteoarthritis guidelines provides a nice summary of the trials. Studies varied by site of osteoarthritis (knee, hand, hip, etc), the type of NSAID studied, the regimen, and trial design. On balance, there’s good evidence to show that topical NSAIDs are clinically- and cost-effective for short term (< 4 weeks) use, especially when pain is localized. Topical and oral versions seem to be similarly effective under these circumstances, and there there’s a significant reduction in non-serious adverse events with topical products. While there’s no conclusive evidence to demonstrate a reduction of serious adverse events, they’re expected to be better than oral products, given the blood levels are much lower. What impressed me is that topical NSAIDs are recommended as a preferred treatment before oral NSAIDs. And given many taking oral NSAIDs need to take stomach protecting drugs like omeprazole, the topical products, while more expensive than their oral versions, may actually be more cost-effective overall.

A Cochrane review from 2010 is equally positive about the treatment of acute pain conditions. Forty-seven trials were included in their analysis that considered topical NSAIDs for strains, sprains, and overuse-type injuries. Compared to placebo, topical NSAIDs were evaluated to be effective, with few side effects, with a number needed to treat (NNT) of 4.5. About 6 or 7 out of 10 users can expect to achieve pain control with a topical NSAID, compared to 4 with a placebo. Side effects are comparable to placebo. And given systemic absorption is lower, the serious toxicity we associate with NSAIDs should be lessened, too. Not bad.

Given there’s no long-term data with topical NSAIDs, the evidence doesn’t give us enough insight to understand the risk profile beyond a few weeks. Consequently it seems reasonable to try using topical products instead of oral products, particularly for intermittent, rather than chronic, pain conditions. While compounding pharmacies have made topical versions of NSAIDs for years, there’s little information on effectiveness and safety of these products. As commercial formulations are supported with pharmacokinetic and clinical studies demonstrating efficacy, they are the preparations of choice.

Conclusion

NSAIDs, which already had a bad side effect profile, cause more harm then we thought. Evidence has emerged to demonstrate that topical NSAIDs are effective for many conditions that might otherwise require oral therapies. There’s little evidence to demonstrate that topical NSAIDs are effective for some types of pain, like back pain, headache, or neuropathic pain. But based on what’s now known about the cardiovascular toxicity of NSAIDs, it’s likely that topical products provide a superior risk/benefit perspective for regular and occasional users. The Cochrane review points out that topical NSAIDs are widely accepted in some parts of the world, but not in others. The reasons why are not clear. But having read the evidence, I’ve changed my opinion. And when I’m recovering from my next marathon, I’ll think about reaching for a topical NSAID, instead of that comforting bottle of vitamin I.

References

Haroutiunian, S., Drennan, D., & Lipman, A. (2010). Topical NSAID Therapy for Musculoskeletal Pain Pain Medicine, 11 (4), 535-549 DOI: 10.1111/j.1526-4637.2010.00809.x

Massey T, Derry S, Moore RA, & McQuay HJ (2010). Topical NSAIDs for acute pain in adults. Cochrane database of systematic reviews (Online) (6) PMID: 20556778

Solomon DH. Up-to-Date: Nonselective NSAIDs: Overview of adverse effects; Nonselective NSAIDs: Overview of adverse effects. From Up-To-Date (Database on the Internet).

Trelle, S., Reichenbach, S., Wandel, S., Hildebrand, P., Tschannen, B., Villiger, P., Egger, M., & Juni, P. (2011). Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis BMJ, 342 (jan11 1) DOI: 10.1136/bmj.c7086