Transcript NSAID use in Athletes

NSAID use in Athletes
Gregory Cain, MD
Activity, Exercise and Sports Medicine
Group Health Physicians
Credits to Trevor Bullock, DO my former mentor at
Summa
Disclosures
 I have no financial conflicts of interest
 A significant portion of this talk was borrowed with
permission from Trevor Bullock, DO – former
Summa staff sports medicine physician
 Dr. Bullock’s talk was updated with new relevant
information post 2010
NSAIDs Overview
 NSAID History/Characteristics
 “Inflammation”
 Mechanism of Action
 COX enzymes
 NSAIDS vs Injuries of:
 Bone
 Ligament
 Muscle
 Tendon
 Side Effects



Gastrointestinal
Renal
Cardiovascular Risk
 Prophylactic Misuse of NSAIDs
 Summary of Recommendations
NSAIDs
• NSAID’s are anti-inflammatory, analgesic,
antipyretic
• Aspirin has antithrombotic effects
• NSAIDs are more efficacious than acetaminophen
for OA across multiple recent trials
• Previously Tylenol was recommended as first-line
treatment for acute and chronic musculoskeletal
pain, but recent evidence (NICE) shows it
ineffective for back pain and no better than
placebo for most knee osteoarthritis
• NSAIDs and acetaminophen may be equivalent for
the mildest forms of knee OA
Inflammation
Mechanism of Action
 Primarily inhibit the cyclooxygenase (COX) pathway
 COX-1 enzyme
(constitutional)
 COX-2 enzyme (inducible)
COX Enzymes
• COX-1
– Found in most tissues and
regulates normal cellular
processes - constitutive
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Gastric cell protection
Vascular hemostasis
Platelet aggregation
Renal blood flow
Ocular pressure
Airway dilatation
Parturition
COX Enzymes
• COX-2
– Undetectable in most tissues
– Induced with an inflammatory response
and is responsible for:
• Sensitizing pain receptors
• Elevating body temperature
• Recruiting inflammatory cells toward areas of
tissue injury
• COX-3 (not functional in humans)
– Active in dogs, not mice and humans due
to a frame shift mechanism
Broader Picture of the ARA Pathway
Mechanism of Analgesia
EFFICACY OF NSAIDS IN THE
TREATMENT OF
MUSCULOSKELETAL INJURIES
Bone
• Injury to bone causes an initial
inflammatory response to begin
fracture repair
• Prostaglandins play a major
role in bone formation and
resorption and are critical in
bone repair
• Because fracture healing relies
on inflammation and formation
of PGs, and medication that
blocks this process has the
potential to impair fracture
healing
Bone
• Several animal models
suggest that NSAIDs
negatively impact fracture
healing
• Studies in humans have
associated NSAID uses with
delayed healing in tibial
fractures and increased risk
for nonunion in various long
bone fractures (Giannoudis
et al)
COX-2 in Fracture Healing
 COX-2 (not Cox-1)
mediates the negative
effect of NSAIDs
 Fracture healing is
normal in COX-1
knockout mice
 Healing impaired in
COX-2-selective,
NSAID-treated
 Healing impaired in
COX-2 knockout mice
“Heterotopic ossification prophylaxis with
indomethacin increases long-bone nonunion”
Burd, et. al. in 2003–
The best evidence to date in humans
 Looked at the concominant fx of surgicaly treated
acetabular fractures that were prophylaxed with radiation
or indomethacin
 282 patients with 112 (40%) concomitant fx of femur, tibia,
humerus, and/or forearm
 36 needed no prophylaxis, 38 received focal radiation and
38 received indomethacin
 No indomethacin – fractures with a non-union – 2.2%
(no difference between radiation and no radiation
patients)
 Indomethacin - fractures with a non-union
– 15.3%
Adverse effect mediated on
chondrocyte differentiation
 Fracture healing mesenchymal cells
differentiate into chondrocytes
without COX-2.
 COX-2 required for
chondrocytes to hypertrophy
 Hypertrophied chondrocytes
secrete angiogenic and
osteoclastogenic factors
Endochondral vs. Primary Healing

Primary Fracture Healing with internal
fixation

A form of intramembranous healing without a cartilage model akin to
embryonic flat bone formation

