NMDA antagonists and
opioids relieve experimentally produced
hyperalgesia in animals and humans, presumably by attenuating a heightened central nervous system response to afferent input. A few small studies in patients have suggested that intravenous boluses or rapid infusions of the
N-methyl-D-aspartate (
NMDA) antagonist
ketamine relieve some
neuropathic pains but also produce disturbances of cognition and mood. In a randomized, double-blind, crossover trial, we treated eight patients with chronic posttraumatic
pain and widespread
mechanical allodynia with 2-h
intravenous infusions of the
NMDA antagonist
ketamine (mean dose, 58 mg), the
opioid mu-receptor agonist
alfentanil (mean dose, 11 mg), and placebo. The patients were selected because extensive sensory testing suggested that altered central processing contributed to their symptoms. The slow rate of
drug infusion was chosen to see if
pain relief would precede dose-limiting side effects. Means of the peak effect scores achieved during the 2-h infusion were for
pain relief:
ketamine, 65%,
alfentanil, 46%, and placebo, 22% (p < 0.01 for
ketamine and p = 0.08 for
alfentanil, each compared to placebo); and for relief of
allodynia:
ketamine, 71%,
alfentanil, 57%, and placebo, 21% (p < 0.01 for both
ketamine and
alfentanil). Appreciable symptomatic relief developed only after the onset of unpleasant
drug side effects. After the infusion was stopped,
pain relief disappeared before the side effects resolved. We conclude that
NMDA antagonists may have promise for the treatment of
neuropathic pain, but strategies are needed to improve their therapeutic ratio, such as intrathecal administration or systemic treatment with more selective drugs.