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Nonsteroidal anti-inflammatory drugs
and their effects in the elderly
Ki E Park, Yi Qin & Anthony A Bavry*
Management of chronic pain can often be a challenging task, especially in the elderly. Patients
over the age of 65 years have altered metabolism and pharmacodynamics that increase their
susceptibility to adverse side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common
component of pain management in this population. Nonselective NSAIDs as well as selective Cox-2
inhibitors have been associated with side effects, including renal dysfunction, heart failure,
gastrointestinal toxicity and increased risk of cardiovascular side effects. These adverse effects are
particularly important in the elderly, and thus use of NSAIDs in this population must be scrutinized
carefully. If NSAIDs are utilized, they should be tailored to the individual patient and administered
in the lowest dose and for the shortest duration possible. It is hoped that future studies will provide
further insight into the safety of these agents in elderly patients.
Chronic pain remains a significant source of distress and disability, particularly in the elderly
population. It is estimated that 20% of individuals suffer from various forms of chronic
pain worldwide [1] . Among this population,
over 30 million people utilize nonsteroidal
anti-inflammatory drugs (NSAIDs) for treatment of their discomfort. Approximately half
of these patients are over the age of 65 years
and use NSAIDs on a daily basis [2,3] . It is these
patients that have the most comorbidities, which
places them at highest risk of side effects. As
the population ages, it is anticipated that the
use of chronic pain medications for degenerative joint disease and other chronic ailments
will only continue to increase. The most common pain medications used in these patients are
NSAIDs as an alternative to opioid analgesics.
Although initially viewed as a safer alternative
in this particular population, emerging evidence
suggests that the adverse effects on a variety of
end organ systems may sometimes outweigh the
analgesic benefits. Additionally, treatment costs
of NSAID-induced cardiovascular (CV) and
gastrointestinal (GI) side effects may negate the
cost–effectiveness of oral administration of this
class of medications when compared with topical preparations as measured by quality-adjusted
life years [4] .
The majority of elderly populations suffer
from osteoarthritis; however, pain medication
requirements can also stem from a variety of other
conditions, including cancer-related discomfort
and neuropathic pain from diabetes or zoster.
Thus, the elderly often have unique requirements for treatment of pain, which could be
compounded by a variety of medical conditions.
10.2217/AHE.12.6 © 2012 Future Medicine Ltd
Although they are perhaps the population that
can benefit the most from use of chronic pain
medications, they are also the most susceptible
to side effects due to altered pharmaco­dynamics
secondary to changes in drug distribution
dynamics, reduced metabolism and impaired
absorption. NSAIDs, along with aspirin, have
been implicated in increasing the risk of hospital
admissions in elderly populations attributed to
adverse drug reactions. In this review, we aim
to discuss the current literature regarding the
benefits and adverse effects of NSAID use in
the elderly, in addition to highlighting future
areas of study. Guideline recommendations from
the American College of Cardiology/American
Heart Association as well as the American
Geriatric Society are included. We additionally queried the MEDLINE database as well
as clinicaltrials.gov with keywords including
elderly, nonsteroidal anti-inflammatory drugs,
heart failure, myocardial infarction (MI), GI
toxicity and renal dysfunction. We have synthesized these results in this review to provide
a summary of the currently available literature
on NSAID use in the elderly and the associated
potential for adverse side effects.
Aspirin
Acetylsalicylic acid (ASA), better known as
aspirin, was originally discovered in the 18th
century although anecdotal use dates back to
ancient Greek times. GI toxicity was noted as
a use-limiting side effect early on, thus efforts
to produce NSAIDs with improved efficacy and
reduced toxicity led to the development of various
forms of this medication. Although aspirin was
one of the original NSAIDs developed for the
Aging Health (2012) 8(2), 167–177
Department of Medicine,
Division of Cardiovascular Medicine,
University of Florida, College of
Medicine, 1600 SW Archer Road,
Gainesville, FL 32610-0277, USA
*Author for correspondence:
Tel.: +1 352 273 9075
Fax: +1 352 846 0314
[email protected]
Keywords
• adverse events • coronary artery
disease • cyclooxygenase enzyme
• elderly • gastrointestinal toxicity
• heart failure • nonsteroidal
anti-inflammatory drug • pain
• renal dysfunction
part of
ISSN 1745-509X
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Review – Park, Qin & Bavry
treatment of pain, there are limited data available
on how often aspirin is used for this purpose.
