NSAIDs: Not as Safe as Patients May Think

Laurie Scudder, DNP, NP; Bill H. McCarberg, MD

Disclosures

April 02, 2014

Editor's Note:
A survey of over 9000 patients published in 2005 concluded that over-the-counter (OTC) analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are widely used, frequently by patients who are generally unaware of the potential for dangerous adverse side effects.[1] Given recent concerns about use of acetaminophen products, particularly products with 500 mg or more per tablet,[2] and the potential that patients will turn to NSAIDs as an alternative, it is more important than ever that clinicians provide accurate education about their use. Medscape spoke with Bill H. McCarberg, MD, founder of the Chronic Pain Management Program at Kaiser Permanente in Escondido, California, and a board member of the Alliance for the Rational Use of NSAIDs, about the latest evidence regarding these ubiquitous products.

Safety Issues With NSAIDs

Medscape: NSAIDs continue to be a widely used medication, particularly for patients with inflammatory conditions. A 2013 analysis of 7 years of data from the National Ambulatory Care Survey reported that they were used in 95% of the almost 7 million patients in the study sample who used at least 1 chronic pain medication.[3] The next closest agent was only used in one quarter of patients. Are there any data indicating that the concerns about a lack of patient knowledge about safe and appropriate use have changed since the survey published almost a decade ago?

Dr. McCarberg: It's an interesting conundrum. When patients have pain, they may not know what to do about it. They are unwilling to go in to be seen and pay a copay, because that is an increasing financial burden for them. The recent acetaminophen warnings, particularly noting that it is included in multiple different products and that excess doses could cause liver damage, are worrisome. The cardiovascular (CV) and gastrointestinal (GI) risks associated with NSAIDs have been widely reported; renal risk has not received as much attention in the lay press, but must be considered. And of course everybody talks about the opioids, the prescription painkillers, and the overdose deaths that are occurring in the United States. I think patients are confused and concerned about what they should do when they have pain.

The National Ambulatory Care Survey, conducted over a period of 7 years, found that 95% of patients said they took NSAIDs, illuminating just how common the experience of pain is. Although warnings about risk have been widely reported, patients don't necessarily know how hazardous NSAIDs can be; otherwise, there wouldn't be as many people taking them. Yet pain is so common that they have to take something, and they believe this is as safe as anything.

If you had a problem, what would you take? You would probably take an NSAID or acetaminophen, because there's nothing else. What do you take when you have a headache, sprain your ankle, or have a recurrent back problem? Most of us would take something. And if you ask patients whether there is a risk involved, they would answer "yes," but also note that these agents are available OTC and they wouldn't be OTC unless they were safe.

I recently looked into use of NSAIDs by athletes, and the number of high school, college, and professional athletes who use NSAIDs regularly to help with muscle aches and pains from competition is astounding. And potentially hazardous. These agents have never been proven to help with those muscle aches. Gastrointestinal issues can be significant, because you don't necessarily eat before an event. Athletes get dehydrated in an event, and with dehydration, there is more risk to the kidney. Now you put an NSAID on top of that, increasing renal risk. It's interesting that even our healthy athletes are using NSAIDs. There are side effects even in the group that you would think is the healthiest in our society.

So, the reasons that so many people take these drugs are complicated, and it is a function of just how common pain is in our society and confusion on the part of patients who don't know what to take.

Patients are also turning to alternative care -- which we're now calling "integrative care" because we don't think it is alternative treatment but rather more mainstream treatment and includes acupuncture, chiropractic, herbal therapies, yoga, and massage. People are paying out of pocket for these therapies because there is some worry that regular medical care is too expensive, and that OTCs may not be safe.

So back to your original question about patient recognition of risk. Patients may not know the exact risk profiles of NSAIDs, but they know there is some risk. And they don't know what else to do.

Medscape: Virtually all clinicians are familiar with the potential for GI mucosal damage from use of NSAIDs. Can you review the latest data regarding GI adverse events with these agents? Has the more recent trend toward combining them with gastroprotective agents mitigated some of these concerns? How does the combination of nonselective NSAIDs with proton pump inhibitors compare with cyclooxygenase type 2 (COX-2)-selective NSAIDs in terms of GI safety?