Unite by direct extenson of Haversian
canals between fragments

Forms lamellar bone later replaced by
longitudinally oriented osteons

Periosteal or endosteal mesenchymal
cells not activated
NSAIDs adverse effect on Primary Healing
– indirect evidence in animals
 Effects of NSAIDs on primary bone healing less clear
 PGs produced by COX-1 or COX-2 promote osteoblast and
osteoclast activity suggests NSAIDs can affect primary
bone healing
 Bone ingrowth into porous metal implants impaired by
NSAIDs in rabbits but not dogs
 Intramembranous bone formation inhibited in rabbits by
treatment with COX-1 or COX-2 inhibitors
 COX-2 inhibition of intramembranous bone formation time
dependent whereas even brief exposure to COX-2 disrupts
endochondral bone formation
Related Topic: Myositis Ossificans
 No RCT documenting efficacy
of NSAIDs in the prevention or
treatment of Myositis
Ossificans (MO)
 Use for MO inferred from
reduction of Heterotopic
Ossification
 A 7-day course of
indomethacin or other NSAID
has been recommended for
preventing MO after significant
muscle contusions at risk
Bone – Take Home Message
• Difficult to draw definitive
conclusions
• Animal studies suggest that
NSAIDs inhibit osteogenic
activity
• Majority of human studies
support the negative effect of
NSAIDs on fracture healing
• Recommended that NSAIDs
be avoided in the setting of
bone injury
Ligaments & Tendons
Criteria for Successful Tendon
& Ligament Healing
1) Mechanical strength must
be reestablished
2) Tendons must glide freely
through the tendon sheath
3) Ligament healing
must prevent
joint laxity
Ligament
• 3 Stages of healing
1. Initial inflammatory response to clear
away damaged tissue
2. Proliferative phase during which new
collagen is formed
3. Remodeling phase (may continue for
up to 1 year)
Ligament
•
Animal studies show conflicting results
on ligament healing
– studies on rat MCL sprains
1. Those treated with piroxicam
were stronger than placebo at
14 days (Dahners, et al)
2. Separate study showed no
difference with piroxicam from
placebo at 21 days (Dahners, et
al)
3. Celcoxib significantly
weakened ligament healing at
14 days (Elder et al)
– Other studies have shown no
significant effect of ibuprofen,
naproxen and rofecoxib on
ligament strength as compared
with placebo
Tendon
• The histopathology of tendinopathy
is typically degenerative, with an
absence of inflammatory cells or
biochemical markers of
inflammation
In the lab - Tendon
 NSAIDs inhibit tenocyte proliferation & migration
 Increase protein synthesis in human tendon
fibroblasts increasing collagen deposition
 Indomethacin or celecoxib increase strength of
transected rat Achilles tendons, even though…
 cross-sectional area of the tendon was decreased
 NSAID treatment could minimize thickening of
healed tendons, balanced by the positive effects of
NSAIDs on collagen synthesis.
Tendon
Randomized study
of Achilles
tendinopathy found
that piroxicam was
no more effective
than placebo
(Astrom and
Westlin)
Tendon Glide
 Indomethacin (4 weeks) reduced
adhesions post FDP tendon
transection in rabbits
 Prevention of adhesion formation
is a COX-1 mediated
mechanism….
 Occurs in the late healing stages
 COX-2 selective inhibitors lack
this effect.
Ankle Sprain
• NSAIDs are effective at
decreasing pain on weight
bearing and swelling in
short (<72h) and
intermediate (<2wk)
• No data to support faster
return to activity
• Piroxicam and diclofenac
more effective than placebo
for overall reduction of pain
and inflammation after acute
ankle sprains. (Moran)
• Diclofenac and naproxin
equivalent to celecoxib in
pain relief and increasing
functional ability after ankle
sprains
• Dyspepsia less with oral
celecoxib than naproxin
(Peter)
Ankle Sprains
– Piroxicam decreased pain and allowed army
recruits with acute ankle sprains to return to
training more rapidly than placebo (Slayter, et
al).
– Celecoxib was as effective as naproxen for pain
reduction in treating acute ankle sprains
(Petrella et al)
• All of these studies are limited by lack of
objective measure of ankle stability
• On the basis of available evidence, a short
course (3 to 7 days) of NSAIDs after a
ligament sprain is likely beneficial
Ligament Laxity
 Only one study of NSAIDs on
joint laxity following ligament
injury.
 Ketorolac for 6 wk after BPB
autograft ACLreconstruction
had significant increased in
anterior-posterior laxity at 6 wk
