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Recognizing the Risks of Chronic Nonsteroidal Anti-Inflammatory Drug Use in Older Adults
Older adults commonly take nonsteroidal anti-inflammatory drugs (NSAIDs) chronically. Studies of older adults show that chronic NSAID use increases the risk of peptic ulcer disease, acute renal failure, and stroke/myocardial infarction. Moreover, chronic NSAID use can exacerbate a number of chronic diseases including heart failure and hypertension, and can interact with a number of drugs (eg, warfarin, corticosteroids). Preferred analgesics in older adults that may have a lower risk of these adverse drug reactions include acetaminophen, a nonacetylated salicylate (eg, salsalate), a short half-life NSAID (eg, ibuprofen), or low-dose opioid/opioid-like agents in combination with acetaminophen (in appropriate patients). (Annals of Long-Term Care: Clinical Care and Aging 2010;18[9]:24-27)
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Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common class of analgesics used chronically for persistent pain due to osteoarthritis and other musculoskeletal disorders in older adults.1-3 Specifically, an estimated 40% of people age 65 years and older fill one or more prescriptions for a NSAID each year.4 Considering that NSAIDs are also currently available over the counter, it is clear to see that even larger numbers of older adults are exposed to NSAIDs in the United States.
While these agents can be effective in treating inflammation and pain, older adults are at increased risk for adverse drug reactions (ADRs) due to age-related loss of physiological organ reserve, increased comorbidities, polypharmacy, and changes in pharmacokinetics.5 As a result, NSAID use causes an estimated 41,000 hospitalizations and 3300 deaths each year among older adults.2 Some specific ADRs of concern with chronic use of NSAIDs include gastrointestinal (GI), renal, cardiovascular (CV), cerebrovascular, and central nervous system (CNS) adverse effects.6 This review will begin by describing key evidence for these organ-specific ADRs associated with the chronic use of NSAIDs in older adults and finish with general recommendations for healthcare providers to avoid/minimize these ADRs.
GI Risks Associated with Chronic NSAID Use
The spectrum of potential NSAID-related GI adverse effects is wide, ranging from dyspepsia to life-threatening gastric bleeding.2 A nested case control study from nearly two decades ago (before the introduction of cyclooxygenase-2 [COX-2] selective NSAIDs) showed that NSAIDs increase the risk of fatal peptic ulcers by nearly fivefold in older adults7; other studies have shown that the risk of peptic ulcer complications is increased by three- to fivefold in older adults using NSAIDs.2 This risk is much more pronounced in those taking concomitant systemic corticosteroids and warfarin.8,9 In addition, the risk is increased as early as within the first month of treatment and is sustained over time.3,10 Often, these peptic ulcers are asymptomatic but can lead to significant morbidity and mortality. The evidence for which NSAIDs are less risky is limited. One retrospective cohort study found that celecoxib, as compared to nonselective NSAIDs (ibuprofen, diclofenac, naproxen) carried the least risk of hospitalization for GI bleeding among elderly persons.11 Of note, all NSAIDs (ie, nonselective and COX-2 selective) carry a boxed warning for adverse GI events. Overall, the rate of hospitalizations for peptic ulcer disease (PUD) increases with age, from 1 per 1000 per year in populations younger than age 50 years to 2-6 per 1000 per year in older adults (> 65 yr), with an estimated 15-35% of all peptic ulcer complications being due to NSAID use.2,12
Renal Risks Associated with Chronic NSAID Use
Similar to NSAID-related GI adverse effects, NSAID-induced renal dysfunction has a wide spectrum of negative effects, including decreased glomerular perfusion, decreased glomerular filtration rate, and acute renal failure (ARF). While it is important to recognize that ARF can develop at any point during long-term NSAID therapy, the risk may be highest among those who have recently initiated therapy. Specifically, in a nested case control study of older adults, the risk of ARF was increased nearly twofold for all NSAIDs (nonselective and COX-2 selective NSAIDs) within 30 days of initial use/prescribing.13 This is consistent with previous studies reporting that NSAIDs increase the risk of ARF in the elderly.14,15 This risk is further increased in those older adults with preexisting chronic kidney disease (CKD) and in those who use long half-life NSAIDs.16 Thus, diligent monitoring of renal function (eg, blood urea nitrogen/serum creatinine to estimate creatinine clearance) is critical in older adults receiving NSAIDs, especially those who are at increased risk.14 Of note, salsalate may be preferred among the NSAIDs as it is rarely associated with nephrotoxicity.5 Overall, it is estimated that 2.5 million individuals in the United States experience adverse renal effects from NSAID use annually,17 with older adults being in the highest-risk group in the population.
CV/Cerebrovascular Risks Associated with Chronic NSAID Use
NSAIDs have been shown to worsen/increase the risk of various CV and cerebrovascular outcomes, with some studies suggesting a greater risk associated with COX-2 selective NSAIDs as compared to nonselective NSAIDs.11,18-23 One retrospective cohort study of older adults showed that naproxen carried the least risk of hospitalization for acute myocardial infarction (MI) among users of aspirin as compared to other nonselective NSAIDs (ibuprofen, diclofenac) and COX-2 selective NSAIDs (celecoxib, rofecoxib) used with aspirin.11 In contrast, a prospective, population-based cohort study found an increased risk of stroke with the use of nonselective NSAIDs (including naproxen), as well as with COX-2 selective NSAIDs (including celecoxib) in those not taking aspirin. On an individual NSAID analysis, naproxen users were found to have more than a twofold increased risk of stroke.20 Of note, all NSAIDs (ie, nonselective and COX-2 selective) carry a boxed warning for adverse CV events, including MI and stroke. Further research is needed to confirm individual NSAID adverse CV risk profiles.
