Sedative, Hypnotic, Anxiolytic Use Disorders
- Author: Christopher L Sola, DO; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych (UK) more...
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, 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.
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.
Case report:
Ms X is a 50-year-old married Caucasian female who has past psychiatric history significant for major depression and medical history significant for chronic low back pain. She presented to the ED for evaluation of worsening anxiety.
She had been recently discharged from a pain rehabilitation center 1 week ago. She was tapered off clonazepam during her stay in the pain rehabilitation program due to concerns regarding her taking excess clonazepam in the past. Oxycodone was also tapered off at this time, and she was prescribed clonidine for opiate withdrawal symptoms at her dismissal. She presented with symptoms of worsening anxiety, restlessness, insomnia, tremors, and irritable mood with passive suicidal ideations. She denied any recent psychosocial stressors and did not endorse feelings of guilt, helplessness, or hopelessness. She denied any fever, nausea, vomiting, diarrhea, myalgias, abdominal cramps, and seizures. She denied any worsening of pain symptoms and found her pain rehabilitation program to be successful. She denied any recent alcohol/illicit drug use.
She was found to be tachycardic (pulse, 110 beats/min) and hypertensive (blood pressure, 170/90) on physical examination. Her medical workup including CBC, electrolyte panel, liver function tests, blood glucose level, and urine drug screen were within normal limits. Her mental status examination revealed a casually dressed female who appeared to be restless and irritable. Her speech was normal in rate and content. Her mood was subjectively anxious, objectively dysphoric and her affect was congruent with mood. Her thought form was linear and goal directed. No evidence of paranoid ideations/delusions. She denied any auditory or visual hallucinations. She was oriented to time, place, and person. She scored 30/30 on Mini-Mental State Examination. She had good insight and judgment. She endorsed passive suicidal ideations. She denied any homicidal ideations.
Ms X was diagnosed with benzodiazepine withdrawal due to recent quick taper of clonazepam, which she had been taking for a duration of 1 year with evidence of benzodiazepine abuse. She did not have symptoms suggestive of opiate withdrawal, and there were no apparent stressors/neurovegetative symptoms to explain recurrence of depressive episode.
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Diagnostic Formulation:
- Axis I: Benzodiazepine withdrawal, benzodiazepine abuse, recurrent major depression, in remission
- Axis II: Deferred
- Axis III: Chronic low back pain
- Axis IV: None significant
- Axis V: GAF 50
Pathophysiology
Gamma-aminobutyric acid (GABA) is one of the key inhibitory neurotransmitters 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.[1]
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.[1]
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.[1]
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.[2]
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.
Epidemiology
Frequency
United States
Sedative-hypnotics are the most commonly prescribed psychoactive drugs. 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. About 6% of persons have used these drugs illicitly, including 0.3% who reported illicit use of sedatives in the prior year and 0.1% who reported use of sedatives in the prior month.[2] The age group with highest lifetime prevalence of sedative (3%) and tranquilizer (6%) was 26-34 year olds, while those aged 18-25 years were most likely to have used them in the prior year.[2]
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.[3] The nonmedical use of anxiety prescriptions should be given greater clinical attention as abuse by patients continues to increase.[4]
According to one study, the early onset of nonmedical use of prescription drugs (NMUPD) 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.[5] Furthermore, nearly 10% of those with nonmedical use meet criteria for abuse/dependence. Anxiety symptoms associated with nonmedical use (panic symptoms) and abuse/dependence (agoraphobia) should alert clinicians to screen for these problems and consider alternate treatment or referral.[6]
International
In Western Europe and parts of Asia, use of a hypnotic in the course of a year approaches 25-30%.
Race
Hypnotic usage ratio in whites-to-black is 2:1.[2]
Sex
The male-to-female ratio is 1:3.[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 26-35 years.
Stahl SM. Anxiety disorders and anxiolytics. In: Stahl's Essential Psychopharmacology-Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge Press; 2008.
Kaplan, Sadock. Comprehensive Textbook of Psychiatry VI. 6th ed. 1995.
McCabe SE, Cranford JA, West BT. Trends in prescription drug abuse and dependence, co-occurrence with other substance use disorders, and treatment utilization: results from two national surveys. Addict Behav. Oct 2008;33(10):1297-305. [Medline].
Fenton MC, Keyes KM, Martins SS, Hasin DS. The role of a prescription in anxiety medication use, abuse, and dependence. Am J Psychiatry. Oct 2010;167(10):1247-53. [Medline].
McCabe SE, West BT, Morales M, Cranford JA, Boyd CJ. Does early onset of non-medical use of prescription drugs predict subsequent prescription drug abuse and dependence? Results from a national study. Addiction. Dec 2007;102(12):1920-30. [Medline].
Becker WC, Fiellin DA, Desai RA. Non-medical use, abuse and dependence on sedatives and tranquilizers among U.S. adults: psychiatric and socio-demographic correlates. Drug Alcohol Depend. Oct 8 2007;90(2-3):280-7. [Medline].
Stern TA, Fricchione G, Cassem NH, Jellinek MS, Rosenbaum JF. Drug addicted patients. In: Massachusetts General Hospital Handbook of General Hospital Psychiatry. 5th ed. Mosby Press; 2004.
Weinbroum AA, Flaishon R, Sorkine P, Szold O, Rudick V. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf. Sep 1997;17(3):181-96. [Medline].
Zullino DF, Khazaal Y, Hättenschwiler J, Borgeat F, Besson J. Anticonvulsant drugs in the treatment of substance withdrawal. Drugs Today (Barc). Jul 2004;40(7):603-19. [Medline].
Zavesicka L, Brunovsky M, Matousek M, Sos P. Discontinuation of hypnotics during cognitive behavioural therapy for insomnia. BMC Psychiatry. 2008;8:80. [Medline].
Rickels K, Case WG, Schweizer E, Garcia-Espana F, Fridman R. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry. Jun 1991;148(6):757-61. [Medline].
Allgulander C, Borg S, Vikander B. A 4-6-year follow-up of 50 patients with primary dependence on sedative and hypnotic drugs. Am J Psychiatry. Dec 1984;141(12):1580-2. [Medline].
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 4th ed. Washington, DC: American Psychiatric Press, Inc; 2000.
Bernstein J. Handbook of Drug Treatment in Psychiatry. 3rd ed. 1995.
Freidman L, Flemming N F. Source book of Substance Abuse and Addiction. 1996.
Galanter M, Kleber HD, eds. Textbook of Substance Abuse Treatment. 3rd ed. American Psychiatric Publishing; 2004.
Gilman, Ruddon, Limgird. Goodman & Gilman: Pharmacological Basis Therapeutics. 9th ed. 1996.
Karch SB, ed. Drug Abuse Handbook. CRC Press; 1997.
Katzung. Basic & Clinical Pharmacology. 7th ed. 1996.
Rabe-Jablonska J, Bienkiewicz W. [Anxiety disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association: diagnostic and statistical manual of mental disorders (DMS-IV -- options book]. Psychiatr Pol. Mar-Apr 1994;28(2):255-68. [Medline].
Simon R. Psychiatry and Law for Clinicians. 2nd ed. 1998.
Teifion Davies, TKJ Craig. ABC of Mental Health British Medical Journal. BMJ Books. 1998;39-42.
Weaver MF, Jarvis MA, Schnoll SH. Role of the primary care physician in problems of substance abuse. Arch Intern Med. May 10 1999;159(9):913-24. [Medline].
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