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The Use of Nonsteroidal
Anti-Inflammatory Drugs for
Exercise-Induced Muscle Damage
Implications for Skeletal Muscle Development
Brad J. Schoenfeld
Department of Health Sciences, Program of Exercise Science, Lehman College, CUNY, Bronx, NY, USA
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
2. Effects of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) on Muscle Protein Synthesis . . . . . . . . . . . 1020
3. Effects of NSAIDs on Satellite Cell Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
4. Effects of NSAIDs on Muscle Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
5. Contradictions in Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Abstract Exercise-induced muscle damage (EIMD) is a common condition result-
ing from a bout of vigorous exercise, particularly if the individual is un-
accustomed to performance of the given movement. Symptoms of EIMD
include delayed-onset muscle soreness (DOMS) and a loss of physical func-
tion. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely pre-
scribed post-exercise to alleviate these symptoms and restore normal physical
function. Of potential concern for those who use NSAIDs to treat EIMD is
the possibility that they may impair the adaptive response to exercise. Spe-
cifically, there is emerging evidence that the action of cyclo-oxygenase (COX)
enzymes, and COX-2 in particular, are important and even necessary to
achieve maximal skeletal muscle hypertrophy in response to functional
overload. Given that NSAIDs exert their actions by blocking COX and thus
suppressing prostaglandin production, a theoretical rationale exists whereby
these drugs may have detrimental effects on muscle regeneration and super-
compensation. Therefore, the purpose of this article is to extensively review
the literature and evaluate the effects of NSAIDs on muscle growth and
development. Based on current evidence, there is little reason to believe that
the occasional use of NSAIDs will negatively affect muscle growth, although
the efficacy for their use in alleviating inflammatory symptoms remains
questionable. Evidence on the hypertrophic effects of the chronic use of
NSAIDs is less clear. In those who are untrained, it does not appear that
regular NSAID use will impede growth in the short term, and at least one
study indicates that it may in fact have a positive impact. Given their reported
REVIEW ARTICLE
Sports Med 2012; 42 (12): 1017-1028
0112-1642/12/0012-1017/$49.95/0
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impairment of satellite cell activity, however, longer-term NSAID use
may well be detrimental, particularly in those who possess greater growth
potential.
1. Introduction
Exercise-induced muscle damage (EIMD) is
a common condition resulting from a bout of
vigorous exercise, particularly if the individual is
unaccustomed to performance of the given move-
ment. Damage can be specific to just a few mac-
romolecules of tis sue or manifest as large tears in
the sarcolemma, basal lamina and supportive
connective tissue, as well as altering the function
of contractile elements and the cytoske leton.
[1]
While concentric and isometric actions can cause
EIMD,
[2,3]
damage is increased by the perfor-
mance of eccentric exercise whereby muscles are
forcibly lengthened.
[4]
For an in-depth review of
the topic, see Clarkson and Hubal.
[4]
Muscle soreness is a frequently reported con-
sequence of EIMD. This phenomenon has been
termed delayed-onset muscle soreness (DOMS),
as the associated symptoms of pain and tender-
ness generally peak 24–48 hours post-exercise.
DOMS is believed to be the result of a sensitization
of nociceptors by tissue breakdown products and
noxious chemicals such as histamines, bradykinins,
prostaglandins and free radicals.
[4,5]
Soreness may
also involve mechanoreceptors, including muscle
spindle afferents that are able to access the pain
pathway at the level of the spinal cord.
[5]
In ad-
dition, biochemical changes due to structural dis-
ruption of the extracellular matrix (ECM) has been
implicated with playing a role in the process.
[6]
It has been postulated that damage to myofibres
facilitates the escape and entrance of intracellular
and extracellular proteins, respectively, while
disturbance of the ECM media tes the inflamma-
tory response.
[6]
Symptoms can be exacerbated
by swelling within muscle fibres that exerts pres-
sure on nociceptors and thus increases the sen-
sation of pain.
[4]
EIMD can also decrease physical function, with
the degree of impairment modulated by the type,
intensity and/or duration of training.
[7]
Func-
tional post-exercise decrements have been attrib-
uted to damage to the excitation-contraction coup-
ling system and disruption of the sarcomere.
[5]
Swelling and stiffness can also contribute to the
process by limit ing range of motion.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
are routinely prescribed to alleviate EIMD-related
symptoms and restore normal physical function.
This class of drugs can be obtained either by pre-
scription or purchased over the counter. It is
estimated that 30 million people worldwide use
NSAIDs on a daily basis,
[8]
and their consump-
tion is particularly prevalent among athletes and
others who engage in vigorous physical activity.
