When taken orally, methadone is absorbed slowly through the gastrointestinal tract. The maximum concentration is reached around the second to fourth hour after the ingestion, after which it falls gradually until the moment of the next ingestion (Figure 1).
If the daily dosage of methadone dosage is correlated with its concentration in blood, a graph of the type shown in figure 2 is ob-
tained. This graph refers to 100 patients in methadone maintenance treatment, 24 hours after their previous dose. As can seen from the graph, the general rule according to which the higher the daily methadone dosage, the higher the concentrations in the blood will be is not necessarily respected. It can, in fact, be noted that there are patients who, even when they take methadone doses as high as 70–170 mg per day, have blood concentrations similar to those of patients whose doses are as low as 25 mg per day.
Blood concentrations of methadone are more reliable as an indicator of its concentra- tion in the action sites than the dose taken. For this reason, methadone plasma concentrations measured after 24 hours have repeatedly been proposed as a parameter for the evaluation of the adequacy of treatment. At first it was thought that a methadone plasma concentra- tion of 150 ng/ml would be required to provide sufficient protection against the use of heroin [1, 9]. Subsequently this value was modified: at present, a plasma concentration of between 150 and 600 ng/ml is considered necessary to
gain control over craving [1, 6, 8]. Actually, important differences are found to persist in the way subjects respond to methadone, even when reference is made to methadone con- centrations in plasma rather than methadone doses taken. Therefore, the therapeutic aims of terminating the use of heroin and ending craving can be achieved with plasma concen- trations which differ in different subjects and differ too in a single subject under different conditions.
One aspect to be considered in evaluat- ing the pharmacokinetic components of this variability it is the chirality of methadone. Methadone is usually produced and traded as a raceme divided fifty-fifty between its two isomers, R and S. Some of the features of the two enantiomers differ: these include half- life, receptor binding and opioid activity. For our practical purposes, we can assume that the R component is the active one. Metha- done is mainly metabolized in the body by the enzymes of the P450 cytochrome system. The literature contains observations on the in- volvement of cytochromes CYP1A2, CYP2D6, Fig. 1 Concentration of methadone in plasma: percentage variations over 24 hours
CYP3A4, CYP2C9 and CYP2C19, even though the contribution of each of these has not yet been clearly defined.
The existence of inter- and intra-individual variability in the enzymatic activity of these cytochromes on the two enantiomers is surely the foundation for the major variations found in the relative concentrations of S and R meth- adone in blood. In practice, while an individ- ual taking his/her daily dose consumes 50% of R-methadone and 50% of S-methadone, the relative percentages of the two isomers in the blood show wide-ranging variations. The lit- erature reports ratios between R and S metha- done that vary as widely as 0.63-2.4 [7]. Since the R isomer of methadone is the active one, for practical purposes it would be better to mea- sure the R isomer, rather than total methadone. Actually, patients treated with a given dose of methadone, present variability in plasma concentrations of up to 58 times, while dosing with R-methadone alone reduces variability to 41 times. Considering only patients who take no other medications, interindividual variabil- ity for the same dose of methadone ingested
falls to 35 times for methadone as a whole and to 17 times for R-methadone [5]. One possible outcome, therefore, is that a subject may have a plasma concentration of methadone that is supposed to be appropriate, but actually con- sists predominantly of inactive S-methadone. Ideally, to have a more realistic picture of opi- oid activity at the receptor sites, the best pa- rameter to refer to is the plasma R-methadone concentration.
With the aim of using methadone plasma concentration as a predictor of abstention from the use of opioids, the sensitivity and specifici- ty of various different values of plasmatic con- centration have been studied. When using the negativeness of the toxicological urinalyses for morphine over the previous two months as a parameter for abstention from the use of her- oin, it has been observed, for example, that a level of 400 ng/ml whole methadone in plasma corresponds to a specificity of 81.1% and a sen- sitivity of 31.8%. This means that the probabil- ity of using heroin falls to 18.9% above 400 ng/ ml, while the probability of ending the use of heroin is 68.2% at this concentration in plasma.
Fig. 2 Correlation between doses of methadone taken and concentrations in plasma 24 hours after administration in 100 subjects on methadone maintenance treatment
Moving now from the methadone raceme to R-methadone, it has been shown, by contrast, that a level of 250 ng/ml for plasma concentra- tion corresponds to a specificity of 92.6% and a sensitivity of 24.7%. This means that the prob- ability of using heroin falls to 7.4% when the R-methadone level exceeds 250 ng/ml, while the probability of ending the use of heroin is 75.3% for this plasma concentration [5].