One clinical trial of patients with hypertension (HTN) showed that piroxicam and ibuprofen blunted the effects of antihypertensive drugs (lisinopril/hydrochlorothiazide), significantly increasing systolic blood pressure (SBP) by 7.7-9.9%. An acetaminophen (APAP) period (in place of the NSAID) led to a significant decrease in blood pressure toward baseline, and a second exposure to the NSAIDs led to another significant increase in SBP of 7.0-7.7%, adding strong support to the evidence of causality.21 In addition, a cohort study of community-dwelling elderly individuals found that those who were taking antihypertensive therapy and NSAIDs had SBPs approximately 5 mmHg higher than those not taking NSAIDs, and were more likely to have SBP higher than 140 mmHg.18
NSAIDs have also been shown to cause or exacerbate heart failure (HF) in older adults. Specifically, a cohort study of older adults found that rofecoxib and nonselective NSAIDS (naproxen, ibuprofen, and diclofenac), but not celecoxib, were significantly associated with an increased risk of admission for HF as compared to those not taking NSAIDs.19 In contrast, another cohort study found that among patients who had survived their first hospitalization because of HF, subsequent use of any NSAID (including celecoxib, as well as ibuprofen, diclofenac, naproxen, and other NSAIDs) led to a significantly increased risk of death.22
Finally, an important point of clinical debate is the interaction between low-dose, cardioprotective aspirin and NSAIDs, potentially interfering with the antiplatelet effect of aspirin. The American Geriatrics Society5 recommends avoiding the coadministration of aspirin and ibuprofen based on a 2006 Food and Drug Administration warning. However, it is important to recognize that evidence suggests that this warning should also apply to naproxen, but not celecoxib.23,24
CNS Risks Associated with Chronic NSAID Use
NSAID use has been shown to be associated with a number of CNS effects including aseptic meningitis, psychosis, and cognitive dysfunction.1,2 This latter point may seem to be inaccurate, but the literature suggests otherwise. At the time of this writing, the studies to date have not consistently shown a benefit from chronic NSAID use in reducing the risk of dementia or cognitive impairment.25 Interestingly, though, several studies have shown that high-dose NSAIDs (ie, anti-inflammatory doses) may actually increase the risk of cognitive impairment.26,27 In particular, indomethacin appears to cause more CNS effects than other NSAIDs in the elderly.28
What Should Clinicians Do to Avoid/Minimize ADRs Associated with Chronic NSAID Use in Older Adults?
One approach to reducing ADRs associated with NSAIDs is to avoid the use of specific agents and use preferred alternative analgesics (Table). This is particularly important in those older adults with preexisting HTN, CKD, HF, and/or PUD, or those taking concomitant warfarin or corticosteroids. An alternative option would be to use APAP, which has been shown to be equally effective to NSAIDs in a number of studies of patients with mild-to-moderate osteoarthritis pain. Of note, patients who say that APAP does not work for them may not have used an optimal dose (3-4 g/day in divided doses for at least 2 wk), which would be required in order to show a lack of effectiveness. If APAP does not work and NSAID use is not contraindicated, a trial of analgesic dosing of a nonacetylated salicylate (eg, salsalate) or ibuprofen or celecoxib may be acceptable. For those with moderate-to-moderately severe osteoarthritis pain, a trial of a low-dose opioid or opioid-like agent (eg, codeine, tramadol) in combination with APAP is another option. The rationale for this approach is to combine two different mechanisms of analgesic action. In those elderly persons who require chronic NSAIDs, a proton pump inhibitor or misoprostol should be used to avoid the risk of PUD.9,12 In general, long half-life NSAIDs (eg, naproxen, oxaprozin, piroxicam) and specific other NSAIDs (eg, indomethacin, ketorolac) should be avoided because their risk outweighs their potential benefits.28
Conclusion
This review has summarized the potential risks associated with chronic NSAID use in older adults, including GI, renal, CV/cerebrovascular, and CNS adverse effects. Although only ADRs affecting these four organ systems were discussed in this review, it is important to recognize that NSAIDs can cause various other adverse effects (eg, hepatotoxicity, cutaneous toxicity).2 Moreover, it is important to note that nonpharmacological approaches (weight reduction, increasing physical activity) may also help patients who are experiencing musculoskeletal pain.29 For patients already taking NSAIDS chronically, healthcare providers should assess whether the patient could switch to APAP or salsalate. If the patient still requires a NSAID, GI prophylaxis should be considered in all older patients, especially those with other risk factors; importantly, the NSAID should be used at the lowest effective dose for the shortest period of time.
As the aging population rapidly grows over the next few decades, the risks associated with chronic NSAID use will remain an important public health issue. Hopefully, healthcare providers armed with the above information who carefully and consistently monitor chronic NSAID use in their older patients will avoid these preventable complications.
Drs. Marcum and Hanlon are in the Division of Geriatric Medicine, Department of Medicine, School of Medicine, University of Pittsburgh, PA; and Dr. Hanlon is also at the Geriatric Research Education and Clinical Center (GRECC), and the Center for Health Equity Research and Promotion (CHERP), Veterans Affairs Pittsburgh Healthcare System (VAPHS).
Acknowledgments
The writing of this paper was supported by National Institute on Aging grants (R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01 NR010135), and an Agency for Healthcare Research and Quality grant (R01 HS017695). The authors report no relevant financial relationships.
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