[9]
A primary way in which NSAIDs are believed
to exert their pain-reducing effects is by inhibiting
the activity of cyclo-oxygenase (COX), a family
of enzymes that catalyze the conversion of ara-
chidonic acid (AA) to proinflammatory prosta-
noids.
[10,11]
Although the exact details have not
been fully elucidated, it is believed that damage to
skeletal muscle leads to activatio n of phospholipase
A
2
, which cleaves AA from the cell membrane,
ultimately resulting in COX-mediated produc-
tion of prostaglandins
[12]
(see figure 1). Prosta-
noids are subsequently released outside the cell,
influencing biological functions by interacting
with G protein-coupled cell surface receptors in
an autocrine/paracrine manner.
[12]
In addition to
their role in promoting pain and oedema, specific
prostanoid receptors are theorized to induce anab-
olic signal ling, conceivably via stimulation of up-
stream protein synthetic regulators that include
PI3K and extracellular signal-regulated kinases.
[13]
It also has been shown that prostanoid-mediated
signalling through calcium-dependent pathways
influences satellite cell-derived myonuclear ac-
cretion, directly leading to increased myofibre
growth.
[14]
These data strongly suggest that COX
activity is necessary to achieve maximal skeletal
muscle hypertrophy in response to functional
overload.
[15]
1018 Schoenfeld
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Three COX isoforms have been identified:
COX-1, COX-2 and COX-3. Of these isoforms,
only COX-1 and COX-2 are e xpressed in skeletal
muscle
[16,17]
and appear to be upregulated in re-
sponse to physical exercise.
[16,18,19]
It has been pro-
posed that COX-2 provides the primary impetus
for the inflammatory response following EIMD,
although emerging data seem to support an im-
portant role for COX-1 in the process.
[18,20]
In-
terestingly, recent studies seem to show that certain
NSAIDs may upregulate COX-2 production, pos-
sibly as a means to compensate for the anti-
inflammatory blockade.
[18,21]
Other mechanisms of
action have been attributed to NSAIDs including
activation of descending serotonergic pathways,
upregulation of cannabinoid receptors and inhibi-
tion of leukocyte adhesion pathways.
[22-24]
Despite their immense popularity as an an-
algesic and anti-inflammatory agent, the ability
of NSAIDs to relieve symptoms associated with
EIMD remains dubious. Although several re-
searchers have shown that NSAID administration
facilitates recovery of muscle function following
EIMD,
[25-27]
others have failed to note improve-
ments in comparison with placebo.
[28-31]
Similarly,
while some studies have reported reductions in
ratings of perceived soreness with post-exercise
NSAID consumption,
[27,28]
Connolly et al.
[32]
found
that the preponderance of evidence reveals no
therapeutic effect from their use.
Of potential concern for those who use NSAIDs
to treat EIMD is the possibility that they may
impair the adaptive response to exercise. Specifi-
cally, there is emerging evidence that COX enzymes
are important and even necessary to achieve
maximal skeletal muscle hypertrophy in response
to functional overload.
[15]
The hypertrophic ef-
fects of COX appear to be related to the synthesis
Muscle damage
Phospholipase A
2
AA
PGG
2
PGH
2
Prostacyclin Thromboxane
Prostaglandin
Selective COX-2
NSAIDs
COX-2COX-1
Nonselective
NSAIDs
Nonselective
NSAIDs
Inflammation/pain
Fig. 1. Simplified schematic of the COX inflammatory pathway from exercise-induced muscle damage and the proposed mechanism of
NSAID action on the process. Damage to skeletal muscle leads to activation of phospholipase A
2
, which cleaves AA from the cell membrane.
AA is then converted to PGG
2
by COX. PGG
2
, in turn, is converted to PGH
2
, which serves as a common precursor to all of the prostaglandins,
prostacyclin and thromboxane. NSAIDs exert their action by inhibiting COX, thereby ultimately blocking prostaglandin synthesis and thus
reducing the inflammatory response. AA = arachidonic acid; COX = cyclo-oxygenase; NSAID = nonsteroidal anti-inflammatory drug; PGG
2
and
PGH
2
= prostaglandin G
2
and H
2
.
The Use of NSAIDs for EIMD 1019
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of various prostaglandins, which have been shown
to stimulate satellite cell proliferation, differentia-
tion and fusion,
[19]
and increa se muscle protein
synthesis.
