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A plain-language summary of the cited sources below. Informational only — not medical advice.
Methadone is a strong opioid medication with two main uses: treating dependence on opioid drugs, and managing severe ongoing pain when other pain treatments haven't worked or can't be used. It works differently from many other opioids because it acts on two separate systems in the body. The levomethadone part activates opioid receptors (which is how it relieves pain and prevents withdrawal symptoms), while both parts of the molecule block NMDA receptors in the brain. This NMDA blocking action may help reduce the development of tolerance and appears to make methadone particularly effective for nerve pain that doesn't respond well to other opioids. The combination of these two actions provides pain relief while potentially limiting how quickly the body adapts to the medication.
Methadone stays in the body for a long time—its half-life ranges from 15 to 60 hours, which means it can take several days for the medication to reach stable levels or to clear after stopping. This long and variable half-life is why dosing needs careful adjustment when someone first starts taking it or when doses change. The body breaks methadone down mainly using the CYP3A4 enzyme, though other enzymes including CYP2D6 are also involved, which means medications that affect these enzymes can alter how methadone works.
Common side effects your family member might experience include nausea, vomiting, dry mouth, dizziness, and drowsiness. More serious effects that require immediate medical attention include slowed or difficult breathing (respiratory depression), very low blood pressure or collapse, and heart rhythm problems—specifically QT prolongation, which can lead to a dangerous irregular heartbeat called Torsade de Pointes. Methadone can also cause adrenal insufficiency and a breathing problem during sleep called central sleep apnoea syndrome.
Methadone cannot be used in people with severe lung disease, acute breathing problems, or during an asthma attack. It's also contraindicated in people with severe liver impairment, existing heart rhythm problems (including congenital long QT syndrome), head injury with raised pressure in the skull, acute alcohol intoxication, or ulcerative colitis. Your family member should not receive methadone if they are taking monoamine oxidase inhibitors or have stopped taking them within the past 14 days.
Severe disabling pain Clinical criteria: Patient must not be opioid naive, AND Patient must have had or would have inadequate pain management with maximum tolerated doses of non-opioid and other opioid analgesics; OR Patient must be unable to use non-opioid and other opioid analgesics due to contraindications or intolerance. Treatment criteria: Patient must be undergoing palliative care. Authority requests for treatment duration up to 1 month may be requested through the Online PBS Authorities system or by calling Services Australia. Authority requests extending treatment duration beyond 1 month may be requested through the Online PBS Authorities system or in writing and must not provide a treatment duration exceeding 3 months (quantity sufficient for up to 1 month treatment and sufficient repeats).
“The combination of opioid agonism and N-methyl-d-asparate (NMDA) antagonism by methadone produces an additive analgesic response while limiting opioid tolerance.”
“Elimination half-lives vary considerably (a range of 15 to 60 hours has been reported) and careful adjustment of dosage is necessary with repeated administration.”
A plain-language summary of the cited sources below. Informational only — not medical advice.
Methadone is a long-acting μ-opioid receptor agonist with NMDA receptor antagonism, indicated for treatment of opioid dependence and management of severe pain where other options have failed or are inappropriate and the pain is opioid-responsive requiring daily, continuous, long-term treatment. The dual mechanism—opioid agonism combined with NMDA antagonism—produces additive analgesia while limiting opioid tolerance, and may contribute to methadone's efficacy in neuropathic pain states. Levomethadone carries higher intrinsic activity than morphine; dextromethadone has much lower μ-receptor affinity but both enantiomers act as non-competitive NMDA antagonists.
Elimination half-life ranges from 15 to 60 hours, necessitating careful dose titration with repeated administration. Methadone undergoes N-demethylation primarily via CYP3A4, with CYP2D6 and other CYP450 enzymes also involved; co-administration of CYP3A4 inducers or inhibitors may alter plasma levels significantly. Common adverse effects include nausea, vomiting, dry mouth, dizziness and drowsiness. Serious risks include respiratory depression, QT prolongation with potential for Torsades de Pointes, hypotension, adrenal insufficiency and central sleep apnoea syndrome.
Methadone is contraindicated in severe or acute respiratory disease, respiratory depression, bronchial asthma exacerbation, acute alcoholism, head injury, raised intracranial pressure, concurrent monoamine oxidase inhibitor use, ulcerative colitis, severe hepatic impairment, biliary or renal tract spasm, and pre-existing QT prolongation including congenital long QT syndrome.
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Opioid dependence Clinical criteria: The treatment must be within a framework of medical, social and psychological treatment. The prescriber must request a quantity (in millilitres) sufficient for up to 28 days of supply per dispensing according to the patient's daily dose. Up to 5 repeats will be authorised. The maximum listed quantity or number of repeats must not be prescribed if lesser quantity or repeats are sufficient for the patient's needs.
Chronic severe disabling pain Clinical criteria: Treatment Phase: Initial PBS treatment after 1 June 2020 where patient has been treated with opioids for less than 12 months The condition must require daily, continuous, long term opioid treatment, AND Patient must not be opioid naive, AND Patient must have cancer pain; OR Patient must have had or would have inadequate pain management with maximum tolerated doses of non-opioid and other opioid analgesics; OR Patient must be unable to use non-opioid and other opioid analgesics due to contraindications or intolerance. Treatment criteria: Must be treated by a health practitioner who is any of: (i) a medical practitioner, (ii) an authorised PBS prescriber who is not a medical practitioner, but who is: (a) sharing care of the patient with at least one medical practitioner; (b) intending to share care of the patient with a medical practitioner. Authorities for increased maximum quantities and/or repeats under this restriction must only be considered for chronic severe disabling pain where the total duration of non-PBS and PBS opioid analgesic treatment is less than 12 months. Authority requests extending treatment duration up to 1 month may be requested through the Online PBS Authorities system or by calling Services Australia. Authority requests extending treatment duration beyond 1 month may be requested through the Online PBS Authorities system or in writing and must not provide a treatment duration exceeding 3 months (quantity sufficient for up to 1 month treatment and sufficient repeats).
Curated subset. The full adverse-effect list is in the TGA Product Information; click any citation above to open it.
“Methadone undergoes N-demethylation to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrilidine (EDDP) with CYP3A4 being the main enzyme responsible. However, other CYP450 enzymes, including CYP2D6, are also likely to be involved in methadone's metabolism.”