2025ADVANCE Describe the pharmacology of methadone.

 

Physicochemical:

Origin

·     First synthesised in Germany… in 1937…

Presentation

·     Oral (tablet, liquid)

·     IV methadone HCl 10mg/mL

Chemistry

·     Synthetic diphenylheptanone

·     MW 346g/mol

·     pKa 8.5, 10% unionised

·     Highly lipid soluble (Octanol:Water 115)

Stereochemistry

·     Racemic mixture

·     R-methadone: opioid

·     S-methadone: NMDA antagonist, monoamine reuptake inhibitor, ↑QTc

 

Pharmacokinetic

Administration

·     PO

·     IV, IM, SC

Dosing

·     ≤0.1mg/kg -> day case

·     0.15-0.25mg/kg -> overnight stay

·     ≥0.3mg/kg -> ICU

Time course

·     Onset: within minutes

·     Peak: analgesia 10 mins, resp depression later

·     Duration: dose-dependent

o   10mg: few hours

o   20mg: 1 day

o   30mg: 3 days

Absorption

·     Oral bioavailability 75%: low first pass hepatic metabolism

·     Variable time to peak effect 1-5 hours

Distribution

·     Highly bound to plasma proteins (α1AG, 90%)

·     Extensively distributed (VDss 6L/kg)

·     Moderately quick distribution to tissues (t1/2α 6 mins)

·     Moderately quick equilibration with CNS (t1/2ke0 8 mins)

·     Crosses placenta. Pregnancy Class C

·     Small amounts in breast milk (N.B. minimal intake first week of life)

Metabolism

Pathways:

·     Hepatic Phase 1 N-demethylation

·     2B6 > 3A4 > 2C19, 2C9, 2D6

·     Major metabolite inactive (EDDP -> EMDP)

·     Minor metabolite weakly active (nor-methadol)

Speed:

·     Longest duration of all opioids

·     Cl 6mL/kg/min

·     t1/2β 15-60 hours, mean 1 day

Variability:

·     Significant 2B6 polymorphism

·     Reduced function alleles common worldwide

·     Oceania (60%) > Africa (40%) > Europe (30%) > Asia (20%)

·     Affects S-methadone >> R-methadone

·     Slow phenotype -> ↑S-methadone -> ↑QTc with repeat dosing

·     Minimal effect on duration of opioid activity

Excretion

·     Parent -> Urine (10%)

o   ↑ if ↓pH (up to 30%)

·     Metabolites -> bile, urine

 

Pharmacodynamic

Receptor effects

·     Full μ opioid agonist

·     NMDA antagonist (contribution unknown, likely less than ketamine)

·     NAd and 5HT reuptake inhibitor

Thresholds

·     Severe Resp Depression: ~100ng/mL

·     Complete Analgesia: ~60ng/mL

·     Partial Analgesia: ~30ng/mL

Uses

·     Opioid addiction

·     Opioid withdrawal

·     Acute & chronic pain

·     Somatic & visceral & neuropathic pain

·     Evidence base across many surgical specialties

Benefits

·     ↓Opioid side effects (cf. pure opioids at equi-analgesic doses)

·     ↓Opioid use (up to 3/12 post-op)

·     ↓Pain scores (up to 3/12 post-op)

·     The above could reduce the risk of long-term use and addiction

Respiratory depression

·     Especially with benzodiazapines, gabapentinoids

·     Especially if sleep-disordered breathing

·     Partial reversal of effect with naloxone

·     Highest risk 30-45 mins (cf. intrathecal morphine 6-12 hours)

Serotonin syndrome

·     Mostly with high doses

·     Mostly if combined with other serotonergic drugs

·     MAOi (14 days offset), tramadol, pethidine, TCA, SSRI*

·     (*Methadone + SSRI is common and appears safe)

Torsades de Pointes

·     Inhibits cardiac K+ (IKr) channels -> ↑QTc and ↑risk TdP

·     Risk factors:

o   Congenital long QT

o   Class 3 antiarrhythmic

o   Electrolyte disturbance (↓K+, ↓Mg2+)

·     Usually with repeated high dose (>100mg/day)

·     Could be mimicked with a big IV push

 

PK & PD:

User’s Guide:

Dosing

·     Day case: 5-10mg (e.g. elective lap chole)

·     Overnight stay: 10-20mg (e.g. joint replacement)

·     ICU major: 20-30mg (e.g. upper midline laparotomy)

Timing

·     Give a bit at a time, e.g. 2-3mg q2 mins

·     Give most of it early: anaesthetic room vs induction vs pre-incision

·     Give a small top up at end of case if needed

·     Titrate against pupil size, RR, PaCO2

Adjuvants

Ketamine: Yes

·     Significant extra benefit

·     Give as you normally would

Benzodiazepines: Careful

·     Avoid if short procedure / day case / sleep-disordered breathing

·     Small dose (0.5-2mg) ok when lining up for major procedure

·     Opioids aren’t anxiolytic, come at me

Pure Opioids: Careful

·     Induction: use short-acting opioid

·     Recovery: as usual

·     Ward: as usual. Lower dose or PCA if concerned.

·     Long acting: no intrathecal morphine. No slow-release opioid.

Anaesthetic

Wakeup Strategies: (for long procedure + comfortable patient)

·     Processed EEG for titration

·     Sevoflurane -> propofol +/- remifentanil (mid-procedure switch)

·     Sevoflurane -> desflurane (mid-procedure switch, if in stock)

·     (Sevoflurane’s 90% decrement time climbs steeply after 2 hours)