Pharmacokinetics of methadone in methadone maintenance treatment: Characterization of therapeutic failures

Summary

Deuterated methadone (M-d₃) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d₃ was administered intravenously instead of the oral M-dose (M-d₀). The pharmacokinetic parameters, half-life in the β-phase (t_1/2β), volume of distribution during the postdistributive phase (Vd_β) and during steady state (Vd_ss) were determined as well as the body (Cl_S) and renal (Cl_R) clearances of M. Pronounced differences in Vd_β and Vd_ss were found between the two groups. The therapeutic failures had a smaller Vd_β and Vd_ss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t_1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p<0.001) in the comparison group. However, the change in t_1/2β was probably a consequence of the change in Vd_β, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.