Instead, it is well validated role in primary and
secondary prevention of CV disease places it in
unique category compared with other NSAIDs.
Multiple trials including a meta-ana­lysis by the
Antithrombotic Trialists’ Collaboration have
demonstrated that anti-platelet therapy with aspirin reduces occurrence of major vascular events in
patients with evidence of prior CV disease including MI, angina and stroke [5] . In patients with
prior MI, aspirin therapy resulted in 36 fewer
adverse events for every 1000 treated patients. For
primary prevention, an updated meta-ana­lysis
in 2009 demonstrated a 12% risk reduction in
major CV events primarily driven by reduction in
MI; however, this benefit was mostly observed in
men [6] . Although efficacy in reducing CV events
is validated, aspirin still has an associated risk of
bleeding. Unlike other NSAIDs, ASA irreversibly
inhibits platelet function for the life of the platelet (7–10 days). The same 2009 meta-­a nalysis
also demonstrated a trend towards increased risk
of hemorrhagic stroke and a 50% relative risk
increase of major GI bleeding.
Although data is not definitive, there have
been concerns raised over the potential for interaction between aspirin and NSAIDs. The belief
is that concurrent NSAID use may interfere with
the beneficial effects of aspirin, since nonselective
NSAIDs compete with aspirin for binding to the
Cox-1 enzyme. Studies have suggested the highest interaction to be with ibuprofen or naproxen,
but this theoretical interaction could occur with
any NSAID [7,8] . These studies mainly analyzed
healthy subjects and have not clearly demonstrated that these interaction effects are clinically
significant and results have been conflicting [9,10] .
However, the US FDA suggests separating the
time of administration of these compounds at
least 2 h apart to avoid any possible interaction.
Although ASA has clearly been demonstrated
to be effective in CV risk reduction, its use
in the elderly population is not as clear. The
US Preventive Services Task Force recommendations for use of ASA in patients 80 years or
older state that the evidence is insufficient to
determine the balance risks and benefits of aspirin for CV disease prevention [11] . An ongoing
large, placebo-controlled trial of low-dose ASA in
subjects over the age of 65 years without known
CV disease is designed to assess the efficacy and
safety of primary prevention of CV disease and
dementia [12] . This study should significantly
contribute to our understanding of ASA use in
the elderly.
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Nonselective NSAIDs
The primary mechanism of action of NSAIDs
is inhibition of the Cox enzyme (prostaglandin
synthase), thus impairing conversion of arachidonic acid to prostaglandins, prostacyclins and
thromboxanes. Extent of enzyme inhibition varies by different NSAIDs and subclasses. Cox-1
and -2 are the primary isoforms of the Cox
enzyme. They differ in the tissues in which they
are present, which is important to understanding their different effects. Cox-1 is expressed in
a wide variety of tissues, but to different degrees
and is involved in regulation of gastric protection,
kidney function and platelet function. Cox-2 is
primarily upregulated in states of inflammation
[13] . Although NSAIDs are deemed ‘nonselective’
they are known to differ in their affinity for Cox-1
versus -2 inhibition with older NSAIDs, including etodolac and nabumetone having relatively
more selectivity for Cox-2. Concordantly, adverse
effects between these more selective agents may
be similar to selective Cox-2 inhibitors.
A wide variety of NSAIDs are available without prescription with six different classes, including over 20 different medications currently available in the USA (see Table 1). Currently available
nonselective NSAIDs inhibit both Cox pathways
and include ibuprofen, which is one of the most
commonly used and widely available over-thecounter NSAIDs. This agent, although available over-the-counter, can still produce toxicity
if administered at high doses and for extended
periods of time. In the elderly, enterohepatic
circulation is often reduced, thus increasing the
length of mucosal exposure to NSAIDs leading
to increased incidence of GI bleeding. Therefore,
in this particular population it may be best to
avoid long-acting NSAID preparations.
