The Influence of NSAIDs on Physiologic Processes and Exercise
As physical therapists, it is important to understand the effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on the human body because many of our patients will be taking NSAIDs to alleviate their pain. Some patients may take NSAIDs prior to a physical therapy session to avoid pain that may arise from certain interventions that require movement of previously immobilized joints or muscles. Thus, understanding the physiological effects of NSAIDs on the body will improve the ability to appropriately prescribe exercise and accurately assess an individuals response to exercise while using NSAIDs.
Non-Sterodial Anti-Inflammatory Drugs (NSAIDs), simply put, reduce inflammation and pain. NSAIDs such as acetylsalicylic acid (Asprin) and Ibuprophen are commonly used, which is why researchers are continuously studying the risks and benefits of their effects on the human body.
NSAIDs work by inhibiting the activity of an enzyme called cycoloxygenase (COX), which is crucial in the formation of prostaglandins. Prostaglandins play a role in the generation of pain and in the inflammatory response; however, they also have roles in many other bodily functions. When NSAID's inhibit prostaglandin synthesis they can reduce pain and inflammation, but they can also hamper gastrointestinal functions and post-exercise protein synthesis, as well as cause a number of other positive and negative side effects. These effects on physiological processes and exercise are further discussed for the following body systems: muscular, cardiovascular, metabolic, pulmonary, neuromotor and gastrointestinal.
NSAIDs are often used to help people who are sore after exercise. Researchers have looked at this use of NSAIDs and have determined that NSAID “use for brief periods of time is beneficial to short term recovery of muscle function.”  NSAIDs do this by helping to manage inflammation. A short term use of NSAIDs seems to work well despite the impact on muscle repair, but long term use can lead to gastrointestinal complications, renal failure, liver failure, and heart failure. NSAIDs are best used for short term relief of soreness for muscles.
Young vs. Old
Recent studies have revealed that older adults who consume NSAIDs have greater muscle strength gain and hypertrophy from resistance training compared to older adults who do not consume NSAIDs . These findings were contrary to the researchers initial beliefs on the effects of NSAIDs on the muscular system adaptations to resistance training. The mechanisms are, at least, partially responsible for the\ initial findings are,
- NSAIDs reduced muscle loss by reducing the amount of IL-6 and MuRF-1, which promote muscle loss
- NSAIDs induced PGF2a receptor upregulation, which causes increased skeletal muscle sensitivity to PGF2a resulting in stimulation of protein synthesis. On the contrary, NSAIDs also suppressed PGF2a, which reduces protein synthesis stimulation.
Although overall, these mechanisms inhibited protein breakdown more than they inhibited protein synthesis, which resulted in an increased net muscle protein balance. These studies involved participants between the ages of 60 and 85, which shows that the effects of NSAIDs may be age-dependent. NSAIDs may have a beneficial effect on the muscular system in older adults, but consumers of NSAIDs need to be aware of the effects of NSAIDs have on other body systems. Unfortunately current research primarily focuses on the impacts on the muscular system. Further research should address the effects of NSAIDs on all body systems and over longer periods of time.
Acute vs. Chronic
NSAIDS are readily available over-the-counter and are among the most commonly used drugs. Because of this easy access, patients take NSAIDS to address pain and inflammation, often without the doses and duration being monitored by a professional. The Food and Drug Administration recommends that regular use of NSAIDS exceeding ten consecutive days to be accompanied by a consultation with a health care provider .
Most of the adverse effects addressed here involve extended use (over ten days). It is important for therapists to be aware that existing conditions can lead to adverse effects even during acute use. For example, NSAIDS are commonly linked to cardiovascular risk after prolonged use. But it has recently become more understood that there is no safe dosage of/treatment duration of NSAIDS for patients with existing cardiovascular disease . Thoroughly check and understand each patient's chart and medical history and be sure to compile a complete list of medications. Even acute use of NSAIDS can pose a threat to our patients' health, so we must be aware of each preexisting condition and how medication affects it before we can proceed with a treatment plan.
Timing of Use
Many athletes take NSAIDs before physical activity in order to prevent the inflammation and/or pain that may occur. Some clinical evidence involving surgical trials supports these claims, finding that using NSAIDS prior to an inflammatory event could reduce inflammatory response, pain, and recovery time. In exercise induced muscle damage, rather than surgically induced, studies have shown that pre-exercise administration of NSAIDs could reduce the amounts of creatine kinase circulating after exercise as compared to a placebo group. This difference in creatine kinase levels may illustrate that less muscle damage occurred in the treatment group.
