The long-term objective of this research is to improve clinical management of persistent pian states. The goal of the proposed work is to evaluate the ability for a norepinephrine re-uptake inhibitor and a serotonin releaser (desipramine and fenfluramine) to enhance human opioid analgesia. Analgesia effect measures will be derived from a human testing model based on painful tooth pulp stimulation: Subjective pain report, dental evoked potentials, and EEG measures will be obtained. The first stage in this work will address the hypothesis that desipramine and fenfluramins exert an analgesic effect when administered alone. The second stage of the work will evaluate the ability of these drugs to enhance opioid analgesia. To accomplish the latter we will administer the opioid alfentanil at three different plasma concentrations to normal volunteers using pharmacokinetically tailored infusions. These infusions will permit the evaluation of the effects of the candidates enhancers (also infuse at steady-state concentrations) while the subject is experiencing opioid analgesia at steady- state, We predict that neither of the candidate enhancers used above will demonstrated analgesic effects, but each of the enhancers when used in combination with the alfentanil infusion is predicted to increase opioid analgesia and alter the relationship of opioid side effects to plasma concentration. Finally, we will evaluate the effects of proglumide, a cholecystokinin antagonist, alone and in combination with alfentanil, on measures of analgesia. A model is proposed for the modulation of opioid analgesia in which norepinephrine and serotonin systems are balanced against the cholecystokinin system in an opponent process relationship.
