Methadone

Where it fits clinically

Strong opioid used for analgesia and for opioid dependence therapy; distinctive for long and variable half-life and additional NMDA antagonism.
- Perioperative relevance: patients on maintenance methadone, chronic pain, opioid tolerance/hyperalgesia, difficult postoperative pain.
Common scenarios: elective surgery in a patient on daily methadone; acute pain in opioid-tolerant patient; ICU sedation/analgesia weaning; neuropathic component pain (adjunct effect via NMDA).

Perioperative approach (practical)

Continue the patient’s usual methadone dose on the day of surgery where possible; it prevents withdrawal but does not reliably cover acute surgical pain.
- If NBM: give oral dose with a sip of water if permitted; if not possible, seek specialist advice for alternative route/temporary regimen.
Treat acute pain with multimodal analgesia and additional short-acting opioids titrated to effect; expect higher requirements due to tolerance.
Monitor for delayed respiratory depression due to long/variable half-life and accumulation; consider HDU/extended monitoring if high doses or interacting drugs.
Check ECG/QTc if high dose, risk factors, or interacting drugs; correct electrolytes (K+, Mg2+, Ca2+).

If asked to prescribe (adult, general principles)

Start low and go slow due to accumulation and inter-individual variability; avoid rapid up-titration.
Use specialist/local guidance for initiation and conversion; conversion from other opioids is non-linear and dose-dependent.

Class & key properties

Synthetic opioid (diphenylheptane). Racemic mixture: R-methadone provides most μ-opioid agonism; S-methadone contributes more to QT effects and NMDA antagonism.
Mechanisms: μ-opioid receptor agonist; NMDA receptor antagonism; inhibits reuptake of serotonin and noradrenaline (variable).
Clinical implications: useful in opioid tolerance/hyperalgesia and neuropathic pain features; but higher risk of accumulation and QT prolongation than many opioids.

Pharmacokinetics

Absorption: good oral bioavailability (often quoted ~70–90%); onset oral ~30–60 min; IV onset minutes.
Distribution: highly lipophilic; large Vd; extensive tissue binding → prolonged effect and accumulation with repeated dosing.
Metabolism: hepatic (CYP3A4, CYP2B6, CYP2D6 involvement); significant inter-patient variability; auto-induction described.
Elimination: metabolites excreted in urine and faeces; renal excretion of parent drug varies with urinary pH (ion trapping).
Half-life: long and highly variable (commonly quoted ~15–60 h; can be longer). Analgesic duration is shorter (often ~4–8 h early in therapy).

Pharmacodynamics

Analgesia via μ-receptor: spinal and supraspinal effects; reduces neurotransmitter release and increases postsynaptic K+ conductance.
Respiratory depression: dose-dependent; risk of delayed depression due to long half-life and accumulation.
Cardiac electrophysiology: can prolong QTc (hERG K+ channel blockade) → torsades de pointes risk.
Other opioid effects: sedation, miosis, nausea/vomiting, constipation, urinary retention, pruritus; endocrine effects with chronic use.

Indications

Opioid dependence maintenance therapy and supervised consumption programmes.
Chronic pain (including cancer pain) when other opioids poorly tolerated or ineffective; may help where neuropathic component suspected.
Perioperative/acute pain: occasionally used (e.g., intraoperative methadone as long-acting opioid) but requires careful dosing/monitoring.

Contraindications & cautions

Caution: respiratory disease, sleep apnoea, frailty, hepatic impairment, severe obesity, concomitant sedatives (benzodiazepines, alcohol, gabapentinoids).
QT risk: congenital long QT, previous torsades, significant bradycardia, heart failure, electrolyte abnormalities, high doses, interacting QT-prolonging drugs.
Caution with serotonergic drugs (SSRIs/SNRIs/MAOIs, tramadol, linezolid): potential serotonin toxicity (rare but important).

Drug interactions (high-yield)

CYP inducers ↓ methadone levels → withdrawal/poor analgesia: rifampicin, carbamazepine, phenytoin, St John’s wort.
CYP inhibitors ↑ methadone levels → toxicity/QT risk: azole antifungals, macrolides, some SSRIs, protease inhibitors.
Additive CNS/respiratory depression: benzodiazepines, alcohol, gabapentinoids, other opioids, sedating antihistamines.
QT-prolonging combinations: antipsychotics (e.g., haloperidol), macrolides, fluoroquinolones, antiemetics (e.g., ondansetron), amiodarone—risk is cumulative.

