Because all processed Electroencephalography-Depth Of Anesthesia (pEEG-DOA) monitors data acquisition is limited to the frontal lobe activity where most pEEG-DOA sensors are placed, this basically denies anesthesiologists the ability to judge events happening in deep cortical regions. A major limitation of the pEEG-DOA devices is the fact that monitoring is confined to the frontal lobe area and does not penetrate deep subcortical structures that could detect noxious stimulation. Furthermore, each anesthetic agent is uniquely characterized by its own spatial electroencephalography (EEG) distribution and evolution. The β activity “frontal predominance” is eventually superseded by an increase in δ and θ low-frequency activities migrating anteriorly in the “anteriorization” phenomena topographic pattern as the anesthesia deepens. Even though opioids do not significantly change the cortical EEG when given in the usual clinical doses because hypnotics and opioids exert their actions at totally different sites, opioids could still influence pEEG-DOA indices in another peculiar fashion known as the “Opioids First Effect”. Several studies have demonstrated that the addition of a μ-agonist opioid to target controlled infusion (TCI) propofol results in loss of consciousness (LOC) at significantly lower propofol effect site concentration (Ce) and as a result at higher Bispectral Index values. In many instances, Bispectral Index changes could be a sensitive indicator of painful stimulation, because when Bispectral Index values suddenly rise in response to noxious stimuli such as endotracheal intubation and laryngoscopy that are far more painful than surgical skin incision, this is a “cortical arousal” reflex as a result of insufficient antinociception component of the general anesthesia that would require increasing the component opioid and not the hypnotic anesthetic. Blunting the noxious stimulation is another mechanism by which opioids could directly influence pEEG-DOA monitoring through blunting or attenuating the pEEG-DOA “cortical arousal” responses to noxious stimuli, the so-called “Opioids Second Effect.”