n Reply:—

For the study of preemptive analgesia, preincisional and postincisional groups or preincisional and post–skin-closure groups are sometimes compared. Nociception at skin incision (skin pain) may have a strong impact on central sensitization, as shown by Katz et al.  1However, nociception may also occur at any time during surgery, and intrasurgical nociception is also considered an important sensitizing factor (deep pain, including visceral pain). Therefore, postincisional analgesia may reduce central sensitization in control subjects. On the other hand, an analgesic administered after skin closure produces its effect after surgery, directly reducing postsurgical pain in control subjects. These observations suggest that postincisional as well as post–skin-closure groups are inadequate controls for studying preemptive analgesia. Consequently, we believed that eliminating the aftereffect of morphine in the preemptive group could be an appropriate control.

Naloxone is widely known to rapidly antagonize the effect of morphine, 2and this has been clearly evidenced in clinical practice. Opioid receptors are expressed on spinal cord neurons. Regardless of administration routes, intravenous or epidural, morphine binds to spinal opioid receptors, and naloxone displaces morphine from its binding sites, also irrespective of the administration route used.

In a recent investigation, the half-life of intrathecally administered morphine was shown to be approximately 2 h. Approximately 60% of the intra–spinal cord morphine was cleared into the systemic circulation. 3In our study, naloxone administered at the end of surgery may have efficiently accelerated the clearance of morphine and shortened its half-life. Furthermore, our dosage of epidural morphine was smaller than that of intravenous morphine. 4The onset of naloxone’s antagonistic effect is rapid, and the duration of the effect is short. 2Therefore, the aftereffect of morphine might be eliminated earlier, suggesting that postsurgical pain control might be achieved smoothly and that the aftereffect of morphine might be negligible at the first observation (6 h).

In our study, 4a statistically significant difference between the epidural morphine and combination (epidural morphine plus intravenous ketamine) groups was observed at every time point measured (6, 12, 24, and 48 h). In contrast, a significant difference between the epidural morphine and control groups was noted only at 24 and 48 h. The significant reduction in pain intensity with epidural morphine may be due to its preemptive effect (although not definitive) rather than to its aftereffect because morphine’s aftereffect must be evident at earlier time points (i.e. , 6 and 12 h).

Ketamine binds to N -methyl-d-aspartate receptors and blocks nociceptive impulses. As stated previously, morphine binds to opioid receptors and also blocks primary afferent nociception. We used the word blockade for nociceptive blockade. As pointed out by Sarantopoulos and Fassoulaki, blockade of N -methyl-d-aspartate receptors and stimulation of opioid receptors (dual blockade of nociception) might potentiate the preemptive analgesic effect, as mentioned in our article. 4 

On the other hand, in gastrectomy, by total nociceptive blockade (T4–L1) over the surgical area (20 ml mepivacaine, 2%, at 60-min intervals was used intermittently; blockade was verified by pin-prick test before general anesthesia), most primary afferents to the spinal cord were intercepted. However, definitive preemptive analgesia was not attained. This fact also suggests the vagal nociception in gastrectomy. However, definitive preemptive analgesia was also attained by concomitant intravenous low-dose ketamine (unpublished data).

Each group in our study received the same premedication and anesthesia. Therefore, premedicated drugs or anesthetics, including nitrous oxide, affected all groups, including the control group, equivalently. Nitrous oxide might have had an effect on nociception. However, the effect of nitrous oxide is small 5and may be negligible because in clinical anesthesia for surgery, analgesic intervention, such as analgesia with morphine or fentanyl, or epidural block, is usually required to avoid intrasurgical reaction to nociception. Thus, central sensitization is established during anesthesia with nitrous oxide.

Katz J, Kavanagh PB, Sandler AN, Nierenberg H, Boylan JF, Friedlander M, Shaw BF: Preemptive analgesia. A nesthesiology 1992; 77: 439–46
Ngai SH: Pharmacokinetics of naloxone in rats and in man: Basis for its potency and short duration of action. A nesthesiology 1976; 44: 398–401
Ummenhofer WC, Arends RH, Shen DD, Bernards CM: Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. A nesthesiology 2000; 92: 39–53
Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K: Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: A randomized double-blind study. A nesthesiology 2000; 92: 1642–30
Goto T, Marota JJA, Crosby G: Nitrous oxide induces preemptive analgesia in the rat that is antagonized by halothane. A nesthesiology 1994; 80: 409–16