Products
Methadone is commercially available as tablets, injectable solution, and oral solution (e.g., Ketalgin, Methadone Streuli). Methadone solutions are also prepared in pharmacies as extemporaneous preparations.
Structure and properties
Methadone (C21H27NO, Mr = 309.45 g/mol) is a synthetically prepared derivative of pethidine, which is itself a derivative of atropine. It is chiral and exists as a racemate, a mixture composed of the D and an L isomer. Levomethadone (L-methadone) is predominantly active. In drugs, methadone is usually present as methadone hydrochloride, a white crystalline powder that is soluble in water.
Effects
Methadone (ATC N07BC02) has analgesic, cough-irritant, sedative, respiratory depressant, mild constipating, miotic, and emetic properties. The effects are due to binding to opioid receptors, mainly the µ- and κ-receptors in the central nevus system, with much higher affinity at the µ-receptors than at the κ-receptors. Methadone differs from other opioids in having additional noncompetitive antagonistic activity at the NMDA receptor. NMDA is responsible for central pain transmission and plays an important role in the development of opioid tolerance and resistance.
Indications
- For the treatment of moderate to severe pain
- Indicated for substitution as part of heroin withdrawal treatment (see under methadone substitution).
Dosage
According to the drug label. Methadone has a variable half-life. Typically, it is approximately 24 hours and therefore once-daily administration is usually sufficient. Due to interindividual variability in pharmacokinetics, the dose must be adjusted individually for each patient. If it is not taken into account during dosing, accumulation can occur, leading to methadone intoxication, which can result in respiratory arrest and death. Methadone, as a solution for addicts, is usually diluted or dyed with syrup or juice, which prevents injection.
Contraindications
- Hypersensitivity
- Pregnancy and lactation
- Chronic respiratory insufficiency
- Pancreatitis
- Severe liver and kidney failure
- Methadone should also not be administered to patients with acute alcohol intoxication.
Full precautions can be found in the drug label.
Interactions
Methadone is metabolized mainly in the liver. CYP3A4, in particular, plays an important role in this process, metabolizing methadone via -demethylation to EDDP, an inactive metabolite. Other enzymes involved in biotransformation are CYP2D6, 2B6 and 1A2. Because many drugs are substrates, inducers, or inhibitors of CYP3A4, numerous interactions are possible. Co-administration of MAO inhibitors and methadone can cause a fatal drop in blood pressure and, in the worst case, can put patients into a coma. An increased depressant effect can be expected with centrally depressant substances, such as alcohol and sleeping pills.
Adverse effects
The most common adverse effects include nausea, vomiting, respiratory depression, constipation, sweating, dizziness, dry mouth, pruritus, drowsiness, sedation, euphoria, and dysphoria. A rare and serious adverse effect is prolongation of the QT interval, which can lead to cardiac arrhythmias. The most common reason for the occurrence of QT prolongation is concomitant administration of other QT-prolonging drugs or concomitant consumption of cocaine.
Methadone and heroin addiction
See under methadone substitution