Selective Cox-2 inhibitors
Cox-2 inhibitors differ mainly in their tissue
specificity and enhanced expression of Cox-2
during states of inflammation. Examples of
these agents, along with those withdrawn from
the market, are listed in Table 2 . As inhibition of
Cox-2 avoids interference with pathways protective of GI mucosa, selective Cox-2 inhibitors
were originally developed to decrease potential
GI side effects. Although they are selective for
Cox-2 inhibition, they are generally felt to be as
efficacious in regards to analgesia as nonselective NSAIDs [14,15] . The most commonly cited
Cox-2 inhibitors are celecoxib, valdecoxib and
rofecoxib. In 2004, rofecoxib was withdrawn
worldwide after continued evidence of increased
risk of CV events was observed.
future science group
NSAIDs in the elderly –
Review
Table 1. Nonsteroidal anti-inflammatory drugs available in the USA.
NSAID
Typical adult dosing
Aspirin
Oral: 325–650 mg every 4–6 h; maximum daily dose: 4 g; rectal suppository available
Diflunisal
Oral: 500–1000 mg followed by 250–500 mg every 8–12 h; maximum daily dose: 1.5 g
Salsalate
Oral: 3 g/day in two to three divided doses
Ibuprofen
Oral: 400–800 mg every 6 h as needed; maximum daily dose: 3.2 g
Naproxen
Oral: 500 mg, then 250 mg every 6–8 h; maximum daily dose: 1.25 g
Fenoprofen
Oral: 300–600 mg three- to four-times/day; maximum daily dose: 3.2 g
Ketoprofen
Oral: 50 mg four-times/day or 75 mg three-times/day; maximum daily dose: 300 mg
Flurbiprofen
Oral: 200–300 mg/day in two, three or four divided doses; maximum daily dose: 300 mg
Oxaprozin
Oral: 600–1200 mg/day
Indomethacin
Oral: 25–50 mg two- to three-times/day; maximum daily dose: 200 mg; iv. rectal suppository also available
Sulindac
Oral: 150 mg twice daily; maximum daily dose: 400 mg
Tolmetin
Oral: 600 mg to 1.8 g/day; maximum daily dose: 1.8 g
Etodolac
Oral: 400 mg twice daily or 300 mg two- to three-times/day or 500 mg twice daily
Ketorolac
Oral: 20 mg, followed by 10 mg every 4–6 h; maximum daily dose: 40 mg; oral dosing is intended to be a
continuation of im. or iv. therapy only
Im.: 60 mg as a single dose or 30 mg every 6 h; maximum daily dose: 120 mg
Iv.: 30 mg as a single dose or 30 mg every 6 h; maximum daily dose: 120 mg
Diclofenac
Oral: 150–200 mg/day in three to four divided doses;
Transdermal:
• Gel: apply 4 g of 1% gel to affected area four-times/day; maximum daily dose: 16 g/joint
• Solution: apply 40 drops to each affected knee(s) four-times/day
Topical patch also available
Nabumetone
Oral: 1000 mg/day; maximum daily dose: 2000 mg
Piroxicam
Oral: 10–20 mg/day; maximum daily dose: 20 mg
Meloxicam
Oral: 7.5–15 mg once daily; maximum daily dose: 15 mg
Mefenamic acid
Oral: 500–250 mg every 4 h as needed; maximum therapy: 1 week
Meclofenamic acid
Oral: 200–400 mg/day in three to four divided doses; maximum daily dose: 400 mg
im.: Intramuscular; iv.: Intravenous; NSAID: Nonsteroidal anti-inflammatory drug.
Data taken from [68,69,101].
Although Cox-2 inhibition is believed to
have less GI toxicity [16,17] , this reduction in GI
risk compared with nonselective NSAIDs may
not be present with concurrent use of ASA. In
one study that analyzed ulcer occurrence, the
incidence of ulcers was similar in patients taking either celecoxib or a nonselective NSAID if
taken in conjunction with a low-dose ASA [16] .
Therefore, the benefits of specific Cox-2 inhibition may be negated by ASA use for CV disease
prevention in regards to GI side effects although
another study by Altman et al. demonstrated
benefit in reduction of adverse CV outcomes in
acute coronary syndrome patients with meloxicam used in conjunction with heparin and ASA
without excess GI effects [18] . Although evidence
is inconclusive, it may be prudent to incorporate a proton pump inhibitor or other mucosal protective measures to prevent GI toxicity
future science group
especially in the elderly who are at highest risk
for GI complications.
