Methadone

Methadone is a full mu-opioid agonist with high oral bioavailability (80–95%), very long and variable half-life (24–36 hrs, up to 120 hrs in some patients), and NMDA receptor antagonism. It accumulates significantly; dose titration must be slow to avoid inadvertent overdose. Unlike buprenorphine, there is no ceiling effect for respiratory depression.

Before initiation: In Victoria, methadone prescribers need completed RACGP MATOD training and Department of Health approval to prescribe methadone, plus a permit for each patient (apply through SafeScript; do not start until it is issued, usually within one working day). SafeScript must be checked each time a prescription is written. Establish dispensing pharmacy and supervised consumption arrangements before the first dose is given, and offer take-home naloxone.

Induction, Day 1: Assess opioid tolerance carefully. Start 10–30 mg orally (use 10–20 mg if tolerance is uncertain, mixed opioid use pattern, or any concern about over-sedation risk). Do not re-dose on Day 1: methadone accumulates and delayed toxicity typically occurs 24–72 hrs after initiation. Clinical review within 24–48 hrs is mandatory. Overdose risk is highest in the first 14 days of treatment. Unlike buprenorphine, no COWS threshold is required before initiation; methadone is a full agonist and does not precipitate withdrawal.

Titration: Increase by 5–10 mg no more frequently than every 3–5 days. This interval is not negotiable. The long, variable half-life means each dose increase has a delayed peak effect; increases made more frequently cause inadvertent accumulation and fatal toxicity. Reassess at each titration step.

Maintenance: Typically 60–120 mg/day. Adequate dosing (>60 mg/day) is strongly associated with improved retention in treatment and suppression of illicit opioid use. Under-dosing is a common and avoidable cause of treatment failure: dose should reflect clinical response, not an arbitrary ceiling.

Supervised dispensing: Initially daily supervised consumption at the dispensing pharmacy. Only the prescriber can authorise take-away doses (TADs). The Victorian ODT Guidelines base TADs on stability (engagement, safe storage, no recent overdose or injection of TADs), not on time in treatment alone; use their checklist (Appendix 5) and confirm with the pharmacist. A patient who misses 4 or more consecutive doses must be reviewed by the prescriber before the next dose. PBS prescriptions: 28 days' supply with up to 5 repeats. SafeScript monitoring applies throughout treatment.

Physeptone® 5 mg tablets: scored, divisible. Not registered or funded for ODT, so the patient meets the cost. Use in ODT is limited to the circumstance described in the Victorian ODT Guidelines (see below). Conversion from liquid: 1:1 mg-for-mg, bioequivalent pharmacokinetics; no dose adjustment required when switching a stable patient.

Outside ODT (for example, methadone prescribed for pain), use of methadone tablets is a matter of clinical and professional judgement; in Victoria a Schedule 8 permit is still needed to prescribe to a person who is drug dependent. Document reasoning clearly.

The evidence base for methadone treatment is derived from oral liquid formulation studies. Dole & Nyswander (1965): foundational evidence for methadone maintenance. Mattick RP et al. Cochrane Database Syst Rev 2009: methadone significantly superior to placebo for retention and heroin abstinence. No RCTs compare tablet to liquid formulation in OUD; tablets are bioequivalent (equivalent C_max, AUC, half-life). Tablet-specific risks documented in literature include higher diversion rates and injection misuse risk relative to supervised liquid dispensing.

• QTc prolongation: dose-dependent; baseline ECG required, repeat at 30–40 mg/day and 100+ mg/day; avoid concurrent QTc-prolonging drugs
• Accumulation risk: long, variable half-life causes delayed toxicity; never increase dose more frequently than every 3–5 days during induction
• No ceiling effect: unlike buprenorphine, respiratory depression increases linearly with dose; concurrent CNS depressants (benzodiazepines, alcohol, opioids) are particularly dangerous
• CYP3A4 and CYP2D6 interactions: many common drugs raise or lower methadone levels (fluconazole, rifampicin, carbamazepine, HIV antiretrovirals); check all interactions before prescribing
• Concurrent benzodiazepines or alcohol: compound respiratory depression; assess risk vs benefit carefully; dose reduction may be required
• Tablets: diversion risk higher than liquid; tablets can be concealed, shared, or sold; assess carefully and document rationale before prescribing take-away doses in tablet form
• Tablets: injection misuse risk; tablets can be crushed and injected; this is a key reason the Victorian ODT Guidelines ask prescriber and pharmacist to assess and document these risks before tablets are supplied
• SafeScript monitoring required in Victoria for all methadone prescribing
• Victoria: MATOD training and Department of Health approval to prescribe methadone, plus a permit for each patient; send the Notification of termination form when treatment ends; other states differ
• Document capacity, consent, clinical rationale, and risk assessment before prescribing tablets (the Victorian ODT Guidelines advise that prescriber and pharmacist both fully document their reasons)