Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain

Both mu opioid agonists and N-methyl-D-aspartate (NMDA) receptor antagonist s are implicated in the regulation of neuropathic pain in post-nerve injury preclinical pain models. This study characterizes the effects of intraveno usly infused alfentanil (a mu -receptor agonist) and ketamine (an NMDA-rece ptor antagonist) on human neuropathic pain states, characterized by allodyn ia and hyperalgesia. Using diphenhydramine as the placebo, alfentanil and k etamine infusions were given in a randomized double-blind fashion 1 week ap art via a computer-controlled infusion (CCI) pump that was programmed to ta rget 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 pla sma 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 be ginning and the end of each infusion. A total of seven males and five femal es with post-nerve injury allodynia and hyperalgesia were enrolled in the s tudy. Elevations of cold, warm, hot pain and von Frey tactile thresholds we re noted. Dose-dependent increases in cold and cold pain thresholds, and re ductions in stroking pain scores were noted in both the alfentanil and the ketamine infusions. In addition, alfentanil showed a statistically signific ant dose-dependent reduction in both spontaneous and von Frey pain scores. Both the alfentanil and ketamine infusions showed a reduction in the stroki ng hyperalgesic area and ketamine showed a significant reduction in the von Frey hyperalgesia area. No significant CNS side effects and changes in vit al signs were noted. A partial deafferentation state was found in the post- nerve injury patients who presented with allodynia and hyperalgesia. The ef fects of alfentanil on cold and cold pain thresholds and spontaneous pain s cores correlates with previous studies suggesting an opiate central analges ic effect. In addition, the reduction of the hyperalgesic area and evoked p ain 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-ner ve injury patients with partial deafferentation. With the absence of signif icant CNS side effects, the ketamine infusion not only demonstrated the wel l-documented spinal cord mechanism of the NMDA receptor, but the result of the current study also suggests that a peripheral mechanism of NMDA recepto r may exist. The relationship between central sensitization and regulation of peripheral NMDA-receptor expression requires further investigation. (C) 2001 International Association for the Study of Pain. published by Elsevier Science B.V. All rights reserved.