Combination of tramadol 37.5 mg/paracetamol 325 mg (a), or codeine 30 mg/paracetamol 500 mg (b) or 300 mg have similar pain efficacy but a difference has been suggested concerning their adverse events on vigilance. In clinical practice, combinations are usually given at the above-mentioned dosage three to four times a day. The aim of this study was to compare a single dose of these two combinations (a) and (b) in 24 healthy young volunteers on visual choice reaction time (CRT, ms). Results show a longer CRT (P < 0.05) (up to 4% of the control value 3 h post-dosing) and a higher report of somnolence in the codeine/paracetamol group compared with tramadol/paracetamol group (50% vs. 4% of the subjects). This observation is important and proves that even a single dosage of these largely used drugs may have a significant effect. This finding should be further investigated in elderly subjects who consume largely these drugs for chronic pain alleviation and who are more prone to this kind of adverse event.