One of the products of the Cox pathway is
thromboxane, which is an important component of platelet function. Preferential blockade
of Cox-2 avoids interaction with thromboxane
production and, therefore, does not affect platelet
function (as opposed to nonselective NSAIDs).
This was seen in a study assessing very high
doses of celecoxib compared with placebo and
naproxen, which demonstrated no change in
platelet function compared with significant
increase in bleeding time and decreased platelet
aggregation and adhesion with naproxen [19] . This
preferential lack of effect may be beneficial when
use of a NSAID is needed in the setting of additional anticoagulation for other conditions, such
as atrial fibrillation or mechanical valves; both
conditions that are more common in the elderly.
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Table 2. Selective Cox-2 inhibitors.
Selective Cox-2 inhibitors
Typical adult dosing
Celecoxib (Celebrex )
Oral: 200 mg/day as a single dose or in divided doses twice daily
Rofecoxib (Vioxx )
Withdrawn
®
®
Valdecoxib (Bextra )
Withdrawn
Parecoxib (Dynastat®)
Im., iv.: 40 mg, followed by 20–40 mg every 6–12 h; maximum
daily dose: 80 mg
Withdrawn, available in Europe
Lumiracoxib (Prexige®)
Oral: 400 mg once daily
Withdrawn, available in Mexico
Etoricoxib (Arcoxia®)
Oral: 30–60 mg once daily
Withdrawn, available in Europe
®
im.: Intramuscular; iv.: Intravenous.
Data taken from [68,69,101].
This was demonstrated in a study assessing bleeding in patients on warfarin in a
case–control study. Patients with bleeding were
much more likely to have used a nonselective
NSAID compared with patients without bleeding who were more likely to have used a Cox-2
inhibitor [20] .
NSAIDs & potential adverse side effects
In the elderly, a variety of factors can play into elevated risk of adverse end-organ effects, which may
outweigh any benefits with regards to NSAIDs.
Altered mechanisms of drug metabolism may
prolong exposure to the harmful end products
of the Cox pathways. Most analgesic doses are
not adjusted for age; therefore, the most prudent
way to prescribe these medications is to start at
the lowest dose and titrate up as needed for effect.
In patients with swallowing difficulties, alternative forms of NSAID therapy (i.e., transdermal
preparations) can be considered, although absorption may be more variable. Although NSAIDs
can provide significant pain relief, the risks and
benefits, particularly in the elderly, must be considered carefully. We review the most common
known adverse side effects in this section.
Hypertension
All NSAIDs elevate blood pressure to some
degree in both normotensive and hypertensive
individuals [21] . Elevation in blood pressure varies, but ranges from 2 to 5 mmHg across a wide
range of studies. Hypertensive effects of NSAIDs
are most likely due to Cox-2 inhibition and subsequent effects on renal physiology. In the kidneys, Cox-2 inhibition leads to decreased sodium
excretion and increased intravascular volume.
Aspirin has minimal effect on Cox-2, and does
not elevate blood pressure [22,23] .
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Multiple meta-analyses have studied the association between NSAIDs and hypertension. In one
study by Pope et al., subjects with a mean duration of NSAID therapy for 15 days experienced an
increase in mean arterial pressure of 3.3 mmHg
with noticeable differences between specific
NSAIDs. After adjustment for sodium intake,
naproxen demonstrated the highest increase in
blood pressure (3.7 mmHg) [23] . Another metaana­lysis by Johnson et al evaluated 50 randomized
control trials with the mean age of participants
being 47 years [22] . In two-thirds of these trials the
duration of NSAID use was at least 1 week and
was associated with an increase in blood pressure
of 5 mmHg. However, sub-analyses demonstrated
significant increases in only those with controlled
hypertension, with piroxicam, ibuprofen and indomethacin all demonstrating the highest increases
in mean arterial pressure when compared with placebo. Overall, these two analyses showed elevation
in blood pressures that varied by specific NSAID
and presence of underlying hypertension.
