Both mu
opioid agonists and
N-methyl-D-aspartate (
NMDA) receptor antagonists are implicated in the regulation of
neuropathic pain in post-nerve injury preclinical
pain models. This study characterizes the effects of intravenously infused
alfentanil (a
mu-receptor agonist) and
ketamine (an
NMDA-receptor antagonist) on human
neuropathic pain states, characterized by
allodynia and
hyperalgesia. Using
diphenhydramine as the placebo,
alfentanil and
ketamine infusions were given in a randomized double-blind fashion 1 week apart via a computer-controlled infusion (CCI) pump that was programmed to target plasma levels of
alfentanil at 25, 50 and 75 ng/ml and
ketamine at 50, 100 and 150 ng/ml. At the beginning of each infusion and each targeted plasma level, baseline vital signs, neurosensory testing that included thermal thresholds, thermal
pain and von Frey filament thresholds, and spontaneous and evoked
pain scores were obtained. Moreover, the areas of
allodynia or
hyperalgesia to stroking and a 5.18 von Frey filament were mapped at the beginning and the end of each infusion. A total of seven males and five females with post-nerve injury
allodynia and
hyperalgesia were enrolled in the study. Elevations of cold, warm, hot
pain and von Frey tactile thresholds were noted. Dose-dependent increases in cold and cold pain thresholds, and reductions in stroking
pain scores were noted in both the
alfentanil and the
ketamine infusions. In addition,
alfentanil showed a statistically significant dose-dependent reduction in both spontaneous and von Frey
pain scores. Both the
alfentanil and
ketamine infusions showed a reduction in the stroking hyperalgesic area and
ketamine showed a significant reduction in the von Frey
hyperalgesia area. No significant CNS side effects and changes in vital signs were noted. A partial deafferentation state was found in the post-nerve injury patients who presented with
allodynia and
hyperalgesia. The effects of
alfentanil on cold and cold pain thresholds and spontaneous
pain scores correlates with previous studies suggesting an
opiate central
analgesic effect. In addition, the reduction of the hyperalgesic area and evoked
pain scores with the
alfentanil infusion suggests that
opioids may have some peripheral effects in the post-nerve injury patients. Therefore, clinical utilization of
opioids with careful titration may be beneficial in post-nerve injury patients with partial deafferentation. With the absence of significant CNS side effects, the
ketamine infusion not only demonstrated the well-documented spinal cord mechanism of the
NMDA receptor, but the result of the current study also suggests that a peripheral mechanism of
NMDA receptor may exist. The relationship between central sensitization and regulation of peripheral
NMDA-receptor expression requires further investigation.