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Am J Physiol Endocrinol Metab 282: E551–E556, 2002.
First published October 30, 2001; 10.1152/ajpendo.00352.2001.
Effect of ibuprofen and acetaminophen on postexercisemuscle protein synthesis T. A. TRAPPE,1 F. WHITE,1 C. P. LAMBERT,1 D. CESAR,2M. HELLERSTEIN,2 AND W. J. EVANS11Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Center on Aging,Departments of Geriatrics and Physiology and Biophysics, University of Arkansas for MedicalSciences, and the Central Arkansas Veterans HealthCare System, Little Rock, Arkansas 72205;and 2Department of Nutritional Sciences, University of California, Berkeley, California 94720-3104 Received 3 August 2001; accepted in final form 29 October 2001 Trappe, T. A., F. White, C. P. Lambert, D. Cesar, M.
that ϳ5.5 million people in the United States consume Hellerstein, and W. J. Evans. Effect of ibuprofen and
an analgesic, antipyretic, or nonsteroidal anti-inflam- acetaminophen on postexercise muscle protein synthesis. Am J Physiol Endocrinol Metab 282: E551–E556, 2002. First Ibuprofen and acetaminophen are purported to re- published October 30, 2001; 10.1152/ajpendo.00352.2001.— lieve muscle soreness and pain through separate mech- We examined the effect of two commonly consumed over-the- anisms. Ibuprofen is known to block cyclooxgenase (EC counter analgesics, ibuprofen and acetaminophen, on muscleprotein synthesis and soreness after high-intensity eccentric 1.14.99.1), which then reduces metabolites produced by resistance exercise. Twenty-four males (25 Ϯ 3 yr, 180 Ϯ 6 this enzyme, such as prostaglandins, that are at least cm, 81 Ϯ 6 kg, and 17 Ϯ 8% body fat) were assigned to one of partially responsible for inflammation and algesia (14, three groups that received either the maximal over-the- 35, 36). However, prostaglandins have also been shown counter dose of ibuprofen (IBU; 1,200 mg/day), acetamino- to regulate protein metabolism, and NSAIDs similar to phen (ACET; 4,000 mg/day), or a placebo (PLA) after 10–14 ibuprofen have been shown to blunt protein metabo- sets of 10 eccentric repetitions at 120% of concentric one- lism in animal skeletal muscle (24, 30). Therefore, repetition maximum with the knee extensors. Postexercise skeletal muscle protein metabolism may be influenced (24 h) skeletal muscle fractional synthesis rate (FSR) was in individuals who consume ibuprofen after unaccus- increased 76 Ϯ 19% (P Ͻ 0.05) in PLA (0.058 Ϯ 0.012%/h) and tomed exercise. The mechanism of analgesic action of was unchanged (P Ͼ 0.05) in IBU (35 Ϯ 21%; 0.021 Ϯ acetaminophen, also known as paracetamol, is less 0.014%/h) and ACET (22 Ϯ 23%; 0.010 Ϯ 0.019%/h). Neitherdrug had any influence on whole body protein breakdown, as clear; however, it is believed to have its analgesic measured by rate of phenylalanine appearance, on serum action within the central nervous system (8, 11, 15, 32, creatine kinase, or on rating of perceived muscle soreness 36). Thus acetaminophen would not be expected to compared with PLA. These results suggest that over-the- interfere with muscle protein metabolism after exer- counter doses of both ibuprofen and acetaminophen suppress the protein synthesis response in skeletal muscle after eccen- An important question is whether or not these drugs, tric resistance exercise. Thus these two analgesics may work when consumed at nonprescription levels, have any through a common mechanism to influence protein metabo- influence on metabolism and pain in humans after unaccustomed exercise. Therefore, we studied the in- paracetamol; analgesics; nonsteroidal anti-inflammatory fluence of ibuprofen and acetaminophen, at their max- imal over-the-counter daily dose, on skeletal muscleprotein fractional synthesis rate (FSR) and musclesoreness after high-intensity eccentric resistance exer- ANALGESIC DRUGS ARE COMMONLY CONSUMED to reduce or cise. This type of exercise has been shown to cause prevent the pain and soreness encountered after com- muscle soreness and damage and to stimulate a pro- pletion of unaccustomed exercise. This is especially tein metabolism response (13, 26). We hypothesized true when the exercise contains eccentric (muscle that a group that consumed no drug (placebo) or acet- lengthening) contractions, which have been demon- aminophen would elicit a large increase in FSR, strated to result in relatively large amounts of muscle whereas the ibuprofen group would respond with a damage and soreness (13). Ibuprofen and acetamino- blunted protein turnover response. We also hypothe- phen are two popular over-the-counter analgesics con- sized that both drugs would have an equal effect on sumed for muscle soreness. In fact, it has been reported reducing muscle soreness compared with placebo.