The SUCCESS VI and VII studies analyzed
the relationship between blood pressure and
Cox-2 inhibition in a large group of patients with
hypertension. These studies included a large proportion of elderly subjects over the age of 65 years
and demonstrated a significant increase in number of patients with blood pressure elevation
with rofecoxib compared with celecoxib [24,25] .
Additionally, the CRESCENT trial evaluated
changes in blood pressure among diabetics with
controlled hypertension (mean age 63 years old).
Patients on rofecoxib demonstrated the highest
elevations in blood pressure [26] .
GI toxicity
Prostaglandins and prostanoids are critical in
maintaining gastric mucosal integrity. The GI
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NSAIDs in the elderly –
mucosa uses local Cox-1 to produce these protective prostaglandins. Inhibition of Cox pathways
by aspirin doses as low as 10 mg per day have
been associated with subclinical mucosal damage with higher doses associated with increased
risk of clinically apparent toxicity [27] . Aspirin
has also been shown to increase the incidence
of duodenal ulcers [28,29] with concurrent
Helicobacter pylori infection potentially playing an independent role in ulcer formation in
the setting of NSAID use [30] . Multiple studies
have sought to identify additional risk factors
for GI hemorrhage associated with NSAID use.
Duration of treatment appears to be an important risk factor, along with older age, prior history of NSAID-induced GI toxicity, history of
peptic ulcer disease, concurrent use of steroids or
antiplatelet agents, such as clopidogrel and use
of other anticoagulants [31] .
Renal dysfunction
Nonselective NSAIDs may induce both acute
and chronic renal injury. Acute injury is secondary to prostaglandin-mediated vaso­constriction
[32] . Although injury can occur with any NSAID,
a large study conducted in an elderly population
demonstrated an increased risk of acute kidney
injury within 30 days of initiation of naproxen,
rofecoxib and celecoxib [33] . It has been suggested
that low-dose ASA, ibuprofen and sulindac are
safer agents [34,35] ; however, low-dose ASA in the
elderly may still have an associated risk of renal
dysfunction [36] .
In relatively healthy patients, large clinical trials have not demonstrated a significant risk of
renal dysfunction with use of Cox-2 inhibitors;
however, in high-risk patients with underlying
renal disease and other precipitating factors,
such as heart failure and volume depletion, these
agents can affect renal function. In several studies, older patients seemed to be particularly susceptible to significant reductions in glomerular
filtration rate [37,38] . Thus, elderly patients with
underlying renal function or other conditions
that may predispose to renal dysfunction should
avoid selective Cox-2 inhibitors.
Heart failure
Several large cohort studies have looked at the
association between heart failure and NSAID
use. In one study, relative risk for first occurrence
of heart failure was not significantly different
among NSAID users compared with nonusers [39] . However, risk of rehospitalization for
heart failure appears to be significantly increased
with NSAID use, specifically diclofenac and
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Review
ibuprofen, and appears dose dependent [40] . In
another study, ibuprofen given in total doses of at
least 1200 mg/day and naproxen at least 500 mg
day, were associated with increased risk of death
as well [41] . The primary mechanism of NSAIDinduced heart failure may be due to increased
afterload from NSAID-induced vasoconstriction
[42] . Although patients with pre-existing hyponatremia appear to be at greatest risk, this likely
serves more as a marker for those patients with
more severe heart failure who are thereby more
susceptible to fluid and sodium shifts induced
by NSAIDs as opposed to an actual risk factor
for heart failure [43] .
Selective Cox-2 inhibitors have also been
studied in relation to heart failure. In patients
older than 66 years of age without known heart
failure, rofecoxib was associated with increased
risk of hospitalization for heart failure [44] . In
patients with known heart failure, there appears
to be a dose-dependent relationship between risk
of death with rofecoxib, celecoxib and diclofenac [41] . High-dose ibuprofen (1200 mg) and
naproxen (>500 mg daily), were associated with
increased risk of death [41] . NSAID-induced vasoconstriction may also negate the beneficial afterload reducing effects of angiotensin-converting
enzyme inhibition [40,45] .
Adverse CV events
In 2004, rofecoxib was withdrawn from the
market due to evidence of increased CV events.
