Today we will discuss sedative-hypnotics, focusing on benzodiazepines, but also discussing barbiturates and Z-drugs. Today's post includes an introduction, diagnostic criteria, epidemiology, pathogenesis, clinical pearls, management of intoxication and withdrawal, and treatment.
Today's Content Level: Intermediate
Sedative-hypnotics (aka anxiolytics) are a class of medications that depress the central nervous system (CNS), primarily used to treat anxiety, insomnia, seizures, muscle spasms, and anesthesia.
Sedative-hypnotics can be effective, but they carry significant risks of dependence, tolerance, withdrawal, and abuse.
The most commonly prescribed are benzodiazepines (BZDs) and the non-benzodiazepine "Z-drugs" (zolpidem, zaleplon, eszopiclone), which are marketed as safer alternatives for sleep. Barbiturates, once widely used, have largely been replaced due to their narrow therapeutic index and high abuse potential.
Mechanism of action:
Benzodiazepines: Increase GABA-A receptor activity by enhancing chloride channel opening frequency, causing CNS depression.
Z-drugs: Selectively bind to the BZD site on GABA-A receptors, primarily targeting subtypes associated with sleep regulation, thereby enhancing GABAergic inhibition with fewer anxiolytic and muscle-relaxant effects compared to BZDs.
Barbiturates: Increase GABA-A receptor activity by prolonging chloride channel opening duration. They also directly activate receptors at high doses, increasing toxicity and risk of respiratory depression.
Due to similar mechanisms, alcohol and all drugs of this class are cross-tolerant, and their effects are additive.
Diagnostic Criteria 3
Diagnostic criteria for all substance use disorders are the same, characterized by a ≥ 12-month period of problematic substance use that leads to impairment or distress and requires ≥2 additional criteria. See Day #160: Introduction to Substance Use Disorders for complete diagnostic criteria and severity specifiers.
Genetics, environmental influences, and mental health comorbidities contribute to vulnerability.
Epidemiology:
12-month prevalence of sedative-hypnotic use disorder is ~0.2-0.5% of the U.S. population.
Benzodiazepines: Widely used for anxiety, sleep disorders, and epilepsy. In the U.S., approximately 12.5% of adults use benzodiazepines annually, with misuse accounting for nearly 20% of use overall. Misuse is more common among those with co-occurring psychiatric or substance use disorders.
Z-Drugs: Frequently prescribed for insomnia, accounting for a large proportion of sedative-hypnotic prescriptions. Despite their marketing as safer alternatives, they carry similar risks of dependence and withdrawal.
Barbiturates: Rarely used in modern clinical practice outside of anesthesia, but still encountered in polysubstance abuse cases. Most barbiturate-related deaths involve concurrent use with other CNS depressants.
Pathogenesis: Chronic sedative-hypnotic use downregulates GABA receptors and upregulates excitatory neurotransmission. This adaptation leads to CNS hyperexcitability upon withdrawal, increasing seizure risk and autonomic instability. Cross-tolerance with alcohol further exacerbates withdrawal severity.
Clinical Pearls 6
History: If positive screening, obtain a detailed history (onset, frequency, quantity, last use), prior treatment attempts, periods of sobriety, withdrawal symptoms (particularly any history of withdrawal seizures or delirium tremens), impact on daily functioning, legal obligations, and co-occurring psychiatric or medical conditions.
Screen for polysubstance use, especially alcohol, opioids, or stimulants.
Screening questionnaires: DAST (Drug Abuse Screening Test).
Labs: Urine drug screen → detects BZDs, but often misses Z-drugs and some barbiturates. Serum toxicology panel → confirms specific drugs and levels (useful for barbiturate toxicity). Liver function tests → assess for hepatic function in chronic users.
Short-acting BZDs (e.g., alprazolam) have higher abuse potential due to rapid onset and withdrawal symptoms.
Z-drugs can cause dependence and withdrawal similar to BZDs, particularly with prolonged use.
Combining sedative-hypnotics with alcohol or opioids significantly increases overdose risk and respiratory depression.
Rebound insomnia and anxiety often occur upon discontinuation of these medications, reinforcing dependence.
Intoxication 7
Symptoms:
Drowsiness, confusion, respiratory depression (especially with barbiturates), ataxia, slurred speech, coma in severe cases.
Exclude other causes of altered mental status (e.g., head trauma, hypoxia, hypoglycemia, hypothermia, electrolyte abnormalities, encephalopathy, other intoxications).
