What barbiturates are commonly used in Medical Assistance in Dying (MAID)?

Barbiturate Examples

Barbiturates commonly used in clinical practice include phenobarbital (long-acting), pentobarbital (short-acting), secobarbital (intermediate-acting), amobarbital (intermediate-acting), butalbital (intermediate-acting), and thiopental (ultrashort-acting). 1

Classification by Duration of Action

Barbiturates are derivatives of barbituric acid and are classified according to their pharmacokinetic properties into distinct categories: 2

Long-Acting Barbiturates

• Phenobarbital is the representative long-acting agent with an elimination half-life of 80-120 hours and duration of action of 6-12 hours 1
• Phenobarbital has lower protein binding (20-60%) and lower lipid solubility compared to short-acting agents 2
• Approximately 20-25% of phenobarbital is excreted unchanged in urine, making it more amenable to renal elimination 2, 1

Short-Acting Barbiturates

• Pentobarbital is the representative short-acting agent with an elimination half-life of 15-48 hours and duration of action of 3-4 hours 1
• Less than 5% of pentobarbital is excreted unchanged in urine, as it undergoes nearly exclusive hepatic metabolism 1
• Short-acting barbiturates have higher protein binding (35-70%), greater lipid solubility, more rapid onset, and higher pKa (7.9 vs 7.2) compared to long-acting agents 2, 1

Intermediate-Acting Barbiturates

• Secobarbital and amobarbital are intermediate-acting agents that are no longer licensed for use in the United States, United Kingdom, and most developed countries 1
• These agents can only be prescribed to patients already taking them for intractable insomnia 1
• Butalbital is an intermediate-acting barbiturate no longer licensed as a standalone agent but remains available in combination products (e.g., butalbital-acetaminophen-caffeine) 1
• Butalbital-containing combinations are classified as Schedule III controlled substances and are metabolized through the hepatic cytochrome P450 system 1

Ultrashort-Acting Barbiturates

• Thiopental is an ultrashort-acting barbiturate used primarily for anesthesia induction 1

Specific Use in Medical Assistance in Dying (MAID)

Intravenous Protocols

• Barbiturates are the most commonly used agents for intravenous MAID, appearing in 34 of 163 studies reviewed 3
• Barbiturates have emerged as the most efficacious and tolerable agents based on global experience, particularly from the Netherlands 4
• Phenobarbital is used as an alternative barbiturate option with dosing of 1-3 mg/kg IV or subcutaneous bolus, followed by infusion of 0.5 mg/kg/h, with usual maintenance of 50-100 mg/h 5
• Phenobarbital offers rapid onset and anticonvulsant properties when used in MAID 5

Oral Protocols

• Barbiturates alone are the most common oral MAID regimen, used in 37 of 163 studies 3
• Barbiturates in conjunction with opioid medications were used in 7 of 163 studies for oral MAID 3
• Secobarbital suspension combined with antiemetic prophylaxis is recommended for oral MAID based on global experience, particularly from the Netherlands 4
• High doses of barbiturates are usually effective for physician-assisted suicide 6
• A combination of a barbiturate and a derivative of curare are effective for euthanasia 6

Important Clinical Considerations

Metabolism and Drug Interactions

• All barbiturates undergo hepatic metabolism as their main route of endogenous clearance 2
• Barbiturates are potent inducers of the hepatic CYP450 enzyme system, increasing metabolic clearance of other medications that are CYP substrates 1
• Barbiturates exhibit auto-induction, leading to tolerance development in long-term users 2
• Critical caveat: While tolerance to sedative-hypnotic effects develops, tolerance to lethal serum concentrations does not appear to develop 2

Toxicity Thresholds

• Potentially fatal ingested dose for phenobarbital is >5 grams 2
• Potentially fatal ingested dose for pentobarbital is >3 grams 2
• Potentially fatal serum concentration for phenobarbital is 80 mg/L 2
• Potentially fatal serum concentration for pentobarbital is 50 mg/L 2

Additive Effects

• Barbiturates have additive depressant effects on the CNS and respiratory system when combined with other CNS depressants 1