Additionally, valdecoxib (and its intravenous
prodrug parecoxib) were withdrawn from the
market in 2005 over similar concerns. Although
celecoxib remains on the market, caution has
been advised with regard to dose-dependent
CV risks associated with these agents. Although
many trials have highlighted the risks associated
with selective Cox-2 inhibitors, CV events are
not just limited to these agents. Nonselective
NSAIDs, particularly those that are more selective for Cox-2, such as diclofenac, have been
associated with adverse CV events, primarily
MI [46,47] . However, other studies have been less
conclusive [48,49] . In a recent post-hoc ana­lysis
from the INVEST trial, patients with coronary
artery disease and hypertension who endorsed
chronic use of NSAIDs over an average length
of 2.7 years were found to have a significant
(47%) increase in adverse CV events (death,
nonfatal MI or nonfatal stroke). The exact data
on the type of NSAID was not collected, thus
it was presumed to be a class effect. The results
of this ana­lysis are particularly important as
the average age of study subjects was 65 years
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and one-third of patients were over the age of
70 years [50] .
Various studies have demonstrated increased
risk of CV events with Cox-2 inhibition
although the extent of elevated risk appears to
depend on dose [51] and may differ among specific NSAIDs [52] . A recent meta-ana­lysis from
Trelle et al. assessed CV safety of NSAIDs in 31
trials in over 100,000 patients. The investigators found that rofecoxib was associated with
the highest risk of MI and ibuprofen was associated with the highest risk of stroke. Eterocoxib
and diclofenac were associated with the highest
risk of CV death, while naproxen was associated
with the least harm [52] . After MI, short-term use
of celecoxib and rofecoxib has been associated
with an increase risk of death [53] . In a study of
patients older than 65 years of age, first-time
use of rofecoxib was associated with significant increased risk of MI [54] . In 2011, a large
meta-ana­lysis found risk of MI with Celebrex®
(Pfizer, NY, USA) to be lower than rofecoxib or
ibuprofen, but greater than naproxen [52] . The
ACP trial for polyp prevention was terminated
prematurely due to increased CV events and
risk of CV death [55] . However, although these
trials suggest an association between celecoxib
and CV risk, several other studies including
CLASS and SUCCESS-1 did not support these
assertions [16,56] .
The ADAPT was developed to test the
hypothesis that use of naproxen or celecoxib in
a healthy elderly population would reduce the
incidence of dementia [57] . This trial, however,
was stopped in 2004 after increasing concerns
over CV toxicity associated with Cox-2 inhibitors in general in light of the withdrawal of
rofecoxib from the market and suspension of
celecoxib use in clinical trials.
Guidelines
Several different advisory guidelines have been
published addressing NSAID use and the association between various adverse side effects
(Table 3) . These include the American Heart
Association, the American College of Cardiology
and the American College of Rheumatology.
All of these agencies advise caution with prolonged use of any NSAID. Specific caution
is recommended by the American College of
Cardiology/American Heart Association against
use of NSAIDs in heart failure patients and in
those presenting with acute MI or unstable
angina [58,59] . However, the American College
of Rheumatology does acknowledge that, in
patients with severe arthritis, the potential risks
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associated with NSAIDs use may be outweighed
by the benefits of adequate pain management
and therapy should be tailored to the individual
patient [60] .
The most recent guidelines from the American
Geriatrics Society Panel on the management of
persistent pain in the elderly published in 2009
focused primarily on discussion of pharmacotherapeutic options [61] . They advise that alternate routes of administration including transdermal preparations may be suitable option in
some patients. Additionally, as the elderly often
demonstrate varied absorption of medications,
the shortest acting form of any pain medication should be used for intermittently occurring
pain. Acetaminophen is recommended as a first
choice as it is not associated with adverse side
effects, such as GI bleeding, renal or CV toxicity.
However, it is not a targeted anti-inflammatory,
which often makes acetaminophen less effective for treatment of chronic pain conditions,
such as osteoarthritis or rheumatoid arthritis.
If NSAIDs are used it is recommended that the
lowest dose for the shortest duration be utilized
and that consideration be given for concurrent
administration of a mucosal protective agent,
such as a proton pump inhibitor or H2-receptor
antagonist.
