Exploration of the biochemical differences between high and low dose methadone clients on stable maintenance therapy
Date
2013-01-11
Authors
Journal Title
Journal ISSN
Volume Title
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ORCID
Type
Degree Level
Doctoral
Abstract
There is large variability in the dose of methadone required to prevent
withdrawal symptoms in chronic, stable methadone users. The difference in dose
between low-dose and high-dose patients may vary >50 fold, and could be as
low as < 5-10 mg/day, or greater than >300 mg/day. Our Objective was to
identify factors which account for the difference in biochemical response of
patients to low- and high-dose administration of methadone. We hypothesized
that differences in high dose vs. low dose methadone clients are due to lower
number of human μ-opioid receptors (hMORs) in high dose maintenance therapy
patients than in those on lower doses, and/or desensitization down-stream from
the opioid receptor that manifests as an attenuated cyclic AMP (cAMP) response
to opioid agonists. We also hypothesized that concurrent drug use as well as Pglycoprotein
levels may influence dosing requirements.
Using white blood cells as a model, we measured hMOR expression, in
vivo cAMP levels, cAMP levels in response to exposure to increasing levels of
methadone, P-GP expression and the presence of other drugs.
Our findings indicated that hMOR numbers on lymphocytes, granulocytes
and monocytes did not vary for controls, low-dose, and high-dose methadonetreated
patients. Baseline levels of cAMP in white blood cells were higher in
controls than in low-dose methadone patients, and significantly lower in highdose
patients than either controls or low-dose patients. Increasing concentrations
of methadone exposure for control leucocytes resulted in a dose-related
reduction in cAMP. In contrast, increasing doses of methadone treatment had no
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effect on cAMP levels in white cells of either low- or high-dose methadone
patients. P-glycoprotein levels did not correlate with dose requirements.
Concurrent drug use was detected in a high percentage of patients.
In conclusion, the dose of methadone required to prevent withdrawal
symptoms in high-dose and low-dose methadone patients is not related to
changes in hMOR number. In contrast, baseline cAMP levels were significantly
lower in high-dose patients than in low-dose patients. Chronic treatment also
abolished the methadone dose-related reduction in cAMP in-vitro in lymphocytes,
indicating desensitization. Concurrent drug use may play some part in dosing
requirements; however P-glycoprotein levels appeared not to. It is possible that
mechanisms of the hMOR signal transduction cascade are responsible for these
dosing discrepancies as related to of methadone-treated patients, however, more
research is required to determine exact mechanisms
Description
Keywords
methadone, receptors, tandem mass spectrometry, dosing
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pathology and Laboratory Medicine
Program
Pathology