Address for reprint requests and other correspondence: T. Trappe, The costs of publication of this article were defrayed in part by the Nutrition, Metabolism, and Exercise Laboratory, DWR Center on payment of page charges. The article must therefore be hereby Aging, Univ. of Arkansas for Medical Sciences, 4301 W. Markham, marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734 Slot 806, Little Rock, AR 72205 (E-mail: trappetodda@uams.edu).
each morning and, if necessary to maintain body weight, thecarbohydrate and fat content of the diet was altered.
In the morning on days 5 and 8, each subject underwent a stable isotope infusion protocol (see Isotope infusion protocol)for the measurement of skeletal muscle protein FSR before and after (24 h) a bout of high-intensity eccentric exercise (day 7, see Eccentric exercise protocol). The evening beforeeach infusion protocol, the subjects spent the night in the Values are means Ϯ SD. * Nondominant leg. ACET, acetamino- NMEL and were instructed to eat their evening meal so as to provide a fast of 10 h before the beginning of the FSRmeasurements.
Before and each morning after the exercise bout, each subject came to the laboratory in the fasted state for a resting Subjects. Twenty-four males were recruited and randomly blood draw for creatine kinase (CK) determination and a divided into three groups of eight: placebo (PLA), ibuprofen rating of perceived soreness (see Measurement of perceived (IBU), or acetaminophen (ACET) (Table 1). All subjects were muscle soreness). The blood draw and soreness rating were accepted into the study after giving informed consent and completed in the supine position after ϳ10 min of supine after a screening for any metabolic abnormalities via a blood draw, urinalysis, and medical history questionnaire. Subjects Isotope infusion protocol. On the morning of the infusions were sedentary or recreationally active and were not com- (Fig. 1), each subject had an 18-gauge catheter placed in an pleting any formal exercise during the study or any resis- antecubital vein for the infusion of a stable, isotopically tance exercise for Ն6 mo before the investigation. None of the subjects was chronically consuming ibuprofen, acetamino- Woburn, MA) for the measurement of skeletal muscle protein phen, or any analgesic or anti-inflammatory drug before the FSR. A 20-gauge catheter was placed in retrograde fashion in study. This investigation was approved by the Institutional a dorsal vein of the hand, which was heated to provide an Review Board of the University of Arkansas for Medical arterialized blood sample (1). [2H5]phenylalanine was dis- solved in sterile 0.9% saline, filtered through a 0.2-␮m filter Overall experimental protocol. After enrollment in the before infusion, and infused with a calibrated infusion pump study, each subject completed a 16-day protocol (Fig. 1). To (PHD 2000, Harvard Apparatus, Natick, MA) at a rate of 0.05 standardize protein intake, all of the subjects’ meals were ␮mol⅐kgϪ1⅐minϪ1 after a priming dose of 2.0 ␮mol/kg as prepared and provided by the metabolic kitchen of the Nu- previously described (26). This protocol has been shown to trition, Metabolism, and Exercise Laboratory (NMEL) during result in steady-state [2H5]phenylalanine enrichments in the the 16 days. Total caloric content of the meals was deter- blood and muscle intracellular free amino acid pool within mined by estimating the daily energy expenditure from the 120 min (6, 26, 37). Before and during each infusion, blood Harris-Benedict equation (17) multiplied by an activity factor samples were drawn (t ϭ 0, 120, 180, 210, 240, 260, 280, and of 1.5. Each diet was composed of 1.2 g protein ⅐ kg body 300 min) for the measurement of plasma enrichment of wtϪ1 ⅐ dayϪ1, with the remaining calories coming from carbo- [2H5]phenylalanine. Muscle biopsies were taken from the hydrate (ϳ55%) and fat (ϳ25%). Body weight was measured vastus lateralis muscle of the dominant leg before and from Fig. 1. A: overall experimental proto-col. Nos. represent days of the protocol.