Dr. McCarberg: There have been multiple published guidelines for NSAID use. All state that persons with 1 or more GI risk factor (longer duration of use, higher dose, age 60 years or older, history of peptic ulcer disease, alcohol use, concomitant use of corticosteroids or anticoagulants, or general frailty[4]) should either lower their NSAID dose take the drug intermittently -- or even better, try not to take it at all. If NSAIDs are used in this population, they should be combined with gastroprotective agents.

What we've found is that despite those guidelines, primary care providers are not following those recommendations, at least with regard to prescription products. I have had primary care providers tell me that they've never had a patient experience a serious GI event, or that these recommendations are not practical. I have heard such statements as, "My experience is that I know these drugs pretty well, I wouldn't put my patient at risk, and I don't have to use gastroprotective agents." There are providers who believe that they know better than the recommendations.

Some of the recognized risk factors are fairly common in many patients. Patients 60 years of age and older are often seen in medical practices, and taking more than 1 NSAID at the same time is also a very common scenario. Many patients are taking aspirin as a cardioprotective agent and may have a comorbid inflammatory condition, for example arthritis, and be prescribed an NSAID or decide to take an OTC NSAID without consulting a healthcare provider. And these are likely to be older patients.

As I said earlier, 95% of patients are taking NSAIDs. Providers may neglect to ask about OTC use, and patients may not mention it even if asked. I have frequently had patients deny that they are taking other medications, only to respond, after I press them, that they are taking ibuprofen. They say, "But that's not a drug -- that's over-the-counter." And of course, it is a drug. Patients may be taking herbal agents that they also don't think are drugs, and there are drug/herbal interactions as well.

Medscape: The CV risks of nonselective NSAIDs have been known for several decades. Concerns regarding COX-2-selective NSAIDs were raised a number of years later, primarily after licensure. Can you speak about data comparing the CV risk of these 2 types of NSAIDs? Are there new data that can shed some light on relative safety of these 2 types of agents in differing populations?

Dr. McCarberg: Rofecoxib (Vioxx) was studied to see whether long-term use would protect patients from cancer of the colon. There was an idea that inhibiting cyclooxygenase, which is what these drugs do, provides protection from developing polyps and later cancer. The result? It probably did protect from cancer, but there were more people dying from CV events. So, as we well remember, rofecoxib got pulled off the market.

After that, a number of researchers began looking at large databases with literally thousands of patients (including at Kaiser Permanente, where I worked at the time) and found that not only did rofecoxib produce this CV incidence, but it looked like all of the drugs in this class were associated events; all of the NSAIDs were producing CV events. And it appeared that this CV risk was dependent on how long the drugs were taken and the dose. The higher the dose and the longer period of time taken, the more risk. At the highest dose of rofecoxib, there was significantly more risk. At a lower dose, the risk was really much less.

Some drugs, even with regular exposure, had less risk than other drugs. For example, naproxen, even at regular doses, didn't seem to have as much CV risk as other drugs in this class. So certain drugs are safer, and others, especially at higher doses, are more dangerous. That's one of the reasons that the US Food and Drug Administration (FDA) came out with the recommendation to use NSAIDs at the lowest dose for the shortest period of time.[5]

The Alliance for Rational Use of NSAIDs, which I'm a part of, has also tried to promote this idea. Our message to patients is that they should not just take an NSAID because of a headache, but should think about it, take the lowest dose, and not take it all the time.

Medscape: Could you speak about the FDA Advisory Panel's recent decision not to loosen the CV risk warning with naproxen, and some of the data that underpinned that decision?

Dr. McCarberg: Data do seem to suggest that naproxen is associated with less CV risk than other drugs in this class. I think one of the problems that had to be considered in making this decision is the very common belief in some patients that if 1 pill works, 2 pills are better. So if the FDA was to state that naproxen is safer, which it appears to be, a concern must be that the public would start using it preferentially and not hear safer as a relative risk, but rather hear that naproxen is safe. And if you take any drug in excess -- start taking not 1-2 tablets, but rather 3-4 tablets, the kind of dose escalation that is common -- all of a sudden, the drug isn't very safe because it is taken at higher doses for longer periods of time. Had I been on this advisory panel, I would have had some concerns about pushing the concept of relative safety for fear that increased use may lead to more adverse events.

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