By using opiates with differing lipid solubilities, protein binding, molecular weight and molecular volume (morphine, fentanyl, alfentanyl, sufentanyl) the investigators will use established microdialysis techniques to provide measurements of drug concentrations over time in the spinal cord, CSF and epidural space following either epidural or intrathecal drug delivery. Compartmental and noncompartmental pharmacokinetic parameters determined from those experiments will be correlated with physicochemical properties of the study drugs in order to determine how each property influences drug redistribution to each anatomic site. Having defined characteristics of drugs which are likely to help in the development of new drugs which will minimize onset time, maximize analgesia duration, and minimize redistribution to supraspinal sites, the investigators will proceed to develop the liposome and cyclodextrin drug delivery systems to favorably modify epidural and intrathecal drug redistribution so as to prolong spinal drug action while simultaneously minimizing extraspinal effects. These studies will use in vitro models to identify promising liposome/opioid and cyclodextrin/opioid formulations for in vivo animal testing. In vivo studies will use an intrathecal rat model; the screen for effective liposome formulation will employ a dog model to evaluate the effect of cyclodextrins and liposomes on opioid analgesia and side effects following both intrathecal and epidural drug level.
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