NMEL, Nutrition, Metabolism, andExercise Laboratory; FSR, fractionalsynthesis rate. Nos. represent time indays. B: isotope infusion schematic.
Nos. represent time in minutes.
AJP-Endocrinol Metab • VOL 282 • MARCH 2002 • www.ajpendo.org the nondominant leg after the eccentric exercise protocol (t ϭ and selected ion monitoring of mass-to-charge ratios (m/z) 120 and 300 min). Each muscle biopsy was taken through a 264, 267, 269, and 272 for the mϩ0, mϩ3, mϩ5, and mϩ8 new incision proximal to the previous biopsy. Tissue was ions, respectively. Protein-bound enrichment was deter- obtained after local anesthetic (lidocaine HCl 1%) with the mined by monitoring m/z 267 and 269, which are the mϩ3 use of a 6-mm Bergstrom needle with suction (5). The muscle and mϩ5 enrichments, respectively, where mϩ0 is the lowest was cleansed of excess blood, connective tissue, and fat and mass isotopomer in the ion envelope. Enrichment of the immediately frozen in liquid nitrogen. The tissue was stored protein-bound samples was determined using a linear stan- in liquid nitrogen (Ϫ190°C) until analysis.
dard curve from mixtures of known mϩ5-to-mϩ3 ratios.
Eccentric exercise protocol. On day 7, each subject com- Precursor enrichment for calculation of FSR was determined pleted a bout of unilateral high-intensity eccentric exercise from intracellular [2H5]phenylalanine by monitoring the with each leg. The maximal load that each subject could lift mϩ5-to-mϩ0 ratio (mass 269 and 264 amu) enrichment of concentrically with his knee extensors (i.e., one repetition the NABE-phenylalanine. Plasma [2H5]phenylalanine en- maximum, 1RM) was first determined and the eccentric richments were measured from the mϩ5-to-mϩ0 ratio.
workload set to 120% of 1RM. The eccentric exercise con- Calculations. FSR was calculated as the rate of [2H5]phenyl- sisted of 10–14 sets of 10 repetitions with a 60-s rest between alanine tracer incorporation into muscle protein, using the sets of knee extensor exercise on a muscle dynamometer in muscle intracellular free phenylalanine enrichment as the the isotonic mode (Cybex Norm, Lumenex, Ronkonkoma, NY). The range of 10–14 sets was achieved as a result of the FSR ͑%/h͒ ϭ ͕͑Et Ϫ Et ͒/͓E ⅐ ͑t Ϫ t ͔͖͒ ⅐ 100 variation in fatigue of the muscles of each subject. When the weight was lowered in less than 0.5 s, the subject completed where Et0 is the enrichment in the protein-bound phenylal- that set, was deemed fatigued, and the protocol was stopped.
anine tracer from the t ϭ 120-min biopsy, Et1 is the enrich- Drug dose and administration. Drugs were administered ment in the protein-bound phenylalanine tracer from t ϭ in a double-blind placebo-controlled fashion. Each drug was 300-min biopsy, (t1 Ϫ t0) is the phenylalanine tracer incorpo- administered in three doses each day (8 AM, 2 PM, and 8 PM) ration time, and Ep is the mean intracellular free [2H5]phe- corresponding to the maximal over-the-counter daily dose nylalanine enrichment from both biopsies (t ϭ 120 and 300 (ibuprofen: 400 mg per dose, total of 1,200 mg; acetamino- phen: 1,500, 1,500, and 1,000 mg, total of 4,000 mg). The Whole body phenylalanine appearance, taken as a mea- placebo group was given the same number of pills, which sure of whole body protein breakdown, was calculated using were indistinguishable from the drug doses. The first dose was given at the start of the eccentric exercise protocol (ϳ8AM on day 7). On the day of the postexercise infusion proto- col, the 8 AM dose was given at the start of the [2H5]phenyl- alanine infusion. The times of dosing were chosen to divide a is the rate of appearance (␮mol ⅐ kgϪ1 ⅐ minϪ1), F is the infusion rate (␮mol ⅐ kgϪ1 ⅐ minϪ1), and E the maximal over-the-counter dose evenly over the day and as a result of the pharmacokinetic studies that had previ- CK measurement. Serum CK activity was measured using ously been completed on these drugs (2, 11, 19). When single a commercial assay kit (Sigma Chemical, St. Louis, MO).
