La méthadone est un opiacé de synthèse aux propriétés pharmacocinétiques spécifiques qui permettent un traitement de la substitution des pharmacodépendances opiacées. Après une prise orale, la méthadone est absorbée à 75 % en moyenne et subit un métabolisme hépatique. La méthadone a un volume de distribution de 4 L/kg environ. Sa demi-vie est de 22 heures en moyenne. Ces propriétés pharmacocinétiques permettent une prise quotidienne unique. Le faible pic plasmatique et l’effet plateau des concentrations sanguines n’induisent pas les effets habituellement engendrés par l’héroïne ou les médicaments opiacés détournés de leur usage. La variabilité interindividuelle du métabolisme de la méthadone entraîne de grandes variations des paramètres pharmacocinétiques et peut être à l’origine d’un syndrome de sevrage ou d’un surdosage. Par ailleurs, les voies métaboliques sont communes à de nombreux médicaments. Les in-teractions médicamenteuses qui en résultent peuvent être responsables d’un échec thérapeutique en raison d’un sous- ou d’un surdosage. Le clinicien doit connaître ces différentes propriétés, les interactions médicamenteuses et utiliser des outils comme le suivi pharmaco-thérapeutique des concentrations résiduelles plasmatiques afin de réussir son approche thérapeutique substitutive.

In January 2002, the official French methadone legislation prescription was modified. Thus, the number of clinicians authorized to introduce methadone substitution was increased. Knowledge of the pharmacokinetic and pharmacological properties of this compound remains particularly important for its appropriate prescription. Bearing this in mind, we linked methadone pharmokinetics to its pharmacological use in this article.

Methadone is a synthetic opiate. Its mean bioavailability is around 75 %. Cytochrome P450 3A4 and 2D6 are involved in its hepatic metabolism. Its volume of distribution is of around 4 L/kg. The value of half-life elimination is of around 22 hours. These pharmacokinetic properties (long half-life, steady state concentration) are in favour of substitution use of this opiate. In practice, clinicians progressively introduce this substitution therapy to reach 80 mg +/− 20 mg per day, once daily. Therapeutic clinical goals are mainly to reduce craving, withdrawal symptoms, and to manage psychosocial problems and psychiatric co-morbidity. Practitioners should bear the latter in mind once substitution therapy has been appropriately initiated and stabilized. However, wide, interpatient, interindividual variability impacts on pharmacokinetic parameters. Subjects may be either high or poor metabolizers. Thus, bioavibility ranges from 36 to 100 %. Induction or inhibition of CYP450 significantly modifies methadone pharmacodynamic properties. Genetic variability and medication can induce non response to substitution, craving, or withdrawal symptoms.

We describe here a large number of medications involved in pharmacokinetic or pharmacological interactions. Classical enzymatic inductors, such as antiepileptic molecules (phenobarbital, carbamazepin), antituberculosis compounds (rifampicin), or antiretroviral therapy (efavirenz, nevirapin, ritonavir), could possibly lead to respiratory depression for example. Metabolism inhibitors such as selective serotonin reuptake inhibitors (fluvoxamine, fluoxetine, paroxetine, sertraline) or antifungals of the azol groups could enhance plasma concentration and may sometimes lead to respiratory depression or death. Nevertheless, clinicians should know methadone pharmacokinetic properties and pharmacological interactions for the optimal opiate-dependant patients’ management.

Clinicians can use plasma concentrations as a useful indicator to reach substitution goals. The methadone plasmatic target value of 400g/ml can be recommended for therapeutic drug monitoring. This dosage not only facilitates interaction detection, but also hand encourages communication with the patient.