Treatment:
Supportive care (+ airway protection if needed for severely depressed consciousness)
IV fluids
If drug was ingested in the prior 4–6 hours → activated charcoal and gastric lavage to prevent further gastrointestinal absorption.
Flumazenil, a benzodiazepine antagonist, is rarely used due to its risk of precipitating seizures in chronic users.
For barbiturates only → alkalinize urine with sodium bicarbonate to promote renal excretion.
Withdrawal 8
Remember that withdrawal symptoms of a drug are usually opposite of its intoxication effects. For example, sedative-hypnotics are sedating, but withdrawal can → brain excitation, anxiety, and seizures. Severe withdrawal from sedative-hypnotics can be life-threatening.
Chronic sedative-hypnotic use →
↑ GABA activity (enhanced inhibition, relaxation)
↓ Glutamate activity (suppressed excitation)
Brain adapts: ↓ GABA receptor sensitivity & ↑ glutamate receptor activity to compensate.
Abrupt cessation →
↓ GABA activity (reduced inhibition)
↑ Glutamate activity (excess excitation)
CNS overreactivity → withdrawal symptoms.
Symptoms:
Due to similar mechanism of action, sedative-hypnotic withdrawal can mirror alcohol withdrawal and it's management, with some key differences.
Compared to alcohol, withdrawal symptoms of sedative-hypnotics may occur earlier vs much later (short vs long-acting BZDs).
Uncomplicated withdrawal: anxiety, agitation, tremors, headache, insomnia, nausea, tachycardia, sweating, hyperreflexia.
Complicated withdrawal: severe benzodiazepine or barbiturate withdrawal can produce a syndrome similar to delirium tremens (DT), characterized by:
Severe autonomic instability (hypertension, tachycardia, hyperthermia)
Profound confusion and agitation
Hallucinations (visual or tactile)
Seizures (often precede DT-like symptoms)
Treatment:
Benzodiazepine tapering with long-acting agents (e.g., diazepam, clonazepam) is preferred to prevent severe withdrawal symptoms. The duration of the taper depends on factors like dose, duration of use, half-life of the drug, and patient tolerance.
IV fluids and supportive therapy
ICU admission: If complicated withdrawals or severe autonomic instability.
•Effective treatment requires a combination of medical, psychological, and social interventions. A multi-disciplinary team—often including psychiatrists, primary care providers, therapists, social workers, and peer support specialists collaborates to address all aspects of the disorder.
Determine the Appropriate Treatment Setting: Choosing the right level of care depends on substance use severity, comorbid conditions, and prior treatment history. See Day 60: Intro to SUD for a description of each level of care.
Severe cases (history of complicated withdrawal) → inpatient detox, ideally followed by a residential treatment program, aka "rehab."
Mild/moderate cases → outpatient management with close follow-up. If outpatient treatment has failed, consider IOP or PHP.
Regardless of treatment setting, best practice may include random drug screening.
Monitoring for relapse and overdose risk is important in patients with polysubstance use histories.
Psychosocial Interventions:
Individual and/or group therapy should be part of every SUD treatment approach. See Day 60: Intro to SUD for a discussion of interventions that include behavioral therapies, peer support & 12-step programs, and family support resources.
CBT for insomnia and anxiety disorders can help reduce reliance on sedative-hypnotics.
Medications:
Gradual tapering of benzodiazepines is the gold standard to prevent withdrawal complications. Some clinicians recommend switching to longer-acting BZDs (e.g., diazepam, clonazepam), stabilizing, then reduce the dosage by 10-25% every few days if tolerated. In outpatient settings, slower tapers (e.g., (≤5% reduction every 2–4 weeks) improve adherence and reduce relapse risk.
Pharmacologic adjuncts (e.g., SSRIs, gabapentin, pregabalin, beta-agonists) may aid in anxiety management and withdrawal symptom reduction, but their efficacy has not been established.
Avoidance of cross-tolerant substances like alcohol and other CNS depressants is crucial for recovery.
Conclusion
•Sedative-hypnotics have important clinical applications but carry significant risks of misuse, dependence, and withdrawal. Benzodiazepines and Z-drugs, though effective, should be used with caution, particularly in populations at higher risk of abuse or adverse effects. Discontinuation should be approached with a structured taper, behavioral interventions, and close monitoring. Alternative non-pharmacologic treatments should be prioritized for insomnia and anxiety whenever possible to minimize the risks associated with long-term sedative-hypnotic use.
•In our next post we will discuss opioids.
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