Anesthesia-assisted opioid detoxification offers an opportunity for patients who have undergone unsuccessful conventional detoxifications. Little is known of excitatory effects taking place in the central nervous system during this procedure. Because acute withdrawal is accompanied by N-methyl-d-aspartic acid (NMDA)-receptor activation we tested whether the administration of the nonspecific N-methyl-d-aspartic acid antagonist S(+)-ketamine results in a reduction of hyperactivity in the central nervous system. Thirty-one patients with a long history of opioid abuse were acutely withdrawn with naltrexone during propofol/clonidine anesthesia and mechanical ventilation. Electroencephalogram (EEG) power spectra as well as median nerve-evoked somatosensory potentials (SSEP) were determined at the following times: evening before detoxification (control), steady-state propofol/clonidine-anesthesia, 30 min after naltrexone administration, and 5 min and 60 min after additional S(+)-ketamine (1.5 mg/kg). Compared to steady-state anesthesia, naltrexone induced a decrease by 270% in the low δ (0.5–3 Hz) and an increase by 110% in the fast β (13–30 Hz) domain of the EEG with only minor changes in the θ-(3–7 Hz) and α-(7–13 Hz) band. Simultaneously, mean amplitude of the late N100 peak of the SSEP increased from 3.3 μV to 10.5 μV. The changes could be attenuated by the additional administration of S(+)-ketamine, 5 min and 60 min after injection. Cardiovascular changes were not a reliable index for monitoring acute withdrawal symptoms and determining termination of rapid opioid detoxification. In this regard, EEG power spectra and SSEP were more consistent and clinically useful variables. S(+)-ketamine is a valuable adjunct in the anesthetic regimen, since it attenuates hyperactivity of the central nervous system during rapid opioid detoxification.