[33,34]
Given that NSAIDs supposedly
exert their actions by blocking COX and thus
suppressing prostaglandin production, a theore-
tical rationale exists whereby these drugs may
have detrimental effects on muscle regeneration
and supercompensation. Therefore, the purpose
of this article is to extensively review the literature
and evaluate the effects of NSAIDs on muscl e
growth and development. To carry out this re-
view, English language literature searches of the
PubMed and EBSCO databases were conducted
for all time periods up to December 2011. Com-
binations of the following keywords were used as
search terms : ‘NSAID’, ‘anti-inflamma tory drug’,
‘cyclo-oxygenase inhibitor’, ‘exercise’, ‘muscle
hypertrophy’, ‘growth’, ‘satellite cell’, ‘myoblast’
and ‘protein synthesis’. The reference lists of ar-
ticles retrieved in the search were then screened
for any additional articles that had relevance to
the topic. All applicable studies were included for
discussion, with a focus on the results of in vivo
protocols, particularly those involving human
subjects.
2. Effects of Nonsteroidal
Anti-Inflammatory Drugs (NSAIDs)
on Muscle Protein Synthesis
The maintenance of skeletal muscle tissue
involves the dynamic balance between muscle pro-
tein synthesis and degradation.
[35,36]
Muscle hy-
pertrophy occurs when protein synthesis exceeds
proteolysis. Protein synthetic rates are markedly
increased following resistance exercise in both
young and old individuals alike, facilitating ad-
aptation to imposed demands.
[37,38]
The post-
exercise accretion of muscle proteins is carried
out via a complex cascade of an abolic signalling
pathways, although the exact mechanisms and
interplay between these pathways are not clearly
understood at this time.
[36]
Early studies in animal models demonstrated
that NSAIDs impaired protein metabolism.
[33,34,39]
These findings were attributed to an attenuation
of prostaglandin production via COX inhibition.
A suppression of prostaglandin F
2a
(PGF
2a
), in
particular, was purported to play a primary role
in blunting the muscle protein synthetic rate.
To date, four trials have investigated the ef-
fects of NSAID administration on post-exercise
muscle protein synthesis in humans (see table I).
The first of these studies was conducted by Trappe
et al.
[40]
Twenty-four sedentary or recreationally
active males (mea n – standard deviation [SD] age
25 – 3 years) were randomly assigned to receive
either 1200 mg of ibuprofen, 4000 mg of parace-
tamol (acetaminophen) or placebo following a
bout of supramaximal eccentric exercise. Exercise
consisted of 10–14 sets of 10 lengthening actions
for the knee extensors at a workload set to 120%
of concentric 1-repetition maximum (RM). Com-
pared with pre-exercise levels, skeletal muscle
fractional synthetic rate (FSR) was significantly
greater in those receiving placebo compared with
ibuprofen or paracetamol (mean – SD 76 – 19%
vs 35 – 21% vs 22 – 23%, respectively) at 24 hours
post-exercise. In addition, levels of PGF
2a
were
significantly increased (77%)intheplacebogroup
but remained unchanged in the treatment groups.
Based on this data, it was concluded that NSAIDs
blunt post-exercise protein synthesis by suppres-
sing production of PGF
2a
via the COX enzyme.
A limitation of the study was that researchers
only analysed mixed muscle protein synthesis.
Therefore, it is not clear what percentage of the
FSR represented myofibrillar versus noncontractile
proteins such as collagen.
In contrast to these findings, Burd et al.
[18]
employed a similar study design but found that
NSAID consumption did not impair mixed muscle
protein FSR foll owing performance of 10 sets
of 10 lengthening contractions for the knee ex-
tensors at a workload equating to 120% of con-
centric 1-RM. Subjects were 16 recreationally
active males (mean – SD age 23 – 1 years) randomly
assigned to receive eithe r 600 mg of celecoxib or
placebo in double-blind fashion. The primary
difference between this study and that of Trappe
et al.
[40]
was the use of a selective COX-2 inhibitor
(celecoxib) rather than a nonselective COX in-
hibitor (ibuprofen). Results suggest that the COX-1
enzyme may play a primary role in mediating
post-exercise muscle protein synthesis and that
1020 Schoenfeld
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COX-2 may be more reactive to injur y-related
stimuli. As with the study by Trappe et al.,
[40]
however, results were limited by a n inability to
isolate the contractile component of muscle pro-
tein synthesis.
Petersen et al.
