At what methadone (opioid agonist) dosage does it start to slow metabolism and cause weight gain?

From the Guidelines

Methadone's effect on metabolism and weight gain typically begins at daily doses of 80-120mg. There is no precise threshold dose that universally triggers metabolic changes, as factors like genetics, duration of treatment, and individual physiology play important roles 1. Patients on methadone maintenance therapy (MMT) commonly experience weight gain of 5-10 pounds within the first year of treatment, with some gaining more. This weight gain occurs because methadone can slow metabolism through multiple mechanisms: it may affect thyroid function, alter glucose metabolism, increase appetite, reduce physical activity due to sedation, and disrupt normal hormone regulation.

Some key points to consider when prescribing methadone include:

• Monitoring for drug accumulation and adverse effects, particularly over the first 4 to 7 days, as a steady state may not be reached for several days to 2 weeks 1
• Providing the patient with access to adequate, short-acting, breakthrough pain medications during the titration period
• Being aware that high doses of methadone (120 mg and above) may lead to QTc prolongation and torsades de pointes, which may lead to sudden cardiac death 1
• Regular metabolic screening is advisable, especially for those on higher doses or long-term therapy. Patients on methadone should monitor their weight, maintain a balanced diet, engage in regular physical activity as tolerated, and discuss any significant weight changes with their healthcare provider.

From the Research

Methadone Dosage and Metabolism

• The relationship between methadone dosage and its effect on metabolism and weight gain is complex and not entirely understood 2, 3.
• Studies have shown that methadone treatment can lead to an increase in body mass index (BMI) and body fat percentage, as well as a decrease in muscle mass and bone mass 2.
• However, the increase in BMI and weight gain during methadone maintenance treatment (MMT) has been found to be independent of methadone dosage and blood levels 3.

Factors Influencing Weight Gain

• Factors such as eating habits, food preferences, and nutrition knowledge have been found to play a role in weight gain during MMT 3.
• Patients with healthier status, such as those who are hepatitis C seronegative and do not abuse benzodiazepines, may be more likely to experience weight gain during MMT 3.
• A study found that weight gain uniformly began 3 to 6 months after initiation of methadone or a sharp increase in the dosage, and resolved when methadone was reduced or discontinued 4.

Methadone Metabolism

• Methadone is metabolized in the liver, primarily by the enzyme CYP2B6, which can influence methadone metabolism and clearance 5, 6.
• The activity of CYP2B6 can vary among individuals, leading to differences in methadone bioavailability and pharmacological effect 5, 6.
• Methadone disposition is susceptible to inductive and inhibitory drug interactions, which can alter its clinical effect and drug safety 5, 6.