Pharmacology Notes

Methadone is a mu agonist with several features that differentiate it from most opioids:

Methadone has no active metabolites, an oral bioavailability of around 80%, high lipid solubility and is relatively inexpensive. It is well absorbed orally and does not undergo extensive first-pass metabolism. It has an elimination half-life of 30 to 35 hours.

Methadone is metabolised by several cytochrome P450 enzymes (3A4, 1A2 and 2D6), and this accounts for the large number of potential interactions between methadone and other drugs that are also metabolised by this system of enzymes. Some SSRIs, antifungals, and macrolide antibiotics can increase the plasma methadone concentration, and potentiate action.

Methadone can be used twice daily for maintenance management of chronic pain. Initiation of methadone for pain, or conversion to methadone from other opioids must be done with understanding of its complicated kinetics, and careful observation of the patient for cumulative toxicity, which is heralded by sedation and confusion. Patients unable to tolerate oral methadone may nevertheless benefit from parenteral administration.

Care needs to be taken with methadone to avoid toxicity because the time to reach steady-state concentrations following a change in dosage may be up to 12 days. Dose conversion ratios from other opioids are not static, but are a function of previous opioid exposure. These complexities make it an unsuitable drug for all but those practitioners experienced in its use. Published tables of equianalgesic doses of opioids, established in healthy opioid-naive individuals, indicate that methadone is 1 to 2 times as potent as morphine in single-dose studies, but in individuals on long-term morphine, methadone can be more than 10 times as potent as morphine 

Methadone can be used once daily to prevent withdrawal in opioid-dependent patients. It is used as short-term treatment in opioid withdrawal and as maintenance therapy (the long-term substitution of oral methadone for heroin and other opioids). It has the advantages of high acceptability, particularly in comparison to withdrawal- and abstinence-based approaches, and proven effectiveness in reducing illicit opioid use.

The methadone dose needs to be determined individually, taking into account the amount of opioids used prior to commencement and the initial response to methadone. Care needs to be taken to avoid toxicity because the time to reach steady-state concentrations following a change in dosage may be up to 12 days. Cumulative toxicity is usually heralded by sedation and confusion.

It is important for physical health to be assessed before starting methadone. Deaths have usually occurred in patients with poor physical health and in the early weeks of treatment. Liver function tests and hepatitis B, hepatitis C and human immunodeficiency virus serology are useful tests to consider.