HEMODYNAMIC AND ANALGESIC ACTIONS OF EPIDURALLY ADMINISTERED CLONIDINE

Background: Alpha2-Adrenergic agonists such as clonidine produce behavioral analgesia and cardiovascular depression in animals, but clonidine's site of action in clinical analgesia and cerebrospinal fluid (CSF) pharmacokinetics have not been defined. Methods: Clonidine was administered in the lumbar epidural space to nine volunteers while monitoring blood pressure, heart rate, finger and toe blood flow, and response to cold pain testing, and while sampling CSF and arterial plasma for clonidine analysis. Effects were correlated to plasma and CSF clonidine concentrations. Ten other volunteers received stepped intravenous infusions of the opioid alfentanil with similar testing. Results: Clonidine decreased pain report in the foot but not the hand, and this effect correlated stronger with CSF than with plasma clonidine, suggesting a spinal site for analgesia. Extrapolation of CSF clonidine pharmacokinetics suggests the minimum effective CSF clonidine concentration for postoperative pain relief is 76 +/- 15 ng/ml. Clonidine increased finger and toe blood flow, decreased blood pressure and heart rate, produced sedation, and mildly increased arterial P(CO2) in most cases correlating better with plasma than CSF clonidine concentrations, suggesting actions at central sites. In 10 other volunteers, intravenous infusion of the opioid alfentanil produced analgesia of similar intensity to clonidine but was accompanied by significant respiratory depression. Conclusions. These data support previous studies in animals and provide the scientific rationale for this novel analgesic therapy. In comparison to the potent opioid alfentanil, epidural clonidine produces a similar degree of analgesia but less respiratory depression.