Caffeine but not acetaminophen increases 4-km cycling time-trial performance

Acetaminophen has been combined with caffeine for therapeutic purpose, but the effect of co-ingestion of acetaminophen and caffeine on exercise performance has not been investigated. The aim of this study was to determine the effect of isolated and combined ingestion of caffeine and acetaminophen on performance during a 4-km cycling time-trial. In a double-blind, crossover design, eleven men, accustomed to cycling recreationally, completed a 4-km cycling time-trial one hour after the ingestion of cellulose (PLA), acetaminophen (20 mg·kg−1 body mass, ACT), caffeine (5 mg·kg−1 body mass, CAF) or combined acetaminophen and caffeine (20 and 5 mg·kg−1 body mass, respectively, ACTCAF). The perception of pain and rating of perceived exertion were recorded every 1-km, and electromyography and oxygen uptake were continually recorded and averaged each 1-km. Plasma lactate concentration was measured before and immediately after the trial. The time and mean power during the 4-km cycling time-trial was significantly improved (P < 0.05) in CAF (407.9 ± 24.5 s, 241.4 ± 16.1 W) compared to PLA (416.1 ± 34.1 s, 234.1 ± 19.2 W) and ACT (416.2 ± 26.6 s, 235.8 ± 19.7 W). However, there was no difference between ACTCAF (411.6 ± 27.7 s, 238.7 ± 18.7 W) and the other conditions (P > 0.05). The perception of pain, rating of perceived exertion, electromyography, oxygen uptake, and plasma lactate were similar across the conditions (P > 0.05). In conclusion, caffeine but not acetaminophen increases power output ultimately increasing performance during a 4-km cycling time-trial.


56
During a self-paced, high-intensity cycling time-trial (e.g., 4-km cycling TT), the 57 exercise intensity must be strictly regulated to avoid an exacerbated early accumulation of 58 metabolites that can lead to fatigue [1][2][3]. A disturbance in the intramuscular metabolic milieu 59 (i.e., accumulation of the H + , ADP, AMP and Pi) at the beginning of a high-intensity cycling Acetaminophen (commonly known as paracetamol) has recently been introduced as a 66 potential pharmacological agent to increase exercise performance due to its analgesic 67 proprieties [7-9]. The mechanism by which acetaminophen reliefs pain feelings in humans is 68 not fully known, but it has been attributed to the inhibition of the cyclooxygenase enzymes [10-69 13], potentiation of descending serotoninergic pathways [14,15], and modulation of opioid and 70 cannabinoid CB 1 receptors [11,16]. Although there is not a consensus [17,18], several studies 71 have reported improved performance during high-intensity exercises after a single clinical dose 72 (1-1.5 g or 20 mg . kg -1 ) of acetaminophen [7][8][9]19].

74
It is interesting to note that acetaminophen has been combined with caffeine for 75 therapeutic purpose [20,21], but the effect of co-ingestion of acetaminophen and caffeine on 76 exercise performance has not been investigated. The precise mechanism by which caffeine 77 assists acetaminophen in reduction of pain is not fully known, but caffeine might act as an 78 adenosine antagonist at the A 2 adenosine receptors of the peripheral sensorial nerves, blocking 79 adenosine-induced pain transmission [22]. The analgesic effect of caffeine may also involve 4 80 inhibition of presynaptic adenosine receptors on cholinergic nerve terminals in supraspinal sites 81 [23] and increased release of β-endorphin [24]. Although caffeine has other central and 82 peripheral mechanisms of action [25-28] potentially more prominent to exercise performance 83 than analgesia, it would be interesting to explore whether a combination of acetaminophen with 84 caffeine would improve exercise performance to a larger extent than when they are ingested in 85 isolation.

87
Therefore, the aim of the present study was to investigate the effect of isolated and 88 combined ingestion of acetaminophen and caffeine on performance during a 4-km cycling TT. 89 We hypothesized that exercise performance might improve to a larger extent when 90 acetaminophen and caffeine are combined, when compared to acetaminophen or caffeine alone.

121
The substances were encapsulated in capsules of the same colour and shape (Pharmapele ® , 122 Recife, PE, Brazil). Experimental trials were performed in a randomized, counterbalanced and 123 double-blind manner. A 7-day period between the four experimental trials was adopted for 124 washout. Participants were instructed to cover the 4-km cycling TT as fast as possible during 125 the trials and received visual feedback for distance completed, but not for exercise time, power 126 output, pedal frequency or physiological parameters. Participants were asked to refrain from 127 consuming caffeine-containing substances and from taking any analgesic medications as well 128 as to restrain from doing exercise during the 24h before each experimental trial. Participants were also asked to complete a 24-h food recall before the first experimental trial and to replicate 130 it in the following trials. Participants were inquired before trial whether they had adhered to 131 dietary intake and abstaining from caffeine and analgesic medications. All tests were performed 132 at the same time of day to avoid the circadian variation on TT performance [       improving exercise performance, when compared to placebo and acetaminophen alone.

231
However, this effect is lacking when caffeine is combined with acetaminophen. Acetaminophen 232 alone had no effect on exercise performance.

234
Acetaminophen alone 235 In the present study, the ingestion of acetaminophen alone (20 mg . kg -1 ) did not increase suggest that caffeine has a greater ergogenic potential than acetaminophen, at least during a 259 high-intensity cycling TT as used in the present study. The present study has some limitations that should be mentioned. We recruited 302 participants who did cycling recreationally, whose day-by-day variation may be greater than in 303 trained cyclists. However, participants performed four familiarization trials, which helped to 304 reduce the potential effect of learning. This assumption is supported by the low coefficient of 305 variation between the two "fresh" familiarization trials (~1.7%), which is very close to that In conclusion, acute caffeine ingestion but not acetaminophen increases cycling power 310 output, improving performance of a 4-km cycling TT. The acetaminophen seems, however, to 311 negatively affect the ergogenicity of caffeine. Therefore, the combined use of caffeine and 312 acetaminophen should be avoided. Data are shown as mean ± SD. *Significantly faster than PLA and ACT (P < 0.05).  higher than previous one (P < 0.05).