Sedatives, Hypnotics, and Anxiolytics Use Disorder

Sedative, hypnotic, and anxiolytic agents include benzodiazepines (BZDs), barbiturates, and other hypnotics. Symptoms of intoxication include ataxia, minor respiratory depression, and short-term memory loss. Withdrawal symptoms include insomnia, anxiety, psychosis, and seizures. These drugs are often taken in conjunction with other substances. Chronic use can be managed with medication taper as well as psychosocial interventions.

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Classification and Epidemiology

Classification

Sedatives, hypnotics, and anxiolytics use disorder is the chronic (> 12 months), problematic pattern of sedative, hypnotic, or anxiolytic use causing significant distress. These types of drugs subdue excitement, promote calm, or induce/maintain sleep. 

  • Intoxication:
    • Recent usage history
    • State of decreased responsiveness to any level of stimulation; associated with some decrease in motor activity and ideation
  • Withdrawal: 
    • Development of a substance-specific syndrome due to the cessation (or reduction) of substance use.
    • Patients experience physical (nausea, diarrhea, chills, body aches) and/or psychological symptoms (compulsion or perceived need to use the substance). 
  • Tolerance: 
    • The need to increase the dose of the substance to achieve the desired effect (diminished effect if using the same amount of the substance).

Epidemiology

  • Benzodiazepines (BZDs) and hypnotic agents are among the most widely prescribed medications in the United States. 
  • Prevalence in the United States: up to 5 million estimated misusers of sedatives

Pharmacology

Benzodiazepines

  • BZDs are categorized into short-, intermediate-, and long-acting agents.
  • Most prominent substances: 
    • Long acting:
      • Diazepam 
      • Chlordiazepoxide 
    • Short acting:
      • Lorazepam 
      • Alprazolam 
      • Oxazepam
  • Also includes:
    • Flunitrazepam (Rohypnol, or “roofies”)
    • Gamma-hydroxybutyrate 
    • Misused as so-called “club drugs” 
  • BZDs bind to GABA-A receptors to potentiate GABA activity.

Barbiturates

  • Includes phenobarbital, secobarbital  
  • Mechanism of action similar to BZD, binding to GABA-A receptors to potentiate GABA activity
  • Older medication class 
  • Rarely seen today due to high abuse potential and narrower therapeutic index than BZDs

Other hypnotics

  • Includes zolpidem, zaleplon, and eszopiclone (so-called “Z drugs”)
  • Mechanism of action is similar to BZDs while being chemically different. 
  • High potential for misuse and dependence

Clinical Presentation and Diagnosis

Intoxication

  • CNS
    • Drowsiness
    • Confusion
    • Slurred speech
    • Incoordination
    • Ataxia
    • Seizures
    • Mood lability
    • Impaired judgment
    • Nystagmus
    • Impaired memory
  • Cardiovascular: hypotension
  • Respiratory: 
    • Respiratory depression
    • Coma or death in overdose
    • Synergistic effect if combined with other depressants (alcohol, opioids)

Withdrawal

Patients must taper the medications instead of discontinuing use abruptly, as this can lead to life-threatening symptoms.

  • CNS: 
    • Anxiety
    • Psychosis
    • Perceptual disturbances 
    • Seizures
    • Insomnia
    • Tremor
  • Cardiovascular: 
    • Tachycardia
    • Hypertension

Management and Complications

Intoxication

  • Ensure patient safety (ABC →  maintain Airway, Breathing, and Circulation).
  • Activated charcoal is not recommended due to risk of aspiration. 
  • For barbiturates only: 
    • Urine alkalinization: converts barbiturate to be more easily excreted via the urine
    • Hemodialysis in severe cases 
  • For BZDs only: 
    • Flumazenil (nonspecific competitive antagonist of the BZD receptor) 
    • Used for overdose, especially in the pediatric population

Withdrawal

  • Taper treatment:
    • Goal is to eliminate withdrawal symptoms without causing excessive sedation or respiratory depression
    • BZD withdrawal: Use a long-acting BZD. 
    • Barbiturate withdrawal: Use phenobarbital or long-acting BZD.
  • Propranolol: used to decrease sympathetic activity
  • Be mindful of withdrawal from other substances that may also have been ingested.

Use disorder

  • Psychotherapy: 
    • CBT or motivational enhancement (1st-line options)
    • Therapy with medication taper is more effective than medication taper alone. 
  • Medications:
    • Substitute shorter half-life BZDs with those that have a longer half-life. 
    • The tapering process must be gradual to avoid withdrawal symptoms or relapse.
    • Anticonvulsants and pregabalin may be effective.

Complications

Cognitive impairment: 

  • Long-term treatment with BZDs is reported to be linked to impairment in multiple cognitive domains.
  • While cognitive functioning improved after BZDs were withdrawn, patients were often unable to return to levels of functioning of controls who never received BZDs. 

Falls and fractures in the elderly:

  • Older adults (age > 65) have a higher baseline risk for falls and fractures. 
  • BZD use is associated with an increased risks of falls by increasing reaction time, sedation, and visual disturbances.
  • BZDs are also associated with a greater likelihood of hip fractures and increased mortality.
  • The use of BZDs must therefore be avoided.
  • Patients already taking the medication need to be educated and the medication’s use gradually discontinued.

Differential Diagnosis

  • Opioid intoxication: opioids are central nervous system depressants that are used medically as potent analgesics. Opioids have a significant potential for misuse because of their euphoric effect. Features of opioid intoxication include respiratory depression and drowsiness, which are similar to intoxication with sedatives, hypnotics, or anxiolytics. Opioids and sedatives are often ingested together. Opioid intoxication can be managed with administration of naloxone.
  • Alcohol withdrawal: alcohol is the most commonly misused substance in the United States. Withdrawal symptoms occur after cessation or reduction in patients with severe, chronic alcohol use. Symptoms include tremors, nausea, psychomotor agitation, anxiety, and, in severe cases, seizures and hallucinations. All these symptoms may appear similar to withdrawal from sedatives, hypnotics, or anxiolytics. Management includes BZDs as well as supportive care.

References

  1. Sadock, B. J., Sadock, V. A., & Ruiz, P. (2014). Kaplan and Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry (11th ed.). Chapter 20, Substance use and addictive disorders, pages 666-671. Philadelphia, PA: Lippincott Williams and Wilkins.
  2. Thompson, A. (2021). Clinical management of drug use disorders. DeckerMed Medicine. Retrieved March 6, 2021 from https://www.researchgate.net/publication/348485124_Clinical_Management_of_Drug_Use_Disorders
  3. Park, T. (2020). Benzodiazepine use disorder. UpToDate. Retrieved March 6, 2021 from https://www.uptodate.com/contents/benzodiazepine-use-disorder
  4. Greller, H. (2020). Benzodiazepine poisoning and withdrawal. UpToDate. Retrieved March 6, 2021 from https://www.uptodate.com/contents/benzodiazepine-poisoning-and-withdrawal
  5. Markota, M., Rummans, T. A., Bostwick, J. M., & Lapid, M. I. (2016). Benzodiazepine Use in Older Adults: Dangers, Management, and Alternative Therapies. Mayo Clinic Proceedings, 91(11), 1632–1639. https://doi.org/10.1016/j.mayocp.2016.07.024

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