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Sedative, Hypnotic, Anxiolytic Use Disorders

  • Author: Lorin M Scher, MD; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych(UK)  more...
 
Updated: Feb 18, 2014
 

Background

Psychiatry has been given the role of investigating, understanding, and treating the effects of stress, including anxiety, dysphoria, and feelings of discomfort. In addition to conventional psychotherapy models, psychiatrists worked on pharmacological therapies and consequently, sedatives, anxiolytics, and hypnotics were created. The oldest of these is ethanol. By the 19th century, bromide salts, chloral 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.[1]

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.

While the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has been replaced by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), in which the Axis diagnoses have been removed, the Diagnostic Formulation for the DSM-IV would include the following:

  • Axis I: Benzodiazepine withdrawal, benzodiazepine abuse, recurrent major depression, in remission
  • Axis II: Deferred
  • Axis III: Sinus infections
  • Axis IV: None significant
  • Axis V: GAF 50

Case report

Mr. X is a 27-year-old white male with a past psychiatric history of anxiety, insomnia, and substance abuse and no past medical history who presents in the emergency department with a friend for confusion and diaphoresis.

He was recently seen at a community clinic 1 week ago for a sinus infection and was given a 10-day course of antibiotics, but did not receive his alprazolam refill. He states he has taken his antibiotics as prescribed for the past 10 days, but that his heart has been racing and his insomnia has worsened; his friend states that for the past 4 days he has been having difficulty following conversations and focusing on daily tasks. He has been off his alprazolam for 7 days because he ran out of his prescription. He denied any recent psychosocial stressors and did not endorse feelings of guilt, helplessness, or hopelessness. Furthermore, he denied any fever, nausea, vomiting, diarrhea, myalgias, abdominal cramps, and seizures. He denied any recent alcohol/illicit drug use.

Upon physical examination, he was found to be tachycardia (pulse, 110 beats/min) and hypertensive (blood pressure, 170/90 mm Hg). His medical workup, including CBC count, electrolyte panel, liver function tests, blood glucose level, and urine toxicology screen, and his lumbar puncture were within normal limits. His mental status examination revealed a casually dressed male who appeared to be restless and irritable. His speech was normal in rate and content. His mood was subjectively anxious and objectively dysphoric, and his affect was congruent with mood. His thought form was linear and goal directed. There was no evidence of paranoid ideations/delusions. He denied any auditory or visual hallucinations. He was oriented to time, place, and person. He scored 30/30 on the Mini-Mental State Examination. He had good insight and judgment. He endorsed passive suicidal ideations. He denied any homicidal ideations.

Mr X was diagnosed with benzodiazepine withdrawal due to recent abrupt discontinuation of benzodiazepine. He did not have symptoms suggestive of worsening infection, and there were no apparent stressors/neurovegetative symptoms to explain recurrence of depressive episode.

Medicolegal issues

While no foolproof techniques exist to prevent malpractice, there are ways to reduce exposure to litigation procedures. An estimated 7% of all malpractice claims against psychiatrists result from medication errors and drug-related reactions. The most common pitfalls are as follows[2] :

  • Failure to prescribe the appropriate dosages of medication for patient's requirements
  • Failure to monitor and treat medication adverse effects
  • Negligent prescription practices
  • Prescription of addictive drugs to vulnerable patients
  • Failure to refer a patient for consultation or treatment by a specialist
  • Failure to communicate with other medical professionals who are involved with the care of the patient

All physicians are judged by certain standards of care and guidelines. Their actions are compared to the standards expected of an average physician in their community under the circumstances.

