The Effect of Acetaminophen on Running Economy and Performance in Collegiate Distance Runners

cetaminophen (ACT) may decrease perception of pain during exercise, which could allow runners to improve running economy (RE) and performance. The aim of this study was to determine the effects of ACT on RE and 3 km time trial (TT) performance in collegiate distance runners. A randomized, double blind, crossover study was employed in which 11 track athletes (9M/2F; age: 18.8 0.6 years; VO 2max: 60.6 7.7 mL/kg/min) completed three intervention sessions. Participants ingested either nothing (baseline, BSL), three gelatin capsules (placebo, PLA), or three 500 mg ACT caplets (ACT). One hour after ingestion, participants completed a graded exercise test consisting of 4 5 min steady-state stages at ~55–75% of VO 2max followed by a 3 km TT. There was no in uence of ACT on RE in any stage. Similarly, ACT did not favorably modify 3 km TT performance [mean SD: BSL = 613 71 s; PLA = 617 70 s; ACT = 618 70 s;p= 0.076]. The results indicate that ACT does not improve RE or TT performance in collegiate runners at the 3 km distance. Those wanting to utilize ACT for performance must understand that ACT's bene ts have yet to be signi cant amongst well-trained runners. Future studies should examine the effects of ACT on

617 70 s; ACT = 618 70 s;p= 0.076]. The results indicate that ACT does not improve RE or TT performance in collegiate runners at the 3 km distance. Those wanting to utilize ACT for performance must understand that ACT's bene ts have yet to be signi cant amongst well-trained runners. Future studies should examine the effects of ACT on well-trained runners over longer trial distances and under more controlled conditions with appropriate medical oversight. Keywords:endurance; time trial; perceived exertion; pain reliever 1. Introduction During high intensity efforts runners experience a great deal of pain [1]. This pain can be a result of muscle fatigue, tissue damage, or aggravation of previous injury [1]. In elite races, where all runners are well-trained with comparable aerobic capacities, pain management is often the primary factor for determining success [2]. Taking pain-relieving medications, which are not banned by the governing body of the sport, and which are safe to ingest for healthy individuals with no allergies to their ingredients or contraindications to the medication, has been investigated as a way to enhance exercise performance. Ac- etaminophen (ACT), also known as paracetamol, is an over-the-counter pain reliever and fever reducer. ACT can alter acute and chronic responses to exercise by increasing pain threshold and demanding a greater amount of a stimulus before pain is felt [3]. The use of analgesics is extremely prevalent among runners [4]. In a study of 806 runners conducted by Rosenbloom et al., researchers found that 87.8% of subjects had utilized analgesics within the last year [4]. Over 200 of the subjects in the study reported the use of non-steroidal anti-in ammatory drugs (NSAIDs) directly prior to a race event. The top three reasons for use before a race are: (1) to reduce in ammation/swelling (58%), (2) to increase pain tolerance (42.7%), and (3) to continue running through an injury (42.7%) [4]. As the use of NSAIDs and analgesics in running is highly prevalent for these three primary reasons, it is important for runners that wish to utilize these drugs to understand how the drug they choose to use acts on

to reduce in ammation/swelling (58%), (2) to increase pain tolerance (42.7%), and (3) to continue running through an injury (42.7%) [4]. As the use of NSAIDs and analgesics in running is highly prevalent for these three primary reasons, it is important for runners that wish to utilize these drugs to understand how the drug they choose to use acts on the body and the risks associated with each drug. Int. J. Environ. Res. Public Health2022,19, 2927.

