Research Review By Dr. Demetry Assimakopoulos©

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Date Posted:

March 2013

Review Title:

Ibuprofen – Relation to Exercise-Induced Intestinal Injury & Muscle Damage

Studies Reviewed:

  1. Wijck KV, Lenaerts K, Van Bijnen AA et al. Aggravation of Exercise-Induced Intestinal Injury by Ibuprofen in Athletes. Medicine and Sciences in Sports & Exercise 2012; 44(12): 2257-2262.
  2. Schoenfeld BJ. The use of Nonsteroidal Anti-Inflammatory Drugs for Exercise-Induced Muscle Damage: Implications for Skeletal Muscle Development. Sports Medicine 2012; 42(12): 1017-1028.

Background Information:

Many recreational and professional athletes take non-steroidal anti-inflammatory drugs (NSAIDs) to reduce unwanted swelling from an injury and to prevent unwanted musculoskeletal pain resulting from exercise. It is also assumed by many individuals within this population that taking NSAIDs allows for higher training intensities, because of the perceived increased tolerance to pain. Unfortunately, no clear, high-quality evidence exists to support this particular theory.

Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are both found in skeletal muscle and are up-regulated with exercise. Specifically, COX-2 up-regulation is involved in exercise induced muscle damage (EIMD). While many NSAIDs exist, the two that are primarily used are selective COX-2 NSAIDs and non-selective NSAIDs; both of these act to decrease the two COX isoforms to reduce inflammation and pain.

There is, however, a dark side to NSAID use. Regular use of NSAIDs comes with certain potential side-effects, including gastrointestinal (GI) bleeding, perforation and strictures (1-3). These side-effects are thought to stem from the inhibition of COX-1 and a reduction of local nitric oxide, which impairs perfusion of the upper GI tract. Similarly, it has been demonstrated that 1 hour of exhaustive exercise can lead to small intestinal injury and compromise of the gut-barrier in healthy individuals (4). Additionally, the literature shows that NSAID use for EIMD can reduce the adaptive response to exercise, because COX enzymes may be important in the process of skeletal muscle hypertrophy. In light of these facts, the authors of study #1 sought to determine whether the combination of NSAIDs and exhaustive exercise can have an additive effect and create more severe abdominal distress in athletes. The authors of study #2 endeavored to determine the effects of NSAIDs on muscle growth, protein synthesis and muscle hypertrophy by performing a systematic review of the current literature.

Pertinent Results:

Study #1: NSAIDs & Exercise-Induced Intestinal Injury:

The results of study 1 showed that fatty acid binding protein levels (I-FABP = a protein which diffuses into circulation from injured enterocytes) in plasma gradually increased during cycling at an intensity of 70% workload maximum (Wmax) from baseline measurements. Peak post-exercise I-FABP levels in cyclists who ingested ibuprofen were significantly higher than plasma concentrations of cyclists who did not ingest ibuprofen. Further, permeability of the upper GI system increased after cycling with ibuprofen compared to ingesting ibuprofen at rest.

Two of the 9 subjects reported abdominal discomfort, epigastric pain, flatulence and belching subsequent to ingesting ibuprofen at rest. These results imply that ingestion of ibuprofen can also cause small intestinal injury at rest (this has been well-established in the literature).

Study #2: Effects of NSAIDs on Exercise-Induced Muscle Damage:

NSAID use also has an effect on muscle protein synthesis and potentially muscle hypertrophy. Animal models have demonstrated that NSAIDs can impair protein metabolism due to a decrease in prostaglandin production (especially PGF2?) via COX inhibition. This was found by Trappe et al. (5), who provided subjects who performed 10-14 sets of 10 eccentric contractions of the knee extensors at 120% of 1RM with 1200 mg of ibuprofen or 4000 mg of paracetamol. However, it should be noted that other research groups (6) who employed a similar research design found that NSAID consumption did not impair mixed protein synthesis.

At rest, satellite cells in the muscle remain quiescent in the basal lamina connective tissues and sacrolemma of muscle fibers, waiting to be aroused by mechanical stimulation. Once stimulated, they produce myoblasts (muscle precursor cells), that ultimately fuse to existing cells to repair damaged muscle and enable growth of new muscle tissue. Some studies have shown that satellite cells are crucial in muscle growth (7). Animal cell cultures have shown a marked decrease of the fusion of chick myoblasts when they are subjected to non-selective COX inhibitors, and inhibition of COX-1 and 2 isomers independently. COX-2 suppression has also been shown to reduce satellite cell activation, proliferation and differentiation. Tests in human subjects have shown that NSAIDs have a detrimental effect on satellite activity in muscles that have been subjected to a single infusion of indomethacin. This is significant, as indomethacin was administered in the early post-exercise period, which suggests that this particular NSAID may interfere with the pathways necessary for satellite cell proliferation.

Studies have also shown that selective and non-selective NSAIDs can have a detrimental effect on muscle hypertrophy following chronic overload. It has been demonstrated that administration of ibuprofen and selective COX-2 inhibitors can result in a 50% decrease in hypertrophy of the plantaris muscle of rats. However, 3 human studies have failed to demonstrate similar results. Two of the 3 human trials which contradict the results of the rodent studies have actually found benefit of consuming NSAIDs in terms of muscle hypertrophy. Thus, whether or not NSAID use actually does limit the potential for muscle hypertrophy is a debatable issue that warrants further study.

