A control system for administration of a drug comprises a drug administration actuator for administering the drug to a patient at a controllable dosage; a monitor for measuring an effect of the drug on the patient; and a controller configured to determine a control signal to the drug administration actuator; wherein the controller is configured to implement a closed loop model-predictive control scheme comprising, for each of a series of time steps, minimizing a cost function subject to one or more constraints to determine the control signal, the cost function based at least in part on a reference level and the monitor measurement; wherein the control signal is used as an input to an auxiliary model to estimate at least one concentration level of the drug in the patient; and wherein the constraints comprise at least one constraint on the estimate of the concentration level of the drug.