Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone.

To the Editor: The use of N-methyl-D-aspartate (NMDA) receptor antagonists to decrease opioid side effects, potentiate opioid actions, and decrease the development of tolerance has been a topic of substantial interest over the last decade. The pioneering work by Trujillo and Akil suggested that tolerance to opioids could be prevented by the non-competitive NMDA receptor antagonist MK-801.1 Subsequent studies indicated that competitive NMDA receptor antagonists could prevent the development of opioid tolerance and reverse it once established.2 To determine the clinical significance of these observations, numerous clinical trials have been performed with the widely used NMDA receptor antagonists ketamine and dextromethorphan. These studies suggest that both antagonists can improve pain scores in patients with certain types of pain, but, in general, the doses must be high, which predisposes to significant side effects.3 The addition of dextromethorphan to morphine has been studied in both animals and humans. Mao et al. conducted animal studies to determine the optimal ratio and concluded that a 1:1 ratio was the most efficacious.4 More recently, clinical trials performed to study this combination yielded inconclusive results, and more studies are needed to determine the correct ratio in humans. In view of the limited benefit obtained by this approach, other strategies to potentiate, decrease side effects, and prevent the development of tolerance to opioids are being explored. One novel strategy was suggested by work performed by Crain and Shen about a decade