When treating a patient with any medication, meeting certain expectations can minimize unnecessary litigation. Note the following:

  • Succinctly record the patient's history, in particular a history of alcohol use and any history of other substance-related disorders and results of physical examination. If possible, support this information with laboratory tests.
  • Clearly instruct the patient about the use and potential side effects of medication. Obtain an informed consent from the patient, especially if the drug has unpleasant effects.
  • Maintain relevant documentation, especially for changes in medication or instructions. Record the precise number of pills given potentially abused substances, such as sedative-hypnotics or anxiolytics.
  • If the physician is uncomfortable prescribing a particular medication or treating a condition requiring that medication, it is advisable to consult a colleague or research the drug and situation through recently updated reference textbooks or other media.
  • After starting the patient on any sedative, it is advisable to monitor his or her reaction to the medication.
  • Remain aware of current guidelines, drugs recently approved by the Food and Drug Administration, current or recent literature (eg, alternative treatment approaches that do not require these medications), and relevant updates by pharmaceutical companies (eg, reports of surveillance of side effects of these medications). Ignorance is not an acceptable excuse in legal action.
  • Be cautious about approving drugs over the telephone without seeing the patient, and always review the pertinent records.

Because hypnotics, especially barbiturates, can mimic signs of brain death (eg, no doll's eyes movement or fixed, dilated pupils), be cautious when labeling an overdose patient with brain death.

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Pathophysiology

Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter involved in anxiety and in the anxiolytic action of psychotropic drugs used to treat anxiety disorders. 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. The action of hyperpolarization is reversed by the influx of calcium into the cell.[3]

The 3 major types of GABA receptors include GABA-A, GABA-B and GABA-C 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. GABA-A receptors can be further classified as benzodiazepine-sensitive and benzodiazepine-insensitive based on structural differences between these receptor subtypes. The GABA-A receptor is a protein, which forms a chloride-selective ion channel and ligands. The metabolized benzodiazepine binds this site and stabilizes 3 different conformations. Classic benzodiazepines exert a positive effect by increasing the affinity of channel opening.[4]

Benzodiazepine-sensitive GABA receptors with alpha-1 subunits may be most important for regulating sleep and are the presumed targets of sedative-hypnotic agents. On the other hand, benzodiazepine-sensitive GABA-A receptors with alpha-2 subunits may be most important for regulating anxiety and are presumed targets of anxiolytic agents. Flumazenil, a benzodiazepine antagonist, interacts with GABA-A receptors and is used clinically to rapidly reverse the effects of benzodiazepine overdoses.[3]

The long-term pharmacodynamic interaction of benzodiazepines with the GABA receptor is thought to be extremely complex. After long-term benzodiazepine use, the receptor effects caused by the agonist are attenuated. This down-regulation of receptor response is not due to decrease in receptor number or to decreased affinity of the receptor for GABA. The basis for down-regulation seems to be in the coupling between GABA-binding site and the activation of the chloride ion channel.[5]

These changes are potential mechanisms of tolerance, withdrawal, and dependence. 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 effect of benzodiazepines is removed, thus leading to a relative excitatory state.[6]

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Epidemiology

Frequency

United States

Sedative-hypnotics are the most commonly prescribed psychoactive drugs by primary care physicians. 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. According to the results from the 2006 National Survey on Drug Use and Health, 2.8% of the US population (ie, 7 million people) used psychotherapeutic drugs for nonmedical purposes; of them, 1.8 million used tranquilizers and 385,000 used sedatives.

A 2010 analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), found that of the 34,653 respondents aged 18-80 years who completed interviews during waves of the research from 2001-2002 and 2004-2005, 11.8% of respondents had received prescriptions for anxiety medication; 16% of this subgroup reported lifetime nonmedical use and 4.6% reported abuse of or dependence on these drugs.[7, 8]

The age group with highest lifetime prevalence of sedative (3%) and tranquilizer (6%) use was 26-34 years, while those aged 18-25 years were most likely to have used them in the prior year.[9] The nonmedical use of anxiety prescriptions continues to garner clinical attention because abuse by patients has been increasing.

According to one study, the early onset of nonmedical use of prescription drugs was a significant predictor of prescription drug abuse and dependence. A higher percentage of individuals who began using prescription drugs nonmedically at or before age 13 years were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after age 21 years.[10] Furthermore, nearly 10% of those with nonmedical use meet criteria for abuse/dependence.

