The opioid analgesics were originally referred to as the “narcotic analgesics,” and the term was applied only to drugs with both analgesic and sedative properties. Although the excitatory properties of opioids have always been recognized, their contribution to the opioid-induced changes in pain behavior, compared with sedative (depressive) properties, has generally been overlooked. In this issue of Anesthesia & Analgesia, Dogrul et al.(1) make an important contribution to the reassessment of the role of enhanced, stimulus-evoked excitatory transmission in the effects of opioids on pain behavior. Their results suggest that blockade of the calcium channels prevents opioid-induced hyperalgesia and the expression of antinociceptive tolerance to spinal morphine, presumably by reducing stimulus-induced excitatory neurotransmitter release. This suggestion is consistent with evidence previously presented by these and other authors indicating that opioids can induce longlasting hyperalgesia and enhanced pain (2, 3). One of the hypotheses presented by Dogrul et al. is related to antinociceptive tolerance. They suggested that the tolerance observed in their experiments was a consequence of the need for additional opioids to overcome the enhanced pain state to maintain a consistent level of antinociception. They induced tolerance in mice by intrathecal injections of morphine (10 μg twice daily for 8 days). This treatment shifted the dose-response curve for the analgesic effect of intrathecal morphine 17-fold to the right along the dose axis. Such a profound decrease in the sensitivity to an opioid in tolerant animals is not unusual. For example, the dose-response curve for morphine analgesia (intrathecal injections) in rats was shifted 55-fold to the right by a 7-day intrathecal infusion of the drug (4). In another example, the implantation of morphine pellets in rats resulted in the development of a profound chronic tolerance: a 10-fold increase in the analgesic ED50 for morphine (5). In acute tolerance, sensitivity to the analgesic effect of opioids decreases much less—by approximately half of the initial effect (6).

There is a striking difference between the profound degree of chronic tolerance to the analgesic effect of opioids observed in animal models and the relative stability of the opioid dose-response relationship in patients with pain. Dose escalation is common in longterm opioid treatment for the management of cancer pain, but tumor growth could be the reason for this increase. When opioids began to be used for the treatment of chronic noncancer pain, it became clear that true pharmacologic tolerance to the analgesic effects of opioids is an uncommon reason for escalating the opioid dose to maintain analgesic effects (7). The recent systematic review of studies on this topic clearly demonstrated this point (8). These authors identified three studies with reliable information on the longterm use of opioids for noncancer pain. One study (9) did not observe tolerance in the majority of patients. Another study (10) concluded that no tolerance occurred over 3 mo. In a third study (11), only 4 of 30 patients needed an increase in opioid doses during 1 yr of follow-up. At the same time, in contrast to the situation in pain patients, the degrees of tolerance in an animal model and in humans are similar if the doses of opioids used by addicts were taken into consideration. The addict, for example, may ultimately use daily 20 to 200 times the ordinary therapeutic dose of opioid (12). Why is there such a profound difference between chronic tolerance to opioid analgesia in animal models and in patients with noncancer pain? Several explanations may be suggested. One is that pain may …