FRCA Notes

Methadone

  • Methadone is a propion anilide, a synthetic opioid primarily used for maintenance treatment of patients with opioid addiction
  • Presents as a racemic mixture of L- and R-methadone, although the R-enantiomer is primarily responsible for its analgesic effects

  • MOP receptor agonism
    • Owing to its long half-life, it functions in a similar function to a modified-release opioid
  • Weak NMDA receptor antagonism, which is beneficial in treating neuropathic pain that may be resistant to typical opioids
  • Weak serotonin and noradrenaline re-uptake inhibitor

Pharmacogenetics

  • There is a wide interindividual variability in plasma concentration following a given dose of methadone (up to 20x difference), which is in part due to genetic polymorphisms

Absorption

  • Relatively low 1st pass metabolism therefore high oral bioavailability of 75%
  • Slow onset of action

Distribution

  • 90% protein bound

Metabolism

  • Long plasma and unpredictable half-life; 18-36hrs
  • Hepatic metabolism by primarily CYP3A4, amongst other CYP450 enzymes, to inactive metabolites
  • Prone to accumulation in hepatic or renal impairment

Excretion

  • Excreted 40% unchanged in the urine
  • Urinary excretion is enhanced by acidic conditions

Respiratory

  • Some suggestion methadone is more likely to cause opioid-induced ventilatory insufficiency

Cardiovascular

  • Can cause cardiovascular side-effects due to inhibition of the cardiac-ion channel KCNH226
  • Most prominent amongst these is dose-dependent prolongation of the QT interval (23-59%)
  • Associated with other dysrythmic effects including:
    • Torsade des pointes
    • Pathological U-waves
    • Brugada-like syndrome
    • Takotsubo cardiomyopathy

Neurological

  • Less sedative than morphine

Metabolic

  • Associated with a dose-dependent risk of hypoglycaemia

Drug interactions

  • Subject to the effect of hepatic enzyme inducers/inhibitors
    • Enzyme induction may increase metabolism and cause withdrawal e.g. anti-retrovirals, carbamazepine, rifampicin, phenytoin
    • Enzyme inhibition may increase risk of adverse effects/toxicity/overdose e.g. anti-retrovirals, anti-fungals, SSRs

Other

  • Less pruritus than morphine

Dosing

  • Up to 120mg PO as an adjunct in opioid dependence
  • 0.1 - 0.3mg/kg IV (approximately 5-10mg); use lower end for opioid naive patients - not licensed in the UK

Continuation

  • Continue existing methadone maintenance regimens through acute pain episodes where possible
  • Intraoperative administration of methadone reduces consumption of short-acting opioids in the 24 hours after surgery
  • Should not, however, be used to treat acute pain because of its function akin to a modified release opioid
  • Not suitable for PCA use

Substitution

  • If a patient is admitted who is usually on methadone, but the dose is unknown use immediate release oral morphine 10-30mg 2hrly based on clinical opiate withdrawal scale severity
  • If a patient is admitted who is usually on methadone but is NBM/unable to take orally, substitute for a morphine PCA:
    • 10-30mg methadone → 0.5-1mg bolus with 0.3-0.5ml/hr background rate
    • >30mg methadone → 1-2mg bolus with 0.5-1ml/hr background rate
  • Consider use of ketamine in the PCA, especially for acute nociceptive pain

  • After 3 days without dose tolerance drops so consider reducing dose

  • If in hospital and find usual dose isn’t lasting consider splitting dose to BD eg 60mg OD becomes 30Mg BD but ensure note to return to normal dose on discharge

Discharge

  • Wean off strong opioids prior to discharge
  • Do not discharge on a day they can’t get a script from their inclusion centre e.g. weekend and bank holiday