Adverse effects

Common opioid: nausea/vomiting, constipation, sedation, pruritus, urinary retention, hypotension (less histamine release than morphine).
Serious: respiratory depression (including delayed), QT prolongation/torsades, overdose due to accumulation, serotonin toxicity (rare).
Withdrawal if abruptly stopped: anxiety, sweating, abdominal cramps, diarrhoea, mydriasis, tachycardia; may be prolonged due to long half-life.

Perioperative management of the patient on maintenance methadone

Pre-op: confirm dose, formulation, time of last dose, supervised vs take-home, other substances (benzodiazepines, alcohol), and baseline ECG/QTc if available.
Intra-op: anticipate opioid tolerance; use regional techniques where possible; consider ketamine, clonidine/dexmedetomidine, NSAIDs/paracetamol.
Post-op: continue baseline methadone; add short-acting opioid (e.g., morphine/oxycodone/fentanyl) titrated; avoid under-treating pain (withdrawal can mimic pain/anxiety).
Safety: monitor sedation/respiration longer than usual if additional opioids given; avoid large long-acting opioid additions without monitoring.

Overdose & reversal

Features: respiratory depression, reduced conscious level, miosis (may be variable), bradycardia, hypotension; consider QT prolongation/arrhythmia.
Naloxone: titrate small IV boluses to restore ventilation (not full arousal). Methadone duration may exceed naloxone → consider infusion and prolonged observation.
Treat torsades if occurs: magnesium, correct electrolytes, stop QT-prolonging drugs, consider overdrive pacing/isoprenaline depending on context.

Describe methadone: class, mechanism of action, and why it is different from morphine.

Aim: hit μ-agonism + NMDA antagonism + long/variable half-life + QT issues.

Synthetic strong opioid (diphenylheptane), racemic mixture.
Primary action: μ-opioid receptor agonist → analgesia, sedation, respiratory depression.
Additional actions: NMDA receptor antagonism and monoamine reuptake inhibition (5-HT/NA) → may help opioid tolerance/hyperalgesia and neuropathic pain features.
Key differences vs morphine: long and highly variable elimination half-life; analgesic duration shorter than half-life; higher risk of accumulation and delayed respiratory depression; QT prolongation risk.

Explain the pharmacokinetics of methadone and the clinical consequences for dosing.

Examiners want: high oral bioavailability, lipophilicity/large Vd, CYP metabolism variability, long half-life vs shorter analgesic duration, accumulation.

Good oral bioavailability (often ~70–90%) → effective oral maintenance dosing.
Highly lipophilic, large Vd, extensive tissue binding → slow release back to plasma and accumulation with repeated dosing.
Hepatic metabolism via CYP enzymes (notably CYP3A4/CYP2B6) with marked inter-individual variability → unpredictable levels and response.
Elimination half-life long/variable (commonly ~15–60 h or longer) but analgesic duration often ~4–8 h early in therapy → temptation to re-dose can cause accumulation and delayed toxicity.
Clinical consequence: initiate and titrate slowly; avoid frequent dose escalations; monitor sedation/respiration and QTc in higher-risk patients.

A patient takes methadone 80 mg once daily for opioid dependence and presents for emergency laparotomy. Outline your perioperative analgesic plan.

Core principles: continue baseline methadone, treat acute pain separately, multimodal/regional, anticipate tolerance, monitor for delayed depression and QTc issues.

Pre-op: confirm dose/time last taken; assess co-ingestants; check ECG/QTc if feasible; correct K+/Mg2+/Ca2+ if abnormal.
Continue usual methadone dose perioperatively (prevents withdrawal) using oral route if possible; if NBM, seek specialist advice for alternative regimen.
Intra-op: balanced anaesthesia; consider regional (epidural/TAP) if appropriate; add ketamine infusion and standard non-opioids (paracetamol ± NSAID).
Opioids for surgical pain: use short-acting opioids titrated to effect (e.g., fentanyl intra-op; PCA morphine post-op) anticipating increased requirements.
Post-op: HDU-level monitoring if large opioid requirements, significant comorbidity, or QT risk; avoid adding additional long-acting opioids without monitoring.

Why does methadone cause QT prolongation, and how would you manage a patient at risk perioperatively?

Need: mechanism (hERG blockade), risk factors, monitoring, mitigation, torsades management.

