http://emedicine.medscape.com/article/290585-overview#showall

Sedative, Hypnotic, Anxiolytic Use Disorders 

Author: Christopher L Sola, DO; Chief Editor: Iqbal Ahmed, MBBS, FRCPsych (UK) 

BackgroundThroughout 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

PathophysiologyGamma-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.

EpidemiologyFrequency

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-IVcriteria 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]

InternationalIn 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.

HistoryPatients who abuse or become dependent on sedative-hypnotics may fall into 2 broad categories:

The first category contains patients being prescribed these drugs for the symptomatic treatment of a psychiatric disorder. Such patients have a high risk of developing sedative-hypnotic dependence, particularly if they have a history of alcohol or prescription drug abuse, are being prescribed high doses of sedative-hypnotics, or are prescribed these drugs for longer than 1

month. Patients with a family history of alcoholism may be genetically predisposed to benzodiazepine dependence. Unless dose escalation is evident or deliberate use to produce high or dangerous states of intoxication, there is no reason to assume that chronic benzodiazepine users are abusers.[7]

The second category includes patients who use sedative-hypnotics in the setting of alcohol or polydrug abuse or dependence. Sometimes, these individuals may use benzodiazepines to manage chronic anxiety or insomnia, to enhance the euphoric effects of opioids, and to lessen the withdrawal associated with cocaine.[2]

Direct toxic actions of sedative-hypnotics:o Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor

skills.o A significant impact on driving ability, job performance, and personal relationships is

possible.o 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.

o 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.

o In the United States, barbiturates are subject to more stringent federal control and are less commonly used, whereas benzodiazepines are more prone to abuse or dependence because of their perceived safety and more frequent prescribing.

o 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.

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.

o High-dose withdrawal: This is a withdrawal state in the setting of discontinuation of high-dose sedative-hypnotics. 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 on the biological half-life of the drug. Drugs with a short half-life (eg, alprazolam) may induce a more rapid onset of withdrawal and a more severe withdrawal than drugs with longer half-life (eg, diazepam). 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.

o Low-dose withdrawal (also called therapeutic dose withdrawal or benzodiazepine discontinuation syndrome): This is a withdrawal state 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.

o 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.

o 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.

o 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.

PhysicalThe most vital aspects in assessing sedative-hypnotic intoxication or withdrawal are detailed mental status and neurologic examinations in addition to comprehensive physical examination.

Physical findings of intoxication include the following:o Hypothermia and hypotensiono Eyes - Nystagmus, miosis, and diplopiao Cardiovascular - Hypotension and bradycardia; patients may develop tachycardia in

response to hypotensiono Pulmonary - Respiratory depression; risk of aspirationo Gastrointestinal - Variableo Musculoskeletal - Prolonged unconsciousness resulting in skin necrosis and rhabdomyolysiso Neurological - Ataxia, dyskinesia, dysarthria, decreased deep tendon reflexes

Mental status examination findings of intoxication include the following:o Appearance - Dependent upon level of intoxication, the patient may be somnolent and

disheveled.o 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.o Speech - Speech is often slurred.o Mood - The patient may report a variety of mood states.o Affect - Affect is variable, and it can range from flat, blunt, dysphoric, labile, and even

euphoric.o Thought process and content - Dependent upon the level of intoxication, the thought content

may range from bizarre content to paranoia. Patients may complain of suicidal ideations.o Perception - Perception may be altered based on level of intoxication, with a wide range of

disturbances, including illusions and hallucinations.o Orientation - The patient can be completely disoriented, with obfuscation of higher functions.

Tasks such as computation, abstraction, memory, and concentration are usually impaired.o Insight and judgment are usually impaired.