Int. J. Environ. Res. Public Health2022,19, 2927 2 of 14 ACT is considered to be a selective cyclooxygenase-2 (COX-2) inhibitor [5]. Being a selective COX-2 inhibitor, ACT lacks the antiplatelet and detrimental effects on gastroin- testinal mucosa of COX-1 inhibition, making it safer on the gastrointestinal tract than other drugs that are not selective inhibitors. Most NSAIDs, such as ibuprofen, are not selective inhibitors and therefore contain a risk of intestinal damage. Unlike NSAIDs, ACT is almost unanimously considered to have no anti-in ammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects [6]. Indeed, a major ad- verse effect of NSAIDs is their known tendency to cause gastrointestinal (GI) complications, such as mucosal ulceration, bleeding, perforation, and the formation of diaphragm-like strictures [7]. In a study analyzing the aggravation of exercise-induced intestinal injury by ibuprofen in athletes, Van Wijck et al. examined four scenarios around ibuprofen and exer- cise (800 mg ibuprofen before cycling, cycling without ibuprofen, 800 mg ibuprofen at rest, and rest without ibuprofen intake). They found that ibuprofen consumption and cycling resulted in increased plasma intestinal fatty acid binding protein (I-FABP) levels, re ecting small intestinal injury. These levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen. Additionally, small intestinal permeability increased, especially after cycling with ibuprofen, re ecting loss of gut barrier integrity. They concluded that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals [7]. This phenomenon does not occur with ACT due to the different mechanisms of action of ACT compared to ibuprofen and other NSAIDs [5]. These studies demonstrate that those wish- ing to utilize drugs prior to races in order to increase pain tolerance are at an increased risk of adverse health effects when choosing NSAIDs, such as ibuprofen, as opposed to an analgesic drug, such as ACT [7]. They also demonstrate that ACT should not be used to treat in ammation or swelling, as ACT does not have an anti-in ammatory effect [5,6]. ACT is a safe drug at appropriate doses [6]. The

are at an increased risk of adverse health effects when choosing NSAIDs, such as ibuprofen, as opposed to an analgesic drug, such as ACT [7]. They also demonstrate that ACT should not be used to treat in ammation or swelling, as ACT does not have an anti-in ammatory effect [5,6]. ACT is a safe drug at appropriate doses [6]. The amount of 7.5 g in adults is widely considered as the lowest acute dose capable of causing toxicity [6]. All studies examining ACT and its effect on performance utilize doses ranging from 0.5 g to 1.5 g [3,8–14], well under the threshold for the potential of toxicity. There have been no reports of acute toxicity in healthy adults ingesting a single dose of ACT below 125 mg/kg [6]. Unlike ibuprofen or other NSAIDs, ACT has only a small peripheral effect and acts primarily on the central nervous system [6]. Even so, the risks of ACT should be fully outlined for coaches and athletes to consider. As with many drugs, ACT can have very harmful effects, speci cally to the liver, if taken above prescribed doses. Unfortunately, ACT overdose is responsible for more acute liver failure cases in the US and UK than all other etiologies combined [15]. The most common reason ACT ingestion results in death by overdose is its use in suicide attempts. Suicide attempts are a frequent cause of exposure to a single, high overdose of ACT [15]. Regrettably, unintentional overdose can occur as a result of combining multiple over-the-counter drugs, such as sleep-aids and cold medications, that may all have components of ACT [15]. Nevertheless, extensive literature reviews suggest that even susceptible people are unlikely to suffer adverse effects from therapeutic doses of ACT [15]. Additionally, there is an antidote against ACT-induced liver injury, the drug, N-acetylcysteine (NAC). NAC acts through facilitating scavenging of a reactive metabolite during the metabolism phase and is most effective when administered within 8 h of the overdose. This allows ACT-induced liver injury and liver failure to have a relatively high survival rate. As ACT is one of the most common over-the-counter

is an antidote against ACT-induced liver injury, the drug, N-acetylcysteine (NAC). NAC acts through facilitating scavenging of a reactive metabolite during the metabolism phase and is most effective when administered within 8 h of the overdose. This allows ACT-induced liver injury and liver failure to have a relatively high survival rate. As ACT is one of the most common over-the-counter drugs and because the vast majority of those who take ACT do not come close to taking over-therapeutic dosages of it, it is one of the safest over-the-counter drugs available [15]. Several studies have demonstrated signi cant endurance performance improvements among participants in ACT conditions compared to placebo conditions during both cy- cling and running. These improvements have been contributed to improved ability to tolerate pain as a result of prolonged exercise or a decreased perception of perceived pain or exertion during exercise. For example, the cycling studies by Delextrat et al. [8], Foster et al. [9], Mauger et al. [10], Mauger et al. [11], and Morgan et al. [12] have demon-

