Am Fam Physician. 2007 Dec 1;76(11):1605-1606.
Each month, three presenters will review an interesting journal article in a conversational manner. These articles will involve “hot topics” that affect family physicians or will “bust” commonly held medical myths. The presenters will give their opinions about the clinical value of the studies discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.
This Month's Article
Dalton JD Jr, Schweinle JE. Randomized controlled noninferiority trial to compare extended release acetaminophen and ibuprofen for the treatment of ankle sprains. Ann Emerg Med 2006;48:615–23.
Are NSAIDs better than acetaminophen for ankle sprains?
Bob: When my residents evaluate a patient with an ankle sprain, they will almost invariably want to prescribe an NSAID. They say that because the ankle is swollen, they want the anti-inflammatory effect. But do NSAIDs really help our patients heal faster? Do they reduce disability? Do they decrease pain better than acetaminophen?
What does this article say?
Bob: This study randomized 260 patients with mild to moderate ankle sprains, in a double-blind fashion, to receive 1,300 mg of extended-release acetaminophen or 400 mg of ibuprofen (Motrin) three times a day. At four days, there was no difference between the drugs regarding pain on walking.
Other end points measured included pain on walking at day 9, change in ability to walk between days 4 and 9, patient satisfaction, time to resume normal activity, and the degree of ankle swelling, bruising, and range of motion. Again, neither drug was superior on any of these measures.
Should we believe this study?
Bob: When I decide to read an article, I first look at the title. Then I go to the last page to see if the study was sponsored by one of the makers of the product being studied. If so, my degree of skepticism heightens exponentially. This particular study happens to be sponsored by McNeil Pharmaceutical (the maker of extended-release acetaminophen).
Andrea: Same here. When pharmaceutical companies are involved in a study, there is a fourfold greater chance that the study will have a positive outcome than if the study was not funded by the industry.1 Somehow, the conclusions almost always come out in favor of the sponsor's product.
Mark: My favorite example is when a review of 56 industry-sponsored trials of NSAIDs for osteoarthritis was performed, all 56 trials found NSAIDs to be beneficial. Not one trial had an unfavorable outcome.1
Bob: So you can understand my trepidation when I reviewed this article. However, I believe the conclusions of the study are correct. First, it was a well-conceived, double-blind study with clear, appropriate end points and excellent follow-up. Second, the results are in step with a previous non sponsored study that showed that acetaminophen and diclofenac (Voltaren) produced similar reductions in pain in patients with acute musculoskeletal injury.2 Lastly, it makes intuitive sense—while NSAIDs are useful in decreasing pain and swelling in prostaglandin-mediated conditions (e.g., gout, rheumatoid arthritis, dysmenorrhea, ureteral colic), ankle sprains and acute musculoskeletal injuries are not prostaglandin-mediated events. Consequently, there is no reason why NSAIDs would be more effective than acetaminophen for ankle sprains.
Andrea: It is what we have been saying for a long time: when it comes to analgesia, acetaminophen is equivalent to NSAIDs.
Mark: And no NSAID has more “analgesic efficacy” than another. An excellent example of this is ketorolac (Toradol, brand not available in the United States). The only advantage of ketorolac is that it can be given intravenously or intramuscularly (which is useful in cases of ureteral or biliary colic). However, it has been clearly shown that intramuscular ketorolac provides no greater analgesic effect than oral ibuprofen for musculoskeletal pain.3,4
Bob: And while some may suggest that inadequate doses of NSAIDs were used in this study, the authors were careful to use the maximal over-the-counter doses of each drug. And remember, the analgesic effects of NSAIDs have a “ceiling effect”—even if you double, triple, or quadruple the dose of an NSAID, no additional analgesia is achieved.
Andrea: Plus, we haven't even mentioned the real downside of NSAIDs, like gastropathy, renal insufficiency, and increased CHF rates.
Bob: That's what scares me the most about NSAIDs. In 1997, there were 16,500 deaths in the U.S. from NSAID-induced gastropathy—that is the same number of deaths as there were from AIDS that year.5 Although this study did not show any increase in side effects, the participants were generally young, healthy patients who took the drugs for a defined short period of time, which would decrease the risk of the expected NSAID side effects.
Mark: Also, the study size (n = 260) would be too small to demonstrate a statistical difference in side effects, such as NSAID-induced gastropathy. Keep in mind that very large numbers of patients are required to statistically demonstrate a side effect because of a treatment or intervention. An excellent example of this would be the recent issue with the discontinued COX-2 inhibitor rofecoxib (Vioxx).
What should the family physician do?
Bob: Despite my apprehension regarding industry-sponsored studies, I feel very comfortable recommending acetaminophen as my first choice to patients with mild to moderate ankle sprains. I cannot justify prescribing an NSAID (which has the potential for harm in a benign, self-limiting condition like an ankle sprain) when acetaminophen works just as well.
Andrea: I agree with you, Bob. Acetaminophen works great for pain when used in appropriate dosages. Patient education regarding the relative risks and benefits of each of these drug classes is really important.
Mark: If you really don't think that acetaminophen is going to be adequate for pain control, consider using a narcotic combination product. And remember, with ankle sprains, immobilization will only prolong the healing process—early mobilization is key to recovery.
Extended-release acetaminophen provides equivalent analgesia and return to activity as an NSAID in patients with mild to moderate ankle sprains.
All NSAIDs have equivalent analgesic effect.
Increased doses of NSAIDs do not produce increased analgesia because of a “ceiling effect.”
NSAID-induced gastropathy results in death rates as high as those of AIDS.
Be skeptical of industry-sponsored studies. These studies are often “spun” to favor the sponsor's drug.
Large numbers of patients are required to demonstrate a deleterious side effect of a drug or intervention.
Address correspondence to Robert Dachs, MD, at firstname.lastname@example.org. Reprints are not available from the authors.
Author disclosure: Nothing to disclose.
1. Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005e138.
2. Woo WW, Man SY, Lam PK, Rainer TH. Randomized double-blind trial comparing oral paracetamol and oral nonsteroidal antiinflammatory drugs for treating pain after musculoskeletal injury. Ann Emerg Med. 2005;46:352–61.
3. Turturro MA, Paris PM, Seaberg DC. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med. 1995;26:117–20.
4. Neighbor ML, Puntillo KA. Intramuscular ketorolac vs oral ibuprofen in emergency department patients with acute pain. Acad Emerg Med. 1998;5:118–22.
5. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs [Published correction appears in N Engl J Med 1999;341:548]. New Engl J Med. 1999;340:1888–99.
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