doses at or near those used in the current study are con- Statistics. Subject characteristics (height, weight, age, sumed, ibuprofen and acetaminophen have similar pharma- %body fat, and eccentric load) among the groups were com- cokinetic parameters. Both drugs appear in the plasma pared using a one-way analysis of variance (ANOVA). FSR, within 10 min; peak levels in plasma occur within 0.5–2.0 h; phenylalanine Ra, CK, and muscle soreness before and after and the half-life of both drugs is ϳ2 h (2, 11, 19). The subjects exercise among the groups were compared using a two-way were asked not to consume any other prescription or nonpre- ANOVA with repeated measures over time. A two-way ANOVA with repeated measures over time was also used to Measurement of perceived muscle soreness. A subjective compare blood and muscle intracellular free [2H5]phenylala- measure of muscle soreness was obtained from each subject nine enrichments over the blood draw and muscle biopsy before the eccentric exercise protocol and each morning time points, respectively, for both trials. Because of sample throughout the protocol. Each subject was presented a scale loss during mass spectrometry processing, FSR data include from 1 to 9, with 1 being the absence of soreness and 9 being n ϭ 7 (IBU), 6 (PLA), and 4 (ACET); all other data are unbearable soreness, and was asked to rate the level of represented by n ϭ 8 per group. When a significant difference soreness after the application of 40 N of force using a force was obtained, a Tukey’s post hoc analysis was used to find transducer with a 2-cm-diameter tip (22, 23). Rating of per- the location of the differences. Significance was accepted at a ceived soreness was measured two times in random order over nine sites over the four heads of the quadriceps femoris.
Each site was maintained over the study period by re-mark- ing with a permanent marker. The average of the two mea-surements and all nine sites was taken to represent the There were no differences in any of the subject char- average level of perceived soreness. The highest average acteristics among the three groups (Table 1). Body value of the nine sites was taken to represent the maximal weight was maintained (P Ͼ 0.05) in all three groups over the study (PLA: 86.5 Ϯ 22.7 vs. 85.6 Ϯ 23.0; IBU: Measurement of isotope enrichment. Blood samples were 78.2 Ϯ 10.5 vs. 78.5 Ϯ 10.2; ACET: 77.6 Ϯ 14.9 vs.
analyzed for [2H5]phenylalanine enrichment, and muscle samples were analyzed for free intracellular and protein-bound [2H Blood and muscle intracellular free [2H5]phenylala- 5]phenylalanine enrichment by mass spectrometry as previously described (6, 26), by use of the N-acetyl-n-butyl nine enrichments did not change significantly over the ester (NABE) derivative of phenylalanine. Derivatives were time course (120–300 min) of both infusions (data not analyzed by gas chromatography-mass spectrometry (Hew- shown), which has been shown previously (6, 26, 37).
lett-Packard 5973, series II) using electron impact ionization Postexercise (24 h) skeletal muscle FSR was increased AJP-Endocrinol Metab • VOL 282 • MARCH 2002 • www.ajpendo.org primary findings of this study were that ibuprofenblunted the protein synthesis response that is nor-mally seen after the type of exercise used in this study;surprisingly, acetaminophen also had a similar effecton protein metabolism.