Mechanism: blockade of cardiac delayed rectifier potassium current (hERG/IKr) → prolonged repolarisation → QTc prolongation and torsades risk.
Risk factors: high methadone dose, congenital long QT, bradycardia, heart failure, female sex, electrolyte disturbance (low K+/Mg2+/Ca2+), interacting QT-prolonging drugs.
Perioperative management: obtain ECG if concerns; avoid/limit other QT-prolonging drugs where possible; correct electrolytes; maintain normothermia and avoid marked bradycardia.
If torsades occurs: magnesium, correct electrolytes, stop precipitating drugs; consider overdrive pacing/isoprenaline depending on haemodynamics.

Compare methadone with morphine in terms of metabolism, active metabolites, and use in renal failure.

Key contrasts: morphine has active renally excreted metabolites; methadone is hepatically metabolised with minimal active metabolites.

Morphine: hepatic glucuronidation → M6G (active analgesic) and M3G (neuro-excitatory); both accumulate in renal failure → increased sedation/respiratory depression and neurotoxicity.
Methadone: hepatic CYP metabolism; no clinically important active metabolites like morphine’s glucuronides; elimination partly faecal/urinary and affected by urinary pH.
Clinical: methadone may be preferred over morphine in renal impairment, but dosing remains complex due to long/variable half-life and interaction potential; specialist input advised.

A patient on methadone becomes very drowsy with a low respiratory rate in PACU. How do you manage this, and what is different about reversal compared with shorter-acting opioids?

Focus: airway/ventilation first, naloxone titration, infusion, prolonged observation, avoid precipitating withdrawal.

Immediate: ABC approach, airway support, oxygen, assist ventilation; check glucose and consider other causes (residual anaesthetic, co-ingestants).
Naloxone: titrate small IV boluses to achieve adequate ventilation (not necessarily full wakefulness) to avoid acute withdrawal and severe pain.
Because methadone lasts much longer than naloxone, recurrent respiratory depression is common → consider naloxone infusion and extended monitoring.
Assess QTc/arrhythmia risk and review interacting sedatives/QT-prolonging drugs; correct electrolytes.

Explain why methadone is associated with accumulation and delayed toxicity.

The classic FRCA point: half-life is long/variable and longer than analgesic duration; repeated dosing before steady state causes accumulation.

Long, variable elimination half-life with large Vd and tissue storage → plasma levels can rise over days even if the dose is unchanged.
Analgesic duration is shorter than elimination half-life, especially early in therapy → clinicians may re-dose for pain before drug has cleared.
CYP interactions and genetic variability (notably CYP2B6) further increase unpredictability.

List important drug interactions with methadone relevant to anaesthesia and critical care.

Cover: CYP inducers/inhibitors, additive sedation, QT-prolongers, serotonergic combinations.

CYP inducers (↓ levels): rifampicin, carbamazepine, phenytoin, St John’s wort.
CYP inhibitors (↑ levels): azoles, macrolides, some SSRIs, protease inhibitors.
Additive respiratory depression: benzodiazepines, alcohol, gabapentinoids, other opioids.
QT-prolonging drugs: haloperidol, ondansetron, macrolides, fluoroquinolones, amiodarone (risk cumulative).
Serotonergic drugs: SSRIs/SNRIs/MAOIs, linezolid, tramadol → serotonin toxicity risk.

You are asked to convert a patient from high-dose morphine to methadone. What principles and safety issues would you highlight?

FRCA angle: conversions are hazardous and non-linear; emphasise specialist involvement and monitoring.

Equianalgesic conversion is non-linear and depends on prior opioid dose and tolerance; published ratios vary and are not reliable without expertise.
High risk of overdose due to accumulation and delayed respiratory depression; dose titration must be slow with close monitoring.
Check QTc and interacting drugs; correct electrolytes; consider inpatient initiation for higher-risk patients.
Involve pain/addiction specialists and follow local protocols.

What are the key differences between using methadone for opioid dependence vs for analgesia?

Dependence: once-daily to prevent withdrawal/craving; analgesia: often requires divided dosing; both require caution due to half-life variability.

Dependence therapy: typically once daily dosing aims to prevent withdrawal/craving; supervised consumption common; steady-state considerations important.
Analgesia: analgesic duration often shorter than half-life → may require divided doses; careful titration to avoid accumulation.
Perioperative: maintenance dose should be continued, but additional analgesia is required for surgical pain.