Exploration of the biochemical differences between high and low dose methadone clients on stable maintenance therapy
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 iii 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
DegreeDoctor of Philosophy (Ph.D.)
DepartmentPathology and Laboratory Medicine
SupervisorLehotay, Denis C.
CommitteeBlondeau, Joseph; Qureshi, Mabood A.; Alcorn, Jane; McKay, Gordon; Dahms, Tanya
Copyright DateNovember 2012
tandem mass spectrometry