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Pain Management and Research Institute, University of Sydney at Royal North Shore Hospital, Sydney, Australia
Address correspondence to Professor Laurence E. Mather, PhD, FANZCA, FRCA, Pain Management Research Institute, University of Sydney at Royal North Shore Hospital, Sydney, NSW 2065, Australia. Address e-mail to lmather{at}med.usyd.edu.au
It is now approaching a quarter of a century since "selective spinal analgesia" was suggested as a goal for the spinal administration of opioids (1). In an ensuing study of epidural meperidine, each patient received the same bolus dose of meperidine (100 mg) IV and epidurally on separate occasions. This study permitted within-subject comparisons of cerebrospinal fluid (CSF) and blood meperidine concentrations after the two routes of administration, in parallel with analgetic response (2). The rigorous study design permitted a clear conclusion that, at early time points, part of the analgetic effect of meperidine was due to CSF-borne drug, presumably acting at the spinal cord. However, at later time points, blood-borne meperidine reached analgetic blood concentrations in some patients, presumably resulting in multimodal analgesia (3). The same group subsequently measured blood, as well as lumbar and cervical CSF concentrations of fentanyl after an epidural fentanyl bolus dose (100 µg); fentanyl concentrations were found to be large in lumbar CSF, negligible in cervical CSF, and small in blood (4). This study, in patients with severe back pain, suggested that single bolus doses of fentanyl exerted a localized spinal analgetic effect. It is extraordinary that at this late stage there is no clear evidence as to whether epidural fentanyl bolus or infusion exert predominantly spinal or supraspinal analgesia.
The studies by Ginosar et al. (5,6) in this issue of Anesthesia & Analgesia provide an inventive attempt to solve an often asked and still controversial question: Does epidurally administered fentanyl act locally, on spinal opioid receptors, or systemically, on supraspinal opioid receptors? While the authors have framed their paper, in many places, in terms of an either/or dichotomy, they have set out to test a milder hypothesis that the analgetic effect observed with two pain stimulus models in healthy volunteers after the epidural administration of fentanyl is predominantly mediated by a spinal mechanism if the drug is injected as a bolus, and by a supraspinal mechanism if infused. Indeed, the experimental results obtained support this hypothesis - QED! Or do they?
Some pharmacokinetic-pharmacodynamic reasoning is appropriately used by the authors in interpreting the results, hence some further background is relevant. It is sensible not to think of supraspinal and spinal mechanisms in terms of a dichotomy. Despite commentary about lipophilic drugs like fentanyl distributing into epidural fat, countless studies with epidurally injected opioids and local anesthetics (remember that fentanyl and bupivacaine have similar physicochemical properties) have demonstrated that systemically absorbed drug has a similar blood concentration profile to that after IM injection. The biphasic absorption patterns found can be interpreted as a "portion" of the dose being absorbed reasonably rapidly with a half-life of around 5 to 10 min, generating the "peak" arterial blood concentration at around 10 min after injection. The remaining "portion," presumably that distributed into fatty tissues, is absorbed more slowly with a half-life of several hours, thereby sustaining the blood drug concentrations compared with IV drug administration. Blood-borne drug will thus be delivered to both supraspinal and spinal receptor sites in proportion to the distribution of cardiac output, in addition to drug delivered by local mechanisms of bulk flow and diffusion (3,4,7). Although the amount of blood-borne drug delivered supraspinally may be small after epidural compared with IV injection, one has to remember, as pointed out in the early days of spinal opioid pharmacology, that the dual spinal and supraspinal opioid actions have a reinforcing action that is relevant both for agonism and antagonism (8,9). The dual actions can be thought of as producing multimodal analgesia, but, clearly, the amount of drug delivered to each region is still important in the overall effect.
Ginosaur et al. used a crossover design in healthy volunteers with bolus and infusions of fentanyl in their attempt to distinguish between the spinal and supraspinal antinociceptive effects in response to phasic painful stimuli. We have no quibble with the results or their interpretation. The results support a segmental spinal effect of epidural fentanyl bolus administration and a nonsegmental dual spinal and supraspinal effect of epidural fentanyl infusion. However, the dose administered by infusion was three times that administered by bolus in an attempt to maintain similar levels of antinociception when tested in the leg. Not surprisingly, the plasma fentanyl concentration was several times larger after infusion than after bolus with both the smaller and larger doses, and this is illustrated by the time course of plasma fentanyl concentrations generated by pharmacokinetic simulation shown in Figure 1. However, given the reinforcement of dual sites argument, it is not possible to differentiate between modes of administration without considering the difference in magnitude of plasma drug concentrations.
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To us, a preferred research plan would be to determine whether an intramuscular injection or an IV infusion designed to mimic the plasma fentanyl concentrations from epidural administration would reproduce the analgesia of epidural administration, but without the side effects. On the other hand, the present study could have also compared intrathecal and IV administration or, if this could not have been incorporated into the same subjects, to have made this comparison instead of the design used. Such experiments would bring us closer to answering this still controversial question.
References
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