Long-Acting Benzodiazepines
Flurazepam is the primary long-acting benzodiazepine used clinically, with a half-life exceeding 20 hours and active metabolites that significantly increase the risk of residual daytime drowsiness, particularly in elderly and debilitated patients. 1
Classification by Duration of Action
Long-acting benzodiazepines:
- Flurazepam (15-30 mg capsules): Dosed at 15-30 mg at bedtime, reduced to 15 mg in elderly or debilitated patients; carries significant risk of residual daytime sedation due to prolonged half-life and active metabolites 1
- Diazepam: Half-life exceeds 20 hours with active metabolites; should be limited to single or intermittent dosing and avoided in elderly patients with liver disease due to accumulation risk 2, 3
- Clonazepam: Long-acting agent with risks of dependence, tolerance, and withdrawal with prolonged use 2
Short- to intermediate-acting benzodiazepines (for comparison):
- Triazolam: 0.125-0.25 mg, short-acting with mean half-life less than 8 hours 1
- Temazepam: 7.5-30 mg, intermediate-acting with moderate half-life 1, 4
- Estazolam: 1-2 mg, short- to intermediate-acting 1
- Lorazepam: Terminal half-life approximately 8-15 hours, no active metabolites 2
Critical Clinical Considerations for Long-Acting Agents
Avoid long-acting benzodiazepines in high-risk populations:
- Elderly patients are at substantially increased risk for accumulation of active metabolites, leading to prolonged sedation, delirium, falls, and cognitive impairment 2
- Patients with hepatic impairment should not receive diazepam or flurazepam due to dangerous accumulation 2, 3
- Long-acting agents are generally not recommended as first-line hypnotics due to residual daytime impairment 1
When long-acting agents may be appropriate:
- Flurazepam may be reserved for refractory insomnia patients in whom some daytime performance impairment is acceptable 5
- Diazepam is effective for single or intermittent dosing in anxiety and insomnia, and is the drug of choice for acute alcohol withdrawal, skeletal muscle spasm, and as adjunctive therapy in convulsive disorders 3, 6
- Insomnia secondary to anxiety may warrant potassium clorazepate 15 mg (which produces the long-acting metabolite nordiazepam) 5
Duration of Treatment Restrictions
All benzodiazepines, regardless of half-life, should be prescribed for the shortest duration possible:
- Ideal maximum duration is 2-4 weeks for insomnia and anxiety 2, 4, 6
- Effectiveness beyond 4 months has not been established by systematic clinical studies 4, 3
- Physicians must periodically reassess usefulness for individual patients 3
Common Pitfalls to Avoid
Long-acting benzodiazepines carry specific hazards:
- Residual daytime drowsiness and "hangover" effects are substantially more common with flurazepam and other long-acting agents 1, 5
- Alcohol dramatically enhances sedative effects and side effects 7
- Abrupt discontinuation produces withdrawal symptoms including rebound insomnia, anxiety, tremor, and rarely seizures or psychosis 1, 7
- Combination with opioids causes dangerous synergistic respiratory depression and must be avoided 2