To the Editor:—

In his editorial, Eisenach 1highlighted an interesting paradox; while attempting to produce profound analgesia with high doses of potent opioids, it is possible to produce a “preemptive hyperalgesic” effect. In the two human studies referenced, 2,3high doses of systemic remifentanil and fentanyl produced acute hyperalgesia.

In a previous human study, we found evidence that intrathecal fentanyl administration can produce acute spinal hyperalgesia. 4Administration of 25 μg intrathecal fentanyl during Cesarean section increased postoperative intravenous morphine requirements by 63% between 6 and 23 h postdelivery.

In his editorial, Bernards 5mentions his concern that “alfentanil and sufentanil (and to some extent fentanyl)” are used in the epidural space, “…despite mounting evidence that these opioids do not produce analgesia by a selective spinal mechanism.” However, there is evidence that epidural fentanyl, when it is administered in the minimal effective dose, has a selective spinal action. 6–10 

In humans, 11lumbar cerebrospinal fluid levels of fentanyl increase rapidly after epidural fentanyl administration, and Bernards and Sorkin 12have shown that, in pigs, “epidural fentanyl moves rapidly from the epidural space to the spinal cord.” Prolonged postoperative epidural fentanyl administration can produce plasma levels similar to those of systemic administration. 13However, spinal cord levels of fentanyl still would be expected to be higher after epidural than after systemic administration. It is therefore surprising that the analgesic effectiveness of epidural and systemic fentanyl often are reported to be comparable, even if plasma levels are similar. This is especially so if, as suggested by Bernards, 5there is synergy between spinal and supraspinal opioid analgesia in humans.

It may be that, by producing relatively high spinal compared with systemic levels of fentanyl, epidural fentanyl administration can induce acute selective spinal hyperalgesia. The greater the magnitude of selective spinal hyperalgesia induced, the smaller the difference in analgesic effectiveness of epidural and systemic fentanyl would be. This could help to explain why several studies have not found a difference between epidural and systemic fentanyl analgesia. Administration of epidural fentanyl in the minimal effective dose may limit the development of spinal hyperalgesia, thereby facilitating selective spinal analgesia.

Eisenach JC: Preemptive hyperalgesia, not analgesia? A nesthesiology 2000; 92: 308–9
Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11
Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST: Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7
Cooper DW, Lindsay SL, Ryall DM, Kokri MS, Eldabe SS, Lear GA: Does intrathecal fentanyl produce acute cross-tolerance to i.v. morphine? Br J Anaesth 1997; 78: 311–3
Bernards CM: Rostral spread of epidural morphine. A nesthesiology 2000; 92: 299–301
Salomaki TE, Laitinen JO, Nuutinen LS: A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after thoracotomy. A nesthesiology 1991; 75: 790–5
Grant RP, Dolman JF, Harper JA, White SA, Parsons DG, Evans KG, Merrick CP: Patient-controlled lumbar epidural fentanyl compared with patient-controlled intravenous fentanyl for post-thoracotomy pain. Can J Anaesth 1992; 39: 214–9
Cooper DW, Ryall DM, Desira WR: Extradural fentanyl for postoperative analgesia: predominant spinal or systemic action? Br J Anaesth 1995; 74: 184–7
Ngan Kee WD, Lam KK, Chen PP, Gin T: Comparison of patient-controlled epidural analgesia with patient-controlled intravenous analgesia using pethidine or fentanyl. Anaesth Intensive Care 1997; 25: 126–32
D’Angelo R, Gerancher JC, Eisenach JC, Raphael BL: Epidural fentanyl produces labor analgesia by a spinal mechanism. A nesthesiology 1998; 88: 1519–23
Gourlay GK, Murphy TM, Plummer JL, Kowalski SR, Cherry DA, Cousins MJ: Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration. Pain 1989; 38: 253–9
Bernards CM, Sorkin LS: Radicular artery blood flow does not redistribute fentanyl from the epidural space to the spinal cord. A nesthesiology 1994; 80: 872–8
de Leon-Casasola OA, Lema MJ: Postoperative epidural opioid analgesia: What are the choices? Anesth Analg 1996; 83: 867–75