eMedicine Specialties > Psychiatry > Addiction

Sedative, Hypnotic, Anxiolytic Use Disorders

Author: Joji Suzuki, MD, Fellow in Addiction Psychiatry, Department of Psychiatry, Boston University School of Medicine
Coauthor(s): Christopher L Sola, DO, Clinical Assistant Professor, University of Vermont, College of Medicine; Director of Consultation-Liaison Psychiatry, Department of Psychiatry, Maine Medical Center; Olakunle PA Akinsoto, MD, Consulting Staff, Family Health Center, Jacksonville Medical Center
Contributor Information and Disclosures

Updated: Jun 8, 2006

Introduction

Background

Throughout history, humans have sought chemical agents to ameliorate the effects of stress and attenuate feelings of discomfort, tension, anxiety, and dysphoria. Consequently, sedatives, anxiolytics, and hypnotics were created. The oldest of these is ethanol. By the 19th century, bromide salts, choral hydrate, and paraldehyde were used in medicine. Subsequently, barbiturates were synthesized in 1903, followed by meprobamate in 1950. By 1959, the benzodiazepine chlordiazepoxide was created, giving rise to at least 3000 different benzodiazepines, of which 50 are currently marketed.

The therapeutic value of these agents as anxiolytics and hypnotics has been well established, and they continue to serve an important role in managing many debilitating anxiety symptoms in the context of both psychiatric disorders and medical illness. However, the toxic effects of these drugs have also been established, including various withdrawal syndromes, dependence, and tolerance.

Pathophysiology

No conclusive data explain how sedative-hypnotics function. Gamma-aminobutyric butyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the central nervous system. GABA opens chloride (Cl) channels, causing an influx of Cl ions. The influx of Cl ions causes hyperpolarization of the neuron, subsequently inhibiting neuronal discharge. Benzodiazepines and barbiturates potentiate the actions of GABA in a similar fashion via specific receptors, which are located near the GABA receptors. The GABA (A) receptor subunit, composed of multiple forms (eg, alpha, beta, gamma) has been proposed as the functional unit on which benzodiazepines and barbiturates operate.

Benzodiazepine receptors in the CNS have been classified as BZ1 and BZ2 subtypes, based on relative affinities for different benzodiazepines and nonbenzodiazepines. As an example, imidazopyridines (eg, zolpidem) may act via the BZ1 receptors, although contradictory evidence exists regarding this. GABA is believed to facilitate the affinity these drugs have for their receptors. The action of hyperpolarization is reversed by the influx of calcium into the cell.

The long-term pharmacodynamics interaction of benzodiazepines with the GABA receptor is thought to be extremely complex. Long-term use of benzodiazepines and barbiturates is thought to result in down-regulation of inhibitory GABA receptors and configurational changes of the receptor-agonist complex, resulting in diminished agonist sensitivity. These changes are potential mechanisms of tolerance, dependence, and withdrawal. The abrupt cessation of benzodiazepines, as in the case of a patient discontinuing a benzodiazepine after long-term use, is thought to result in the classically described acute withdrawal symptoms as the inhibitory pressure is removed, leaving a relative excitatory state.

Frequency

United States

Approximately 12.5% of the adult population uses a prescribed anxiolytic in the course of a year, while about 2% of the population takes one on any given day. More than half of these drugs, especially benzodiazepines, are prescribed by primary care physicians. In 1988, approximately 88 million prescriptions were written, most for emotional distress. Benzodiazepines are one of the most commonly prescribed drugs in this country.

International

In Western Europe and parts of Asia, use of a hypnotic in the course of a year approaches 25-30%.

Race

Use of hypnotics is higher in whites than in other races.

Sex

Male-to-female ratio is 1:2.

Age

Sedatives, anxiolytics, and hypnotics are commonly prescribed for people in the sixth and seventh decades of life; however, nonmedical use is highest in people aged 18-25 years, with rates of 0.7-1.9%.

