Methadone is a synthetic opioid that is effective for the relief of moderate-to-severe pain and for the treatment of opioid dependence. The pharmacokinetics of methadone differ from those of morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are variable and an understanding of the factors that impact the onset, magnitude, and duration of analgesia is required to optimize therapy. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure. Special populations in whom a change from the usual dosage regimen may be necessary include pediatric patients, patients with renal failure, the elderly, and pregnant women. To achieve an optimal dosage regimen, the clinician must have an understanding of the pharmacokinetics and pharmacodynamics of methadone in addition to the relationship between these variables and their patients' demographic and pathophysiologic characteristics. AMEDLINE search was performed to identify literature published between 1966 and May 2005 relevant to the pharmacokinetics of methadone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of methadone disposition including its absorption profile, distribution, and metabolism/excretion. General dosing guidelines, dosage conversions from other opioids and pharmacokinetic issues in special populations are discussed.

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An understanding of how to prevent the conscious perception of pain is an integral part of anaesthetic practice. By using an experimental pain model and healthy volunteers not undergoing surgery, the changes in the perception of a noxious stimulus that occur purely as a result of manipulation of conscious level, rather than the usual clinical combination of anesthesia and analgesia, can be studied. The aim was to explore the interaction between pain, memory and auditory stimuli in healthy volunteers while awake, sedated and anesthetized with a propofol target controlled infusion (TCI), both on the bench and using functional magnetic resonance imaging. Ten healthy volunteers performed a series of baseline cognitive and motors tasks. Thresholds for Auditory Evoked Potentials (AEPs) and pain were also established. Multiple levels of propofol sedation were infused in a stepwise fashion to establish the level at which amnesia occurred. Loss of verbal contact was taken as the level for the onset of anesthesia. AEPs and pain data were recorded at each propofol TCI level. On a second visit the subjects are scanned to obtain matching functional imaging data during three states: the awake, sedated and anesthetized. During the scanning sessions the subjects receive both painful and auditory stimuli and perform a memory task. To date we have successfully completed the bench component of our aim. We have established measures to determine behaviorally the level of sedation at which amnesia starts to occur. This cognitive behavioral measure was found to be reproducible when translated to the imaging environment, where two subjects have been completed. Preliminary analysis suggests that the pain rating is mildly increased at this level of sedation. Imaging data analysis is currently being performed and the data collection from the remaining bench subjects is in progress.

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