OBJECTIVES: The cessation of sedation in brain-injured patients may result in severe agitation and/or acute withdrawal syndrome related to the prolonged administration of large doses of benzodiazepines and/or opioids. The aim of the present study was to assess the clinical efficacy of a written protocol to withdraw sedation for these patients. STUDY DESIGN: Observational prospective study. PATIENTS AND METHODS: After approval by the Institutional Review Board, 40 severely brain-injured patients were included. They had received continuous administration of midazolam and sufentanil or fentanyl for median 15 days. On cessation of midazolam infusion, patients were given clorazepate for 3 days. On cessation of opioid infusion and clorazepate, clinical data were collected for 48 hours: heart rate, systolic blood pressure, respiratory rate, agitation, and pupil diameter. If an opioid withdrawal syndrome occurred, patients received a 48-hour continuous infusion of buprenorphine. RESULTS: Of 40 patients, there were 10 who did not require buprenorphine. An agitation occurred 5 hours (1-21) after cessation of opioid, associated with tachycardia, arterial hypertension, and tachypnea. After 6 hours buprenorphine treatment, these parameters were normalized. No patient needed the reintroduction of the initial sedation. CONCLUSION: The cessation of sedation in severely brain-injured patients can be successfully managed with the use of clorazepate, associated with buprenorphine in the presence of agitation.