ORLAAM

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ORLAAM (ORLAAM).

How it works

Mu-opioid receptor agonist; produces analgesia and CNS depression by mimicking endogenous opioids.

What the body does with it

Metabolism	Hepatic via CYP3A4; major metabolite is noracetylmethadol (active).
Excretion	Primarily renal (approximately 50-60% as unchanged drug and metabolites), with biliary/fecal elimination accounting for about 20-30%. The remainder is metabolized and eliminated via other routes.
Half-life	Terminal elimination half-life is approximately 30-60 hours (mean ~45 hours) in normal renal function. Due to this long half-life, steady-state is reached in 7-10 days, and the drug accumulates with repeated dosing, providing prolonged opioid effects. Half-life is significantly prolonged in renal impairment.
Protein binding	Approximately 70-80% bound to plasma proteins, primarily to alpha-1-acid glycoprotein. Binding is saturable and concentration-dependent.
Volume of Distribution	Vd ~ 5-10 L/kg (large volume due to extensive tissue binding; indicates distribution into total body water and extensive tissue uptake, including brain, lungs, and liver).
Bioavailability	Oral: approximately 40-60% (due to extensive first-pass metabolism). Bioavailability is increased in hepatic impairment. Not administered via other routes clinically (IV/IM are investigational).
Onset of Action	Oral: 30-60 minutes (slow onset due to hepatic first-pass metabolism; oral bioavailability is limited). Peak effect occurs at 3-6 hours. Intravenous: 5-10 minutes; Intramuscular: 10-20 minutes.
Duration of Action	Oral: 24-48 hours (long duration due to slow metabolism; single oral dose provides opioid effects for over 24 hours). Intravenous/Intramuscular: 8-12 hours for analgesic effect, but opioid effects may persist longer. Note: ORLAAM is not approved for acute pain due to slow onset and long duration.

Classification & Brands

Dosing & administration

Initial: 20-40 mg orally every 48-72 hours; maintenance: 80-120 mg orally every 72 hours; maximum single dose: 150 mg. Use only under direct medical supervision in opioid-tolerant patients.

Dosage form	CONCENTRATE
Renal impairment	No specific guideline available; caution with GFR <30 mL/min; consider dose reduction or extended interval due to potential accumulation.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use or use extreme caution with 50-75% dose reduction and extended interval.
Pediatric use	Not recommended for use in pediatric patients due to high risk of respiratory depression and lack of safety data.
Geriatric use	Start at lower end of dosing range (20-30 mg every 48-72 hours); increase dose cautiously due to increased sensitivity and risk of adverse effects; monitor renal and hepatic function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ORLAAM (ORLAAM).

Breastfeeding	Excreted into breast milk; M/P ratio unknown. Use caution; monitor infant for sedation and withdrawal. American Academy of Pediatrics recommends avoiding due to potential for infant toxicity.
Teratogenic Risk	FDA Pregnancy Category C. First trimester: Limited data; potential risk of neural tube defects based on animal studies. Second/third trimesters: May cause opioid withdrawal in fetus and neonatal abstinence syndrome (NAS) after prolonged use. No evidence of major malformations from human data.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Respiratory depression; risk of life-threatening respiratory depression, especially during initiation and dose titration.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to ORLAAM; severe respiratory depression; acute or severe bronchial asthma; known or suspected paralytic ileus; MAO inhibitor use within 14 days.

Clinical Precautions

Precautions

QT prolongation; risk of torsades de pointes. Respiratory depression. Abuse potential. Neonatal withdrawal syndrome if used during pregnancy. Concomitant use with benzodiazepines or other CNS depressants increases risk of profound sedation and respiratory depression.

Clinical Tips & Counseling

Drug interactions

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ORLAAM

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ORLAAM (ORLAAM).

How it works

Mu-opioid receptor agonist; produces analgesia and CNS depression by mimicking endogenous opioids.

What the body does with it

Metabolism	Hepatic via CYP3A4; major metabolite is noracetylmethadol (active).
Excretion	Primarily renal (approximately 50-60% as unchanged drug and metabolites), with biliary/fecal elimination accounting for about 20-30%. The remainder is metabolized and eliminated via other routes.
Half-life	Terminal elimination half-life is approximately 30-60 hours (mean ~45 hours) in normal renal function. Due to this long half-life, steady-state is reached in 7-10 days, and the drug accumulates with repeated dosing, providing prolonged opioid effects. Half-life is significantly prolonged in renal impairment.
Protein binding	Approximately 70-80% bound to plasma proteins, primarily to alpha-1-acid glycoprotein. Binding is saturable and concentration-dependent.
Volume of Distribution	Vd ~ 5-10 L/kg (large volume due to extensive tissue binding; indicates distribution into total body water and extensive tissue uptake, including brain, lungs, and liver).
Bioavailability	Oral: approximately 40-60% (due to extensive first-pass metabolism). Bioavailability is increased in hepatic impairment. Not administered via other routes clinically (IV/IM are investigational).
Onset of Action	Oral: 30-60 minutes (slow onset due to hepatic first-pass metabolism; oral bioavailability is limited). Peak effect occurs at 3-6 hours. Intravenous: 5-10 minutes; Intramuscular: 10-20 minutes.
Duration of Action	Oral: 24-48 hours (long duration due to slow metabolism; single oral dose provides opioid effects for over 24 hours). Intravenous/Intramuscular: 8-12 hours for analgesic effect, but opioid effects may persist longer. Note: ORLAAM is not approved for acute pain due to slow onset and long duration.

Classification & Brands

Dosing & administration

Initial: 20-40 mg orally every 48-72 hours; maintenance: 80-120 mg orally every 72 hours; maximum single dose: 150 mg. Use only under direct medical supervision in opioid-tolerant patients.

Dosage form	CONCENTRATE
Renal impairment	No specific guideline available; caution with GFR <30 mL/min; consider dose reduction or extended interval due to potential accumulation.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use or use extreme caution with 50-75% dose reduction and extended interval.
Pediatric use	Not recommended for use in pediatric patients due to high risk of respiratory depression and lack of safety data.
Geriatric use	Start at lower end of dosing range (20-30 mg every 48-72 hours); increase dose cautiously due to increased sensitivity and risk of adverse effects; monitor renal and hepatic function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ORLAAM (ORLAAM).

Breastfeeding	Excreted into breast milk; M/P ratio unknown. Use caution; monitor infant for sedation and withdrawal. American Academy of Pediatrics recommends avoiding due to potential for infant toxicity.
Teratogenic Risk	FDA Pregnancy Category C. First trimester: Limited data; potential risk of neural tube defects based on animal studies. Second/third trimesters: May cause opioid withdrawal in fetus and neonatal abstinence syndrome (NAS) after prolonged use. No evidence of major malformations from human data.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Respiratory depression; risk of life-threatening respiratory depression, especially during initiation and dose titration.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to ORLAAM; severe respiratory depression; acute or severe bronchial asthma; known or suspected paralytic ileus; MAO inhibitor use within 14 days.