A 28-year-old female with opioid use disorder on stable methadone maintenance therapy reports new-onset drowsiness, constipation, and miosis. Her methadone dose was recently increased. Which investigation is most appropriate to confirm suspected opioid toxicity and guide immediate management?

## Confirmation of Opioid Toxicity in Maintenance Therapy **Key Point:** Serum methadone level (therapeutic drug monitoring) is the gold-standard investigation to confirm opioid toxicity in a patient on maintenance therapy and to guide dose adjustment. ### Rationale for Serum Methadone Level **High-Yield:** Methadone has: - Narrow therapeutic window: 400–1200 ng/mL (therapeutic); >2000 ng/mL (toxic) - Long half-life (24–36 hours), leading to accumulation with dose increases - High inter-individual variability in metabolism (CYP3A4, CYP2B6 polymorphisms) - Risk of overdose if levels exceed safe range ### Clinical Presentation of Methadone Toxicity | Finding | Mechanism | |---|---| | Drowsiness, sedation | CNS depression | | Miosis (pinpoint pupils) | μ-receptor agonism | | Constipation | Opioid-induced bowel dysfunction | | Respiratory depression | Dose-dependent CNS/respiratory center depression | | QT prolongation (ECG) | Methadone's cardiac effects at high levels | **Clinical Pearl:** In this patient, the recent dose increase likely caused serum methadone accumulation. Serum level will quantify toxicity and guide dose reduction to prevent respiratory depression and overdose. **Mnemonic: TDM in Opioid Toxicity** — **T**herapeutic **D**rug **M**onitoring confirms the diagnosis and informs dose adjustment; it is the only investigation that directly measures the offending agent's concentration.