Mechanisms involved:
(1) Methadone is largely metabolized in the liver by cytochrome P450 system.
(2) The half-life of methadone in a person just starting therapy is longer than that seen in a chronic user due to induction of metabolism.
(3) Respiratory depression occurs in patients who accumulate the drug.
(4) A person starting therapy may not experience analgesia at lower doses, and the physician may be tempted to increase the dose.
Risk factors for significant respiratory depression and death:
(1) hepatic impairment (cirrhosis, chronic hepatitis)
(2) exposure to drugs that interfere with CYP3A4, CYP2C9 or CYP2C19.
(3) a high starting dose (a dose > 30 mg per day) or rapid increases in dose
(4) concurrent drug or alcohol abuse
(5) not being tolerant to opiates
(6) respiratory disease (COPD, asthma, pneumonia)
(7) not being properly supervised and monitored
