Supplementary Material for: Pharmacokinetics-driven individualized detoxification procedure in patients dependent on benzodiazepines and other GABA-A receptor modulators.

INTRODUCTION: Despite extreme inter-patient differences in the benzodiazepine (BZD) metabolism rate, patients dependent on BZDs or other GABA-A receptor modulators are treated without laboratory control. The proposed detoxification method is the first to employ concentration feedback to prevent routinely unrecognized problems: overaccumulation of a long-acting BZD substitute, high concentration upon discontinuation (mimicking patients' adaptation to “abstinence”), elimination continuing long after treatment conclusion, resulting in delayed low-concentration crises and relapses of drug intake. METHODS: A new method, although evolved from a typical gradual dose reduction approach, is driven not by a dosage schedule but by an individual BZD concentration evolution. This defines four treatment stages: Substitution, Anti-accumulation paradigm, Elimination, and Readaptation (SAER). The S stage, substitution by titration (using diazepam or clorazepate, well read by immunoassays) ends with achieving a satiation state and establishing individual clinical-state and concentration baselines. During the A stage, to minimize further (unneeded) accumulation, doses are aggressively reduced daily, driven by concentration feedback, until accumulation ceases (a quasi-plateau). Further tapering opens the E stage (actual detoxification), hence slows, depending on the patient's condition and elimination rate, and concentration is tracked with lower frequency (every 3-7 days), including after drug discontinuation. Only after complete elimination (R stage) patients adapt to true abstinence. CONCLUSIONS: The SAER approach can minimize overaccumulation-related errors. The use of serum-BZD feedback curbs the initial overaccumulation. A forced concentration plateau establishes optimized initial conditions for the elimination process. By minimizing a superfluous high-concentration treatment phase, SAER provides more time for a careful escorting of the low-concentration crises, especially the one coinciding with elimination completion, weeks after drug discontinuation. Without extending the usual treatment time, the method aspires to improve both the reliability of the detoxification process and the treatment completion rate.