Background: mu-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 mu opioid, alfentanil, and morphine were compared. Methods: Intrathecal and intraperitoneal remifentanll, alfentanil, and morphine were examined in rats tested for hindpaw 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(50) in mu g) was remifentanil (0.7) > morphine (12.0)> alfentanil (16.3) > GR90291, principal remifentanil metabolite (>810 mu g). Time until onset of analgesia after intrathecal or intraperitoneal delivery was morphine > remifentanil = alfentanil. When matched for analgesis 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 ED(50) in mu g) of remifentanil (4.3) > alfentanil (24.4) > morphine (262). Calculation of Intrathecal or Intraperitoneal ratios for supraspinal side effects/analgesia (supraspinal index ED(50)/analgesia ED(50)) 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.