Clinical Application & Conclusions:

Study #1: NSAIDs & Exercise-Induced Intestinal Injury:

Both upper and lower GI permeability increased subsequent to cycling after ibuprofen intake. This study, even with its small sample size, demonstrates how the use of ibuprofen increases exercise-induced small intestine injury, leading to the loss of intestinal barrier function in healthy athletic men.

The authors suggest that the increased injury is likely due to the inhibition of COX-1 and 2, which results in local inflammation and vascular dysregulation, leading to reduced perfusion and mucosal integrity loss. Additionally, NSAIDs decrease the production of nitric oxide, which also leads to a decrease in mucosal blood flow. Since it has been proven that endurance running without the use of NSAIDs can lead to GI injury (8, 9) the combination of endurance exercise with NSAIDs may have a compounded effect at a much lower dose than the maximum recommended daily dosage.

Study #2: Effects of NSAIDs on Exercise-Induced Muscle Damage:

More research on whether or not COX inhibitors affect post-exercise protein synthesis needs to be performed. Despite of the fact that trials on rodents have shown detrimental effects, human trials have not supported this conclusion. Still, strong evidence exists stating that the use of NSAIDs can decrease satellite cell activity both in humans and in rodents. Based on cellular biology and physiology, one can make the logical conclusion that a decrease in satellite cell activity should lead to a decrease in muscle hypertrophy post-exercise. Based on the available literature, this article concludes that in untrained individuals, NSAID use will not interfere with short term muscle growth. In spite of this conclusion, more research is clearly needed.

Study Methods:

A total of 9 healthy cyclists or triathletes were selected in study #1. These athletes had not taken any medication in at least 1 month and had no history of GI disease or abdominal surgery.

Max Wattage (Wmax, or workload) was determined prior to experimentation using a stationary cycle ergometer. Athletes performed their normal ADLs, but were not allowed to consume alcohol or artificial sweeteners the day prior to testing, and did not perform strenuous physical activity 2 days before the testing days. One 400mg dose of ibuprofen was given to each subject the night prior to their exercise test. An additional 400mg was ingested by the participants the morning of the test days, 1 hour prior to exercising on the stationary bike (it is interesting to know that the maximum daily dose for orally ingested ibuprofen varies from 1.2g for over-the-counter doses to 2.4g for prescribed oral doses. Keep this in mind when interpreting the results).

The 9 subjects were tested randomly in 4 different scenarios:
  1. During and after exercise after their intake of medication;
  2. during and after cycling without ingesting ibuprofen;
  3. rest with prior intake of ibuprofen; or
  4. rest without taking ibuprofen.
At least 7 days of rest were allotted between test days and tests were performed after an overnight fast. A catheter was placed in the anticubital vein for blood sampling. Participants who were assigned to cycling started at a cycling cadence of 60 RPM and a workload of 150 W after taking baseline blood and urine samples. After 3 minutes, the workload increased to 70% of their predetermined Wmax. Subsequent to the test, all individuals ingested 150 mL of a multisugar drink to allow for the whole gut permeability analysis. On off days, patients were tested in exactly the same way described above, only after 1 hour of laying supine, as opposed to cycling.

The concentration of I-FABP was measured in each participant’s plasma. Also, gastroduedenal and small intestine permeability was determined via 0-2 hour urinary excretion analysis of different simple sugars.

The authors of study #2 accessed the PubMed and EBSCO databases for English language studies, using various text words for their search. The reference lists of all articles accessed were screened for additional applicable studies. The authors had a preference for results of in vivo protocols, especially those involving human subjects.

Study Strengths / Weaknesses:

Strengths:
  1. Study 1 experimentally examined how NSAIDs affect different parts of the GI tract during exercise. Also, the inclusion of the 4 separate and contrasting subject groups allowed for more solid conclusions.
Weaknesses:
  1. Study 1 should have included another group which cycled at a higher RPM to show whether or not intensity of long term exercise creates more profound negative changes in the bowel. This may be their next research step.
  2. The great paucity and heterogeneity of literature makes it difficult for study 2 to come to any hard and fast conclusion regarding the impact NSAIDs have on protein synthesis.
  3. The authors of study 2 did not describe which databases they accessed through EBSCO, thus making their search strategy difficult to replicate.

Additional References:

  1. Allison MC, Howatson AG, Torrance CJ et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327(11): 749–54.
  2. Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology 1995; 108(5): 1566–81.
  3. Blikslager AT. Life in the gut without oxygen: adaptive mechanisms and inflammatory bowel disease. Gastroenterology 2008; 134(1): 346–8.
  4. van Wijck K, Lenaerts K, van Loon LJ et al. Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men. PLoS One 2011; 6(7): e22366.
  5. Trappe TA, White F, Lambert CP et al. Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis. Am J Physiol Endocrinol Metab 2002; 282(3): E551-6.
  6. Burd NA, Dickinson JM, Lemoine JK, et al. Effect of a cyclooxygenase-2 inhibitor on postexercise muscle protein synthesis in humans. Am J Physiol Endocrinol Metab 2010; 298(2): E354-61.
  7. Petrella JK, Kim J, Mayhew DL et al. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol 2008; 104(6): 1736-42.
  8. Choi SC, Choi SJ, Kim JA et al. The role of gastrointestinal endoscopy in long-distance runners with gastrointestinal symptoms. Eur J Gastroenterol Hepatol 2001; 13(9): 1089–94.
  9. Oktedalen O, Lunde OC, Opstad PK et al. Changes in the gastrointestinal mucosa after long-distance running. Scand J Gastroenterol 1992; 27(4): 270–4.