Physical signs of withdrawal syndromes include the following:o Vital signs - Hyperthermic temperature above 100°F; pulse rate tachycardic above 100

beats/minute; respiration rate possibly tachypneic above 20; blood pressure variable, eg, hypertensive initially, hypotensive from fluid loses at later stages

o Eyes - Possible dilated pupils as a secondary effect of sympathetic hyperactivityo Cardiovascular - Tachycardia and palpitations

o Pulmonary - Tachypneao Gastrointestinal - Variable bowel sounds, depending on the type of autonomic predominance

(parasympathetic or sympathetic) at the time of presentationo Musculoskeletal - Tremors, potentially leading to muscle spasms and rhabdomyolysiso Neurologic - Tremors, increased deep tendon reflexes, ataxia, with or without dyskinesia

Mental status examination findings in withdrawal syndromes include the following:o Appearance - Hygiene may vary, depending on length of time experiencing withdrawal

symptoms. The patient may be alert but high-strung.o Behavior - The patient may display psychomotor agitation.o Attitude - The patient may be hostile and irritable.o Orientation - Depending on the severity of withdrawal symptoms, the patient may be

disoriented to person, place, or time. The patient may have problems with memory, concentration, abstraction, and performance of intellectual tasks.

o Perception - The patient may exhibit increased sensory perception (smell, sight, taste, touch). Depersonalization or derealization is possible.

o Speech - Speech can vary and may be rapid.o Mood - The patient often reports feeling anxious but may complain of sadness.o Affect - Affect may be expansive, labile, dysphoric, and most likely anxious.o Thought process and content - This may be variable, but the patient may present with

thought disorganization and delusions.o Hallucinations - Auditory, visual, and tactile hallucinations may be present.o Judgment - This may be impaired.o Insight - This may be compromised.

Differential Diagnoses Alcohol-Related Syndromes Amphetamine-Related Psychiatric Disorders Anxiety Disorders Cerebellar Disease CNS Structural or Degenerative Disorders Cocaine-Related Psychiatric Disorders Delirium Tremens Electrolyte Disorders Endocrine Disorders Hyperthyroidism Metabolic Disorders Mood Disorders Pheochromocytoma Schizophrenia Seizure Disorders Thyrotoxicosis Toxicity, Anticholinergic Toxicity, Sympathomimetic Vasculitic or Infectious Disorders

Laboratory Studies Careful review of the patient's history and examination should typically suffice; however, further

studies may be performed to rule out an underlying pathology with a similar presentation. This is particularly relevant if the patient presents with severe symptoms or when a reliable history cannot be obtained. Workup depends on presenting symptoms (intoxication/withdrawal),

especially if no prior knowledge of ingestion of sedatives is known. If a laboratory workup is necessary, it should include the following:

Appropriate laboratory investigations are performed in patients with fever or other signs of infection. CBC, urinalysis, and chest radiography (CXR) should be performed, particularly in elderly patients.

Comprehensive metabolic panel to assess for metabolic encephalopathy seen in hepatic and renal failure and other electrolyte derangements that can mimic sedative and anxiolytic intoxication.

Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status Arterial blood gasses to rule out blood gas abnormalities secondary to respiratory depression.

Carbon monoxide poisoning should be ruled out, if suspected, by obtaining carboxyhemoglobin level measured by cooximetry of a blood gas sample.

Urine drug screen including CNS depressants, cannabis, PCP, and stimulants such as amphetamines and cocaine

Ethanol and phenobarbital intoxication can be ruled out by obtaining serum concentrations. Serum drug levels if the patient is known to take lithium, carbamazepine, valproic acid, or

TCAs, to rule out concomitant psychotropic drug toxicity Acetaminophen and salicylate levels, to rule out these common coingestions Thyroid panel, as thyrotoxicosis and hypothyroidism can mimic sedative-hypnotic withdrawal

and overdose states, respectively

Imaging Studies CT/MRI of the head, to rule out space-occupying lesions and intracranial bleeding

Other Tests ECG may be helpful to rule out arrhythmias, which can increase the probability of emboli to the

brain and cause altered mental status. Consider an EEG, as it may show paroxysmal bursts of high-voltage, slow-frequency activities

that precede the development of seizures in the setting of sedative-hypnotic withdrawal. In the context of hallucinations, EEG may rule out neurologic conditions such as temporal lobe epilepsy.

Procedures Consider a lumbar puncture, if meningitis/encephalitis suspected.

Medical CareTreatment of sedative-hypnotic overdose

Initially, treat a patient who has taken an overdose of sedative-hypnotics like any other patient with drug intoxication.

