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Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Address correspondence to Igor Kissin, MD, Department of Anesthesiology, Brigham and Women’s Hospital, Boston, MA 02115. Address e-mail to kissin{at}zeus.bwh.harvard.edu.
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 long-lasting 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 long-term 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 long-term 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 activate some antitolerance mechanisms (13). However, it was reported that the degree of tolerance in rats to the analgesic effect of opioids is more or less the same with or without inflammatory pain (14). Another explanation for this discrepancy between opioid tolerance in pain patients and in animal models could be based on the fundamental difference between measuring analgesia in human subjects and animals. In human subjects these measurements are based on the assessment of pain sensations reported by a subject. In rats, pain sensation is estimated indirectly through the animal’s pain behavior. Pain behavior (in contrast to pain sensation) has a psychomotor component in addition to a nociceptive component. Is it possible that, in rats, the psychomotor (not nociceptive) component of pain behavior is a dominant factor in measuring the development of tolerance, creating a profound difference between humans and animals? An approach to answer this question might be found by considering the two following developments.
Both developments are in the field of addiction. The first is the concept of "incentive-sensitization" (15). One point summarizing this concept is that brain reward systems sensitized to drug-associated stimuli do not mediate the pleasurable or euphoric effects (drug "liking") but instead mediate a component of reward termed "incentive salience" (drug "wanting"), which is specifically responsible for drug-seeking behavior. Thus, drug wanting, not drug liking, is the component of drug reward sensitized in addiction and can occur even if the patient likes the drug less and less. The second development is the wealth of evidence from experimental animals that the repeated administration of a variety of drugs of abuse, including opioids, progressively increases their psychomotor activating effects, such as enhancing locomotor activity, rotational behavior, and stereotyped motor pattern (16,17). This phenomenon, termed "behavioral sensitization," is thought to be similar to certain aspects of drug addiction. The excitatory effects of morphine in rats are moderate, brief, naloxone-sensitive, and usually masked by the depressive effect of larger morphine doses (18). With the development of sensitization to suppress the enhanced excitatory effects increasingly larger doses of morphine should be used.
The above evidence from the field of addiction makes it possible to suggest the following: Measurement of tolerance to the analgesic effect of opioid in animals is based on pain behavior that has a nociceptive component and a psychomotor component. The effect of morphine on psychomotor response to noxious stimuli, like all other excitatory responses, can be sensitized by repeated morphine administration and, as a result, larger doses of the drug are needed to overcome the sensitization process. The nociceptive component of pain behavior, as indicated by Dogrul et al., can also be sensitized. The question is what process is dominant with regard to the decrease in sensitivity to the analgesic effect of opioids in rats. The likely answer is that sensitization of the psychomotor component is the primary cause of the extraordinary degree of chronic tolerance observed in animal models. In pain patients, the psychomotor component does not play a significant role because the measurement of tolerance is based on the patient’s assessment of pain sensation rather than on the motor response to pain. Therefore, tolerance to opioids in pain patients is not as profound as that in animal experiments. On the other hand, the similarity between the extraordinary degree of tolerance to opioids in animal experiments based on pain behavior and in human addiction, may reflect a similarity in the underlying process of incentive-sensitization in addicts and sensitization of the psychomotor component of pain behavior in animals.
Dogrul et al. demonstrated that blockade of L-type voltage-dependent calcium channels with amlodipine prevented opioid-induced hyperalgesia and tolerance to spinal morphine. They suggested that these effects were attributable to the suppression of spinal sensitization of the excitatory nociceptive transmission. However, it was also demonstrated that L-type calcium channel blockers suppress sensitization to morphine-induced locomotor activity (19). Therefore, the effect of calcium channel blockers on the opioid tolerance in animal models may also be attributable to the elimination of sensitization to the psychomotor component of pain behavior.
As indicated in the title of this editorial, we are quite different from rats when tolerance to opioid analgesia is considered. However, we are not so different from them when we consider tolerance to the behavioral effects of opioids, "incentive-sensitization" in human addiction, and sensitization of psychomotor responses in rats. The above difference in analgesic tolerance indicates that our animal models for the study of pain are far from perfect. This point was excellently demonstrated in the recent article by Mogil and Crager (20) on indices of pain in chronic pain models. We probably should be equally cautious about pain tests in our tolerance models.
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