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Sedatives, Hypnotics, and Anxiolytics Use Disorder

Sedative, hypnotic, and anxiolytic agents include benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (BZDs), barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics, and other hypnotics. Symptoms of intoxication include ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, minor respiratory depression, and short-term memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment loss. Withdrawal symptoms include insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, psychosis, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. These drugs are often taken in conjunction with other substances. Chronic use can be managed with medication taper as well as psychosocial interventions.

Last updated: Nov 14, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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 Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep

  • Intoxication:
    • Recent usage history
    • State of decreased responsiveness to any level of stimulation; associated with some decrease in motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology activity and ideation
  • Withdrawal:
    • Development of a substance-specific syndrome due to the cessation (or reduction) of substance use.
    • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship experience physical ( nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever, body aches) and/or psychological symptoms (compulsion or perceived need to use the substance). 
  • Tolerance Tolerance Pharmacokinetics and Pharmacodynamics:
    • 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 Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (BZDs) and hypnotic agents are among the most widely prescribed medications in the United States. 
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in the United States: up to 5 million estimated misusers of sedatives

Pharmacology

Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines

  • BZDs are categorized into short-, intermediate-, and long-acting agents.
  • Most prominent substances:
    • Long acting:
      • Diazepam Diazepam A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. Benzodiazepines 
      • Chlordiazepoxide Chlordiazepoxide An anxiolytic benzodiazepine derivative with anticonvulsant, sedative, and amnesic properties. It has also been used in the symptomatic treatment of alcohol withdrawal. Benzodiazepines
      • Clonazepam Clonazepam An anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures. The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses. Benzodiazepines 
    • Short acting:
      • Lorazepam Lorazepam A benzodiazepine used as an anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. Benzodiazepines 
      • Alprazolam Alprazolam A triazolobenzodiazepine compound with antianxiety and sedative-hypnotic actions, that is efficacious in the treatment of panic disorders, with or without agoraphobia, and in generalized anxiety disorders. Benzodiazepines 
      • Oxazepam Oxazepam A benzodiazepine used in the treatment of anxiety, alcohol withdrawal, and insomnia. Benzodiazepines
  • Also includes:
    • Flunitrazepam (Rohypnol, or “roofies”)
    • Gamma-hydroxybutyrate 
    • Misused as so-called “club drugs” 
  • BZDs bind BIND Hyperbilirubinemia of the Newborn to GABA-A receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors to potentiate GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS activity.

Barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics

  • Includes phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs, secobarbital  
  • Mechanism of action similar to BZD, binding to GABA-A receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors to potentiate GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS activity
  • Older medication class 
  • Rarely seen today due to high abuse potential and narrower therapeutic index Therapeutic Index An indicator of the benefits and risks of treatment. Dosage Calculation 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 Slurred Speech Cerebellar Disorders
    • Incoordination
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Mood lability
    • Impaired judgment Judgment The process of discovering or asserting an objective or intrinsic relation between two objects or concepts; a faculty or power that enables a person to make judgments; the process of bringing to light and asserting the implicit meaning of a concept; a critical evaluation of a person or situation. Psychiatric Assessment
    • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
    • Impaired memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment
  • Cardiovascular: hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Respiratory:
    • Respiratory depression
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma or death in overdose
    • Synergistic effect if combined with other CNS depressants:
      • Alcohol
      • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
      • Muscle relaxants

Withdrawal

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship must taper the medications instead of discontinuing use abruptly, as this can lead to life-threatening symptoms.

  • CNS: 
    • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • Psychosis
    • Perceptual disturbances 
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies
  • Cardiovascular: 
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension

Management and Complications

Intoxication

  • Ensure patient safety Patient Safety Efforts to reduce risk, to address and reduce incidents and accidents that may negatively impact healthcare consumers. Patient Safety: Types of Medical Errors (ABC →  maintain Airway, Breathing, and Circulation).
  • Activated charcoal Charcoal An amorphous form of carbon prepared from the incomplete combustion of animal or vegetable matter, e.g., wood. The activated form of charcoal is used in the treatment of poisoning. Antidotes of Common Poisonings is not recommended due to risk of aspiration. 
  • For barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics only:
    • Urine alkalinization: converts barbiturate to be more easily excreted via the urine
    • Hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome in severe cases 
  • For BZDs only:
    • Flumazenil Flumazenil A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses. Benzodiazepines (nonspecific competitive antagonist of the BZD receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • 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 Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs or long-acting BZD.
  • Propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs: used to decrease sympathetic activity
  • Be mindful of withdrawal from other substances that may also have been ingested.

Use disorder

  • Psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy:
    • Cognitive behavioral therapy Cognitive behavioral therapy A directive form of psychotherapy based on the interpretation of situations (cognitive structure of experiences) that determine how an individual feels and behaves. It is based on the premise that cognition, the process of acquiring knowledge and forming beliefs, is a primary determinant of mood and behavior. The therapy uses behavioral and verbal techniques to identify and correct negative thinking that is at the root of the aberrant behavior. Psychotherapy (CBT) or motivational enhancement (1st-line options)
    • Therapy with medication taper is more effective than medication taper alone. 
  • Medications:
    • Substitute shorter half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics BZDs with those that have a longer half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics
    • The tapering process must be gradual to avoid withdrawal symptoms or relapse Relapse Relapsing Fever.
    • Anticonvulsants and pregabalin Pregabalin A gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia. Second-Generation Anticonvulsant Drugs 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 Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 Hip fractures A hip fracture is a disruption in the cortex of the femur at the hip joint, either between the trochanters (intertrochanteric) or at the femoral neck. Hip fracture is a serious injury and can result in life-threatening complications. Hip Fractures and increased mortality Mortality All deaths reported in a given population. Measures of Health Status.
  • The use of BZDs must therefore be avoided.
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship already taking the medication need to be educated and the medication’s use gradually discontinued.

Differential Diagnosis

  • Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation intoxication: opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics are central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification depressants that are used medically as potent analgesics. Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics have a significant potential for misuse because of their euphoric effect. Features of opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation intoxication include respiratory depression and drowsiness, which are similar to intoxication with sedatives, hypnotics, or anxiolytics. Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics and sedatives are often ingested together. Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation intoxication can be managed with administration of naloxone Naloxone A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. Opioid Analgesics.
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder: alcohol is the most commonly misused substance in the United States. Withdrawal symptoms occur after cessation or reduction in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with severe, chronic alcohol use. Symptoms include tremors, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, psychomotor agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, and, in severe cases, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia. 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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