[41]
was the first to evaluate the
effects of NSAIDs on post-exercise contractile
muscle protein synthesis. In a double-blind fash-
ion, 20 elderly subjects (aged 50–70 years) with
knee osteoarthritis were divided into either a
treatment group (n = 9) who received 1200 mg of
ibuprofen or a placebo group (n = 11). Exercise
consisted of 60 minutes of one-legged kicking at
55% of maximal workload while the contralateral
leg did not exercise. At 24 hours post-exercise,
plasma levels of PGF
2a
were significantly lower in
the NSAID group compared with placebo but
myofibrillar FSR was not different between groups.
It is difficult to justify these seemingly contradictory
results. Moreover, considering the injury history
and age of the subjects, as well as the endurance-
oriented nature of the exercise protocol, the gen-
eralizability of findings to healthy individuals who
perform resistance exercise is questionable.
Most recently, Mikkelsen et al.
[21]
studied the
effects of NSAIDs on post-exercise protein syn-
thesis in eight healthy male volunteers (mean –
SD age 23 – 3 years) who were experienced in
endurance exercise but not lower body resistance
training. Forty-five mg of indomethacin was
locally infused for 7.5 hours via catheter into the
vastus lateralis muscle of one leg before, during
and after exercise while the contralateral leg was
infused with placebo. Exercise consisted of 200
unilateral maximal isokinetic lengthening con-
tractions for the knee extensors. Muscle biopsies
taken 24–28 hours after training revealed no sig-
nificant differences in eithermyofibrillarorcollagen
mean muscle FSR between the NSAID-infused
leg compared with placebo at 24–28 hours post-
exercise.
3. Effects of NSAIDs on Satellite Cell
Activity
Satellite cells are myogenic stem cells that re-
side between the basal lamina and sarcolemma
of muscle fibres. At rest, the satellite cell pool
Table I. Summary of human studies investigating the effect of nonsteroidal anti-inflammatory drug consumption on post-exercise protein synthesis
Study, y Subjects Age
(y)
a
Exercise protocol NSAID/dosage Measurement
timepoints
Results
Trappe
et al.,
[40]
2002
24 healthy sedentary or
recreationally active M
25 – 310–14 sets of 10 repetitions of
unilateral knee extensor exercise at
120% 1-RM separated by 60 sec
rest intervals
Ibuprofen/1200 mg/day: n = 8, or
paracetamol (acetaminophen)/
4000 mg/day: n = 8, or placebo:
n = 8
Baseline and
24 h post-
exercise
Increase in mixed muscle FSR
significantly greater in placebo group
compared with NSAID group 24 h
post-exercise
Burd
et al.,
[18]
2010
16 healthy recreationally
active M
23 – 1 10 sets of 10 repetitions of
unilateral knee extensor exercise at
120% 1-RM separated by 60 sec
rest intervals
Celecoxib/600 mg/day: n = 8, or
placebo: n = 8
Baseline and
24 h post-
exercise
No significant difference in mixed
muscle protein FSR between groups
24 h post-exercise
Petersen
et al.,
[41]
2011
20 sedentary or
recreationally active M
(n = 11) and F (n = 9) with
knee osteoarthritis
50–70 60 min of one-legged kicking at
55% of workload maximum
Ibuprofen/1200 mg/day: n = 9, or
placebo: n = 11
Baseline and
24 h post-
exercise
No significant difference in
myofibrillar FSR between groups
24 h post-exercise
Mikkelsen
et al.,
[21]
2011
8 healthy endurance-
trained M
23 – 3 200 unilateral maximal eccentric
knee extensor contractions
Indomethacin/45 mg/day: n = 8
(within-subject design)
Baseline and
24–28 h post-
exercise
No significant differences in either
myofibrillar or collagen mean muscle
FSR between groups 24–28 h
post-exercise
a Age data are presented as mean –SD or range where stated.
F = female; FSR = fractional synthetic rate; M = male; NSAID = nonsteroidal anti-inflammatory drug; RM = repetition maximum.
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remains quiescent until aroused by mechanical
stimuli. Once activated, they
[1]
generate precursor
cells (myoblasts) that proliferate and ultimately
fuse to existing cells, providing agents needed for
repair and subsequent growth of new muscle tis-
sue.
[42]
Satellite cells also help to retain the mitotic
capability of muscles by donating their nuclei to
existing muscle fibres, thereby increasing the ca-
pacity to synthesize new contractile proteins.
[43,44]
Since the nuclear content-to-fibre mass ratio of a
muscle remains constant during hypertrophy, the
satellite cell -derived addition of new myonuclei is
believed to be essential for realizing long-term
increases in muscle mass.
[45]
This is consistent
with the concept of myonuclear domain, which
proposes that the myonucleus regulates messen-
ger RNA (mRNA) production for a finite sarco-
plasmic volume, and any increases in fibre size
must be accompanied by a proportional increase
in myonuclei.
