NSAIDs: Not as Safe as Patients May Think
Laurie Scudder, DNP, NP, Bill H. McCarberg, MD
April 02, 2014 (Discussion from the “human” side, which should help you when you are making decisions about medications for yourself and your pet. Similar research has been completed in veterinary medicine as well – RehabDeb)
Safety Issues With NSAIDs (Non-Steroidal Anti-Inflammatories)
Medscape Interviewer: 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.
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) 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.
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.
NSAID Use in Older Patients
Medscape: A recent article you wrote in Pain Medicine noted that 90% of all prescription NSAIDs were taken by patients 65 years of age or older. Can you go over the key findings of your review regarding safety in this population?
Dr. McCarberg: As I said earlier, it’s a complicated answer. Pain and aging go together; osteoarthritis, neuropathic pain, and cancer are all more common in older patients.
Second, older patients have more chronic diseases, such as congestive heart failure, diabetes, hypertension, and emphysema — which means that use of multiple drugs at the same time is more common. Combine chronic diseases that require multiple drugs with a great likelihood of a pain problem, and this sets you up to have more difficulty when you add another drug to that mix, such as an OTC agent.
Older patients often have a decline in liver and kidney function. They may not be as well hydrated as a younger population. They may not have as much circulating protein because they don’t eat as well as a younger population, so that protein binding, one of the ways that the body protects itself from drugs, is lower. All of these factors together put the older population at particular risk for renal failure, bleeding from their stomach, or CV events when taking OTC drugs that they consider to be benign.
Medscape: Are topical NSAIDs a useful alternative to older agents in older patients?
Dr. McCarberg: In my own experience, I have found that older individuals are more interested in topicals than younger populations, who often don’t like the mess of the topical preparations and would rather swallow a pill and be on their way. Maybe it is because older folks grew up with ointments and lotions.
Topical NSAIDs have been found to be effective and, even though they carry the same warnings as the oral products, are much safer for the stomach, kidney, and heart. In fact, it’s a preferred route in older adults because of the safety profile. Patients will frequently use OTC topical agents and tell me that they can get some relief from them. Pain management guidelines all recommend topicals. I recommend them to my patients, but access can be a problem. Many formularies do not include topical NSAIDs, so insurance coverage is often a problem.
Medscape: What about use in the frail elderly: those 75-80 years of age, who have thinning of the stratum corneum and often very fragile skin? is there more concern about skin reactions with topicals in those older patients?
Dr. McCarberg: No; actually, it doesn’t seem to be a problem. Patients who take aspirin or other oral NSAIDs have problems with their skin and can bruise very easily by just bumping their skin against furniture, for example. So this is already an issue with the oral agents. It doesn’t seem that the topical agents produce any more reactions on the skin than the oral agents.
Medscape: The 2012 American Geriatrics Society Beers Criteria includes nonselective NSAIDs in its list of potentially inappropriate medications for use in the geriatric population. In your experience, are most providers aware of the Beers Criteria, and is that resource used in the primary care setting?
Dr. McCarberg: I don’t think they are. When I lecture about pharmacologic management, I often refer to the Beers Criteria. The question I hear most often is, “What is the Beers list”? So many primary care providers don’t even know what it is. When I list some of the drugs that are on that list — muscle relaxants, for example — physicians are often astounded. Often, I hear that a particular drug on the Beers list is “one of the drugs I use all the time.”
Medscape: Can you speak about the Alliance for Rational Use of NSAIDs’ goals and outreach? What are the key messages from the Alliance?
Dr. McCarberg: The main purpose for forming the Alliance was to get the message to people taking these drugs that there are side effects, and they can be serious. Just because a drug is available OTC, doesn’t mean that it’s safe. The consumer groups that are involved in the Alliance are important in getting the message out to their members and readers. Most people want to know about health and are proactive. A recommendation such as the one for limited use of NSAIDs is generally taken to heart.
The idea was pretty simple. Pain causes problems because it interferes with our social life and our sleep. But these drugs aren’t always safe. So the message to consumers is, if you’re going to take something, use the lowest effective dose for the shortest period of time. We don’t want people to suffer pain, because that has consequences as well. But consumers must be aware of issues related to NSAIDs and be educated to not take these drugs all the time.
- Wilcox CM, Cryer B, Triadafilopoulos G. Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs. J Rheumatol. 2005;32:2218-2224. Abstract
- US Food and Drug Administration. Acetaminophen prescription combination drug products with more than 325 mg: FDA statement — recommendation to discontinue prescribing and dispensing. January 14, 2014. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm381650.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery Accessed January 29, 2014.
- Rasu RS, Sohraby R, Cunningham L, Knell ME. Assessing chronic pain treatment practices and evaluating adherence to chronic pain clinical guidelines in outpatient practices in the United States. J Pain. 2013;14:568-578.Abstract
- Meara AS, Simon LS. Advice from professional societies: appropriate use of NSAIDs. Pain Med. 2013;14 Suppl 1:S3-S10. Abstract
- US Food and Drug Administration. Information for healthcare professionals: non-selective non-steroidal anti-inflammatory drugs (NSAIDs). April 5, 2005. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085282.htmAccessed March 21, 2014.
- McCarberg BH. NSAIDs in the older patient: balancing benefits and harm. Pain Med. 2013;14 Suppl 1:S43-S44.Abstract
- McPherson ML, Cimino NM. Topical NSAID formulations. Pain Med. 2013;14 Suppl 1:S35-S39. Abstract
- American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2012;60:616-631. Full textAccessed March 24, 2014.
From Dr. Gabe Mirkin’s Fitness and Health e-Zine
February 25, 2018
Do Not Take NSAIDs to Relieve Muscle Soreness –
Non-steroidal anti-inflammatory drugs (NSAIDs) can block gains in strength and endurance (PNAS, June 27, 2017;114(26):6675–6684; Med & Sci in Sports & Ex, April 2017;49(4):633–640).
The processes that heal damaged tissue in your body use the same immune cells and chemicals that fight infections. Certain prostaglandins that heal damaged tissues are the same prostaglandins that cause muscle soreness.
These prostaglandins can hasten healing of muscles damaged by vigorous exercise by increasing production of stem cells to replace damaged muscle cells.
They also increase endurance by increasing blood flow to damaged muscles, widening blood vessels and increasing the ratio of blood capillaries to muscle fibers.
Taking NSAIDs hinders this process and can prevent the gains in endurance that you would expect to get from your exercise.
Earlier studies in humans showed that taking NSAIDs can reduce the gains in endurance from aerobic exercise by restricting the ratio of blood capillaries to muscle fibers and decreasing the number of fibers in muscles (J Physiol Pharmacol, Oct 2010;61(5):559-63).
NSAIDs in human medicine include: celecoxib (Celebrex), diclofenac (Cambia, Cataflam, Voltaren-XR, Zipsor, Zorvolex), ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen (Ketoprofen), naproxen (Aleve, Anaprox, Naprelan, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene).