A 32-year-old man with opioid use disorder is being managed with methadone maintenance therapy. Regarding the pharmacology and clinical use of methadone in opioid dependence, all of the following are true EXCEPT:

Explanation

## Methadone Pharmacology in Opioid Use Disorder ### Mechanism of Action **Key Point:** Methadone is a **full mu-opioid agonist**, not a partial agonist. This is a critical distinction that is frequently tested. - Full agonism at mu-opioid receptors produces complete opioid effects - Produces cross-tolerance with other opioids, blocking euphoria from illicit opioid use - Prevents withdrawal symptoms due to its long half-life and receptor occupancy ### Pharmacokinetic Properties **High-Yield:** Methadone's long half-life (24–36 hours) is the primary reason it is suitable for once-daily maintenance therapy, distinguishing it from short-acting opioids. ### Clinical Adverse Effects **Warning:** QT prolongation is a serious and dose-dependent adverse effect of methadone, particularly at doses >100 mg/day. This can progress to torsades de pointes and sudden cardiac death. | Feature | Details | |---------|----------| | QT prolongation risk | Dose-dependent; baseline ECG and periodic monitoring recommended | | Drug interactions | CYP3A4, CYP2D6 inhibitors increase methadone levels | | Respiratory depression | Risk, especially in opioid-naive individuals or overdose | | Constipation | Common; prophylactic laxatives often needed | ### Comparison: Methadone vs. Buprenorphine | Property | Methadone | Buprenorphine | |----------|-----------|---------------| | Receptor action | Full mu-agonist | Partial mu-agonist | | Half-life | 24–36 hours | 24–72 hours | | Overdose risk | High (full agonist) | Lower (ceiling effect) | | QT prolongation | Yes, dose-dependent | Rare | | Withdrawal severity | More severe | Milder | **Clinical Pearl:** Buprenorphine's partial agonism provides a "ceiling effect" on respiratory depression, making it safer in overdose; methadone's full agonism carries higher overdose mortality risk. ### Correct Answer Rationale Option 2 (methadone as a partial agonist) is **incorrect**. Methadone is a **full mu-opioid agonist**. This is the distinguishing pharmacological feature that makes it effective for maintenance therapy but also carries higher overdose risk compared to partial agonists like buprenorphine.