Have you ever suggested that a patient take an over-the-counter (OTC) anti-inflammatory or analgesic? Aside from the fact that prescribing medication is outside of the scope of physical therapist practice, the number of reasons against making a casual recommendation that a patient take an OTC medication is growing, almost daily.

The Basics

On July 14th, at theheart.org, Lisa Nainggolan reported on a study published in the July 2011 issue of The American Journal of Medicine. The study was a post-hoc analysis of data from the the INVEST trial. Here we go again with the catchy acronyms. In any case, the purpose of INVEST (the INternational VErapamil Trandolapril STudy) was to compare effects of a calcium channel blocker-based strategy to a beta-blocker based strategy in the control of hypertension (HTN) in patients with stable coronary artery disease (CAD). Trandolapril, an angiotensin-converting enzyme inhibitor and/or hydrochlorothiazide, a diuretic, were added to achieve BP control. Subjects, who were at least 50 years old and had both HTN and stable CAD, were followed for 2 years. The authors of the present study followed subjects for an additional 5 years to investigate the relationship between chronic non-steroidal anti-inflammatory (NSAID) use, blood pressure, and adverse outcomes in people with coronary artery disease and hypertension. The primary outcome was all-cause mortality, non-fatal myocardial infarction (MI), or non-fatal stroke, whichever came first. Secondary outcomes were all-cause mortality (after a non-fatal MI or stroke), total MI, and total stroke. Outcomes were evaluated by a panel blinded to the NSAID-using status of the subjects. Chronic NSAID users reported NSAID use at baseline and at every follow up visit. Non-chronic users only reported use at some visits, or not at all. Chronic users were matched with non chronic users by risk for the outcomes of interest and risk was calculated using Cox regression analysis for the 2 groups. Most subjects were using NSAIDs to manage rheumatoid arthritis, osteoarthritis, or low back pain.

NSAIDs and Rehabilitation

We started to get the message a few years ago, courtesy of Vioxx, that NSAIDs probably create cardiovascular issues for folks, especially older adults who are already at risk because of their age, blood pressure, lipids, smoking history, and, most important for us, a lack of physical activity. Other large studies have since shown that this is probably a class effect, with diclofenac users typically having a higher rate of cardiovascular events, and naproxen and ibuprofen users having a risk not very different from non-users, but the findings have not been consistent across studies.^1,2,3 NSAIDs are important in rehabilitation, if for no other reason than lots of older adults with chronic musculoskeletal symptoms use these drugs, either by prescription or OTC. There is evidence that a large proportion of patients who are in the care of a physical therapist use them, anywhere from 20-80%.^4,5,6 The most recent look at this issue was a multi-center study by Boissonnault and Meek almost 10 years ago, so we don’t really know where things stand right at this moment. But, in their survey of 2311 physical therapy outpatients, 79% were using an anti-inflammatory (ibuprofen, naproxen, and others) or aspirin, either OTC or prescribed. Surprisingly, almost 20% of patients were using duplicate therapy – a prescribed NSAID with an OTC NSAID or prescribed aspirin and OTC aspirin.

So, to recap what we’ve got so far:

• a lot patients seeking rehabilitation are dealing with rheumatoid arthritis, osteoarthritis, or low back pain
• up to 80% of these patients are using NSAIDs, maybe OTC, maybe by prescription
• 20-40% of these patients may be using NSAIDs and/or aspirin inappropriately by taking more than one NSAID, in some combination of OCT and prescription
• many of these patients are also older, have stable CAD, and HTN

Take a second now, and estimate the proportion of patients in your practice that fit those criteria. If your estimate is 10% or less, there’s probably no need for you to read the rest of this post, but if you treat adults over 50 years old with musculoskeletal issues, you’re kidding yourself if you think this doesn’t apply to your patients.

Chronic NSAID Users are at Risk

Of the 22,576 subjects who participated in the study, 882 were chronic NSAID users. As a group, the chronic users were younger, more likely to be female, more likely to have diabetes and peripheral arterial disease, and were less likely to be using aspirin and lipid-lowering medications. The primary outcomes occurred at a rate of 4.4 events per 100 patient years vs. 3.7 events per 100 patient years in the non-chronic users. The adjusted hazard ratio was 1.47 (95% CI 1.19-1.82, p=.0003). So where’s the bad news for NSAIDs here? As usual, it’s in the details. Yes there was a 47% increase in all-cause mortality, non-fatal MI or non-fatal stroke for the chronic NSAID users over the non-users. But, much of that difference was driven by a 90% increase in all-cause mortality, a difference that persisted between the two groups over 5 years of follow-up. And the largest difference between the 2 groups was within the secondary outcomes, a 126% increase in cardiovascular mortality.

