Reference Range: 100-1000ng/mL
Toxic Range: Serum values greater than 1000 ng/mL

Therapeutic monitoring of serum methadone values is based on the patient reaching a steady state of methadone values by dosing with the same milligram dosage for 5 to 6 days. Relative steady state concentrations should be achieved during this time. The pre-dose value (TROUGH) is the lowest serum value for the patient and is measured on a sample drawn just prior to daily dose. The post-dose value (PEAK) is the concentration of a serum sample drawn 4 hours after the dose. Ideally the values should be very nearly the same. This indicates that the methadone absorbed by the patient in the daily dose is distributed uniformly throughout the vascular and organ storage volume of the body. The methadone is then available at a uniform rate at the opiod receptor binding sites. When the pre-dose (TROUGH) and the post-dose (PEAK) values differ greatly, there is an increased metabolism and excretion by the patient. This may result in the patient's claim of withdrawal. Dose timing and/or increase should be considered as options.

Relation of Methadone Dosage to Serum Concentrations

Pre-dose values (TROUGH): As an approximation the relationship of serum values to dosage is 263 ng/mL for every milligram of methadone consumed per kilogram of body weight. This assumes normal hydration, the absence of liver disease and any other drug interactions.

Sample calculations:

63.6 Kg (140lb) Patient 81.8 Kg (180lb) Patient
Dose (mg/d) Methadone (ng/mL) Dose (mg/dL) Methadone (ng/mL)
60 248 80 257
100 413 120 385
140 578 160 514
180 744 200 642
220 909 240 771

Post-dose 4 hours (PEAK): The half-life for methadone in plasma is 15-55 hours. This is the time for 50% of the dose to be metabolized and excreted in the urine. Using 24 hours as the half-life, one can very easily estimate the PEAK value as being two times the TROUGH value. However, the most important factor in evaluating the PEAK concentration is the difference in magnitude between the PEAK and TROUGH. If the difference is very great this indicates that the patient is experiencing a change in the physiological effect of the drug. The patient would probably be experiencing withdrawal symptoms late in the day. Splitting or increasing the dose might be considered for these patients

Useful Information and Calculations

Table 1. Patient samples analyzed for PEAK and TROUGH levels of methadone.

% Variation
370 634 264 42
404 787 383 49
286 586 300 51
339 535 196 37
185 351 166 47
107 154 47 31
271 446 175 39
452 752 300 40
640 693 53 8
45 240 195 81
408 630 222 35
436 627 191 31
375 716 341 48

TROUGH Calculation:

Meth Conc.= 263ng/mL (Dose, mg/d)/Wgt(Kg) (1.)

Plasma Half-Life: 15 to 55 Hours

Major metabolites: EDDP and EMDP


  1. Wolff, K., Sanderson, M., Hay, AWM, and Raistrick, D., Methadone Concentrations in plasma and Their Relationship to Drug Dosage. Clin. Chem. 37/2, pgs. 205-209 (1971)