Clinical Implications

10.1. Chronic Pain

One of the most obvious possibilities for therapeutic intervention with NMDA receptor drugs is in the treatment of chronic pain. Because NMDA receptor antagonists have the ability to prevent the development of tolerance, sensitization, and physical dependence, these drugs may be useful adjuncts to opiates in situations in which long-term administration of opiates is necessary. Administration of an NMDA receptor antagonist together with an opiate should inhibit the development of tolerance, thereby allowing the opiate to maintain effectiveness for a greater period of time. The development of physical dependence is not typically considered to be a major problem in the treatment of chronic pain, as it can easily be managed by a well-trained physician. However, decreased physical dependence should offer reassurance to both patients and physicians overly concerned about "addiction" and decrease the time necessary to withdraw patients from opiates when necessary. Sensitization is not typically discussed in relation to chronic pain management. However, in theory, it is possible that sensitization to certain side effects of opiates may lead to their escalation during chronic administration. Inhibition of sensitization may, therefore, help to diminish the impact of such side effects in pain patients.

Other research, not discussed in the present review, suggests further uses for NMDA receptor antagonists in the treatment of pain. First, considerable evidence suggests that NMDA receptors may be involved in the development of sensitization to pain, in which pain increases in a pathological manner (17,22,136,137,176). NMDA receptor antagonists have the ability to inhibit such sensitization, providing for their potential use in situations in which pain sensitization may be expected to occur. Second, although the majority of evidence suggests that NMDA receptor antagonists do not affect the acute analgesic actions of opiates at doses that inhibit the development of tolerance (discussed earlier), some studies suggest that these drugs may, in fact, potentiate opiate analgesia (42,49,84,101,176-180). This potentiation is typically seen as a prolongation of opiate analgesia and is interpreted by most researchers as inhibition of the earliest phase of opiate tolerance (42,49,101,106,178-180). Regardless of the interpretation, however, if NMDA antagonists have the ability to prolong opiate analgesia when administered acutely with an opiate, they may be useful adjuncts in the treatment of acute, as well as chronic pain. The potential for combination medications including an NMDA receptor antagonist and an opiate in the treatment of pain appears to be well on its way to being realized, as clinical testing of such combinations is currently underway (181-184).

10.2. Addiction

The use of NMDA receptor antagonists in the treatment of addiction is less obvious if one views these drugs as inhibiting the development but not the expression of tolerance, sensitization, and physical dependence (2,3,25,126). Because these processes should already be well established in an addict, it appears that the drugs would be of little use. On the other hand, under these conditions, there still might be a role for NMDA receptor antagonists as adjuncts in opiate maintenance therapy. Coadministration of these drugs during methadone treatment, for example, might lead to less tolerance and dependence arising from the maintenance therapy and easier cessation of treatment for the motivated individual.

The potential role of NMDA receptor antagonists in addiction becomes more evident when considering the findings, discussed earlier, that NMDA receptor antagonists may reverse opiate tolerance and dependence when administered over days. The ability to accelerate the extinction of tolerance and physical dependence (and perhaps sensitization) would offer a means to speed up the detoxification process and perhaps reverse some of the physiological processes responsible for addiction. Although very intriguing, further research is necessary in order to more firmly establish the conditions under which these drugs may reverse these phenomena and to demonstrate whether or not NMDA receptor antagonists will act in a similar manner in opiate addicts.

Evidence demonstrating that NMDA receptor antagonists may inhibit the expression of physical dependence under certain circumstances suggests that these drugs may be useful in acute detoxification. Preliminary clinical research offers conflicting views on this possibility. Whereas two studies suggest that NMDA receptor antagonists may block some symptoms of withdrawal in opiate addicts (110,185), two other studies demonstrate no significant effects (186,187). Perhaps in support of the use of these drugs, ibogaine, which is used in some clinics for acute detoxification, is thought to alleviate withdrawal, at least in part, through blockade of NMDA receptors (188-194). Clearly, more research is necessary in order to determine the potential for NMDA receptor antagonists in alleviating the signs and symptoms of acute opiate withdrawal.

One final area related to opiate addiction where NMDA receptors may have a role is in the rewarding effects of these drugs. Opiate reward is thought to play a critical role in drug-seeking behavior in addicts. NMDA receptor antagonists have been found, in several studies, to block the ability of opiates to establish a conditioned place preference, an experimental procedure commonly used to study drug reward (119,120,195-201). In support of the their ability to inhibit opiate reward, preliminary evidence suggests that some NMDA receptor antagonists may also inhibit the acquisition of opiate self-administration (202). However, these drugs appear to increase the rewarding effects of opiates as measured by intracranial self-stimulation (203,204). Thus, the role of NMDA receptors in opiate reward is presently unclear. However, the results on conditioned place preference and self-administration indicates that future studies should investigate the ability of NMDA receptor antagonists to modify opiate reward, and thereby impact opiate abuse.

10.3. Side Effects and the Therapeutic Potential of NMDA Receptor Antagonists

In discussions of the therapeutic potential of NMDA receptor antagonists, the issue of adverse side effects inevitably arises. High-affinity noncompetitive NMDA receptor antagonists, such as phencycli-dine, produce significant effects on behavior that may limit their therapeutic use. In rodents, these effects are expressed as dose-dependent changes in locomotion and coordination—at relatively low doses, no significant effects are evident; at higher doses, increases in locomotor behavior are seen; at still higher doses, the increases in locomotor behavior are accompained by significant ataxia; at the highest doses, animals become limp and show a complete lack of voluntary movement (25,205-208). In addition, high-affinity noncompetitive NMDA receptor antagonists can show disruptive effects on learning and cognition (209,210) and show evidence of neurotoxicity (211,212). Historically, these drugs (primarily ketamine and phencyclidine) have been used at relatively high doses as dissociative anesthetics (213-218). Phencyclidine was withdrawn for use in humans because of problematic side effects—when individuals awakened from phencyclidine anesthesia, they sometimes reported disturbing hallucinations, thoughts, and dreams, and these were occasionally accompanied by behavioral disturbances (213,214,216,218). Despite some evidence of the same symptoms, ketamine is still used clinically in humans. In addition to these effects, phencyclidine and ketamine are considered drugs of abuse. They show abuse potential in animals models and, according to news reports, are becoming increasingly popular. Given these effects, it is not surprising that caution is advised when considering clinical use of these compounds.

On the other hand, it appears that many of the concerning side effects of NMDA receptor blockers may be restricted to high-affinity noncompetitive antagonists. In preclinical studies, low-affinity noncompetitive antagonists, competitive antagonists, glycine-site antagonists, and polyamine-site antagonists produce fewer problematic side effects (205,206,219-227). Moreover, the doses at which high-affinity noncompetitive antagonists inhibit opiate-induced neural and behavioral plasticity are often quite low, well below doses that cause significant side effects. Further research on these compounds will help to determine the therapeutic potential for NMDA receptor antagonists not only in pain and addiction but also in other clinical problems.

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