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NSAIDs and Musculoskeletal Treatment
What Is the Clinical Evidence?
Steven D. Stovitz, MD
Robert J. Johnson, MD
T HE PHYSIC I AN AND SPORTSMEDIC I NE - VOL 31 - NO. 1 - JANUARY 20 03
In Brief: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for musculoskeletal injuries
because the conditions are believed to be inflammatory in nature. However, because inflammation is a necessary
component in the healing process, decreasing inflammation may prove counterproductive. Also, many tendon
injuries called 'tendinitis' are, in fact, degenerative and not inflammatory conditions. An analysis of the
pathophysiology and healing of musculoskeletal injuries questions the use of NSAIDs in many treatment
protocols. Because NSAIDs have profound side effects, they should not automatically be the first choice for
treating musculoskeletal injuries.
Musculoskeletal concerns rank with upper respiratory illness as the most common reason patients seek medical
attention in family practice. [1] Treatment algorithms for musculoskeletal injuries tend to reflexively include the
use of nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). Currently, NSAIDs are among the most
widely prescribed drugs in this country . [2]
Despite the widespread use of NSAIDs, we question their role in many treatment protocols for musculoskeletal
complaints--in particular, the clinical value of their anti-inflammatory properties. Although originally marketed as
the "safe" alternative to aspirin, NSAIDs are known to have serious gastrointestinal toxicity and other side
effects. We review the pathophysiology and healing of musculoskeletal injuries and the clinical evidence regarding
the efficacy of NSAIDs in treating a variety of nonrheumatic musculoskeletal injuries.
Mechanism of Action
NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic properties. Their therapeutic actions are
thought to stem primarily from their ability to block the formation of certain prostaglandins through inhibition of
the cyclooxygenase (COX) enzymes (Figure 1 ). In general, COX-1 catalyzes the production of several
cytoprotective prostaglandins that coat the stomach lining with mucus and aid platelet aggregation, among other
functions. COX-2 catalyzes the conversion of arachidonic acid into the inflammatory prostaglandins that are
involved in three key biological functions: sensitizing skin pain receptors, elevating body temperature through the
hypothalamus, and recruiting inflammatory cells toward injured body parts. (The delineation between COX-1 and
COX-2 enzymes may be more complex, as described in the section on COX-2 inhibitors below.)
In addition to their effects on prostaglandins, NSAIDs exhibit other properties that have uncertain clinical
relevance (eg, inhibition of neutrophil migration, oxidative phosphorylation, and lysosomal enzyme release). [3]
Inflammation and Healing
A major rationale for using NSAIDs in the treatment of musculoskeletal injuries has been their anti-inflammatory
quality. The prev ailing argument is that healthy tissue is not inflamed; therefore, if we stop the inflammation in
an injured tissue, the tissue will be healthy. The problem with this v iewpoint is that, in addition to being a sign of
injury, inflammation is a necessary component of the healing process. As noted by Leadbetter, [4] "inflammation
can occur without healing, but healing cannot occur without inflammation."
Whether the injured tissue is a ligament, tendon, or muscle, the body responds to injury with a sequence of events
that begins with an influx of inflammatory cells and blood. The inflammatory cells remove debris and recruit
cytokines and other growth factors toward the injury site. This inflammatory phase is partly mediated by the
same prostaglandins that are blocked by NSAIDs. In a healthy healing process, a proliferative phase consisting of
a mixture of inflammatory cells and fibroblasts naturally follows the inflammatory phase. The fibroblasts build a
new extracellular matrix and persist into the final phase of repair, the maturation phase, where, if all goes well,
functional tissue is laid down. The key point is that each phase of repair is necessary for the subsequent phase. By
blocking the inflammatory phase, NSAIDs can, at least theoretically, delay the healing of musculoskeletal injuries.
NSAIDs and Musculoskeletal Injuries
NSAIDs are commonly prescribed for the treatment of musculoskeletal complaints such as muscle injuries,
ligament sprains, tendon injuries, low-back pain, and osteoarthritis. However, an examination of the
pathophysiology and healing of such injuries, as well as a remarkable dearth of clinical trials supporting the
efficacy of NSAIDs, raises questions about their use in many treatment protocols.
