Comparison of the Spinal Actions of the micro‐Opioid Remifentanil with Alfentanil and Morphine in the Rat

Background micro‐Opioids administered spinally produce a potent, dose‐dependent analgesic response in preclinical and clinical investigations. Side‐effect profile of these compounds may be altered as a function of pharmacokinetics. The effects of intrathecal and intraperitoneal remifentanil, an esterase‐metabolized micro opioid, alfentanil, and morphine were compared. Methods Intrathecal and intraperitoneal remifentanil, alfentanil, and morphine were examined in rats tested for hind‐paw thermal withdrawal latency. The antinociceptive response was assessed and in parallel a scoring of four different parameters summarized as a supraspinal index to assess supraspinal side‐effect profiles after the several drugs were delivered by the different routes. Results All opioids produced a dose‐dependent analgesic response after intrathecal administration. The ordering of potency (intrathecal ED sub 50 in micro gram) was remifentanil (0.7) > morphine (12.0) > alfentanil (16.3) > GR90291, principal remifentanil metabolite (> 810 micro gram). Time until onset of analgesia after intrathecal or intraperitoneal delivery was morphine > remifentanil = alfentanil. When matched for analgesic effect, the relative duration of action was morphine >> alfentanil > remifentanil. The supraspinal index showed a dose‐dependent increase for all agents. All intraperitoneal drugs showed dose‐dependent increases in antinociception with potency (intraperitoneal ED50 in micro gram) of remifentanil (4.3) > alfentanil (24.4) > morphine (262). Calculation of intrathecal or intraperitoneal ratios for supraspinal side effects/analgesia (supraspinal index ED50 /analgesia ED50) revealed remifentanil to be greatest when intrathecally administered: remifentanil (4 intrathecal: 1.4 intraperitoneal); alfentanil (0.7 intrathecal: 1.5 intraperitoneal); and morphine (1 intrathecal: 5.6 intraperitoneal). Conclusions These observations indicate that remifentanil has a powerful spinal opioid action. Consistent with its lipid‐solubility, it has an early onset like alfentanil but displays a shorter duration of action after bolus delivery. Despite lipid solubility, remifentanil has a significant spinal therapeutic ratio. These observations likely reflect the rapid inactivation of systemically redistributed agent by plasma esterases.

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