Opioid drugs disrupt signalling in the brainstem respiratory network affecting respiratory rhythm. We evaluated the influence of a steady state infusion of a model opioid, remifentanil, on respiratory variability during spontaneous respiration in a group of 11 healthy human volunteers. We used dynamic linear and nonlinear models to examine the effects of remifentanil upon both directions of the ventilatory loop, i.e. on the influence of natural variations in end-tidal carbon dioxide (PETCO₂) on ventilatory variability, which was assessed by tidal volume (V_T) and breath-to-breath ventilation (i.e., the ratio of tidal volume over total breath time V_T/T_TOT), and vice versa. Breath-by-breath recordings of expired CO₂ and respiration were made during a target-controlled infusion of remifentanil, for 15 minutes at estimated effect site (i.e. brain tissue) concentrations of 0, 0.7, 1.1, and 1.5 ng/ml respectively. Remifentanil caused a profound increase in the duration of expiration. The obtained models revealed a decrease in the strength of the dynamic effect of PETCO₂ variability on V_T (the "controller" part of the ventilatory loop) and a more pronounced increase in the effect of V_T variability upon PETCO₂ (the "plant" part of the loop). Nonlinear models explained these dynamic interrelationships better than linear models. Our approach allows detailed investigation of drug effects in the resting state at the systems level using non-invasive and minimally perturbing experimental protocols, which can closely represent real life clinical situations.