Muscle injuries. Whether caused by direct trauma or excessive strain, muscle injury is the
most common sports injury. [5] Although NSAIDs are commonly recommended in treatment
protocols, clinical studies documenting their efficacy are notably lacking. We searched MEDLINE
(1966 to 2002) using keywords "anti-inflammatories, nonsteroidal," "NSAIDs," "skeletal muscle," or
(1966 to 2002) using keywords "anti-inflammatories, nonsteroidal," "NSAIDs," "skeletal muscle," or
"athletic injuries" and "randomized controlled trials" and found none involving oral NSAIDs. A recent
review of studies on strains, contusions, and delayed-onset muscle soreness revealed minimal benefit
at best when NSAIDs are compared with placebo. [5]
While some literature [6,7] suggests that NSAIDs may delay the rate of muscle fiber regeneration, the
clinical ramifications of this remain unclear. Clinical outcome studies of muscle injuries are difficult to
conduct because the injuries tend to heal within days without intervention. Many clinicians in our
sports medicine community are turning to short (24- to 48-hour) courses of NSAIDs, hoping to
combine the benefits of pain relief and decreased swelling without affecting the regenerative phases of
healing. Furthermore, several physicians in our community are now advocating the newer COX-2
inhibitors (discussed below) for muscle injuries with the idea that the drugs' lack of platelet inhibition
might further diminish bleeding and swelling in the injured tissue. We are unaware of any studies to
substantiate these claims.
Interestingly, users of anabolic steroids anecdotally report that these drugs--which actually increase
inflammation--hasten the healing of muscle injuries. A recent animal study [8] supports these claims.
If anabolic steroids prove helpful for tissue healing in humans, the medical profession may be faced
with some interesting ethical decisions.
Ligament injuries. Data on the efficacy of NSAIDs in the treatment of ligament sprains is
extremely limited. In 1990, a review by Almekinders [9] found only 15 studies that he felt were
"carried out in a scientifically appropriate manner," and 8 of those focused on a single joint. NSAIDs
were beneficial in half of these single-joint studies (2 of the 6 that examined ankle ligament sprains
and the 2 that focused on knee ligament injuries). In 1995, a clinical review [10] on treatment
modalities for soft-tissue injuries of the ankle stated that "NSAIDs tended to offer significant
improvement in recovery time and sy mptomatic relief over placebo." However, the authors do not
state how the papers were selected for review or assessed for validity. Our own search of MEDLINE
(1966 to 2002) using keywords "anti-inflammatories, nonsteroidal" or "NSAIDs," "ligaments," and
"clinical trials" revealed no studies using oral NSAIDs in the outpatient setting. A 1997 study [11] of
364 Australian army recruits who had ankle sprains showed that the group given NSAIDs returned to
activity sooner, but had increased instability and decreased range of motion, compared with those
given placebo.
The study of ligament sprains is limited, because sprains tend to heal with time and because the
outcomes are subjective and favor NSAIDs, which are excellent analgesics. Controlled mobilization of
injured ligaments assists healing, [1 2] and, in this context, if NSAIDs decrease pain and thus
encourage activity, they may provide some therapeutic benefit. It is unknown whether a similar effect
could be obtained with other analgesics, including simply ice.
Tendon injuries. When it comes to tendinitis, the use of NSAIDs as anti-inflammatory agents
becomes especially controversial. Contrary to what their name implies (the suffix "itis" denotes an
inflammatory process), these injuries may not be inflammatory in nature. Indeed, several experts in
this area have pointed out this misnomer and emphasized its unfortunate effect of furthering a false
perception that an anti-inflammatory medicine should be used in treatment. [13-1 5]
Several large studies [14,16,17] have looked at tissue biopsies from chronic injuries of the extensor
carpi radialis brevis ("tennis elbow"), Achilles, patellar, and rotator cuff tendons. Results show the
tendons to be degenerative and lacking in inflammatory cells. Thus, a more proper term would be
either "tendinosis," meaning tendon degeneration, or "tendinopathy," signifying nonspecific tendon
pathology. Some have argued that a poor inflammatory process is the precipitant that causes tendon
degeneration. [13,16]
Controlled trials of NSAID use have not resolved this issue. A review [1 5] of MEDLINE from 1 966 to
1996 found only 9 prospective studies comparing NSAIDs with placebo. The review noted that
NSAIDs provided better pain relief in 5 of the 9 studies. This result is hardly unexpected, given the
potent analgesic effect of NSAIDs. The maximum study follow-up was only 1 to 4 weeks; therefore,
the long-term effect of NSAIDs on these tendons is unknown.
Low-Back Pain and Osteoarthritis
NSAIDs are frequently used to treat common musculoskeletal conditions, such as low-back pain and
osteoarthritis, though they are not classically sports-related injuries.
Low-back pain. The study of treatments for low-back pain is limited by its multiple and poorly
understood causes. Two large meta-analyses [18,19] were recently conducted, including a Cochrane
review in 2000. Both searched MEDLINE for literature from the 1960s to the 1990s; the Cochrane
study [19] also included Embase studies from 1988 to 1998. Both found very few well-designed trials,
and those that were found had small numbers of patients. T here were some subtle differences in the
reviews, but overall their methods and conclusions were similar.
