Anesth Analg 2003;97:1211-1213
© 2003 International Anesthesia Research Society
EDITORIAL
The Site of Action of Epidural Fentanyl: What Can Be Learned by Studying the Difference Between Infusion and Bolus Administration? The Importance of History, One Hopes
Laurence E. Mather, PhD FANZCA, FRCA, and
Michael J. Cousins, MD FANZCA, FRCA, FFPMANZCA, FAChPM (RACP)
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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Figure 1. Simulated plasma fentanyl concentrations in a typical healthy male subject with the dosage regimens used by Ginosar et al. Based on data from Mather et al. (12) with an assumed average absorption half-life of fentanyl of 10 min after epidural administration.
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Another issue is in the interpretation of drug plasma concentration-effect data. From the data presented, the authors claimed that there was no significant relationship between the analgetic effect measures and the plasma fentanyl concentration after bolus, but a significant linear relation was demonstrated after infusion. Indeed, this is apparent from the data presented. The data from bolus administration varied over a much smaller range than those after infusion, with the majority of fentanyl concentrations being less than those found to be analgetic when infused IV in a patient-controlled analgesia (PCA) paradigm (10,11). Conversely, the median fentanyl plasma concentrations from infusion range well into the measured "analgetic concentrations." Moreover, countless studies have now shown, with a variety of opioids, both a steep drug plasma concentration-effect curve and between-subject differences in drug plasma concentration-analgesic effect that varies some eight-fold (10,11). When a sigmoidal relationship at a receptor level pertains, the finding of a linear relationship between fentanyl plasma concentration and effect is experiment phenomenology, not pharmacology. Thus, treating the data as a combined set is fraught with danger, especially when again considered with the reinforcement of the dual sites argument. Without some individual subject calibration of effect against plasma fentanyl concentration, these data, regrettably, also do not provide definitive data for the case for a predominant systemic effect from infusion but a predominant spinal effect from bolus.
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
- Cousins MJ, Mather LE, Glynn CJ, et al. Selective spinal analgesia. Lancet 1979; 1: 1141–2.[Web of Science][Medline]
- Glynn CJ, Mather LE, Cousins MJ, et al. Peridural meperidine in humans: analgetic response, pharmacokinetics and transmission into CSF. Anesthesiology 1981; 55: 520–6.[Web of Science][Medline]
- Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61: 276–309.[Web of Science][Medline]
- Gourlay GK, Murphy TM, Plummer JL, et al. Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous injection. Pain 1989; 38: 253–9.[Web of Science][Medline]
- Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl in humans: the difference between infusion and bolus administration. Anesth Analg 2003; 97: 1428–38.[Abstract/Free Full Text]
- Ginosar Y, Columb MO, Cohen SE, et al. The site of action of epidural fentanyl infusions in the presence of local anesthetics: a minimum local analgesic concentration infusion study in nulliparous labor. Anesth Analg 2003; 97: 1439–45.[Abstract/Free Full Text]
- Tucker GT, Mather LE. Properties, absorption and disposition of local anesthetics. In: Cousins MJ, Bridenbaugh PO, eds. Neural blockade. 3rd ed. Lippincott: Philadelphia, 1998: 55–95.
- Yeung JC, Rudy TA. Sites of antinociceptive action of systemically injected morphine: involvement of supraspinal loci as revealed by intracerebroventricular injection of naloxone. J Pharmacol Exp Ther 1980; 215: 626–32.[Abstract/Free Full Text]
- Yeung JC, Rudy TA. Multiplicative interaction between narcotic agonisms expressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebroventricular injections of morphine. J Pharmacol Exp Ther 1980; 215: 633–42.[Abstract/Free Full Text]
- Gourlay GK, Kowalski SR, Plummer JL, et al. Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain Anesth Analg 1988; 67: 329–37.[Abstract/Free Full Text]
- Woodhouse A, Mather LE. The minimum effective concentration (MEC) of opioids: a revisitation with PCA fentanyl. Reg Anesth Pain Med 2000; 25: 259–67.[Web of Science][Medline]
- Mather LE, Woodhouse A, Ward ME, et al. Pulmonary administration of aerosolised fentanyl: pharmacokinetic evaluation of systemic delivery. Brit J Clin Pharmacol 1998; 46: 37–43.[Web of Science][Medline]
Accepted for publication August 13, 2003.
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