Glutamate is the primary excitatory neurotransmitter in the central nervous system, and activates both ionotropic (gated ion channels) and metabotropic (G-protein coupled) receptors.1 Since the ionotropic N-methyl-d-aspartic acid (NMDA) receptor has been shown to have a role in neuropathic pain, it was hoped that NMDA receptor antagonists would be clinically effective in patients with neuropathic pain.2 However, the most commonly used NMDA antagonist, ketamine, has been associated with psychomimetic side effects, such as drowsiness or hallucinations. In addition, the need to administer the drug IV to achieve meaningful results in many patients limits its long-term clinical use. Memantine is a noncompetitive NMDA antagonist that is better tolerated in patients because memantine is an open channel blocker with a fast off-rate compared with ketamine.3 In rats with nerve injury-induced tactile allodynia, intrathecal memantine had the greatest potency among all NMDA antagonists (dextrorphan, MK801, ketamine) in relieving allodynia, and produced the least motor impairment.4 Memantine is approved for the treatment of dementia in moderate to severe Alzheimer's disease. Clinical trials have used doses of 20–30 mg/d with the most common adverse event being dizziness.5 The drug should be used cautiously in patients with severe hepatic impairment.
In this issue of Anesthesia & Analgesia, Hackworth et al. describe the early use of oral memantine to treat phantom limb pain in two patients.6 This chronic pain is an even greater challenge, because the current conflicts in Afghanistan and Iraq produced 8058 military casualties between October 2001 and June 2006 (reported), of which 423 underwent limb amputations.7 Lower extremity amputations produce a 70% prevalence of chronic phantom limb pain.8 Previous placebo-controlled trials of memantine for patients with established chronic neuropathic pain have not been encouraging. In a randomized, crossover study on 15 patients with chronic pain for 1–28 yr after amputation, the analgesic efficacy of memantine could not be demonstrated at a dose of 20 mg/d versus placebo on any of the measured outcomes: pain scale and allodynia.9 The efficacy of memantine for established (at least 12 mo) chronic phantom limb pain was studied in a randomized, placebo-controlled trial on 36 patients.10 Memantine was titrated up to 30 mg/d; however, there was no significant benefit for reduction of chronic pain scores. Similar results were obtained in a small crossover trial (n = 8) for chronic phantom limb pain, in patients with mean duration of pain for 13 yr before study enrollment.11
In contrast, a more recent randomized, double-blind, placebo-controlled trial with memantine 20–30 mg/d initiated immediately after upper limb amputation (n = 19) for 4 wk postoperatively demonstrated a nearly four-fold decrease in the incidence of phantom limb pain at 6 mo from 38% to 10%.12 In this trial, patients received postoperative analgesia by continuous brachial plexus ropivacaine infusion for 1 wk. After cessation of ropivacaine infusion on Day 7, patients maintained on memantine 30 mg/d had reduced intensity [0–100 visual analog scale (VAS) scoring] of phantom limb pain at 4 wk (VAS of 3 in the memantine group vs 24 in the placebo group) and 6 mo (VAS of 7 in the memantine group vs 17 in the placebo group). This trial exemplifies the benefit of preventive analgesia, which is: “postoperative pain or analgesic consumption is reduced relative to another treatment, a placebo treatment or no treatment, as long as the effect is observed at a point in time that exceeds the expected duration of action of the target agent. The intervention may or may not be initiated before surgery.”13 The latter trial suggests great potential benefit if memantine can be administered early in the postoperative period after amputation.
The current report of Hackworth et al.6 describes two young military personnel who were treated successfully with memantine initiated within 2 mo after the patients complained of severe phantom limb pain. Both patients were weaned from a large dose of IV hydromorphone (≈100 mg/d) in addition to multiple adjuvant analgesics after commencing memantine (20–45 mg/d). These findings, together with those of the Schley et al.,12 suggest that memantine may be a useful adjuvant medication for treatment of early stage phantom limb pain and, if therapy is commenced early in the postamputation period, may prevent or reduce the likelihood to develop chronic pain.
The second article by Grande et al.14 in this issue describes a patient with severe neuropathic pain of 1 mo duration after metastatic spinal tumor resection. The pain was resistant to opioid therapy and responded initially to ketamine infusion. The ketamine infusion was then transitioned to oral memantine (20 mg/d) as an adjuvant medication, in combination with methadone, gabapentin, and naproxen; this drug combination controlled the patient's pain until his death 3 mo later. Although this report is encouraging, it is difficult to quantify the impact of memantine alone, since it was used in combination with other drugs.
There are multiple binding sites for NMDA antagonists, and differences in pharmacological effect of each drug are attributed to differences in binding sites and receptor affinity.1 The NMDA receptor requires binding at both glycine (NR1 subunit) and glutamate (NR2 subunit) binding sites for ion channel activation. The primary reason that NMDA antagonists alone are not useful as sole analgesics is that at effective doses they can produce side effects in the brain, such as hallucinations. It would appear from the published findings that memantine may be effective in producing analgesia when administered early to patients developing neuropathic pain from surgery. This potential benefit of early treatment may occur because the NMDA channels are involved with the transition of acute postoperative nociception to neuropathic pain. It is likely that once “pain memories” are established in the cerebral cortex, and persistent pain is established as in patients with chronic phantom limb pain,9–11 analgesic therapy with a NMDA antagonist becomes ineffective as the pain has already induced persistent functional and structural alterations in nociceptive structures. Although there are several NMDA antagonists that have been investigated in basic research, very few have demonstrated efficacy in clinical use.
In summary, although memantine does not appear to be beneficial as an analgesic therapy for long-term established chronic neuropathic pain, it may be a useful adjunct when used early in specific settings such as the initial phases of phantom limb pain or soon after surgery in opioid-tolerant subjects. Well designed, controlled clinical studies are needed to confirm that the approach of early intervention with memantine to modulate NMDA channels can reduce the severity of neuropathic pain.
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