Koes et al [18] found 1 0 acceptable trials comparing NSAIDs with placebo and concluded that NSAIDs
"might be effective for short-term sy mptomatic relief in patients with uncomplicated low-back pain."
The Cochrane review [19] identified 11 controlled studies of adequate design and concluded that there
is "conflicting evidence that NSAIDs provide better pain relief than placebo for acute low-back pain."
The Cochrane review found 5 "acceptable" studies comparing NSAID efficacy to that of
acetaminophen and only 1 that was considered "high quality." This high-quality study included only
30 patients. It concluded that there is, at best, level 3 (ie, conflicting or limited) ev idence that NSAIDs
are more effective than acetaminophen for acute or chronic low-back pain.
Osteoarthritis. Eighty percent of individuals older than 65 have radiographic signs of
osteoarthritis (OA), and a large percentage have sy mptoms. [20] Given the chronic nature of the
disease and the high incidence of medication side effects in the elderly, an understanding of the risks
and benefits of NSAIDs in treating OA is crucial. T he two main issues are pain relief and disease
progression.
In reviews of clinical trials on OA of the hip and knee, NSAIDs perform significantly better as
analgesics compared with placebo. [21,22] Most studies comparing different NSAIDs have found no
significant difference in their analgesic effects and provide no strong basis for recommending one
NSAID over another. A recent randomized controlled trial [23] comparing NSAIDs with
acetaminophen found a significant benefit in using NSAIDs for moderate-to-sev ere OA. Previously,
only two studies on OA had compared an NSAID with acetaminophen; neither supported a benefit for
either medication. Given that the adverse effects of NSAIDs (see below) tend to disproportionately
strike the elderly (hence, sufferers of OA), numerous guidelines, including those put forth by the
American College of Rheumatology, recommend trying acetaminophen before an NSAID. [24-26] An
increasing number of small trials are being conducted that compare glucosamine and chondroitin
sulfate with NSAIDs. The emerging evidence suggests a trend whereby pain relief during the first 4
weeks is superior with an NSAID, but then plateaus after 1 month. [27,28]
Whether NSAIDs hasten, attenuate, or have no effect on the progression of OA is unknown. In vitro
studies are beginning to show evidence that certain NSAIDs stimulate the synthesis of
glycosaminoglycan, whereas others either have no effect or degrade it. [29,30] Given this variation in
response among NSAIDs, their effects on articular cartilage are likely mediated by a mechanism other
than prostaglandin inhibition. If certain NSAIDs prove beneficial to articular cartilage while others
prove harmful, future treatment recommendations could change dramatically.
Weighing Side Effects
Although strong and consistent evidence is lacking that NSAIDs clinically benefit the healing of musculoskeletal
injuries, they remain potent pain relievers. Their use in this capacity, however, is limited by notable side effects;
gastrointestinal (GI) effects are the most common and serious.
GI bleeding secondary to NSAID use is the 15th leading cause of death in the United States. [31] Unfortunately,
dyspepsia cannot be used as a screening criterion, because only 40% of those who have NSAID-induced GI
bleeding report abdominal symptoms before the bleed. [32] T his might be due to their analgesic effects. Perhaps
as a result of their inhibition of platelet aggregation, individuals who have GI bleeding while taking NSAIDs have a
as a result of their inhibition of platelet aggregation, individuals who have GI bleeding while taking NSAIDs have a
significantly higher mortality than those with GI bleeds who are not taking NSAIDs. [32]
The renal and cardiovascular systems are also affected, because prostaglandins are necessary for renal blood flow
and the secretion of sodium and chloride. Prostaglandin inhibition has been shown to raise mean arterial blood
pressure by an av erage of 3 to 5 mm Hg, a small but potentially harmful amount. [33] Endurance athletes are
often hypohydrated as a consequence of prolonged training. NSAIDs can superimpose further decreases in renal
blood flow through prostaglandin inhibition. T his combination has been implicated in case reports of acute renal
failure in marathoners. [34,35] NSAIDs have historically been perceived to be either neutral or beneficial
regarding cardiovascular occlusive events. However, a recent study [36] suggests that the drugs' temporary
platelet inhibition may limit the cardioprotective effects of aspirin by antagonizing aspirin's irreversible platelet
inhibition.