[46]
Moreover, satellite cells co-express
various myogenic regulatory factors such as Myf5,
MyoD, myogenin, and myogenic regulatory factor
(MRF)-4
[47]
that bind to sequence-specific DNA
elements present in the promoter of muscle genes
to aid in the hypertrophic process.
[48,49]
Although somewhat controversial, current
theory suggests that satellite cells are crucial for
the regulation of muscular growth.
[50]
In sup-
port of this view, a recent cluster analysis by
Petrella et al.
[46]
demonstrated that subjects who
experienced extreme increases in mean myo fibre
cross-sectional area of the vastus lateralis (>50%)
possessed a much greater ability to expand the
satellite cell pool compared with those who ex-
perienced moderate or negligible increases in hy-
pertrophy. Further support for the theory comes
from studies showing that muscle hypertrophy is
significantly attenuated when satellite cells are
obliterated by g-irradiation.
[51]
It should be noted
that some researchers dispute the importance of
satellite cells in exercise-induced muscle hyper-
trophy. A complete discussion of the topic is be-
yond the scope of this article and those interested
are referred to the point/counterpoint articles
by O’Connor and Pavlath
[50]
and McCarthy and
Esser.
[52]
Evidence that NSAIDs might have a negative
impact on satellite cell activity was initially
documented in animal cell culture. Zalin
[53]
dis-
played a marked suppression of fusion of chick
myoblasts when they were subjected to non-
selective COX inhibitors. Subsequently, Santini
et al.
[54]
found that the differentiation into myo-
tubes was impaired when myoblasts wer e main-
tained in indomethacin. Follow-up in vitro studies
have confirmed these results for both the COX-1
and COX-2 enzymes independently.
[55,56]
In vivo
research on rodents has similarly demonstrated
that selective COX-2 suppression reduced satellite
cell activation, proliferation and differentiation,
as well as inhibiting myonuclear incorporation
into muscle.
[19,57]
Interestingly, COX-1 was not
found to play a significant role in these studies,
leading to the supposition that COX-1 and COX-2
pathways have distinct roles during muscle repair.
More recently, researchers have conducted
human trials to investigate the topic (see table II).
Mackey et al.
[58]
examined the influence of NSAID
use on satellite cell activity following a single bout
of intense exercise in 14 healthy, well trained male
endurance athletes. Subjects were divided into
two groups, receiving either a 100 mg daily dose
of the nonspecific COX inhibitor indomethacin
for 12 days or placebo. Exercise for both groups
consisted of a 36 km run, with muscle biopsies
collected 1, 3 and 8 days post-exercise. Compared
with pre-exercise levels, results showed a 27%
increase in the number of neural cell adhesion
molecule-positive cells on day 8 post-exercise in
placebo, while levels remained unchanged at all
timepoints for the NSAID group.
Mikkelsen et al.
[59]
investigated the effects of
NSAID administration on the satellite cell response
to a bout of eccentric exercise. Eight healthy male
volunteers (mea n – SD age 23 – 3 years) per-
formed 200 unilateral maximal isokinetic length-
ening contractions for both legs. Subjects were
considered well trained but had not performed
resistance training of the lower limbs for at least
1 year. On the day of the exercise bout, 45 mg of
indomethacin was locally infused for 7.5 hours
via catheter into the vastus lateralis muscle of one
leg before, during and after exercise. The control
leg was infused with placebo. Results showed that
the number of Pax7(+) cells per myofibre was
significantly increased by 96% in the control leg
1022 Schoenfeld
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8 days post-exercise but remained unchanged in
the muscles infused with indomet hacin, indicat-
ing a decidedly detrimental effect of NSAID admin-
istration on satellite cell activity. A noteworthy
aspect of the study was that these findings were
seen with a single infusion of NSAID, suggesting
that COX blockage in the early post-exercise
period may interfere with pathways necessary for
satellite cell proliferation.
In a double-blind, placebo-controlled experi-
ment, Paulsen et al.
[31]
evaluated the effects of a
selective COX-2 inhibitor on muscle recovery
following damaging exercise. Thirty-three young,
physically active volunteers (22 males; 11 females)
performed 2 bouts of maximal lengthening ac-
tions of the elbow flexors. The bouts were sepa-
rated by 3 weeks and only one arm was trained
per session, with the other arm serving as a non-
exercise control. Participants were randomized to
either an NSAID group or a placebo group. Those
in the NSAID group received 400 mg of celecoxib
daily for 9 days, with the first dose administered
approximately 45 minutes prior to each exercise
bout. The placebo group received lactose pills over
the same time periods. In contrast to the findings
of Mackey et al.