post-op compared to controls
 Suggests that NSAID therapy
may increase joint laxity after a
ligament injury or repair
NSAIDs May Inhibit
Enthesis Repair
 Celecoxib &
Indomethacin caused
inconsistent regrowth of
the fibrocartilage zone
in acute supraspinatus
repair compared to
control in rats
 Celecoxib &
Indomethacin reduced
failure loads for rotator
cuff repairs in rats
Cartilage/Joint
 Intra-articular ketorolac – 2004
Dogan
 Can induce minimal to moderate
articular cartilage inflammation in rabbit
knee joints
 Can induce synovial membrane
inflammatory cell infiltration
 Can induce synovial membrane cell
hyperplasia
 Can induce synovial membrane cell
hypertrophy
 Authors recommended caution when
injecting ketorolac into the joint
space
Cartilage/Joint
 Intra-articular tibiofemoral injection of
ketorolac has no detrimental effects on joint
mechanics in a rat model – 2014
 64 rats injected withsaline or ketorolac
 Animals euthanized at 2, 7, 28, and 84 days postinjection for histological & mechanical analyses
 No differences at any time point
 NSAID injection could be considered for clinical
application in humans
 Intra-articular ketorolac reduces pain following ACL surgery
 Ketorolac + morphine & ropivacaine better postop analgesia than
morphine + ropivacaine without ketorolac – 2005
 And after Arthroscopic Shoulder Surgery
 Ketorolac + fentanyl + ropivacaine better postop analgesia than
ropivacaine alone or fentanyl + ropivacaine – 2009
Bursa
 NSAID Intrabursal Injection
Superior to Cortisone for
Shoulder Pain – 2013 DBRCT
 32 patients external shoulder
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impingement
40 mg triamcinolone vs. 60 mg
ketorolac (both w lido)
UCLA Shoulder Asses Score –
2.13 vs. 7.15 at 1 mo
Ketorolac inc forward flexion
strength (0.26 vs −0.07; P = .04)
Improved patient satisfaction
over the steroid group; P = .03.
Muscle
• Muscle injury can be caused by strain,
contusion, or laceration.
• Heals similar to ligaments:
1. Destruction (inflammatory cell reaction)
2. Repair
3. Remodeling
Muscle
• Initial inflammatory response
initiates macrophage action
– Subsequent phagocytosis
of necrotic tissue and
stimulation of new capillary
formation
• Inflammation also causes
edema with resultant anoxia
and further cell death
• Modulation of the inflammatory
response with low-dose NSAID in the
subacute phase, may have beneficial
effects in limiting edema
Muscle
• NSAIDs can decrease
eccentrically induced
muscle soreness
(Altman, et al)
• NSAID patches can be
beneficial in early
management of
contusion type injuries
(Predel, et al)
Exercise Induced Muscle Damage
 NSAIDS hurt muscle
development if you’re
a mouse;
 No problem if your
human
 Rodent studies show NSAIDS reduce muscle growth
after chronic overload
 NSAIDS have a negative effect on satellite cell activity in
rodents and humans
 (satellite cells are myogenic stem cells that respond to prostaglandin by
proliferating and fusing to existing muscle cells and donating their nuclei)
 NSAIDS do not reduce human muscle hypertrophy in
short term use and may increase it in the untrained
Gout
 Moderate quality evidence - NSAIDS
and systemic glucocorticoids (GC)
effective as NSAID but GCs are safer. –
review 2014
 Low quality evidence (1 trial) showed
no difference between NSAID and
placebo with regard to pain or
inflammation
 No NSAID was superior to another
 Low quality evidence (1 trial) showed
that both high- and low-dose colchicine
more effective than placebo & low-dose
colchicine is safe as placebo & safer
than high dose colchicine
Adverse Effects
• More frequent when used on a chronic basis than
on an acute intermittent administration
• GI Toxicity
– Contribute to an estimated
100,000 hospital admissions and
16,500 deaths each year from GI
complications
• Reduce risk with short dosing
periods, take medication with
food, use of PPI or
misoprostol
• Use Selective COX-2 inhibitor
(Celebrex)
NSAID Adverse Effects
• May have adverse cardiovascular,
neurovascular and renal effects – most
concern involves long-term use
– Increasing incidence of hypertension
with greater NSAID use
• Coxibs and non-selective NSAIDs
associated with increased likelihood of
cardiovascular events; naproxen has
lowest risk
– Minimal side effects with short-term use
in a typical sports medicine population
NSAID Renal Effects in
Elderly
 NSAID use in Elderly with Co-morbidity
 Congestive heart failure
