The treatment of acute pain, with effective agents that produce only minimal side-effects, is key to the management of ambulatory surgery patients. Unfortunately, a large number of ambulatory surgeries each year are followed by hospital admission, and admission is often due to either opioid-induced side-effects or inadequate pain control. Recent attempts to avoid these difficulties have focused on combining an opioid with a non- opioid drug, usually a non-opiate analgesic, or a drug promoting action in the endogenous pain control circuits activated by administered opioids. We have been successful in producing enhanced analgesia by combining opioids of different receptor classes, or by administering a tricyclic agent or an alpha2-adrenergic agent, with an opioid. A large amount of experimental evidence from animal studies exists demonstrating that GABAergic mechanisms are involved in opioid analgesia at both spinal and supraspinal sites. Activity of the GABA(A) receptor appears to antagonize opioid analgesia, while activity at the GABA(B) receptor appears to promote opioid analgesia. In this proposal we will employ our standardized model of outpatient surgery, surgical removal of bony impacted mandibular third molars, to evaluate the effect of the combination of baclofen or flumazenil with morphine, on postoperative pain. Flumazenil, a benzodiazepine antagonist would be expected to inhibit activity at the GABA(A) receptor; baclofen is a GABA(B) agonist. We will assess analgesic efficacy of these combinations compared to administration of morphine alone. In addition, to assess the clinical usefulness of these analgesic drug combinations, we will evaluate other outcome measures, including severity of side-effects, amount of postoperative opioid administered, and patient satisfaction with the various regimens. All of these measures will be evaluated through the second postoperative day. Finally, since gender, menstrual cycle phase, and ethnicity may influence pain intensity and drug-induced side-effects, we will also evaluate, for each drug group, the effect of these factors on pain intensity and severity of side-effects. This study has the potential to develop drug combinations that offer a significantly enhanced analgesia and reduced side-effects, and greater patient comfort and satisfaction, compared to regimens currently available. In addition, since it should be possible to discharge patients earlier after ambulatory surgery and avoid post-surgery hospital admissions, clinical use of such drug combinations may result in substantial decreases in health care expenses. The study will also provide important novel information on interactions between GABAergic and opioidergic mechanisms in pain and endogenous analgesic neuronal circuitry in humans.
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