[58]
and Mikkelsen et al.,
[59]
re-
sults showed no significant differences in the
number of satellite cells/ myoblasts per myofibre
between groups following either exercise bout
at any of the timepoints studied. No significant
differences were found in the number of macro-
phages, although the five highest peak values
were all found in samples from those in the pla-
cebo group. Whether the discrepancy between
this study and those reporting a negative effect on
satellite cell activity are due to the use of a selec-
tive COX-2 inhibitor versus a nonselective COX
inhibitor are not clear at this time.
Interestingly, Mikkelsen et al.
[21]
found that
nonselective NSAID use downregulated insulin-
like growth factor (IGF)-1Ea expression at 5 hours
post-exercise. IGF-1Ea has been shown to en-
hance fusi on of satellite cells with existing muscle
fibres, facilitating the donation of myonuclei and
helping to maintain optimal DNA to protein
ratios in muscle tissue.
[35,51]
Levels of the muscle
specific IGF-1Ec isoform (i.e. mechano growth
factor), however, were unaffected by NSAID
Table II. Summary of human studies investigating the effect of nonsteroidal anti-inflammatory drug consumption on satellite cell activity
Study, y Subjects Age (y)
a
Exercise protocol NSAID/dosage Measurement
timepoints
Results
Mackey et al.,
[58]
2007
14 healthy M
endurance athletes
25 – 3 Running 36 km Indomethacin/
100 mg/day: n = 7,
or placebo: n = 7
Baseline, and 1, 3
and 8 days post-exercise
Significant increase in number of
NCAM+ cells on day 8 post-exercise
in placebo group vs no change in the
NSAID
Mikkelsen et al.,
[59]
2010
8 healthy endurance-
trained M
23 – 3 200 unilateral maximal
eccentric knee extensor
contractions
Indomethacin/
45 mg/day: n = 8
(within-subject design)
Baseline and 8 days
post-exercise
Significant blunting of satellite cell
number in NSAID group compared
with placebo 8 days post-exercise
Paulsen et al.,
[31]
2011
33 healthy recreationally
active M (n = 22) and
F(n= 11)
~25 2 bouts of 70 maximal
unilateral eccentric actions
of the elbow flexors
separated by 3 wk
Celecoxib/
400 mg/day: n = 15,
or placebo: n = 18
Baseline and 1, 2,
4 and 7 days post-exercise
No significant differences in satellite
cell activity between groups at
1, 2, 4 and 7 days post-exercise
a Age data are presented as mean –SD or approximate where stated.
F = female; M = male; NCAM+ = neural cell adhesion molecule; NSAID = nonsteroidal anti-inflammatory drug.
The Use of NSAIDs for EIMD 1023
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administration. This is intriguing, because the
initial pulse of IGF-1Ec has been shown to acti-
vate satellite cells and mediate their proliferation
and differentiation.
[60,61]
The implication s of these
findings require further study.
4. Effects of NSAIDs on Muscle
Hypertrophy
Studies on rodents have consistently shown that
treatment with both selective and nonselective
NSAIDs following chron ic overload have a pro-
foundly detrimental effect on muscle growth.
Soltow et al.
[15]
demonstrated that ibuprofen ad-
ministration in Sprague-Dawley rats resulted in
a50% decrease in hypertrophy of the plantaris
muscle 14 days post-surgical removal of the gas-
trocnemius and soleus. Similar impairments in
compensatory hypertrophic increases have been
reported from the use of selective COX- 2 in-
hibitors following synergist ablation of the tri-
ceps surae
[62]
and chronic hind limb suspension
in mice.
[57]
In contrast to the aforementioned animal
studies, the three human trials conducted to date
have failed to demonstrate a negative impact of
NSAIDs on hypertrophy (see table III). Krentz
et al.
[63]
examined the impact of a moderate dose of
NSAID on hypertrophy in 18 young volunteers
(12 males, 6 females; ~24 years of age). Employ-
ing a counterbalanced double-blind design, sub-
jects were randomly assigned to receive a daily
dose of 400 mg of ibuprofen following resistance
exercise for the elbow flexors of one arm and
placebo after working the other arm the next day.
