The clinical use of methadone in cancer and chronic pain medicine

Abstract

### Key points Methadone is an opioid invented in Germany during the Second World War. Clinical trials were initiated in the USA in 1947, and methadone was originally marketed as Dolophine, with etymological origins from the Latin words dolor (pain) and fins (end). It was recognized in 1964 that it could be used to diminish or prevent the symptoms of craving and withdrawal in heroin users, and continues to be widely used in the management of opioid addiction. During the last 50 years it has also found a place in the management of cancer and chronic pain. Methadone is a synthetic phenylheptylamine μ-opioid agonist with a molecular weight of 345.9. It is lipophilic and has a volume of distribution of 4 l kg−1. It has p K a of 9.2, and so at physiological pH only 1% of the drug is ionized.1 It is presented as a racemic mixture of R- and S -methadone, with the R -enantiomer being primarily accountable for μ-receptor agonism and therefore analgesia. The S -enantiomer is responsible for N-Methyl-D-Aspartate (NMDA) antagonism, having an affinity at the NMDA receptor similar to ketamine, and serotonin and norepinephrine reuptake inhibition.2 This NMDA antagonism may help to prevent opioid tolerance, withdrawal, and opioid-induced hyperalgesia. Finally, methadone may also interact with Na channels in a similar manner to local anaesthetics. A summary of the pharmacokinetic characteristics of the drug are summarized in Table …