Additionally, although the FDA has released
warnings on the use of selective and nonselective
NSAIDs, there is a lack of specific information
on use of these agents in the elderly. As the literature highlights, there are significant specific
CV, GI and other end-organ side effects that
are heightened in the elderly population. Future
public health campaigns by the FDA and other
government agencies should focus on highlighting these various potential harmful side
effects in the elderly as use of NSAIDs in this
population will only continue to increase as the
population ages.
Alternative analgesics
& nonpharmacologic therapies
Due to the previously discussed potential for
side effects, particularly prominent in the elderly,
alternative therapies for treatment of chronic pain
should be considered. As discussed previously,
acetaminophen may be considered as a first-line
therapy for pain. Acetaminophen penetrates the
CNS and produces analgesia by altering pain
perception resulting in a higher pain threshold.
Opioid therapy is another alternative for pain
treatment. Although these agents are still associated with some risk of cardiac events as compared with NSAIDs [62] , opioids are associated
future science group
NSAIDs in the elderly –
Review
Table 3. Summary of nonsteroidal anti-inflammatory drug guidelines.
Writing group
Patient
population
Position on NSAIDs
Additional recommendations on
NSAIDs
American Geriatrics
Society
Age ≥65 years
Acetaminophen recommended as
first-line therapy in the elderly
If NSAIDs are used, it should be for the
shortest time period and lowest dose.
Consider use of concurrent mucosal
protective agent
[61]
American Heart
Association/American
College of Cardiology
Heart failure
Recommends against use of NSAIDs in
patients with heart failure
Consider gastroprotective therapy for
patients on concurrent ASA and NSAID
[59]
American Heart
Association/American
College of Cardiology
Patients
hospitalized for
MI, unstable
angina
Recommends immediate cessation of all
nonaspirin NSAIDs upon hospital
admission
Upon hospital discharge, can consider
naproxen if acetaminophen is ineffective
[58]
American College of
Gastroenterology
Age ≥65 years
Helicobacter pylori infection increases the Testing and treatment for Helicobacter
risk of NSAID-related GI complications
pylori in high-risk patients prior to the
initiation of NSAID therapy may reduce
the risk of GI complications
[70]
American College of
Rheumatology
Patients with
chronic arthritis
Benefits of NSAIDs in patients with
severe arthritis may outweigh risks
[60]
Naproxen is the NSAID of choice in
patients at increased CV risk
Ref.
ASA: Acetylsalicylic acid; CV: Cardiovascular; GI: Gastrointestinal; MI: Myocardial infarction; NSAID: Nonsteroidal anti-inflammatory drug.
with less GI toxicity. However, other side effects
such as constipation, respiratory depression and
sedation can be use limiting. Still, opioids are
a reasonable option for treatment of chronic
pain, especially in the elderly who demonstrate the lowest risk of abuse of these agents
[61] . However, if concerns over abuse potential
or side effects exist, tramadol may be another
alternative agent. Tramadol is a centrally acting analgesic alternative with both mono­
aminergic and opioid effects [63] . In fact, this
dual mechanism of pain control gives tramadol
some advantages in the management of neuropathic pain. However, the use of tramadol is
limited because abuse potential still exists, and
serious drug interactions are possible due to its
meta­bolism. Tapentadol is a newer similar analgesic with combined opioid and noradrenergic
actions that has been found to be as effective
for the management of osteoarthritis and lower
back pain as oxycodone and morphine. It also
has superior GI tolerability [64] . Since no metabolic activation is necessary, tapentadol has less
drug interactions than tramadol and may be a
preferred analgesic in patients with mild hepatic
or renal impairment.
Unlike oral therapies, targeted topical
administration of analgesics can minimize systemic side effects. Topical NSAIDs are designed
to provide analgesia, but with much lower systemic exposure. Specifically, topical ibuprofen
has been shown to have similar efficacy to
oral ibuprofen, and was in fact the preferred
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administration method by patients [65] . In
another small study, lidocaine 5% transdermal
patch was found to be no different than celecoxib in effectiveness and tolerability for treatment of osteoarthritic knee pain [66] . Although
these topical/transdermal agents are not always
feasible, they may present a reasonable option
for chronic management of mild-to-moderate
pain, especially in the elderly.
