Remifentanil by bolus injection: a safety, pharmacokinetic, pharmacodynamic, and age effect investigation in human volunteers

Background. Although remifentanil’s short-acting pharmacokineticprofile makes it well suited for procedures during which a briefperiod of intense analgesia is required, setting up an infusionpump for brief procedures is inconvenient. The clinical pharmacologyof remifentanil administered by bolus injection, a more convenientalternative, has not been explored in detail. The primary aimof this study was to examine the safety of single bolus dosesof remifentanil in conscious, healthy, adult volunteers breathingroom air. Secondary aims included the evaluation of remifentanilpharmacokinetics and analgesic effects after bolus injectionand a comparison of these issues in younger vs older adults. Methods. Using a randomized, double-blind, placebo-controlled,dose-escalation, crossover study design, 64 subjects (16 over60 years old) received remifentanil or placebo by bolus injectionin a fixed unit dose separated by a 1 h washout period. Respiratoryeffects were assessed using a respiratory intervention scale.Analgesic effects were assessed using pressure algometry. Apopulation pharmacokinetic model was constructed using non-linear,mixed-effects modelling techniques based on arterial blood samples.Computer simulations were performed to illustrate the clinicalapplication of the pharmacokinetic model. Results. Dose-related increases in both respiratory and analgesiceffects were observed. In general, the respiratory depressionobserved was mild and easily treated with requests to breatheor the administration of oxygen, although the older cohort (andsome younger subjects) experienced more substantial respiratorydepression at lower doses. The pharmacokinetics of bolus-doseremifentanil were adequately described by a two-compartmentmodel. The pharmacokinetic simulations illustrated the potentialutility of bolus-dose remifentanil. Conclusions. Bolus injection could potentially be a safe andeffective means of administering remifentanil in clinical situationsrequiring a brief period of intense analgesia. Because somesubjects, both old and young, experienced significant respiratorydepression even at low doses, careful monitoring of respiratoryfunction is essential. Br J Anaesth 2004; 92: 335–43