Another potential complication for athletes involves the respiratory system. Blocking cyclooxygenase can shunt
arachidonic acid toward the formation of the bronchoconstricting leukotrienes (see figure 1 ). It is estimated that
10% of patients who have asthma experience a decline in their respiratory function as a result of NSAID inhibition
of cyclooxygenase. [37]
COX-2 Inhibitors
The new COX-2 inhibitors are being marketed as the safe alternative to other NSAIDs. Given the recent entry of
COX-2 inhibitors into the market, little is known about their in vivo effects (either intended or adverse). Data
from clinical trials suggest that their analgesic effects are similar to traditional NSAIDs. [38]
As their name implies, the COX-2 inhibitors preferentially block the COX-2 enzyme while allowing the pathways
catalyzed by COX-1 to proceed. Theoretically, this inhibits the formation of the inflammatory prostaglandins
while allowing the production of the homeostatic prostaglandins. Unfortunately, as Oscar Wilde said, "the pure
and simple truth is rarely pure and never simple." [39] In fact, increasing evidence indicates that the COX-2
enzyme also has some homeostatic functions.
Breyer and Harris [40] suggest that the COX-2 enzyme plays an integral role in kidney function and will likely
affect blood pressure to an ex tent similar to traditional NSAIDs. COX-2 inhibitors seem to cause fewer new GI
ulcers, although this has not been definitively shown to decrease the number of complications from GI bleeds.
[41] Interestingly, this might be because the inflammatory pathway is necessary for healing preexisting ulcers.
A concern is that selective inhibition of antithrombotic prostaglandins might increase cardiovascular ev ents.
Patients receiving rofecoxib during the VIGOR study [42] suffered cardiovascular events at a higher rate than
those in the naproxy n group. This prompted a meta-analysis of trials with COX-2 inhibitors [43] to state that
"the available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors." A more
recent analysis [44] suggests that the increased rate of cardiovascular ev ents noted above was actually due to a
cardioprotective effect of naproxen and not to increased events in the rofecoxib group.
The expense of COX-2 inhibitors is another major concern; treatment can cost as much as $70 or more than
generic NSAIDs per month. [45] Certainly, if this decreases other medical costs, this might prove beneficial.
Finally, given their inhibition of the inflammatory pathway, all of the concerns regarding delayed healing of
injured tissues remain the same when using COX-2 inhibitors.
Clarifying the Role of NSAIDs
Reviewing the most current updates on the use of NSAIDs in the treatment of musculoskeletal injuries is
challenging. Although we mention randomized controlled trials, or lack thereof, this review is not intended to be a
meta-analysis. Any attempt at a meta-analysis on this topic would be fraught with either a tremendous lack of
data (if stringent criteria were used) or controversy (if criteria were loosened).
Given the paucity of data, we are unable to draw any definitive conclusion in support of or against the use of
NSAIDs. We realize that many clinicians use anti-inflammatories for musculoskeletal conditions so routinely that
NSAIDs. We realize that many clinicians use anti-inflammatories for musculoskeletal conditions so routinely that
any suggestion that little evidence supports their use is interpreted as a condemnation. This discussion is meant
to clarify, not simply diminish, the role of NSAIDs. To effectively treat musculoskeletal injuries, the clinician must
have realistic expectations about the capabilities of NSAIDs and convey them to the patient. NSAIDs are rarely a
substitute for rehabilitation and activity modification.
When used properly, NSAIDs can be a useful, but limited, adjunct. T hey certainly play a key therapeutic role in
the treatment of the crystalline and rheumatoid arthritides and may be beneficial in treating pathologic edema of
bursa and synovial tissue (eg, tenosynovitis). For most common sprains, strains, and overuse injuries, however,
their therapeutic properties are unproven. It is crucial to keep a proper perspective regarding the role of NSAIDs,
especially given their risk of side effects and their potential to blunt the normal healing response. Too many
physicians and patients view NSAIDs as critical to recovery. Additional research is needed to define more
explicitly the role of NSAIDs in interfering with or delaying healing and the role of other, potentially safer, means
to control the pain of musculoskeletal injuries.
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The authors thank Anne Marie Weber-Main, PhD, for her editorial assistance with this manuscript.
Dr Stovitz is an assistant professor and coordinator of sports medicine education in the department of family
practice and community health at the University of Minnesota in Minneapolis. Dr Johnson is the director of
primary care sports medicine in the department of family practice at Hennepin County Medical Center in
Minneapolis and is president of the American Medical Society for Sports Medicine. Address correspondence
to Steven D. Stovitz, MD, Smiley's Clinic, 2615 E Franklin Ave, Minneapolis, MN 55406; e-mail to
stovi001@umn.edu.
Disclosure information: Drs Stovitz and Johnson disclose no significant relationship with any manufacturer of
any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.