Training con sisted of 6 sets of 4–10 repetitions,
and was performed 5 days a week. After 6 weeks
of training, no differences in muscle thickness
were noted between arms (~0.29 cm change in
muscle thickness for NSAID arm vs ~0.28 cm for
placebo). The study was limited by its short du-
ration and thus it is not clear wheth er differences
Table III. Summary of human studies investigating the effect of nonsteroidal anti-inflammatory drug consumption on muscle hypertrophy
Study, y Subjects Age
(y)
a
Exercise protocol Study
duration
(wk)
NSAID/dosage Measurement
instrument
Results
Krentz
et al.,
[63]
2008
18 healthy
M(n= 12) and
F(n= 6)
experienced
in resistance
training
~24 3 sets of 8–10 concentric
repetitions at 70% of 1-
RM, and 3 sets of 4–6
eccentric repetitions at
100% of 1-RM for the
elbow flexors with 1 min
rest interval performed on
alternate days for each
arm for 5 days/wk
6 Ibuprofen/
400 mg/day: n = 18
(within-subject design)
B-mode
ultrasound
No differences in
muscle thickness
of the upper arm
between groups
after 6 wk
Trappe
et al.,
[64]
2011
36 healthy
untrained
M(n= 24) and
F(n= 12)
60–85 2 sets of 5 knee
extensions at a light
weight, followed by 3 sets
of 10 repetitions with
2 min rest interval
performed 3 days/wk on
nonconsecutive days
12 Paracetamol
(acetaminophen)/
4000 mg/day: n = 11, or
ibuprofen/1200 mg/day:
n = 13, or placebo: n =12
MRI Significantly
greater increase in
muscle
hypertrophy in
NSAID group
compared with
control after 12 wk
Petersen
et al.,
[65]
2011
20 sedentary
or
recreationally
active
M(n= 16) and
F(n= 20) with
knee
osteoarthritis
50–70 4 sets of 15-RM in the first
wk progressively
increasing to 4 sets of 8-
RM by wk 7 and onward of
the knee extension and
leg press performed 3
nonconsecutive days per
wk
12 Ibuprofen/1200 mg/day:
n = 12 , glucosamine/
1500 mg/day: n = 12, or
placebo: n = 11
MRI No differences in
muscle cross-
sectional area of
quadriceps
between groups
after 12 wk
a Age data are presented as approximate or ranges where stated.
F = female; M = male; MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inflammatory drug; RM = repetition maximum.
1024 Schoenfeld
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may have manifested had a longer-term protocol
been employed. It should also be noted that the
dosage (400 mg of ibuprofen) was substantially
less than that use d in the other studies, making it
difficult to draw relevant conclusions.
Trappe et al.
[64]
conducted a double-blind study
whereby 36 healthy, elderly adults (60–85 years of
age; 24 males, 12 fema les) were randomly as-
signed to receive a daily dose of either 4000 mg/day
of paracetamol (n = 11), 1200 mg/day of ibuprofen
(n = 13) or placebo (n =12). Subjects performed
3 sets of 10 repetitions of progressive resistance
exercise for the knee extensors. Training was
carried out 3 days a week on nonconsecutive
days. After 12 weeks, subjects who consumed
anti-inflammatory drugs displayed a significantly
greater increase in muscle volume compared with
control (placebo: mean – SD 69 – 12; paracetamol:
109 – 14; ibuprofen: 84 – 10 cm
3
). These results
suggest that chronic NSAID use may in some
way promote adaptations that ultimately lead to
greater long-term skeletal muscle protein accre-
tion. Findings were limited to untrained, elderly
subjects, however, and thus it remains unknown
whether similar results would be seen in a young,
athletic population.
Most recently, Petersen et al.
[65]
investigated
the effects of NSAID administration on muscle
hypertrophy in elderly subjects (20 women, 16 men;
age range, 50–70 years) with a history of bilateral
tibiofemoral knee osteoarthritis. Participants
were randomly divided to receive either 1200 mg
of ibuprofen, 1500 mg glucosamine or placebo.
Training consisted of unilateral knee extension
and leg press for both legs, with intensity in-
creasing from 4 sets of 15-RM in the first week to
4 sets of 8-RM by week 7 and onward. Training
was carried out on three, nonconsecutive days per
week. After 12 weeks, results failed to show any
differences in muscle cross-sectional area between
groups. Interestingly, however, consumption of
NSAIDs resulted in greater gains in maximal
isometric strength, maximal eccentric strength
and eccentric work compared with placebo. This
suggests that the alleviation of pain in this pop-
ulation may allow individuals to exert greater
force during resistance training efforts and thereby
enhance strength capacity. That said, the effect
size of the reported gains was rather small, calling
into question whether costs of treatment out-
weigh the benefits.
