Why Barbiturates Are No Longer Commonly Prescribed
Barbiturates were replaced by benzodiazepines and other safer alternatives beginning in the 1970s because of their lethal overdose potential, high abuse liability, severe withdrawal syndrome, and narrow therapeutic index—risks that are particularly dangerous in patients with substance abuse history or mental health disorders. 1
Historical Context and Decline
By mid-20th century, the adverse side effects and lethal overdose potential of barbiturates became widely recognized, leading to curtailment of their use. 1 The introduction of chlordiazepoxide in 1963 and flurazepam in 1970 (the first FDA-approved benzodiazepine hypnotic) rapidly supplanted barbiturates for treatment of insomnia and anxiety. 1
The key turning point: Benzodiazepines demonstrated much less abuse liability and a significantly safer toxicity profile compared to barbiturates, making them the obvious replacement. 2, 3
Primary Safety Concerns
Lethal Overdose Risk
- Barbiturates cause dose-dependent respiratory depression that can progress to apnea and death, with suppression of the medullary respiratory center being the primary mechanism. 4, 5
- Death from barbiturate overdose often results from aspiration pneumonia secondary to respiratory depression and loss of protective airway reflexes. 4
- Unlike benzodiazepines, barbiturates have no reversal agent and a narrow margin between therapeutic and lethal doses. 6
Cardiovascular Collapse
- Barbiturates cause cardiovascular depression through medullary vasomotor center suppression, potentially causing profound hypotension. 4, 5
- This hypotensive effect is additive when combined with other CNS depressants (opioids, benzodiazepines, alcohol), dramatically increasing the risk of death. 4, 7
High Abuse and Dependence Potential
- Experienced drug abusers report feelings of well-being and euphoria with barbiturates, and self-administration experiments demonstrate they are potent reinforcing agents. 2
- In controlled studies, former drug abusers express a preference for barbiturates over benzodiazepines and will "work" to receive them. 2
- Barbiturates may be habit forming, with tolerance and psychological and physical dependence occurring with continued use. 7
- Patients who are psychologically dependent may increase dosage or decrease dosage intervals without consulting a physician, subsequently developing physical dependence. 7
Severe Withdrawal Syndrome
- Long-term consumption leads to dependence characterized by a severe, potentially life-threatening abstinence syndrome. 2
- Withdrawal manifestations include delirium, grand mal seizures, anxiety, restlessness, insomnia, rhythmic intention tremor, dizziness, and psychosis occurring on the second to fourth day after discontinuation. 2, 8
- If not recognized and correctly treated, hyperthermia, circulatory failure, and death may ensue. 8
- Abrupt cessation after prolonged use may result in withdrawal symptoms, including delirium, convulsions, and possibly death. 7
Specific Risks in Vulnerable Populations
Patients with Substance Abuse History
- Barbiturates should not be administered to persons with known previous addiction to the sedative-hypnotic group, since ordinary doses may be ineffectual and may contribute to further addiction. 7
- The prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment to minimize the possibility of overdosage or development of dependence. 7
- Extrapolation from published reports suggests that barbiturate-containing agents have the potential to produce drug dependence and addictive behavior, especially with regular use. 9
Patients with Mental Health Disorders
- Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. 7
- Phenobarbital has been reported to be associated with cognitive defects in children. 7
- The concomitant use of alcohol or other CNS depressants (commonly used by patients with mental health disorders) produces additive CNS depressant effects. 7
Lack of Therapeutic Advantage
- There is no evidence that there is a clinically important enhancement of analgesic efficacy of barbiturate-containing analgesics due to the barbiturate constituent. 9
- Because barbiturate-containing products do not have a therapeutic advantage, there is no clinical reason to choose such a combination when a simpler and often less expensive analgesic formulation or more specific treatment is available. 9
- Safer and equally effective benzodiazepines, which are less associated with dependence, are available for insomnia, acute reactive anxiety, chronic anxiety neurosis, and depressive illnesses. 3
Current Prescribing Patterns
- Dispensed prescriptions of benzodiazepines in England fell from 10.5 million to 7.7 million between 2008 and 2018, reflecting ongoing concerns about dependence even with these safer alternatives. 1
- Secobarbital and amobarbital are no longer licensed for use in the United States, United Kingdom, and most developed countries, and can only be prescribed to patients already taking them for intractable insomnia. 10
- Butalbital is no longer licensed as a standalone agent but remains available in combination products, though it should be avoided in elderly people and should not be used in children. 10, 9
Critical Pitfalls
- Never assume tolerance protects against respiratory failure: While tolerance to sedative effects develops, tolerance to lethal serum concentrations causing respiratory failure does not. 4
- Avoid combining with other CNS depressants: The combination of barbiturates with opioids, benzodiazepines, or alcohol dramatically increases the risk of respiratory failure and death. 4, 7
- Do not use standard dosing in vulnerable populations: Barbiturates require individualized reduced dosing based on specific patient vulnerabilities. 4