Int. J. Environ. Res. Public Health2022,19, 2927 3 of 14 strated that ingestion of ACT before a cycling bout improved performance through an increased average or peak power output or a decreased time to complete a speci ed dis- tance [8–12]. Some researchers concluded that these improvements in performance were a result of the participants' improved ability to tolerate pain during cycling [8–10]. Despite the many studies completed on cycling performance and ACT, there have been few studies conducted to examine the effects of ACT ingestion on running performance. In the only study examining running endurance performance and ACT ingestion, Dagli et al. [3] found that after taking ACT, recreationally active runners were able to improve 3 km time trial performance by 1.9% compared to placebo [3]. However, this study was conducted using exclusively male participants and was performed on a treadmill, which is not as speci c to distance running compared to the running over ground that is characteristic of National Collegiate Athletic Association (NCAA) track and cross-country runners. Indeed, there are no well-controlled randomized studies investigating the potential exercise performance effects of ACT on well-trained, elite level male and female distance runners. Additionally, there have not been any studies examining the effects of ACT on running economy (RE). RE is determined by the steady state oxygen consumption for a standard speed [16–18]. An athlete with improved RE consumes less oxygen for a given steady state running speed [19], thus improving their performance by expending less energy throughout a race [19]. Over the course of a race, runners experience increasing amounts of fatigue, which contributes to reduced mechanical ef ciency and poor economy of motion [1]. For instance, Meardon et al. [1] found that stride time became less consistent over the course of a 5 km time trial while examining stride time variability, indicating that during prolonged running there was an increased need for gate adjustments due to increasing fatigue [1]. Based on the evidence to date in a multitude of studies, ACT has been demonstrated to improve cycling performance [8–12]. Yet, the only study examining the effects of

over the course of a 5 km time trial while examining stride time variability, indicating that during prolonged running there was an increased need for gate adjustments due to increasing fatigue [1]. Based on the evidence to date in a multitude of studies, ACT has been demonstrated to improve cycling performance [8–12]. Yet, the only study examining the effects of ACT ingestion on endurance running performance used recreationally active runners and did not examine its effect on RE [3]. Therefore, the purpose of this randomized, double blind, crossover experiment was to determine the effects of ACT on RE and a 3 km time trial performance in well-trained NCAA collegiate distance runners. It was hypothesized that ACT would improve RE and 3 km time trial performance through a reduction in perceived pain during running. 2. Materials and Methods 2.1. Experimental Approach In this randomized, double blind, crossover experiment, participants reported to the High Altitude Exercise Physiology Laboratory on ve separate occasions (see Figure). The experiment was randomized by order; the research assistant randomly assigned each par- ticipant's rst condition as either a baseline condition (BSL), only water ingestion, placebo condition (PLA), water and placebo ingestion, or ACT condition (ACT), water and ACT ingestion. The random assignment was accomplished using a random number generator, which selected a number at random between one and three. Participants proceeded to complete each session based on their starting condition. For example, if a participant was randomly assigned ACT as their rst condition, their condition order would be ACT then BSL then PLA. The rst session for all participants consisted of completing questionnaires, informed consent, and a treadmill running familiarization. This session lasted 30–45 min and was followed by the next session two days later. In the second session, lasting about an hour, anthropomorphic measurements and determination of VO2max were completed. In the third, fourth, and fth sessions, each occurring one week apart and commencing on the same day of the week at the same time of day, subjects were assigned to ingest either eight ounces of water to serve as their baseline (BSL), eight ounces of

second session, lasting about an hour, anthropomorphic measurements and determination of VO2max were completed. In the third, fourth, and fth sessions, each occurring one week apart and commencing on the same day of the week at the same time of day, subjects were assigned to ingest either eight ounces of water to serve as their baseline (BSL), eight ounces of water paired with three empty red gelatin capsules which served as a placebo (PLA), or eight ounces of water paired with three 500 mg capsules of ACT (1.5 g) (ACT). Following ingestion, participants waited 60 min and then completed a 20-min RE assessment on a treadmill, which also served as a warm-up for their 3 km time trial on the indoor track.