Clinical

History

Patients who abuse or become dependent on benzodiazepines may fall into 2 broad categories. The first category contains patients being prescribed benzodiazepines for the symptomatic treatment of a psychiatric disorder. Such patients risk developing dependence, particularly if they have a history of alcohol or prescription drug abuse, are being prescribed high doses, or are prescribed the anxiolytic for longer than 1 month. Of note, some patients are safely maintained at the same dose for many years without apparent loss of efficacy. Patients with a family history of alcoholism may be genetically predisposed to benzodiazepine dependence, as evidenced by the likelihood that they will report more positive mood effects compared with those without a family history.

The second category includes patients who use benzodiazepines in the setting of alcohol or polydrug abuse or dependence. Sometimes these individuals may use benzodiazepines to manage chronic anxiety or insomnia, to prolong the effects of methadone, to lessen the undesirable effects of other drugs (eg, methamphetamine), or when no other drugs are available. Sedative-hypnotics such as secobarbital and pentobarbital are thought to be more likely to become primary drugs of abuse than benzodiazepines.

• Direct toxic actions
  • Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor skills.
  • A significant impact on driving ability, job performance, and personal relationships is possible.
  • Benzodiazepines may cause dose-related anterograde amnesia; significantly impairing the ability to learn new information while the retrieval of previously learned information remains intact. This effect is exploited when patients undergo uncomfortable procedures, as comfort and postoperative amnesia are beneficial.
  • Other clinical features include slurred speech, ataxia, nystagmus, decreased reflexes, stupor, coma, and cardiorespiratory arrest. The latter are more commonly seen with use of barbiturates (eg, chloral hydrate) due to steep dose-response properties.
  • Benzodiazepines are considered safer because of a higher therapeutic index ratio and flatter dose-response curves. Most cases of coma or respiratory depression usually occur in conjunction with other CNS depressants.
  • In the United States, barbiturates are subject to more stringent federal control and are less commonly used, while benzodiazepines are more prone to abuse or dependence because of their perceived safety and more frequent prescribing.
• Withdrawal, symptom rebound, and symptom reemergence: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) requires 2 or more of the following characteristics to be present for diagnosis of this syndrome: autonomic hyperactivity (eg, sweating, pulse rate >100); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; grand mal seizures.
  • High-dose withdrawal: Early human studies in the 1960s established that discontinuation from high doses of diazepam or chlordiazepoxide taken for 1 month produce a withdrawal syndrome. Symptoms include anxiety, insomnia, postural hypotension, nausea, vomiting, tremor, incoordination, restlessness, blurred vision, sweating, hyperpyrexia, anorexia, seizures, and delirium. Severe dependence confers increased risk for medical complications, including death. Time course of withdrawal symptoms from the last dose taken depend upon the biological half-life of the drug. Short-acting sedatives-hypnotics can trigger withdrawal in 1-2 days, with symptoms peaking between 1 and 3 days. Withdrawal from longer-acting sedatives-hypnotics may peak in approximately 1 week.
  • Low-dose withdrawal (also called therapeutic dose withdrawal or benzodiazepine discontinuation syndrome): This is withdrawal in the setting of therapeutic doses being prescribed. It is thought that withdrawal symptoms generally do not appear if the duration of the treatment is less than 4 months, but it may appear earlier if higher doses are used. While some patients can abruptly discontinue their medications without withdrawal, symptoms associated with this syndrome are the same as high-dose withdrawal, minus seizures and delirium. Depersonalization, heightened perceptions, and illusions have also been described. Symptoms may vary from mild to severe, and a protracted withdrawal syndrome may develop. Patients with a family or personal history of alcoholism or those who also use other sedatives may be at increased risk for this syndrome.
  • Protracted withdrawal syndrome: Some patients who have been maintained on therapeutic doses of benzodiazepines for extended periods may experience a relatively mild form of withdrawal, marked by symptoms of anxiety, irritability and insomnia, which can last for weeks or months. Symptoms may fluctuate throughout this time, making it difficult to assess whether the symptoms are due to symptom reemergence or symptom rebound.
  • Symptom rebound: Symptoms for which the sedative-hypnotic was used to treat (eg, insomnia) may return with increased intensity soon after discontinuation of the medication. The symptoms may last from days to weeks but will subside over time.
  • Symptom reemergence: While not a withdrawal syndrome, symptom reemergence describes the reappearance of symptoms of an underlying mood or anxiety disorder after discontinuation of the medication. Unlike symptom rebound, these symptoms will not subside over time.

