05. Sedative hypnotic use disorders

Overview

Sedative-hypnotics include benzodiazepines, barbiturates, carbamates, and “Z” drugs (zolpidem, zaleplon, and eszopiclone). We will focus on benzodiazepines here.

Mechanism of action

Benzodiazepines bind to GABA-A receptors and increase the frequency of chloride channel opening, while barbiturates increase the duration of chloride channel opening, both leading to a potentiation of the inhibitory effect of GABA in the central nervous system, leading to anxiolysis, muscle-relaxation, and anti-convulsant properties. The “Z” drugs also bind to the GABA receptor.

Pharmacokinetics

Each benzodiazepine has a different half-life.  

  • Short-acting (<5 hours): midazolam.
  • Intermediate-acting (5-24h): alprazolam, lorazepam, oxazepam.
  • Long-acting (>24 hour): clonazepam, diazepam.

Benzodiazepines NOT metabolized by CYP enzymes: oxazepam, temazepam, lorazepam.

Benzodiazepine Use Disorder

Evaluation

  • Determine if patient has a substance use disorder using DSM-V criteria.
  • Ask about type of benzodiazepines used, frequency, use history, attempts to cut down, periods of sobriety, past treatment, other substances used, psychiatric history, etc.
  • Check CURES or appropriate drug monitoring program database.
  • Assess goals, barriers to treatment, readiness for treatment.

Treatment

  • Outpatient taper: poor success rates but may be considered in patients with mild use disorder. No good evidence on short acting or longer-acting benzodiazepines; may take 6-12 months to complete. Usually requires weekly visits and urine toxicology monitoring. If outpatient taper is not an option, consider prolonged taper with residential treatment. Patients with co-occurring active SUDs are not candidates for outpatient benzodiazepine tapers.
  • Inpatient medically supervised withdrawal: appropriate in patients who want fast taper and are not candidates for outpatient taper. Will receive protocolized rapid taper with close monitoring and 24-hour care.
  • Treat concomitant depression, anxiety, panic disorder, and/or PTSD that may be driving benzodiazepine use.
  • Psychosocial treatment should be offered to all patients with substance use disorders.

Benzodiazepine Intoxication

Symptoms: CNS depression with ataxia, slurred speech, somnolence, stupor, coma. (Toxidrome for isolated BZD OD: comatose with normal vital signs).

  • Benzodiazepines alone rarely cause respiratory compromise except in massive overdose; however, even a moderate dose can be deadly if co-ingested with another sedative (particularly alcohol).
     

Evaluation

  • Assess airway, breathing, and circulation.
  • Urine toxicology (not all benzodiazepines show), ethanol level, APAP, salicylate levels.
  • Full work-up of other causes of altered mental status, especially if patient is unable to give history.
  • Pulse oximetry, cardiac monitoring, end tidal CO2 for patients at risk for hypoventilation.

Treatment

  • Intubate if unable to protect airway.
  • Give naloxone IM or IV in case of opioid co-ingestion.
  • Supportive care, close monitoring for decompensation and withdrawal.
  • Controversial: flumazenil. Nonspecific competitive benzodiazepine receptor antagonist. Use in overdose is generally avoided because it can precipitate seizures in patients who have chronic benzodiazepine use. Can be used to reverse procedural sedation following general anesthesia in controlled settings.
  • Avoid: activated charcoal. Has NO role in isolated benzodiazepine overdose, and can increase aspiration risk. Can be administered if high concern for co-ingestion and airway is protected.

 

Benzodiazepine Withdrawal

Symptoms: tremors, anxiety, irritability, tachycardia, hypertension, fever, diaphoresis, hallucinations, seizures, death.

  • Timing of withdrawal symptoms depends on the half-life of benzodiazepine used; usually within 12-24 hours of last use, but may be delayed several days.
  • Higher dose benzodiazepine use over longer period of time will increase risk of withdrawal.
     

Evaluation: CIWA-B monitoring, as with alcohol withdrawal.

Treatment

  • Similar to alcohol withdrawal treatment. Use CIWA to guide therapy with long-acting benzodiazepine in immediate setting to control symptoms. Still may require outpatient taper over a period of months.

Key Points

  • Different benzodiazepines have different onset of action, half-life.
  • CIWA used in both evaluation and treatment of benzodiazepine withdrawal.
  • Avoid flumazenil as benzodiazepine overdose treatment.

 

Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009;67(6):408‐413.

Höjer J, Baehrendtz S, Gustafsson L. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med.

Seger DL. Flumazenil—treatment or toxin?  J Toxicol Clin Toxicol 2004; 42(2): 209-16.

Tanaka E. Toxicological interactions between alcohol and benzodiazepines. J Toxicol Clin Toxicol 2002; 40(1): 69-7