title: Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of methadone in a sample of Iranian (mazandarani) opiate users undergoing methadone maintenance treatment.
abstract: OBJECTIVE
  To investigate the pharmacokinetics (PK) and PK- pharmacodynamic (PD) relationship of methadone in a cohort of outpatients undergoing methadone maintenance treatment (MMT).
  
  
  METHODS
  Sixty male patients undergoing MMT with a mean ±SD methadone daily dosage of 58 ± 34 mg were enrolled in this study. A 5-ml blood sample was collected before the daily intake of methadone. As a PD measure, the Subjective Opioid Withdrawal Scale (SOWS) form was completed immediately after obtaining the blood sample. Blood samples were taken and the forms were completed 4-5 times more (up to 24 hr) after the daily intake of methadone. Plasma methadone was analyzed using HPLC. Population PK/PD analysis was performed using population pharmacokinetics modeling software P-Pharm.
  
  
  RESULTS
  Significant decreases (p< 0.05) were observed in the SOWS scores during 10 hours after methadone intake. The SOWS had returned to baseline by 24 hr after using methaodone (p= 0.98). A considerable interindividual variability in the CL/F (16 fold), EC50 (3 fold) and Emax (6 fold) for methadone was observed.
  
  
  CONCLUSIONS
  Withdrawal symptoms were significantly improved in MMT patients after taking methadone and the PD measure was substantially affected by fluctuations in plasma methadone concentration. However, The SOWS had returned to baseline by 24 hr after using mathadone. Thus, a once daily dosing of methadone may not be suitable for those MMT patients who experience a significant withdrawal disturbance in the latter part of the interdose interval. This may increase the perceived severity of withdrawal and induce a craving for additional opioids.
authors.affiliation: Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Shiran
authors.affiliation: Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Rasa
authors.initials: R
authors.lastname: Hosseinzadeh
authors.affiliation: Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Abolhassan
authors.initials: A
authors.lastname: Hamidikenari
authors.affiliation: Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Mehran
authors.initials: M
authors.lastname: Zarghami
authors.affiliation: Psychiatry and Behavioral Sciences Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Nargess
authors.initials: N
authors.lastname: Lamsehchi
authors.affiliation: Department of Pharmacotherapy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rafati
keywords: Iranian; Methadone; Opiate Users; Pharmacodynamics; Pharmacokinetics