In Asia, a Taiwanese study further corroborated this finding by examining the change in pattern and variation of long-term benzodiazepine users from adolescence to adulthood over a 5-year period. They concluded that with the rise of use of antianxiety and psychotropic drugs in pediatric and adolescent populations, those with a history of psychosis or epilepsy, prescription by providers from multiple specialties, and receipt of benzodiazepines with a long half-life significantly increased one's risk of becoming a chronic or accelerating user.

These are important considerations for clinicians, given that they can screen for potential abuse/dependence in patients who present with anxiety or panic symptoms and be able to offer alternative treatments or referrals.[11]

The past-year prevalence of prescription sedative abuse and sedative dependence has increased from 1991-1992 to 2001-2002. The majority of individuals with past-year sedative (56.8%) and tranquilizer (89.0%) use disorders also met DSM-IV criteria for an additional past-year substance use disorder. The co-occurrence of several forms of prescription drug use disorders and other substance use disorders increased from 1991-1992 to 2001-2002.[12]

International

In Western Europe and parts of Asia, usage rates for hypnotics in the course of a year approaches 25-30%.

A recent study in Amsterdam found that the Dutch population aged 55-64 years showed overall consistent benzodiazepine use from 1992-2002, with a high proportion of long-term users, despite the effort to reduce benzodiazepine use and the renewal of the guidelines. They concluded that effort should be made to decrease prolonged benzodiazepine use in this middle-aged group, because of the increasing risks with aging, including falls and difficulty completing activities of daily living.[13]

Race

Hypnotic usage ratio in whites to blacks is 2:1.[9]

Sex

The male-to-female ratio is 1:3.[9]

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 26-35 years and higher in men compared with women and non-Hispanic whites compared with African Americans or Hispanics.[14]

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Contributor Information and Disclosures
Author

Lorin M Scher, MD Director, Emergency Psychiatric ServicesHealth Sciences Assistant Clinical ProfessorDepartment of Psychiatry and Behavioral SciencesUniversity of California, Davis, School of Medicine

Lorin M Scher, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Alpha Omega Alpha, American Medical Association, American Psychiatric Association, Association for Academic Psychiatry

Disclosure: Nothing to disclose.

Coauthor(s)

Siddarth Puri, MA University of California, Davis, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Iqbal Ahmed, MBBS, FRCPsych(UK) Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of the Health Sciences; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Iqbal Ahmed, MBBS, FRCPsych(UK) is a member of the following medical societies: Academy of Psychosomatic Medicine, American Neuropsychiatric Association, American Society of Clinical Psychopharmacology, Royal College of Psychiatrists, American Association for Geriatric Psychiatry, American Psychiatric Association

Disclosure: Nothing to disclose.

Additional Contributors

Jennifer S Morse, MD Associate Medical Director, Optum Health

Jennifer S Morse, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Aerospace Medical Association, American Psychiatric Association

Disclosure: Nothing to disclose.

Acknowledgements

Olakunle PA Akinsoto, MD, MBBCh Consulting Staff, Family Health Center, Jacksonville Medical Center

Disclosure: Nothing to disclose.

Amit Chopra, MD Resident Physician, Department of Psychiatry, Mayo Clinic, Rochester

Disclosure: Nothing to disclose.

Abhinav Rastogi, MBBS, MRCPsych Resident Psychiatrist, Stratford Road Day Centre, Birmingham, UK

Disclosure: Nothing to disclose.

Christopher L Sola, DO Assistant Professor in Psychiatry, Mayo Clinic School of Medicine; Medical Director of Inpatient Medical Psychiatry Program, Department of Psychiatry and Psychology, Mayo Clinic

Christopher L Sola, DO is a member of the following medical societies: Academy of Psychosomatic Medicine, American Medical Association, American Osteopathic Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Joji Suzuki, MD Fellow in Addiction Psychiatry, Department of Psychiatry, Boston University School of Medicine

Disclosure: Nothing to disclose.

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