Comparison of the spinal actions of the mu-opioid remifentanil with alfentanil and morphine in the rat.
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 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 ED50 in micrograms) was remifentanil (0.7) > morphine (12.0) > alfentanil (16.3) > GR90291, principal remifentanil metabolite (> 810 micrograms). 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 micrograms) 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.
Buerkle
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Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Yaksh
T L
TL
D015760:Alfentanil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000698:Analgesia / Q000009:adverse effects / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D009619:Nociceptors / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects* / Q000648:ultrastructure
D000701:Analgesics, Opioid; D014677:Pharmaceutical Vehicles; D010880:Piperidines; D017450:Receptors, Opioid, mu; D015760:Alfentanil; D009020:Morphine; D000077208:Remifentanil