Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal andconcentration-effect relationships

Objective: To determine plasma racemic methadone concentration-effect relat ionships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity. Methods: Eighteen patients enrolled in a public methadone maintenance progr am, nine of whom experienced significant withdrawal, received constant dose s of methadone once daily for at least 2 months. During an interdosing inte rval, 13 blood samples were collected to measure plasma racemic methadone c oncentrations (patients); subjective (withdrawal severity, direct opioid ef fects, and pain threshold) and objective (pupil diameter and respiratory ra te) opioid effects were quantified on 11 occasions (all participants). The sigmoid E-max model was used to relate plasma concentrations and effects an d to calculate the slope factor (N). The rate of decline in plasma concentr ation during each hour from the peak to the trough concentration was calcul ated. Results: There was an inverse relationship between plasma concentrations an d withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5 .4 +/- 0.9 for withdrawal severity, 5.1 +/- 1.1 for subjective opioid effec ts, 1.2 +/- 0.1 for pupil diameter, and 2.8 +/- 0.7 for pain threshold. Wit hdrawal severity correlated with the maximum rate of decrease in plasma con centration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area unde r the plasma concentration versus time curve and predose plasma concentrati on, but maximal rate of decline was greater in the former group (74.5 versu s 42.1 ng/mL/h). Conclusions:In this group of long-term methadone-maintained recipients, opi oid responses were strongly correlated with changes in plasma racemic metha done concentrations. For the subjective responses, notably withdrawal, smal l changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of m ore rapid decline in methadone concentration.