Population pharmacokinetic analysis of morphine in opioid dependent and control subjects

Background:  Pilot data (n=4 per group) suggests methadone maintenance subjects (MMS) may have increased plasma morphine concentrations compared with controls after the same iv dose (1). Morphine is primarily cleared by hepatic glucuronidation, which is inhibited by methadone in vitro (2).  There has been no previous reported investigation of morphine clearance in the presence of buprenorphine.  Targeting of specific morphine plasma concentrations is important for clinical investigations comparing the analgesic response to morphine in various treatment groups.

Aims:  To investigate the pharmacokinetics of morphine in opioid dependent and control subjects and to develop a pharmacokinetic model that would allow more accurate targeting of specific morphine plasma concentrations in these populations.

Methods:  Various iv morphine infusions were administered and plasma samples collected up to 6 hours post-dose. Population pharmacokinetic analysis was performed with NONMEM V (version 1.1) using 1098 concentration-time data points from 131 study occasions involving 72 subjects (27 MMS, 20 buprenorphine maintenance subjects (BMS), 25 control).  Data on demographics, health status, prescribed drug use and illicit drug use were collected.

Results:  The data were best described by a two-compartment model with a proportional error function, between subject variance (BSV) for all parameters and between occasion variance (BOV) for clearance (CL) and volume of the peripheral compartment (V2).  Inclusion of body surface area (BSA) as a covariate for CL and V2, and MMS as a covariate for CL significantly improved the model fit (p<0.01).  Population estimates from the final model for a typical individual (BSA 1.89 m2) were: CL 76.7 L/h; inter-compartmental clearance (Q) 96.6 L/h; volume of the central compartment (V1) 26.7 L; V2 114.4 L.  The final model predicted a reduction in CL of 20% for MMS.  There was no relationship between methadone dose and CL in these subjects.

Conclusion: This is the first report of reduced morphine clearance in MMS.  A lack of correlation between CL and methadone dose in MMS is consistent with in vitro findings of a non-competitive mechanism of inhibition of morphine glucuronidation by methadone (2).  The development of this model, which incorporates BSA and MMS as covariates, will allow more accurate targeting of specific morphine plasma concentrations in MMS, BUP and control subjects.  This is of particular importance for studies investigating analgesic response at specific morphine concentrations in these groups.

1. Doverty M, et al., Pain. 2001; 93:155-163.

2. Morrish G, et al., Br J Clin Pharmacol.  2006; 61(3) 326-335