As an additional option, a variety of non­
pharmacotherapy-based therapies for treatment
of chronic pain have also been studied. Examples
of more targeted local therapies include pulsation-based thermal therapy, localized nerve
blockade and radiofrequency neurotomy. Such
therapies, along with many other nonpharmacologic therapies currently being developed, have
demonstrated significant promise and further
advancements in these techniques may lead to
reduced need for chronic oral therapies, such as
NSAIDs.
Conclusion & future perspective
Although advances have been made in understanding the potential for adverse effects of
NSAIDs in the elderly population, opportunities exist to further expand our knowledge in
this area. Future trials should focus on improving
our understanding of the safety of NSAID use
in the elderly. One such trial currently underway
is the PRECISION trial. This is a multicenter,
multinational study designed to assess the CV
safety of celecoxib relative to ibuprofen and
Aging Health (2012) 8(2)
173
Review – Park, Qin & Bavry
naproxen [67] . It is targeted to patients with rheumatoid arthritis or osteoarthritis. In addition,
patients had established or were at high risk for
CV disease. Although targeting a diverse population, this trial should have a substantial number
of elderly subjects enrolled due to the high prevalence of osteoarthritis in this population. As the
PRECISION study was designed for assessment
of safety, lack of early termination of the trial
suggests no difference in end points but final
results should shed further light on the safety
of NSAID use in the elderly population, which
is often excluded from clinical trials. Further
research efforts should also focus on targeting the
management of pain in the elderly to create safer
medications for the treatment of chronic pain.
Additionally, alternate approaches to pain management, including nonpharmacologic therapies,
should continue to be developed.
Management of chronic pain in the elderly
remains a challenge and will become increasingly
prominent as the population ages. Although
NSAIDs produce significant analgesia, they are
not without significant risk of adverse CV and
other end-organ side effects. Use of NSAIDs in
the elderly should be monitored carefully and
individualized to each patient’s needs for maximal efficacy in pain management and minimal
risk of adverse effects.
Financial & competing interests disclosure
AA Bavry has received research support from Novartis
Pharmaceuticals and is a contractor for the American
College of Cardiology’s Cardiosource. Publication of this
article was funded, in part, by the University of Florida
Open-Access Publishing Fund. The authors have no other
relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.
Executive summary
Considerations for pain therapy in the elderly
• A significant proportion of patients treated for chronic pain are over the age of 65 years.
• Elderly patients often have multiple comorbidities making treatment of chronic pain challenging.
• Elderly patients have altered metabolism and pharmacodynamics, which can alter drug metabolism.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used agents for chronic pain therapy, but can cause significant
end-organ damage, particularly in the elderly.
Aspirin
• Aspirin was originally designed for the treatment of pain but also has proven benefit in primary and secondary prevention of
cardiovascular disease.
Nonselective NSAIDs
• Wide variety of prescription and over-the-counter preparations available for the treatment of acute and chronic pain.
Selective Cox-2 inhibitors
• Designed to provide equivalent analgesia but less gastrointestinal toxicity compared with nonselective NSAIDs.
NSAIDs & potential adverse side effects
• All NSAIDs, to varying degrees, can elevate blood pressure in both normotensive and hypertensive patients.
• Inhibition of Cox pathways leads to mucosal compromise and increase in gastrointestinal toxicity with increased risk of bleeding.
• Both nonselective NSAIDs and Cox-2 inhibitors may induce renal dysfunction, particularly in the elderly.
• NSAIDs appear to increase the risk of hospitalization in patients with known heart failure.
• Selective Cox-2 inhibitors and nonselective NSAIDs have been associated with an elevated risk of adverse cardiac events, such as
myocardial infarction.
Guidelines
• Published guidelines from a variety of sources advocate caution with use of NSAIDs in those with heart failure, acute myocardial
infarction and the elderly. Acetaminophen is recommended as first-line therapy in the elderly and, if NSAIDs are used, they should be
prescribed in the lowest dose for the shortest duration possible.
Alternative analgesics & nonpharmacologic therapies
• Nonpharmacologic treatments for the management of chronic pain should be considered as an alternative to NSAIDs, particularly in
the elderly.
Future perspective
• Future trials such as the PRECISION study should significantly contribute to our understanding of NSAID safety, particularly in the
elderly.
174
www.futuremedicine.com
future science group
NSAIDs in the elderly –
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