The clinical pharmacology of methadone induction.

Abstract

Methadone is the foremost, long-standing pharmacological treatment for opioid addiction. It has been shown to have considerable cost benefit to the community and to decrease mortality. Despite methadone's decades-long use, much is still unknown regarding its clinical pharmacology, particularly during the induction phase of Methadone Maintenance Treatment (MMT).

Contrary to previous reports, I found systemic methadone clearance does not increase significantly between induction and steady state phases of MMT, and did not approach the previously reported 3-fold increase. Clinical dose prescription based on the premise of metabolism auto-induction could increase risk of respiratory depression.

Significant differences between R- and S-methadone pharmacokinetics showed the importance of stereoselective measurement in a clinical situation and significant plasma concentration-effect relationships demonstrated their potential influence on induction pharmacodynamics.

Small increases in CYP3A4 activity as measured by the Erythromycin Breath Test from Day 1 to Day 40 of MMT were not correlated with changes in methadone clearance. CYP3A4 activities were informative but would be insufficient for use as a sole predictor of methadone clearance during MMT.

Clinically significant respiratory depression occurred in 20% of subjects, at times of peak plasma R-methadone concentrations, after reports of withdrawal symptoms at pre-dose sampling times, and irrespective of illicit opioid use. Utilisation of both respiratory rate and blood oxygen saturation measurements provided a good indication of respiratory risk for individuals.

Although prior opioid use was a strong predictor of continued use during MMT, adoption of a new equation ("abc") and comprehensive documentation of each individual's MMT may increase prediction of MMT success.

Even in light of recent advances in opioid substitution therapies, MMT's advantages ensure it is still at the forefront of addiction treatment. Careful choice of methodology enabled narrowing of this investigation to those factors most relevant in methadone pharmacology and most responsible for MMT success or failure, and therefore extending previous knowledge of this area. Such data might be utilised to develop a clinically applicable model for MMT, and help provide clients with a safe and uncomplicated transition from heroin use to methadone induction in the future.