Two additional findings were surprising. First, the rate of gastrointestinal bleeding was very low in both groups (0% of chronic users vs. 0.8% of non-chronic users). The authors propose that subjects had been taking the drugs before entry into the study and events could also have occurred before study entry. Or, perhaps chronic users were chronic users because they could tolerate chronic use. They also note that bleeding was not a targeted outcome in the trial, and events may have been missed. Second, both systolic and diastolic blood pressure were lower in the chronic group at baseline and throughout follow-up. The common wisdom, derived from short-term data, is that NSAIDs uniformly increase SBP by about 5 mm Hg.⁷
The authors were unable to explain this finding other than to say that NSAID-induced increases in BP have not been shown in long term studies. Additionally, when subjects’ BP was poorly controlled (SBP > 150 mm Hg), the rate at which adverse events occurred was even greater than that seen among the chronic users as a whole. This hazard ratio was only reported in a figure, so it is difficult to establish what the hazard ratio and increased risk really was.

There are certainly things this study doesn’t tell us. There was no information gathered about the specific NSAIDs the subjects were taking and the authors propose that this increase in adverse events, primarily cardiovascular mortality, is a class effect of all NSAIDs until shown otherwise. It’s also possible that NSAID use serves as a marker for other conditions that also increase the risk for adverse events, rheumatoid and osteoarthritis, in particular. Finally, keep in mind that the data regarding NSAID use is all generated through self-report. If subjects did not report NSAID use at each follow-up visit, they were classified as non-chronic users. Subjects may have reported NSAID use when they were not , but it is probably more likely that subjects used NSAIDs and not reported it. In either case, subjects would be misclassified.

The authors reach the conclusion that chronic NSAID use should be avoided with older adults. We don’t know where this increase in cardiovascular mortality comes from. One would think an increase in BP might account for the difference in a large population of individuals. Not that a 5 mm Hg in SBP is deadly, but SBP correlates with cardiovascular mortality risk, so in a large enough group, a small change in BP has a large effect. However, in this cohort of subjects, chronic NSAID users had lower SBPs, so we can’t lay the blame there. As reported on theheart.org, Dr. Anthony A. Bavry, the lead author of the study, recommends that patients not discontinue these medications on their own. Communication with prescribers, a recurring theme here at Pharmacology in Physical Therapy, is the key. He tells his patients that there is evidence of harm. At the least, he makes an effort to decrease the frequency or dose of NSAID use, and attempts to make a switch to acetaminophen. But, he says, “ultimately, it’s up to them if this potential risk is worth taking depending upon the indication for their use.”

The Take Home Message

The bottom line for us in rehabilitation: we can and should play an important role in pain relief, especially when that pain is musculoskeletal in origin, Yes, exercise and physical modalities have risks, but it is likely those risks, in whatever form, are lower than the risks of chronic NSAID use. Rehabilitation professionals need to be extremely cautious with OTC medications. Just because they are available over the counter does not mean that they are benign. We should always ask patients about their medications, and not just prescription medications. It would appear that, with NSAIDs, duplication (more than one NSAID) is common and this may increase overall exposure to the drugs and possible increase the risk of an adverse event. We know – and you’ll hear it over and over here – it is outside of the scope of PT practice (except in the military) to prescribe. Avoid making recommendations about medications in response to a patient’s question. In patients who have had an MI, it appears that the risk increases for any NSAID over any duration, making this an especially concerning situation.⁸ Your response should be to encourage your patient to speak to his physician or to ask patient if you can contact the provider yourself.

References (Back to text)
1. Graham DJ et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365:475-481.

2. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296:1633-1644.

3. Trelle S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. doi: 10.1136/bmj.c7086.

4. Boissonnault WG, Koopmeiners MB. Medical history profile: orthopaedic physical therapy outpatients. J Orthop Sports Phys Ther. 1994;20:2-10.

5. Boissonnault WG. Prevalence of comorbid conditions, surgeries, and medication use in a physical therapy outpatient population: a multicentered study. J Orthop Sports Phys Ther. 1999;29:506-525.

6. Boissonnault WG, Meek PD. Risk factors for anti–inflammatory-drug- or aspirin-induced gastrointestinal complications in individuals receiving outpatient physical therapy services. J Orthop Sports Phys Ther. 2002;32:510-517.

7. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994;121:289-300.

8. Schjerning Olsen, AMB et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study.