5. Contradictions in Findings
Based on the body of current literature, evidence
is lacking that COX inhibitors have a detrimental
acute effect on post-exercise protein synthesis.
Although animal studies have shown an impaired
response when either selective or nonselective
NSAIDs were given following chronic overload,
the majority of human trials fail to support this
finding. Pos sible reasons explaining these dis-
crepancies are differences in methodologies be-
tween studies, physiological differences between
species and/or differences in the mechanisms of
the various drugs used (i.e. selective vs non-
selective COX inhibitors).
Longer-term effects of NSAIDs on exercise-
induced muscle hypertrophy are equivocal at this
time. There is strong evidence that satellite cell
activity is impaired by the use of nonselective
COX inhibitors in both animal and human trials,
although further study is warranted to determine
if such effects persist with the administration
of drugs selective to the COX-2 enzyme. It seems
logical to infer from these data that NSAID con-
sumption would limit a person’s hypertrophic
potential by restricting the satellite cell pool. Some
researchers have proposed that a myonuclear
domain ceiling of ~2000 mm
2
exists beyond which
further hypertrophy cann ot occur unless there is
satellite cell-mediated incorporation of addi-
tional myonuclei.
[66]
If true, NSAIDs would most
certainly be detrimental to those who aspire to
maximize muscle development. Emerging data,
however, suggests this might only have relevance
to a certain segment of the population. As pre-
viously noted, Petrella et al.
[46]
showed that hy-
pertrophic ‘responders’ to resistance training
had a robust capacity to increase satellite cell
activity while ‘nonresponders’ did not. Thus, it
may be that any negative effects of NSAID ad-
ministration on muscle growth may be specific to
those with an increased potential to ad d lean
mass and have a minimal impact on the rest of
the population.
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Direct studies on the topic are contradictory.
The preponderance of data in animal models
shows a marked reduction in exercise-induced
hypertrophy following NSAID administration.
These results are consistent with the use of both
selective and nonselective COX inhibitors. On the
other hand, the limited number of human studies
conducted to date do not indicate that NSAIDs
blunt the hypertrophic response, and one recent
study
[64]
actually found up to a 50% increase in
muscle mass over 12 weeks in subjects consuming
either ibup rofen or paracetamol. These conflict-
ing findings are difficult to reconcile. A pos sible
explanation is that NSAID-mediated reductions
in proteolysis may be greater than any suppres-
sion of protein synthesis, thereby leading to an
overall positive nitrogen balance. In support of
this contention, Rodemann and Goldberg
[33]
dis-
played that COX inhibition of incubated rat soleus
muscle resulted in a 39% increase in net protein
balance, which was attributed to an attenuation of
protein breakdown that exceeded impairments in
protein synthetic rate. However, this would not
explain the marked NSAID-induced impairment
in hypertrophy found in vivo in animal studies.
Another possibility is that the degree of myo-
fibre hypertrophy experienced by subjects in the
human trials did not reach their myonuclear do-
main ceiling. This would conceivably account for
the significant blunting of hypertrophy in animal
models, where the techniques employed (i.e. chronic
stretching, synergist ablation) result in extreme rates
of weekly hypertrophy not seen in traditional
human exercise programmes (~40% vs 1%, re-
spectively)
[18]
and thus would seemingly require a
robust satellite cell pool . Further research is
needed to assess this prospect.
6. Conclusion
In summary, there is little reason to believe
that the occasional use of NSAIDs will negatively
affect muscle growth, although the efficacy for
their use in alleviating inflammatory symptoms
remains questionable. Evidence on the hyper-
trophic effects of the chronic use of NSAIDs is
less clear. In those who are untrai ned, it does
not appear that regular NSAID use will impede
growth in the short term, and at least one study
indicates that it may in fact have a positive im-
pact. Given their reported impairme nt of satellite
cell activity, however, longer-term use may well
be detrimental, particularly in those who possess
greater growth potential. Future research should
seek to clarify inconsistencies between studies, as
well as investigating the effects of NSAIDs on
muscle hypertrophy in trained subjects and ath-
letes who are known to be frequent consumers of
these drugs.
Acknowledgements
This review was not funded by any outside organization.
Brad Schoenfeld is the sole author of this work. There are no
conflicts of interest present that are directly relevant to the
content of this review.
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Correspondence: Dr Brad Schoenfeld, MSc, CSCS, Depart-
ment of Health Sciences, Program of Exercise Science,
APEX Building, Room # 265, Lehman College, CUNY, 250
Bedford Park Blv. West, Lehman College, Bronx, NY 10468,
USA.
E-mail: brad@workout911.com
1028 Schoenfeld
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