In another study researchers investigated the impact of a specific NSAID, ibuprofen, on time until fatigue in runners with muscle damage induced by exercise. The authors found that ibuprofen did not reduce the impact of muscle damage and pain on aerobic performance. Similar studies have also shown that NSAIDs as a preventative measure have little to no effect. In addition to these unclear results, frequent and preemptive NSAID use could allow the pain of an underlying condition to go unnoticed and become further damaged as the athlete continues to put stress on the injury. The overall negative effects of frequent use of NSAIDs as discussed below could outweigh the possible benefits of pre-exercise use. More studies are needed to determine the efficacy of taking NSAIDs before exercise.
Recent studies have looked at the effect of NSAIDs on bone density, with attention to exercise adaptations. This study was the first to run trials on humans. Previous studies have been performed on animals. The randomized, double blinded, placebo controlled study included 95 healthy premenopausal women ages 21 to 40. They participated in an exercising program lasting 9 months. The three groups consisted of a group that took a placebo before and after exercise, a group that took a ibuprofen before and after exercise, and a group that took a placebo before and an ibuprofen after exercise.
The reasoning behind the study was that prostaglandin E2 goes up in bone after exercise. One of the enzymes involved in the production of prostaglandin E2 is cyclooxygenase, which is inhibited by NSAIDs. This inhibits bone formation after any type of mechanical loading. The authors found that “taking 400 mg of ibuprofen immediately after exercise augmented the beneficial adaptions of BMD” compared to the other groups in the study. This group showed the largest increase in BMD, or bone mineral density. This information has important ramifications, but this is the first human study. Further studies need to be done to confirm this information, and understand the mechanism behind this information.
The use of NSAIDs can have negative effects on the cardiovascular system. Chronic use of NSAIDs by individuals with hypertension and coronary artery disease can have negative side effects. Some of the side effects that are mentioned in the article are stroke and myocardial infarction . These are some significant considerations that need to be kept in mind when working with older individuals who may have some of these cardiac issues. It is important to ask these patients what medications they are taking because some of these patients may be taking NSAIDs without a prescription, therefore these medications may not be listed on their chart.
Daily long-term use of NSAIDs, even of low dosage, can have a negative effect on the gastrointestional tract. Cryer and Feldman explored the effect of 10mg, 81mg, and 325mg asprin/day on serum TXB2 and gastrointestinal prostaglandin (PG) levels in the stomach, duodenum, and rectum. Results from their study indicated all three daily doses of asprin significantly decreased serum TXB2 levels after 1.5 months of use. The average stomach PG level was reduced to 34-44% of baseline, with the 10mg dosage reducing levels as much as the 81 and 32mg doses. It was found the 10mg dosage had no significant effect on duodenal PG levels, while the 81 and 325mg doses similarly reduced the levels to 45% of baseline. Lastly, only the 325mg dose affected the rectum by significantly reducing PG levels to 60% of baseline. 
Ibuprofen and, to an extent, acetaminophen have a restrictive effect on the renal system. Both drugs inhibit the kidneys' ability to absorb water and salt, which can lead to rapid dehydration. To avoid dehydration in people taking NSAIDs, it is important to monitor fluid intake and excretion during the person's bout of physical exercise.
Aspirin has been in use for over a century and has been joined by many different NSAIDs over that time period. It has many positive uses, but it can also be linked to negative outcomes as well. Aspirin-exacerbated respiratory disease (AERD) is characterized by the combination of asthma, nasal polyps, and sensitivity to aspirin and other COX-1 inhibitor NSAIDs.  The development of this disease varies, but it typically begins when a person has inflammation in their airways from having high levels of eosinophils in their blood and sinuses. They often have impaired cycolooxygenae pathways and produce high levels of leukotrienes. The adverse reaction occurs after ingesting aspirin or other NSAIDs and the level of leukotrienes are increased even more. 
This is important to physical therapists because people with AERD may have symptoms such as coughing, chest tightness, difficulty breathing, and sometimes dizziness. Therapists need to keep a special eye on these patients to monitor their symptoms in therapy. You don't want to push them too hard in their exercises to the point that they will lose their breath, get dizzy, and fall, potentially making their condition worse.
Implications for Physical Therapy
As physical therapists, it is important to be knowledgeable about the positive and negative effects of NSAIDs on different systems in the body. A physical therapist should inquire their patients if they are taking NSAIDs so that we can give our patients insight about proper and safe use of NSAIDs.