Int. J. Environ. Res. Public Health2022,19, 2927 4 of 14 Figure 1. Experimental owchart. (BSL = baseline) (PLA = placebo) (ACT = acetaminophen) (RE = running economy) (TT = Time Trial). 2.2. Subjects Eleven total participants (9 men and 2 women) were recruited to participate in the study. Participants were well-trained distance runners on the NCAA division II cross- country team at Western Colorado University (WCU). Participants were considered well- trained based on VO2max and were in the 99th percentile for VO2max in their age and sex-group based on tness guidelines [20]. Participants completed the study during the middle of the indoor track season. They typically performed two workouts per week and four low intensity runs per week in addition to the experimental trials. One workout would consist of four to ten intervals of 400 to 1000 m with one to three minutes of jogging between repetitions. The other workout would be a continuous run of 20–35 min at 80–90% of VO2max. Men in the study ran between 80 and 120 km/wk. Women in the study ran between 56 and 96 km/wk. Men and women runners trained at an average running velocity of 14.0 km/h and 12.5 km/h, respectively. Participants were excluded from the study if they were found to be allergic to, or had previous complications with, the drug ACT, if they were heavy alcohol users, or if they had had any liver complications in the past. Participants were also excluded from the study if they were not classi ed as low risk for heart disease based on the American College of Sports Medicine risk algorithm. Exclusion criteria were assessed with the physical activity readiness questionnaire (PAR-Q) [21] and a medical history questionnaire, which included questions regarding over-the-counter drug use and alcohol use. All measurements of participants were conducted in the High Altitude Performance Laboratory at WCU, except for the 3 km time trial, which was performed on the indoor track in the WCU Mountaineer Fieldhouse. All subjects provided written and verbal informed consent prior to participating in the study. This study was approved by the Institutional Review Board

use and alcohol use. All measurements of participants were conducted in the High Altitude Performance Laboratory at WCU, except for the 3 km time trial, which was performed on the indoor track in the WCU Mountaineer Fieldhouse. All subjects provided written and verbal informed consent prior to participating in the study. This study was approved by the Institutional Review Board at WCU [HRC2020-01-01-R12]. 2.3. Procedures 2.3.1. Familiarization and Lead-In Following completion of the informed consent and other screening questionnaires, participants underwent a lead-in period to familiarize them with the VO2max protocol and treadmill RE assessments. The familiarization session was a way for participants to gain an understanding of how to run on a treadmill with open-circuit indirect calorimetry and to get a sense of the rating of the perceived exertion (RPE) scale. In this session the participant did not run to volitional exhaustion. This allowed them to return to the lab within 48 h for the genuine VO2max assessment without the possibility of fatigue. For this familiarization session participants were tted with a mask attached to falconia tubing, which was attached to the metabolic cart (Parvo Medics TrueOne ® 2400, Sandy City, UT, USA) to collect expired gases. Participants were also tted with a chest strap (Polar, Lake Success, NY, USA) to monitor heart rate throughout the test. Participants ran for 10 to

Int. J. Environ. Res. Public Health2022,19, 2927 5 of 14 12 min at increasing speeds on the treadmill (Trackmaster, Newton, KS, USA). This session was paced in a way that participants would reach an RPE of about 7 within 10–12 min, giving them an understanding of the perception of effort they would feel throughout the genuine VO2max assessment and later RE assessments. At the conclusion of the session, participants completed a low intensity cool-down at a self-selected pace for at least ve minutes and were dismissed from the lab. The entirety of the screening and familiarization session lasted 30–45 min. 2.3.2. Anthropomorphic Measurements While wearing only running attire, the participant removed their shoes and stood on a scale (Tanita, Arlington Heights, IL, USA) to be weighed in kilograms (kg). A measuring stick built into the scale was used to measure the participant's height in centimeters (cm). Body mass index (BMI) was later calculated from these measurements using the formula BMI = weight (kg)/height (m) 2 . Body fat percentage was assessed using an Omron HBF-300 handheld body composition analyzer (Omron, Bannockburn, IL, USA). 2.3.3. Maximal Oxygen Consumption Following anthropomorphic measurements, participants completed a self-selected 10-min dynamic warm-up consisting of stretches and other exercises on the indoor track in the WCU Mountaineer Fieldhouse. The same warm-up routine was performed for each participant prior to the RE test and time trial. This allowed the participant to prepare to perform as they would in a typical training session or race. VO2max was determined using open-circuit spirometry combined with indirect calorimetry (Parvo Medics TrueOne ® 2400, Sandy City, UT, USA) in response to incre- mental treadmill running (Trackmaster, Newton, KS, USA). Flow and gas calibrations were performed prior to each test using standard operating procedures provided by the manufacturer. Participants were tted with a mask attached to falconia tubing, which was attached to the metabolic cart to collect expired gases. They were also tted with a chest strap (Polar, Lake Success, NY) to monitor heart rate throughout the test. The treadmill was set to an initial incline of one percent grade, as one percent

This study investigates the effects of acetaminophen on running economy and performance in collegiate distance runners.