Physical

The most vital aspects in assessing sedative-hypnotic intoxication or withdrawal are detailed mental status and neurologic examinations, as independent mood, psychotic, or anxiety disorder may also be present.

• Physical findings of intoxication include the following:
  • Hypothermia and hypotension
  • Head, eyes, ears, nose, and throat - Nystagmus, miosis, and diplopia
  • Cardiovascular - Hypotension and bradycardia; patients may develop tachycardia in response to hypotension
  • Pulmonary - Respiratory depression; risk of aspiration
  • Gastrointestinal - Variable
  • Musculoskeletal - Prolonged unconsciousness resulting in skin necrosis and rhabdomyolysis
  • Neurological - Ataxia, dyskinesia, dysarthria, decreased deep tendon reflexes (For higher functions, see below.)
• Mental status examination findings of intoxication include the following:
  • Appearance - Dependent upon level of intoxication, the patient may be somnolent and disheveled.
  • Behavior - Psychomotor retardation may be seen, but, on occasion, the patient may show inappropriate sexual or aggressive behavior, usually during, or shortly after, sedative use.
  • Attitude is variable.
  • Orientation: The patient can be completely disoriented, with obfuscation of higher functions. Tasks such as computation, abstraction, memory (anterograde memory in benzodiazepines, as seen in Rohypnol misuse), and concentration can be impossible to perform.
  • Perception may be altered based on level of intoxication, with a wide range of disturbances, including hallucinations and illusions.
  • Speech - Speech is often slurred.
  • Mood - The patient may report a variety of mood states.
  • Affect - Affect is variable but could be labile, euphoric, dysphoric, and the intensity ranging from blunt to flat.
  • Thought process and content - Dependent upon the level of intoxication, the thought process and content may range from paranoia to bizarre content. Patients may have suicidal ideation, since patients with depression, anxiety, and dependence personality traits have a higher daily use of sedatives.
  • Judgment is impaired.
  • Insight also is impaired, dependent upon the degree of toxicity.
• Physical signs of withdrawal syndromes including the following:
  • Vital - Hyperthermic temperature above 100 ° F; pulse rate tachycardic above 100 (beats per minute); respiration rate possibly tachypneic above 20; blood pressure variable, eg, starting off hypertensive, later stages hypotensive
  • Head, eyes, ears, nose and throat - Possible dilated pupils as a secondary effect of sympathetic hyperactivity
  • Cardiovascular - Tachycardia, palpitations, with hypertension in earlier phases of withdrawal; later, hypotensive from fluid losses (sweating and hyperventilation)
  • Pulmonary - Tachypnea
  • Gastrointestinal - Variable bowel sounds, depending on the type of autonomic predominance (parasympathetic or sympathetic) at the time of presentation
  • Musculoskeletal - Tremulous state and dehydration, potentially leading to muscle spasms and rhabdomyolysis
  • Neurologic - Tremors, increased deep tendon reflexes, ataxia, with or without dyskinesia (For clinical findings pertaining to the higher centers, please see below.)
• Mental status examination findings in withdrawal syndromes include the following:
  • Appearance - Hygiene will vary, depending on length of time experiencing withdrawal symptoms. The patient may be alert but high-strung.
  • Behavior - Patient may display psychomotor agitation, or responding to internal stimuli
  • Attitude - Patient could be hostile if very irritable.
  • Orientation - Depending on how severe the withdrawal symptoms are, the patient may be disoriented to person, place, or time. Patient may have problems with memory, concentration, abstraction, and performance of intellectual tasks.
  • Perception - Patient may exhibit increased sensory perception (smell, sight, taste, touch). There can be abnormal sensation of movement. Depersonalization or derealization is possible.
  • Speech - Speech can vary, but speech can be rapid, tremulous, or, sometimes, idiosyncratic.
  • Mood - Patient often reports feeling anxious but may also describe other feelings (eg, sadness).
  • Affect - Affect may be expansive, labile, irritable, dysphoric, and, most likely, anxious.
  • Thought process and content - Variable, but may present with disorganized thought, auditory, visual and tactile hallucinations, and delusions.
  • Judgment - May be impaired
  • Insight - May be compromised

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