Although the mechanisms are complex and have yet to be fully elucidated, research implicates the excitatory neurotransmitter glutamate in the development and maintenance of chronic pain. Some evidence suggests that NMDA antagonists (i.e., dextromethorphan, ketamine, memantine, and amantadine) may therefore have a role in mitigating chronic pain, including neuropathy, chronic phantom pain, and fibromyalgia, and pain associated with spinal cord injury (Fisher et al. 2000; Sang et al. 2002). However, the analgesic effects in various trials have been inconsistent (Eisenberg et al. 1998; Enarson et al. 1999).
The side effects associated with the NMDA antagonists include sedation, dry mouth, headache, and constipation; in some cases these effects may be prohibitively severe, limiting usefulness (e.g., ketamine may produce dissociation, hallucinations, frightening nightmares, and delirium) (Eide et al. 1994). Ketamine at a dosage of 50-60 mg four to six times daily (taken in juice or oral suspension) may produce pain relief without incurring these serious effects. Ketamine's hallucinogenic properties have rendered it popular with drug abusers (Dillon et al. 2003). Long-term use of ketamine is not currently advocated, partly because the long-term effects are unknown. It may result in long-term cognitive changes, hepatic dysfunction, and gastric ulcers.
Widely available as an over-the-counter medication, dextromethorphan is notable for its cough-suppressing effects. It is a low-affinity NMDA receptor antagonist that, when combined with opiate analgesics, may enhance opiate analgesia and reduce opiate tolerance (Elliott et al. 1994). Analgesic effects require dosing at rates substantially higher than those for antitussive effects. Dextromethorphan augments 5-HT in the CNS. Consequently, combination with serotonergic antidepressants (e.g., SSRIs) may predispose a patient to serotonin syndrome.
At a dosage of 200-300 mg orally per day, amantadine may have several untoward effects associated with other NMDA antagonists (e.g., nervousness, depression, concentration disturbances, sleep disturbances). Memantine may be better tolerated than other NMDA antagonists and, given its utility among patients with dementia, may be particularly ideal in patients with dementia and complicating pain conditions.
Methadone, too, has NMDA antagonist properties. One isomer of methadone acts by blocking NMDA receptors (Shimoyama et al. 1997), which may contribute to the fact that methadone maintains analgesic efficacy as compared with other opioids and, therefore, might not require opiate rotations (Gorman et al. 1997; see sections "Agents With Multiple Uses" and "Tolerance, Dependence, and Pseudoaddiction" in this chapter).
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