- Ricciotti, E.,FitzGerald, G. A. Prostaglandins and Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 2011; 31(5), 986–1000. doi:10.1161/ATVBAHA.110.207449
- Warden, S. Prophylactic Use of NSAIDs by Athletes: A Risk/Benefit Assessment. The Physician and Sportsmedicine 2010; 38(1), 132-138.
- Trappe, T. A., Standley, R. A., Jemiolo, B., Carroll, C. C., Trappe, S. W. Prostaglandin and myokine involvement in the cyclooxygenase-inhibiting drug enhancement of skeletal muscle adaptations to resistance exercise in older adults. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 2013; 304(3). 198-205.
- Trappe, T. A., Carroll, C. C., Dickinson, J. M., LeMoine, J. K., Haus, J. M.,... Hollon, C. J. Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 2011; 300(3), 655-662.
- Baldwin, A., Stevenson, S., & Dudley, G. Nonsteroidal Anti-Inflammatory Therapy After Eccentric Exercise in Healthy Older Individuals. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2001; 56(8), M510-M513. doi:10.1093/gerona/56.8.M510
- Krentz, J., Quest, B., Farthing, J., Quest, D., & Chilibeck, P. The effects of ibuprofen on muscle hypertrophy, strength, and soreness during resistance training. Applied Physiology, Nutrition, and Metabolism 2008; 33(3), 470-475. doi:10.1139/H08-019
- Warden, S. Prophylactic Use of NSAIDs by Athletes: A Risk/Benefit Assessment. The Physician and Sportsmedicine 2010; 38(1), 132-138.
- Lanier, A.B. Use of nonsteroidal antiinflammatory drugs following exercise-induced muscle injury. Sports Medicine 2003; 33(3), 177-186. retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/12656639
- Aminoshariae, A., Kulild, J.C., & Donaldson, M. Short-term use of nonsteroidal anti-inflammatory drugs and adverse effects: An updated systematic review. JADA 2015; doi: 10.1016/j.adaj.2015.07.020
- Olsen, A., Fosbøl, E., & Gislason, G. The Impact of NSAID Treatment on Cardiovascular Risk - Insight from Danish Observational Data. Basic Clin Pharmacol Toxicol Basic & Clinical Pharmacology & Toxicology 2014; 179-184. doi:10.1111/bcpt.12244
- Warden, S. J. Prophylactic use of NSAIDs by athletes: A risk/benefit assessment. The Physician and Sports Medicine 2010; 38(1), 1-7.
- O'Grady M, Hackney AC, Schneider K, Bossen E, Steinberg K, Douglas JM, Murray WJ. Diclofenac sodium (Voltaren) reduced exercise - induced injury in human skeletal muscle. Medicine Science in Sports Exercise, 32(7), 1191-6
- Da Silva, E., Pinto, R. S., Cadore, E. L., and Kruel, L. F. Nonsteroidal anti-inflammatory drug use fckLRand endurance during running in male long-distance runners. Journal of Athletic Training 2015; 50(3), fckLR295-302.
- Korth WM, Barry DW, Van Pelt RE, Jankowski CM, Wolfe P, Schwartz RS. Timing of ibuprofen use and bone muscle density adaptions to exercise training. Journal of Bone Mineral Research 2010 [cited 2015 Nov 10] 25(6), 1415-22. Available from Wiley Online Library with full text: http://onlinelibrary.wiley.com.webproxy.ouhsc.edu/doi/10.1002/jbmr.24/abstract
- Bavry A, Kaliq A, Gong Y, Handberg E, Cooper-Dehoff R, Pepine C. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. American Journal of Medicine 2011; 124(7): 614-619
- Cryer, B. &a Feldman, M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels on mucosal injury in healthy humans. Gastroenterology 1999; 117 (1). Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/10381905
- Farquhar WB, Morgan AL, Zambraski EJ, Kenney WL. Effects of acetaminophen and ibuprofen on renal function in the stressed kidney. Journal of Applied Physiology 1999;86:598-604.
- Simon RA. Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs. Curr Allergy Asthma Rep Current Allergy and Asthma Reports. 2004;4:17–24. Retrieved from: http://web.a.ebscohost.com.webproxy.ouhsc.edu/ehost/detail
- Aspirin Exacerbated Respiratory Disease. Aspirin Exacerbated Respiratory Disease | Samter's Triad. Retrieved from: http://aerd.partners.org