From our data, it appears that the mechanism of blunting protein metabolism in skeletal muscle by cy-clooxygenase inhibition outlined by Rodemann andGoldberg (30) nearly 20 yr ago in rats may also beintact in humans. These authors showed an inhibitionof protein synthesis in isolated rat skeletal muscle withthree different cyclooxygenase inhibitors (aspirin, in-domethacin, and meclofenamate). In the current study,we hypothesized that ibuprofen would also block cyclo-oxygenase and have a similar effect on muscle protein Fig. 2. FSR (%/h) of mixed skeletal muscle protein before and afterthe eccentric exercise bout. ACET, acetaminophen group (n ϭ 4); metabolism. However, it is difficult to determine how IBU, ibuprofen group (n ϭ 7); PLA, placebo group (n ϭ 6). *P Ͻ 0.05 the amount of inhibitors (drugs) used in the previous studies that showed this effect in isolated muscles (24,25, 30, 34) compare with the levels in human muscle 76 Ϯ 19% (P Ͻ 0.05) in PLA (0.058 Ϯ 0.012%/h), and after consumption of maximal over-the-counter doses was unchanged (P Ͼ 0.05) in IBU (35 Ϯ 21%; 0.021 Ϯ of ibuprofen. Nonetheless, from our data, it is clear 0.014%/h) and ACET (22 Ϯ 23%; 0.010 Ϯ 0.019%/h) that the 1.2 g/day maximal over-the-counter dose of (Fig. 2). Whole body phenylalanine turnover (Ra phenyl- ibuprofen is potent enough to blunt the protein synthe- alanine) was unchanged (P Ͼ 0.05) in response to sis response to resistance exercise.
exercise (PLA: 0.67 Ϯ 0.05 vs. 0.63 Ϯ 0.05 ␮mol ⅐ kgϪ1 ⅐ What is less clear is why acetaminophen also inhib- minϪ1) or either drug (IBU: 0.67 Ϯ 0.04 vs. 0.63 Ϯ 0.03; ited the increase in FSR after the resistance exercise ACET: 0.66 Ϯ 0.05 vs. 0.62 Ϯ 0.03 ␮mol ⅐ kgϪ1 ⅐ minϪ1).
bout. The most logical hypothesis is that acetamino- The CK response to the exercise was large and phen also inhibits cyclooxygenase in skeletal muscle; highly variable among the three groups. CK was sig- however, to our knowledge, no other studies have ex- nificantly elevated in all three groups after the exer- amined the influence of acetaminophen on skeletal cise, but the overall response was not different among muscle metabolism. In addition, all of the previous the groups (Table 2). Because some of the nine sites data and the resultant nonperipheral effect of acet- did not elicit a soreness response, the average level aminophen hypothesis are derived from studies of the of perceived muscle soreness underrepresented the central nervous system and other nonskeletal muscle amount of soreness that the subjects experienced.
However, average and maximal ratings of perceived The small sample size of the FSR values for the muscle soreness were elevated in a similar fashion ACET group may appear to limit the interpretation of after the exercise, and there was no difference among the findings. However, in an attempt to determine an the three groups at any time point in either average or underlying mechanism for the drug-induced blunting maximal soreness. Both average and maximal per- of the postexercise increase in FSR, we measured pros- ceived soreness for the three groups combined in- taglandin (PG)F2␣ in the same muscle samples ana- creased within 1 day postexercise (4 Ϯ 1 and 6 Ϯ 1), lyzed for the measurement of FSR taken during the peaked at 2 days postexercise (5 Ϯ 1 and 7 Ϯ 1), and pre- and postexercise infusions (33). PGF2␣ is a product returned to baseline by days 6 and 7 postexercise.
of the cyclooxygenase enzyme and has been shown tostimulate skeletal muscle protein synthesis (24, 30).
DISCUSSION
Similar to the FSR results, PGF2␣ after exercise was Given the mechanisms of action and the widespread significantly increased (77%) in the PLA group, use of ibuprofen and acetaminophen, we believed it whereas it was unchanged in the ACET and IBU was necessary to better understand the potential groups (33). Thus it appears that both ACET and IBU metabolic implications of consuming these over-the- attenuate the postresistance exercise increase in FSR counter drugs after eccentric resistance exercise. The by blocking the production of PGF2␣ via the cyclooxy- Table 2. Serum creatine kinase levels before and after the eccentric exercise bout 74 Ϯ 13 227 Ϯ 52 828 Ϯ 485 2,568 Ϯ 1,568 4,143 Ϯ 2,857 5,209 Ϯ 3,052 4,837 Ϯ 2,934 2,192 Ϯ 1,118 1,460 Ϯ 919 1,034 Ϯ 647 1,751 Ϯ 1,449 2,246 Ϯ 1,965 1,697 Ϯ 1,416 Values are means Ϯ SE and expressed as units per liter. Pre, preexercise; Post, hours after exercise. There were no differences (P Ͼ 0.05) in the responses among the 3 groups.
