The Efficacy of Non-Steroidal Anti-Inflammatory Drugs in Athletes for Injury Management, Training Response, and Athletic Performance: A Systematic Review

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used medications due to their reputation as first-line remedies for treating and managing pain as well as their generally high tolerability. The fact that they are often readily available over the counter in both oral and topical formulations makes them very convenient pharmaceutical options for people to resort to in times of need. Athletes are no exception to the common use of these medications, especially considering the prevalence of pain or discomfort that they often feel with any injury or that they can experience at any point during or after physical training and exercise or with intense play or competition. The response to treatment can depend on medication dosage and its route of administration, but overall, NSAIDs generally share the same mechanism of action through inhibition of cyclooxygenase (COX), which is the enzyme in the body that produces prostaglandins. Research has revealed that there are at least two COX isoenzymes, COX-1 and COX-2. COX-1 is present in most tissues in the body, but specific to the gastrointestinal tract, it is most known for producing prostaglandins that work to continuously protect the stomach lining by both stimulating gastric mucous production and inhibiting acid secretion. In contrast, COX-2 is generally induced through inflammatory mediators and stimuli, such as cytokines, and while this can lead to individuals subsequently experiencing unpleasant pain and swelling, the cascade of events is generally part of a larger, synchronized effort to ideally address and help resolve the conditions of illness or injury that initially triggered the inflammatory response [1].

Common over-the-counter NSAIDs such as ibuprofen, naproxen, and aspirin are non-selective COX inhibitors that indiscriminately inhibit both COX-1 and COX-2. For this reason, frequent use of these medications can cause adverse side effects such as gastrointestinal issues and bleeding. This risk exists because consistent inhibition of COX-1 can lead to unabated acid production along with insufficient mucous presence to adequately coat or protect the gastrointestinal lining from injury or ulceration. To help mitigate these gastrointestinal issues, people can still use non-selective NSAIDs, but they can instead opt for topical, non-oral formulations such as diclofenac gel or diclofenac patches that can be applied locally to the affected area(s) with less risk for systemic absorption and impact [2]. Additionally, there is the option of people getting official prescriptions for specialized NSAIDs, e.g., celecoxib or meloxicam, that are specifically designed to solely inhibit COX-2. These selective NSAIDs would thus only target the inflammatory process to help relieve pain and swelling while avoiding the undesirable side effects to the gastrointestinal system by not inhibiting COX-1.

Whether discriminately or indiscriminately inhibiting COX-2, it is logical to see why athletes would be willing to take NSAIDs since discomfort, pain, or swelling are not only unpleasant sensations for any individual, but they are also factors that could ultimately disrupt or impair an athlete’s training and sport performance. However, it is important to assess and validate these presumptions especially if there are other unintended consequences for taking these medications. As such, the overall purpose of this systematic review is to broadly investigate the prevalent use of NSAIDs in athletes and to comprehensively review the effectiveness along with the potential results and consequences that these medications can have as they relate particularly to injury management and rehabilitation, physical training and exercise, and overall athletic performance.

All seven articles within this systematic review were thoroughly reviewed and had pertinent study characteristics and information compiled into a data table to include the year that the study was published, the characteristics and number of participants of each study, general details of the study design, relevant measures used, and the outcomes (Table 3). In total, across all seven studies, 346 adult male and female athletes ages 18 years and older from a variety of sporting activities and fitness levels were observed, of which 175 athletes were treated with either oral, topical, or local muscular infusion of an NSAID. The specific NSAIDs used with the participants across the seven studies include treatment doses of a topical 1% diclofenac patch, 10% diclofenac gel, 100 milligrams (mg) of oral indomethacin, 45 mg of indomethacin via infusion, and 200 mg to 400 mg of oral ibuprofen.

Depending on study design, the period of post-treatment analysis ranged from 1 day to 12 weeks and involved comparisons from the results obtained through physical exam, symptom- and function-oriented questionnaires, various performance metrics, or direct soft tissue sampling from microdialysis or muscle biopsies.

Of the seven studies in this systematic review, two specifically involved assessing athletes with known injuries and their treatment response to NSAIDs. In one of these two studies, the focus was primarily on both male and female recreational athletes with chronic Achilles tendinopathy and their treatment response to topical diclofenac gel. In this study, after 4 weeks of treatment, no significant differences were ultimately observed between the placebo and diclofenac groups in any of its outcome measures, including numeric pain rating, patient-reported symptom changes, pressure–pain threshold, tendon stiffness, or Victorian Institute of Sports Assessment—Achilles (VISA-A) questionnaire scores at 4 and 12 weeks [4]. In the other study that assessed injured athletes, the focus was strictly on non-chronic, minor injuries and the athletes’ pain response throughout their treatment and management with an NSAID. This study involved both male and female athletes who had recently sustained an acute sports-related, soft-tissue injury within 3 days prior to the start of the randomized controlled trial. They were treated with either topical diclofenac patches or a placebo daily for 2 weeks. The athletes’ pain intensity was recorded every day and during clinic visits using pain relief scales, and overall, the results showed that those treated with diclofenac patches had significantly reduced pain compared to the placebo group [2].

