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 ASAs introduction in
1897, more than two dozen chemically related drugs have come to market. Theyre 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, its 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 its 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 NSAIDs 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-thecounter anti-inflammatories only occasionally: naproxen seems to be the safest among the
NSAIDs, with little to no increase in risk, and ibuprofens 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 thats 4x that of nonusers. Still, their risk profile suggests that a consideration of their risk and benefits is warranted,
particularly when theyre 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 doserelated, its 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, theres 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 theres a significant reduction in non-serious adverse events with
topical products. While theres no conclusive evidence to demonstrate a reduction of serious
adverse events, theyre 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 theres no long-term data with topical NSAIDs, the evidence doesnt 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, theres 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. Theres little evidence to demonstrate that topical
NSAIDs are effective for some types of pain, like back pain, headache, or neuropathic pain. But
based on whats now known about the cardiovascular toxicity of NSAIDs, its 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, Ive changed my
opinion. And when Im recovering from my next marathon, Ill 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 metaanalysis BMJ, 342 (jan11 1) DOI: 10.1136/bmj.c7086
Pathophysiology
The pathophysiology of overuse injuries is based on the idea that tissues adapt to the stresses
placed on them over time. These stresses include shear, tension, compression, impingement,
vibration, and contraction. Mechanical fatigue within tendons, ligaments, neural tissue, and other
soft tissues results in characteristic changes depending on their individual properties. This fatigue
is theorized to initially lead to adaptations of these tissues. As the tissues attempt to adapt to the
demands placed on them, they can incur injury unless they have appropriate time to heal. The
rate of injury simply exceeds the rate of adaptation and healing in the tissue. Evidence also
suggests that chemical mediators are involved in the initiation and propagation of overuse
injuries.
Nerve tissues are at particular risk for ischemic injuries. This ischemia leads to characteristic
changes in the nerve itself. The timeline generally begins with subperineurial edema, followed

by thickening of the perineurium, thickening of the internal and external epineurium, thinning of
the peripheral myelin, and, eventually, axonal degeneration.
One hypothesis is that the development of muscular pain originates from the nearly continuous
activation of low-threshold motor units that occurs in muscles performing continuous or slow,
repetitive tasks, causing depletion of adenosine 5'-triphosphate (ATP) in those fibers. With
insufficient ATP, sarcoplasmic reuptake of Ca++ could be reduced, resulting in high
concentrations in the cytosol, allowing Ca++ dependent activation of phospholipase, the
generation of free radicals, and damage to the muscle fibers involved. This theory has a rational
physiologic basis, but it remains to be proven. Multiple studies have shown that patients with
more significant work-related, upper extremity disorders exhibit more muscular activity on
electromyelography (EMG) findings; however, these studies are observational and not designed
to exhibit causality