Alterations in cortical causality information flow induced by remifentanil infusion in healthy volunteers was investigated in a placebo-controlled double-blind cross-over study. For each of the 21 enrolled male subjects, 2.5 minutes of resting electroencephalography (EEG) data were collected before and after infusion of remifentanil and placebo. Additionally, to assess cognitive function and analgesic effect, continuous reaction time (CRT) and bone pressure and heat pain were assessed, respectively. The causality information was extracted from the EEG by phase slope index (PSI). Among the features being reproducible between the two baseline recordings, several PSI features were altered by remifentanil administration in comparison to placebo. Furthermore, several of the PSI features altered by remifentanil were correlated to changes in both CRT and pain scores. The results indicate that remifentanil administration influence the information flow between several brain areas. Hence, the EEG causality approach offers the potential to assist in deciphering the cortical effects of remifentanil administration.