In Reply:—

Dr. Cooper’s letter suggests the possibility that opioid-induced hyperalgesia may explain those studies that have not found evidence of selective spinal analgesia after epidural administration of some opioids (particularly fentanyl). The suggestion is interesting, and, as Dr. Cooper points out, data indirectly support his supposition. However, I think this may be an example of showcasing data that support an argument, while, at the same time, ignoring inconsistent data. For example, Dr. Cooper mentions that Eisenach cited two studies 1,2in his editorial 3that support his position; however, Dr. Cooper ignored two other human studies in the same editorial that are antithetical to his position. 4,5In addition, Dr. Cooper states “Bernards and Sorkin 6have shown that, in pigs, ‘epidural fentanyl moves rapidly from the epidural space to the spinal cord.”’ This misses the point that it is the bioavailability of fentanyl at opioid receptors in the spinal cord gray matter that determines its spinal effectiveness. In this regard, a recent study by Ummenhofer et al.  7and a classic study by Schubert et al.  8showed that the bioavailability of fentanyl in spinal cord gray matter is poor. Also, it is by no means clear that fentanyl concentrations at spinal cord opioid receptors would “be expected to be higher after epidural than after systemic administration,” even though the dose needed for analgesia and the resultant plasma concentration have been shown by multiple (though not all) studies to be equivalent by both routes of administration. 9–13This is likely because systemic administration delivers fentanyl to within a few microns of its target site. In contrast, epidural administration delivers the drug several centimeters away from the spinal target site and necessitates that the drug traverse multiple barriers and negotiate several lipophilic environments (e.g. , epidural fat, white matter myelin) into which it can be sequestered and rendered unavailable at opioid receptors. Therefore, administration of a drug in the epidural or intrathecal space does not ensure that it will reach its target site in the spinal cord in high concentration. This is exactly what Ummenhofer et al.  7and Schubert et al.  8demonstrated. Last, Dr. Cooper has offered no explanation for why other opioids (e.g. , morphine) clearly have a long-lasting selective spinal site of action after epidural administration, which is inconsistent with the idea that opioid binding to spinal opioid receptors produces acute hyperalgesia.

Cooper’s suggestion that epidural fentanyl might induce an acute hyperalgesic state is interesting and provocative. There are data that would seem to support it; however, there is also a significant amount of data that does not support it. We are left with a question in need of interesting, well-designed, human studies to decide the issue.

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
Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11
Eisenach JC: Preemptive hyperalgesia, not analgesia? [editorial; comment]. A nesthesiology 2000; 92: 308–9
Tverskoy M, Oz Y, Isakson A, Finger J, Bradley EL Jr, Kissin I: Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia (comments). Anesth Analg 1994; 78: 205–9
Katz J, Clairoux M, Redahan C, Kavanagh BP, Carroll S, Nierenberg H, Jackson M, Beattie J, Taddio A, Sandler AN: High dose alfentanil pre-empts pain after abdominal hysterectomy. Pain 1996; 68: 109–18
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
Ummenhofer WC, Arends RH, Shen DD, Bernards CM: Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil (comments). A nesthesiology 2000; 92: 739–53
Schubert P, Teschemacher H, Kreutzberg G, Herz A: Intracerebral distribution pattern of radioactive morphine and morphine-like drugs after intraventricular and intrathecal injection. Histochemie 1970; 22: 277–88
Guinard JP, Mavrocordatos P, Chiolero R, Carpenter RL: A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy (comments). A nesthesiology 1992; 77: 1108–15
Guinard JP, Carpenter RL, Chassot PG: Epidural and intravenous fentanyl produce equivalent effects during major surgery. A nesthesiology 1995; 82: 377–82
Loper KA, Ready LB, Downey M, Sandler AN, Nessly M, Rapp S, Badner N: Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery (comments). Anesth Analg 1990; 70: 72–5
Ellis DJ, Millar WL, Reisner LS: A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after cesarean section (comments). A nesthesiology 1990; 72: 981–6
Glass PS, Estok P, Ginsberg B, Goldberg JS, Sladen RN: Use of patient-controlled analgesia to compare the efficacy of epidural to intravenous fentanyl administration (comments). Anesth Analg 1992; 74: 345–51