From the Guidelines
Methadone typically reaches steady state in 4 to 7 days, but may take up to 2 weeks in some cases. This timeframe is directly related to methadone's long half-life, which can range from 8 to more than 120 hours 1. When a medication is dosed regularly, it generally takes about 4-5 half-lives to reach steady state plasma concentrations, where the amount of drug entering the body equals the amount being eliminated. For methadone, this means that patients will not experience the full therapeutic effect until about 4 to 7 days after starting treatment or changing doses, and monitoring for drug accumulation and adverse effects is crucial during this period.
Some key points to consider when dosing methadone include:
- Individual variations in methadone pharmacokinetics make its usage complex in patients with cancer 1
- Methadone should be started by or in consultation with an experienced pain or palliative care specialist due to its long half-life, high potency, and interindividual variations in pharmacokinetics 1
- Patients should be informed that they may not feel the full effect of their methadone dose immediately, and dosage adjustments should generally not be made more frequently than every 5-7 days.
- Individual factors such as liver function, genetic variations in metabolism, and drug interactions can influence this timeline, with some patients potentially taking longer to reach steady state.
It is essential to provide the patient with access to adequate, short-acting, breakthrough pain medications during the titration period, as the starting dose may need to be titrated up 1. Additionally, high doses of methadone (120 mg and above) may lead to QTc prolongation and torsades de pointes, which may lead to sudden cardiac death, highlighting the need for careful dose management and monitoring 1.
From the FDA Drug Label
For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing.
- Steady-state for methadone is reached in 3 to 5 days of dosing 2.
- The time to reach steady-state is due to methadone being retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations.
- Key points:
- Steady-state plasma concentrations are reached in 3 to 5 days
- Full analgesic effects are also reached in 3 to 5 days
- Methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.
From the Research
Methadone Steady State
- The time it takes for methadone to reach steady state is not directly stated in the provided studies, but it can be estimated based on the half-life of the drug.
- According to the study 3, the median elimination half-life of methadone in healthy subjects is 33-46 hours, depending on the method used to calculate this parameter.
- Another study 4 found that the half-life of methadone in patients who were therapeutic failures was 24.5 hours, while in the control group it was 34 hours.
- A study on the estimation of attainment of steady-state conditions for compounds with a long half-life 5 suggests that the time to attainment of steady-state conditions is generally derived from the terminal half-life and can vary depending on the definition of half-life used.
- Based on the information provided, it appears that methadone may take around 3-5 days to reach steady state, assuming a half-life of 24-46 hours and considering that it typically takes 4-5 half-lives for a drug to reach steady state 6, 5. However, this is an estimate and may vary depending on individual factors.
Factors Affecting Steady State
- The volume of distribution and clearance of methadone can affect the time it takes to reach steady state 4.
- The study 3 found that the population mean oral clearance of methadone was 6.9 l/h in healthy subjects, and the results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis.
- The absorption rate of methadone can also impact the time to reach steady state, with slower absorption indicated in opiate users 3.