Dr Fraser correctly points out that a major fraction of the methadone measured in blood plasma is unavailable for interaction with specific neuroreceptors because of nonspecific bindings to plasma proteins. A better index of effective concentration (although still imperfect since it does not allow for nonspecific, extravascular binding) would be the free methadone in plasma. Data relating the concentration of free methadone to clinical effect would indeed be welcome both for making prescriptions more precise and for analyzing the molecular basis of the clinical response. I hope Dr Fraser and other clinical chemists will be able to provide such data in the near future.In the meantime, measurements of total methadone in plasma can reveal inadequacy of dose. If the clearance of methadone is exceptionally fast (eg, because of hyperactivity of the hepatic microsomal system), the circulating concentration can fall to a suboptimal level despite prescription of what
Dole VP. Methadone and Theories of Addiction-Reply. JAMA. 1989;261(13):1880. doi:10.1001/jama.1989.03420130041013
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