Using fMRI to Quantify the Time Dependence of Remifentanil Analgesia in the Human Brain

Abstract

To understand and exploit centrally acting drugs requires reliable measures of their time course of action in the human brain. Functional magnetic resonance imaging (fMRI) is able to measure noninvasively, drug-induced changes in task-related brain activity. Here, we have characterized, in a specific region of the brain, the time of onset of action and the half-life of action of a clinically relevant dose of a potent opioid analgesic agent, remifentanil. These times were established from the temporal variation of the amplitude of the blood oxygen level-dependent response in the insular cortex contralateral to a painfully hot thermal stimulus, in volunteers receiving a remifentanil infusion. The insular cortex has repeatedly been reported as activated by noxious thermal stimulation. The times of onset and offset of drug action were each characterized by a half-life for changes in fMRI signal from within the insula. These characteristic times agreed with the observed drug-induced analgesia and previous pharmacokinetic-pharmacodynamic measurements for remifentanil. We have successfully measured, for the first time using fMRI, temporal pharmacological parameters for a CNS-active drug based on its effect on task-related activity in a specific brain region. Comparison of the time course of regional brain activity with pain perception could reveal those regions engaged in drug-induced analgesia.

Neuroimaging as a Tool for Pain Diagnosis and Analgesic Development

“…59 -62 Functional neuroimaging can be also used to study the pharmacodynamics and pharmacokinetics of analgesic drugs. 63 Furthermore, imaging is a tool that can improve or clarify our understanding of the likely mechanism of action of approved analgesic drugs, as well as their side effect profiles, such as the study on the capsaicin-evoked sensitization model and gabapentin by Iannetti et al 38 Moreover, and as previously mentioned, neuroimaging is useful for translation and reverse translation between preclinical models, healthy volunteer models, and patients, 64 as illustrated in FIG. 1.…”

Role of Neuroimaging in Analgesic Drug Development

“…Using the insular cortical time course together with a simple pharmacokinetic model, they predicted the half-life of activity of remifentanil. They demonstrated reductions in BOLD activity in the right insula during remifentanil administration as compared to saline [34,35]. Their work provided important insights and support the concept that pharmacologic fMRI (phfMRI) can be used to investigate both the central neural systems correlates of analgesia and its time course.…”

“…In their paper, they estimated the effect site concentration of remifentanil to identify pharmacologic modulation of evoked pain. They extended this study to use fMRI to monitor the time course of actions of remifentanil in the insula of healthy volunteers during evoked pain [35]. Using the insular cortical time course together with a simple pharmacokinetic model, they predicted the half-life of activity of remifentanil.…”

Intravenous patient-controlled analgesia with remifentanil in early labour

“…In healthy volunteers, the analgesic effect appeared to be reduced to a half in 6 minutes (Glass et al 1993). In a fMRI study, Wise et al (2004) noted a somewhat shorter half time for the offset of the action (3.07 minutes). After termination of the drug infusion, a 50% recovery in minute ventilation was observed in 5.4 minutes (Kapila et al 1995).…”

“…Functional MRI has been employed to identify the locus where the blood-oxygen-leveldependent (BOLD) signal caused by somatic pain is reduced by an administration of systemic analgesic medication (Wise et al 2004). The activation of localised µ-receptor activated systems has been observed with positron emission tomography (PET) -scans using a µ-receptor-specific radiotracer.…”