 Liver cirrhosis
 Chronic kidney disease
May develop acute renal failure
NSAIDs Possible Renal Effects
 Interstitial nephritis
 Nephrotic syndrome
 Acute renal failure
 Acute tubular necrosis
Severe renal impairment with
 Combination with ACE inhibitor (AI) & diuretic
 NSAID inhibits prostaglandin production removing its
vasodilitation effect on the afferent arteriole
 AI removes angiotensin II's vasoconstriction of efferent
arteriole
 Diuretic drops plasma volume, and thereby RPF
 The so-called “Triple
Whammy Effect”
NSAID Renal Effects
on Potassium in
compromised Kidneys
 NSAIDS decrease nephron’s distal sodium delivery
by reducing glomerular filtration.
 Less sodium available for potassium exchange
 NSAIDS inhibit macula densa PGs production they
reduce renin release.
 Less renin results in decreased potassium
excretion.
Effects on Sodium
later in talk
Reducing Risks of Adverse Effects
 Prescribe at the lowest possible dose for short
courses
 Long term use only for those who cannot tolerate
other forms of analgesia and use regularly
reviewed
 Selective COX-2 inhibitors (coxibs) offer greater
UGI safety
 Concurrent low-dose ASA Tx increases GI side
effect risk – avoid unless absolutely necessary
 Coxibs and non-selective NSAIDS increase cardiac
risk; naproxen appears to have the lowest risk
Reducing Risks of Adverse Effects
 Co-Rx of a PPI with the “Safest Possible” non-selective NSAID or
coxib is effective in reducing GI toxicity with long-term use. But,
PPI may increase risk of C. diff, and Fx’s or hip, wrist and spine
 Limited evidence supports H2 blocker at double dose
 “Safest Possible” Risk – ibuprofen (lowest) < indomethacin,
diclofenac, naproxin (intermed) < piroxecam, ketoprofen, ketorolac
(higher) < azopropazone (highest – UK only, now DC’d)
 Misoprostol is alternative but use may be limited by side effects
(abdominal pain, nausea, flatulence, headache, dyspepsia,
vomiting, and constipation) Arthrotec is diclofenac/misoprostol
 Testing and eradicating H. pylori in first time NSAID patients with
hx of dyspepsia or ulceration (no benefit if already taking an
NSAID)
Prophylactic Misuse of
NSAIDs
• Athletes have relatively
unrestricted access to
NSAIDs
– 25% of athletes at Sydney
2000 Olympic Games
reported using NSAIDs 3
days prior to random drug
testing
- 10% of Soccer players at the 2006 World Cup
tournament took NSAIDs before every match
- Players take NSAIDS daily because of
perceived benefits in terms of blocking pain
before it occurs
Prophylactic Misuse of
NSAIDs
• Adverse GI and
cardiovascular effects
become more pronounced
with increased duration of
use.
• NSAIDs taken before activity
may mask pain and cause
athletes to allow pathology to
progress
• NSAIDs’ inhibitory effects on
the COX isozymes and
prostaglandins may impede
the synthesis of the
extracellular matrix (ie
collagen) that confers
strength to the tissue
Prophylactic Misuse of
NSAIDs- Danger for the
Marathoner
 Intrarenal PGs inhibit vasopressindependent transtubularwater
movement.
 NSAIDS remove the inhibitory
effect of PGs on antidiuretic
hormone (ADH) activity.
 NSAIDS also block the PGs
increase of medullary blood flow
increasing medullary interstitial
osmotic drive.
 Free water excretion reduced
producing hyponatremia.
Summary/Recommendations
• NSAID use in sports injuries continues to be
controversial
• Effects are mediated through inhibition of
prostaglandin synthesis in the COX pathway of
inflammation
• NSAIDs may adversely affect healing in some
sports-related injuries
• Conclusive support for NSAID use is limited due to
numerous animal studies, but few randomized
clinical trials in humans
• Use simple analgesia when analgesia is the desired
outcome
• Minimize risks of adverse effects in long term use
Summary/Recommendations
• No clinical evidence to suggest that regular use of
NSAIDs reduces injury risk or improves function in
the typical athlete
• Avoid NSAIDs in the treatment of completed
fractures, stress fractures or in the setting of
chronic muscle injuries
• NSAID use should always be coupled with
appropriate physical rehabilitation
• Judicious short-term uses of NSAIDS, with
consideration of the specific type of injury, level of
dysfunction, and pain, may be useful in the
management of acute ligament sprains, muscle
strains, tendinitis, and eccentric muscle injury
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