Methadone

[SH4:p116, CJA 2005(52(5)):p515]

 

Usage

• Analgesia in the setting of chronic pain syndrome
• Suppression of withdrawal symptoms
• Analgesia, post-operative

Structure

Physical properties

[CJA 2005(52(5)):p515]

• Synthetic opioid agonist
• pKa = 9.2
• Lipophilic
  * Octanol buffer partiton coefficient = 116
  * Similar to alfentanil (129), and between fentanyl (813) and morphine (1)
  * [MR2:p36]
• Base (as with all opioid alkoids)

Stereoenantiomers

[CJA 2005(52(5)):p515]

• R isomer (or l-isomer)
  * Potent MOP and DOP receptor agonist
• S isomer (or d-isomer)
  * Non-competitive antagonism at NMDA receptors (similar to ketamine)
  * Also inhibits 5HT and NA reuptake
  * Inactive at MOP
  * May contribute to neuropathic pain and mitgation of opioid-induced tolerance

Pharmacodynamics

• (Relatively) low abuse potential
• High inter-individual variability

Side effects

[SH4:p166]

• Similar side-effect profile as morphine
• Sedative and euphoric actions are less than morphine
• Miosis is less prominent
  * Addicts can develop complete tolerance to miosis produced by methadone

Methadone may also produce

• Prolonged QTc

QTc

[CJA 2005(52(5)):p518]

Prolonged QTc risk is highest when:

• IV administration of methadone
• Oral administration >200mg/day
• Medications such as:
  * Chlorpromazine
  * Clarithromycin
  * Disopyramide
  * Erythromycin
  * Haloperidol
  * Amiodarone
  * Some anti-arrhythmic drugs

Pharmacokinetics

Absorption

• Highly effective by the oral route (bioavailability = 85%)

Distribution

• Vd is high
  * 4.2 - 9.2 L/kg in opioid addicts
  * 1.7 - 5.3 L/kg in chronic pain patients

NB:

• Vd for morphine in steady state = 3-5L/kg

Plasma protein binding

• 86% bound to plasma proteins
  * Mostly alpha1-acid glycoprotein (AAG)

NB:

• AAG is also an acute-phase protein
• AAG level is increased in:
  * Stress
  * Opioid addiction
  * Cancer
  * Certain medications (e.g. amitriptylline)

Metabolism

[CJA 2005(52(5)):p515]

• Methadone is biotransformed (not conjugated) in liver
  * Phase I CYP450 enzymes
  * N-demethylation
• Most of metabolite cleared in bile when daily dose is less than 55mg

Enzymes responsible for N-demethylation

[CJA 2005(52(5)):p516]

• CYP3A4 (main enzyme)
• CYP1A2
• CYP2D6

NB:

• CYP2B6 may also be involved and may be more significant than CYP3A4

 

Metabolites

• Main metabolites = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)
  --> Inactive
• Minor metabolites (methadol and normethadol) have similar pharmacological activity

Elimination

Renal clearance

[CJA 2005(52(5)):p516]

• Small amount of methadone is excreted unchanged in urine (pH dependent)
  * pH > 6, <4% excreted unchanged in urine
  * pH < 6 (i.e. acidic), 30% excreted unchanged in urine
• Methadone does NOT accumulate in renal failure
• Methadone is poorly removed by haemodialysis

 

Elimination phase

[CJA 2005(52(5)):p516]

• Slow distribution (alpha-elimination) = 8 - 12 hours
  * Correlates with duration of analgesia (6 - 8 hours)
• Beta-elimination phase = 30 - 60 hours
  * Plasma level is subanalgesic, but sufficient to prevent withdrawal symptoms

[SH4:p116]

• Prolonged elimination half-time = 35 hours

Action profile

Oral

Time to peak plasma concentration = 2.5 hours (solution)

Time to peak plasma concentration = 3 hours (tablet)

Pharmaceutics

Formulation

Methadone Hydrochloride powder
--> Can be reconstituted for IV/IM/SC/PO/rectal use

Oral preparation

• Often mixed with orange drink or cherry syrup to deter parenteral use

Parenteral preparation

• Concentration 10mg/mL

Clinical

Administration

• Methandone 20mg IV produces postoperative analgesia lasting more than 24 hours

Opioid withdrawal

• Used for suppression of withdrawal symptoms in physically dependent persons (e.g. heroin addicts)
  * Efficient oral absorption
  * Prompt onset of action
  * Prolonged duration of action
• Methadone can be substituted for morphine in addicts at about 1/4 the dosage.
• Controlled withdrawal from opioids using methadone is
  * Milder
  * Less acute

Treatment of chronic pain

• Methadone has been advocated as an alternative to slow-release formulations for treatment of chronic pain due to low abuse potential.
• Main disadvantage is prolonged and unpredictable half-time
  --> Risk of accumulation and prolonged respiratory depression

Interaction

[CJA 2005(52(5)):p516]

• All 3 enzymes (3A4, 1A2, 2D6) are inhibited by SSRIs
• CYP3A4 is induced by:
  * Carbamazepine
  * Phenobarbitone
  * Phenytoin
  * Methadone itself
• No interaction with gabapentin and valproic acid
• Cross-tolerance with other opioids is variable

Conversion of methadone to other opioids

[CJA 2005(52(5)):p520-521]

• Equianalgesic conversion for methadone is less predictable than with other opioids
  * Incomplete tolerance between opioids
  * Conversion ratio is not bidirectional
• Morphine to methadone = 1:1
  --> Based on single dosing studies over 20 years ago
• Now new studies shown methadone more potent
  --> Median morphine to methadone ratio = 7.75:1