Of the other five studies within this systematic review, three articles specifically assessed how athletes physiologically responded to NSAIDs by performing direct tissue analysis before and after completion of their assigned exertional activities. One study involved healthy male runners who were training for a marathon. They were given either oral indomethacin or a placebo starting from 72 h before the start of their 36 km run through 72 h after their completion of it. Based on microdialysis samples taken directly from the patellar tendon, the placebo group showed unchanged prostaglandin E2 (PGE2) levels with significantly increased levels of procollagen type I N-terminal propeptide (PINP) concentrations, which serves as a surrogate marker indicative of collagen synthesis. Conversely, the group treated with indomethacin showed significantly decreased PGE2 levels with no increase in collagen synthesis [5]. In another study that assessed the physiological impact of NSAIDs after activity, male endurance-trained athletes were also given either oral indomethacin or a placebo and were told to complete a 36 km run. However, the treatment was given from 4 days prior through 8 days after completion of the run, and instead of tissue samples obtained through microdialysis, muscle biopsies were conducted before and on days 1, 3, and 8 after the run, specifically assessing the amount of satellite cell activity. Ultimately, the results revealed that the placebo group had increased satellite cell activity post-exercise, whereas the group treated with NSAIDs had no such increase [8]. Similarly, another study within this group of articles also assessed satellite cell activity, but it did so from a very different study design. Instead of runners, it took male recreational athletes who were considered to be well-trained, as defined by conducting at least 6 h of physical training per week. However, an additional inclusion criterion for its participants was having the requirement of not doing any leg resistance training within the last year. The athletes were ultimately tasked with completing 200 maximal eccentric contractions of each leg, with one leg treated with an infusion of indomethacin while the other leg served as the control. In comparing muscle biopsy samples before and 8 days after the exercise activity, there was a significant increase in satellite cell proliferation in the control leg, while no increase in satellite cell activity was observed in the NSAID-treated extremity [9].

The final two studies of this systematic review assessed the potential impact of NSAIDs specifically from the perspective of athletic performance. In one study, well-conditioned endurance runners completed a muscle-damage protocol that consisted of both concentric and eccentric exercises. They were then given either ibuprofen or a placebo, and two days later, they completed a treadmill running test. Both groups showed reduced endurance performance 48 h after completing the muscle-damage protocol, but no significant difference was ultimately observed between the test groups [5]. The last study in this systematic review also focused on healthy male long-distance runners, and they were given either oral ibuprofen or a placebo 15 min before and 5 h into a 42 km trail run. In the end, it was revealed that the NSAID users had fewer oxidative stress markers but otherwise no significant difference in race performance nor with muscle damage indicators such as creatine kinase [6]. All results in this systematic study have been organized in Table 3.

Despite its limitations, this systematic review did investigate the wide uses of NSAIDs. From selecting a total of seven articles in accordance with the latest recommendations and guidelines per the PRISMA protocol, the systematic review was able to review the effectiveness along with the potential results and consequences that NSAIDs can have on athletes, particularly as it relates to injury management and rehabilitation, physical training and exercise, and athletic performance. Overall, this systematic review affirmed that NSAIDs can be effective for managing acute pain in recent sports injuries. However, the beneficial value of NSAIDs does seemingly diminish when it comes to treating more chronic injuries, as evidence shows that symptomatic relief and functional improvement with NSAIDs for such conditions are negligible. Lastly, there has been a belief that NSAIDs could possibly be ergogenic and provide athletic performance enhancement because of their anti-inflammatory and analgesic properties. However, it is important to make the critical distinction between “performance enhancing” versus “performance enabling”. While more research beyond this systematic review is admittedly needed to support whether the latter is applicable to NSAIDs, this review provided data that NSAIDs are not performance-enhancing agents. In fact, not only does the data in the included studies show that NSAIDs do not improve athletic performance, but there is also evidence to suggest that the use of NSAIDs before, during, or after major physical activity can potentially impair an athlete’s physiological response to exercise as it specifically relates to recovery and training adaptations.

As it has been stated, the use of NSAIDs can be very prevalent in athletes since these medications are often readily available, can provide positive pain relief, and are generally well tolerated, with low risk of major adverse side effects. However, at the same time, resorting to NSAIDs is not a completely benign intervention with zero risk. While NSAIDs can certainly be beneficial for athletes in the right situation, the fact that there are real risks and possible disadvantageous results with their use highlights the importance of promoting the appropriate use of these medications throughout the athletic community. As such, proper education and awareness amongst athletes, parents, coaches, and healthcare professionals is vital for helping ensure that an appropriate risk and benefit analysis is performed every time the use of NSAIDs is being considered. Doing so will help mitigate the prevalence of inappropriate expectations, medication misuse, and ultimately the risks of potential harm and other unintended consequences.