AJP-Endocrinol Metab • VOL 282 • MARCH 2002 • www.ajpendo.org genase enzyme. These results, coupled with the fact one used in the present study. It may appear somewhat that the PGF2␣ measurements were completed on all surprising that neither of these drugs provided any eight subjects from each group, suggest that the effect level of analgesia compared with placebo, given the of ACET on postexercise FSR is valid.
aforementioned study and the proven pain-reducing The implications of our data are important for those benefits of acetaminophen and ibuprofen for individu- individuals that chronically consume either ibuprofen als with arthritis, headaches, and other symptoms (10, or acetaminophen during a period in which muscle 11). However, the level of pain, soreness, and edema hypertrophy is expected (i.e., resistance training). Al- was high enough to severely inhibit the gait of the though we did not measure the long-term effects of subjects in our study during the days after the exercise consumption of either of these drugs on muscle hyper- bout. It is quite possible that the level of soreness and trophy during resistance training, we speculate that pain was too severe for the dose of these drugs to be the continued attenuation of the normal increase in effective. It is also possible that the scale used for the protein synthesis after each resistance training bout measurement of perceived soreness among the groups would result in a blunting of the hypertrophic re- was not able to discern small differences in soreness sponse. Our speculation assumes that the muscle pro- tein breakdown response coincides with the protein We included only males in our study population, and synthesis response. This assumption seems appropri- it is unclear whether these same responses would hold ate, since the resting and postresistance exercise skel- in a similar group of females. However, there are no etal muscle FSR and fractional breakdown rate have data to suggest that the metabolism of ibuprofen or been shown to be significantly correlated (26), suggest- acetaminophen or the mechanism of action of these two ing that these two processes are linked.
drugs is different between men and women. Further- Our resting (preexercise) protein synthesis (FSR) more, several studies of muscle protein metabolism at results are comparable to previous studies of young to rest and after resistance exercise have not shown a middle-aged men in the postabsorptive state that have difference between women and men (26, 27, 31, 38).
examined mixed muscle protein from the vastus late- In conclusion, the increased rate of muscle protein ralis (7, 29). The increase in FSR of the PLA group in synthesis normally seen 24 h after high-intensity ec- the current study (76%) also compares favorably with centric resistance exercise was attenuated by con- previous studies when training status, dietary state, sumption of ibuprofen and acetaminophen at over-the- muscle studied, and the amount of exercise are consid- counter levels. The long-term influence of this acute response after resistance exercise for individuals who In this study, we used the Ra of phenylalanine as a chronically consume these (or similar) drugs cannot be measure of whole body protein breakdown. Our data determined from this study. However, long-term use of suggest, as others have found (26), that whole body these drugs may inhibit the normal hypertrophic re- protein breakdown is unchanged 24 h after resistance sponse to resistance training. Future studies on the exercise. Our data also suggest that neither ibuprofen impact of chronic consumption of over-the-counter nor acetaminophen had any influence on protein doses of these drugs on skeletal muscle are warranted.
breakdown at the whole body level. To this end, Gannet al. (16) have shown that chronic consumption of the We thank the subjects for their participation and effort, the kitchen staff at the Nutrition, Metabolism, and Exercise Laboratory, NSAID indomethacin does not affect whole body pro- and Aaron Roland for the creatine kinase analysis.
tein synthesis or nitrogen retention in elderly subjects.
The work was supported by a grant from The McNeil Consumer This finding is consistent with the fact that the action Products Company (W. J. Evans) and National Institutes of Health of the drugs in the current study appears to be at the level of the skeletal muscle, and muscle protein metab- REFERENCES
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