What are benzodiazepines and what are some commonly prescribed types?

Benzodiazepines: Drug Class Overview and Commonly Prescribed Agents

Benzodiazepines are psychoactive medications that enhance GABA-A receptor activity in the central nervous system, producing anxiolytic, sedative, anticonvulsant, muscle relaxant, and amnestic effects through potentiation of the inhibitory neurotransmitter GABA. 1

Mechanism of Action

• Benzodiazepines activate GABA-A receptors in the brain by binding to specific receptor subunits (α1, α2, α3, and α5), enhancing the activity of GABA, the primary inhibitory neurotransmitter in the central nervous system, thereby reducing neuronal excitability. 1
• The clinical effects vary based on which GABA-A receptor subunits are activated—benzodiazepines with high affinity for the α1 subunit cause more sedation and cognitive impairment, while those targeting α2 subunits provide anxiolysis with less sedation. 1

Commonly Prescribed Benzodiazepines

Long-Acting Agents

• Diazepam (Valium): Non-selective GABA-A receptor agonist with a very long half-life (20-120 hours) due to active metabolites; used for anxiety, seizures, and sedation before procedures. 1
• Clonazepam (Klonopin): Long half-life of 30-40 hours allowing once or twice daily dosing; effective for panic disorder (0.25-2.0 mg dosing range), REM sleep behavior disorder, and seizures, though the American Academy of Sleep Medicine recommends it for specific sleep disorders. 1

Intermediate-Acting Agents

• Lorazepam (Ativan): Intermediate half-life (8-15 hours) with no active metabolites, making it safer in renal failure; preferred for acute agitation due to rapid and complete absorption. 1, 2
• Alprazolam (Xanax): Primarily used for anxiety disorders, particularly panic disorder, though it is not recommended in the UK for long-term use due to higher risk of dependence. 3
• Oxazepam (Serax): Intermediate half-life benzodiazepine used for anxiety and insomnia. 1
• Temazepam, Loprazolam, Lormetazepam: Medium duration of action, suitable for transient or short-term insomnia when limited to courses not exceeding 2 weeks. 3

Short-Acting Agents

• Midazolam: Used primarily in anesthesia and acute seizure management. 3

Clinical Selection Criteria

Choose lorazepam for acute agitation or when renal impairment is present due to its rapid onset, complete absorption, and lack of active metabolites. 1

• Select long-acting agents (diazepam, clonazepam) when prolonged effects are needed, but recognize they accumulate in elderly patients and those with hepatic or renal dysfunction, causing prolonged sedation. 1
• Avoid diazepam for intramuscular administration due to variable absorption and risk of phlebitis with peripheral intravenous injection. 1
• Reduce diazepam doses by 20% or more in patients over 60 years due to decreased clearance and accumulation of active metabolites. 1

Major Risks and Contraindications

Dependence and Withdrawal

• Physical dependence develops from continued therapy, manifested by withdrawal signs after abrupt discontinuation including anxiety, insomnia, tremor, seizures, hallucinations, and potentially life-threatening reactions. 2
• Protracted withdrawal syndrome can persist for weeks to more than 12 months, characterized by anxiety, cognitive impairment, depression, insomnia, motor symptoms, and paresthesia. 2
• Always use a gradual taper to discontinue benzodiazepines—patients at highest risk for severe withdrawal include those on higher dosages and longer durations of use. 2

Respiratory Depression and Drug Interactions

• All benzodiazepines cause respiratory depression with synergistic and cumulative effects when combined with opioids or alcohol, increasing risk of overdose and death. 1, 4
• Combining benzodiazepines with Z-drugs (zolpidem, zaleplon) significantly increases respiratory depression risk and should be avoided. 4

Elderly Patient Risks

• The American Geriatrics Society warns that benzodiazepines in elderly patients increase risk of confusion, ataxia, falls, fractures, cognitive impairment, and reduced functional independence. 5, 1
• Benzodiazepine clearance decreases with age, making prolonged effects more pronounced in elderly patients. 1

Abuse Potential

• Benzodiazepines are Schedule IV controlled substances with potential for abuse, misuse, and addiction even when taken as prescribed. 2
• Abuse often involves doses greater than recommended and concomitant use of other medications, alcohol, or illicit substances, associated with serious adverse outcomes including respiratory depression, overdose, and death. 2

Appropriate Clinical Use

Recommended Indications

• Acute anxiety: Single doses or very short courses (1-7 days) for acute stress reactions, episodic anxiety, or initial treatment of severe panic; diazepam is usually the drug of choice. 3
• Insomnia: Limited to transient or short-term insomnia with prescriptions for a few days, occasional use, or courses not exceeding 2 weeks. 3
• Status epilepticus: First-line treatment with time-critical administration; non-intravenous midazolam is equally efficacious to intravenous lorazepam when IV access is unavailable. 6
• Seizure prophylaxis: Clobazam and clonazepam for refractory epilepsy, with clobazam preferred due to less sedation from α2 subunit affinity. 6

Inappropriate Uses

• BPPV (Benign Paroxysmal Positional Vertigo): The American Academy of Otolaryngology-Head and Neck Surgery recommends against routine use of benzodiazepines for BPPV, as there is no evidence they are effective as definitive treatment or substitute for repositioning maneuvers. 5
• Chronic insomnia: Current consensus guidelines advise benzodiazepine use solely on a short-term basis; the American College of Physicians recommends cognitive behavioral therapy for insomnia (CBT-I) as first-line treatment over benzodiazepines. 5, 4
• Long-term anxiety management: Should generally be used in conjunction with psychological treatments or antidepressants, which have slower onset but better long-term outcomes. 3

Critical Prescribing Principles

• Start at the lowest available dose for all benzodiazepines, particularly in elderly patients. 5
• Limit duration to 4 weeks maximum to prevent tolerance, dependence, and withdrawal effects. 3
• Avoid routine long-term prescribing—while occasionally required for certain patients, most use should be intermittent or short courses. 3
• Consider safer alternatives first: Cognitive behavioral therapy, antidepressants, relaxation techniques, sleep hygiene education, and integrative strategies (massage, aromatherapy, music therapy) should be pursued before or alongside benzodiazepines. 5, 7