Provide an adequate airway and ventilation. Stabilize and maintain the hemodynamic status. Once initial measures have been carried out, consider inducing emesis, performing lavage,

and administering activated charcoal to a patient who has orally ingested the drug, depending on the time of ingestion and level of consciousness.

Emesis, lavage, and/or activated charcoal prevent absorption of the drug into the system and absorption of the drug or active metabolites through enterohepatic recirculation.

Laxatives may be used to induce catharsis. Benzodiazepines are the most commonly prescribed and abused sedative-hypnotics, but they

produce less respiratory depression than barbiturates. Long-acting metabolites often cause intoxication that lasts for several days. Benzodiazepine overdose is most dangerous in combination with other sedative-hypnotics.

Benzodiazepine antagonist, flumazenil, is available for the treatment of benzodiazepine intoxication.[7] It must be used with some caution; in some cases, it has not completely reversed respiratory depression, and it can cause seizures in patients with benzodiazepine dependence. (Weinbroum A et al, 1993; Wiviott SD, Source book of substance abuse and addiction, 1996).

Flumazenil is contraindicated in patients with increased intracranial pressure (ICP) or closed-head injury (CHI), those with a history of epilepsy, or those known to have ingested a tricyclic antidepressant (TCA) agent.[8]

Flumazenil should be administered in an initial IV dose of 0.2 mg given over 30 seconds, followed by a second 0.2 mg IV dose if there is no response after 45 seconds. This procedure can be repeated at 1-minute intervals up to a cumulative dose of 5 mg. In patients who are physically dependent on benzodiazepines, slowly administer repeated doses of flumazenil. (See Flumazenil).

Flumazenil is a short-acting drug; therefore, sedation after an initial awakening may recur. Observe patients with benzodiazepine toxicity for at least 2 hours after recovery from flumazenil for late respiratory depression or resedation.

If the patient overdosed on barbiturates, administer intravenous sodium bicarbonate to alkalinize the urine, which increases the rate of barbiturate excretion. The dose of bicarbonate varies depending on the patient's metabolic state. Urine pH should be monitored and maintained at 7.5. Dialysis may be required, depending on the severity of the patient's condition.

Address all potential complications, such as aspiration, pulmonary edema, and respiratory failure due to sedative-hypnotic drug overdose. If a suicide attempt is suspected, then place the patient on suicide precautions and order a psychiatric evaluation.General principles for treatment of sedative-hypnotic withdrawal syndromes

Treatment of withdrawal syndromes is identical for withdrawal from all sedative-hypnotics because all drugs in this category, including barbiturates, sleeping pills, benzodiazepines, and alcohol, exhibit cross-dependence. The basic principle is to withdraw the addicting agent slowly to avoid convulsions.

The first step in treatment is to objectively determine the patient's approximate drug tolerance level because patients often inaccurately estimate the amount of drug they have been taking. Direct observation is ideal and may be best accomplished in a supervised setting.

The use of a long-acting barbiturate decreases the severity of withdrawal symptoms, and phenobarbital is chosen in preference to other sedatives because it has a longer half-life.

An initial dose is given, usually 30-60 mg of phenobarbital or equivalent. The withdrawal drug is repeated at hourly or 2-hour intervals as needed for 2-7 days.[7] The patient should be monitored closely for acute changes in vital signs or worsening delirium, as well as for other withdrawal symptoms.

After the patient has received similar 24-hour doses for 2 consecutive days, the 24-hour stabilizing dose is given in divided doses every 3-6 hours. This index dose is then tapered, reducing subsequent daily doses by 30-60 mg/day.[7]

Treatment of severe sedative-hypnotic withdrawal

If a patient who has been using sedative-hypnotics on a long-term basis presents with advanced withdrawal (eg, elevated vital signs, delirium), it is important to medicate rapidly and in doses sufficient to suppress withdrawal symptoms.

Advanced withdrawal is most safely managed in an intensive care environment, especially if the patient has been using high doses of sedative-hypnotics, has a history of withdrawal seizures or delirium tremens, or has concurrent medical illness.

Treatment with oral agents: Determine the level of tolerance by giving pentobarbital, 200 mg by mouth and wait 1 hour. Look for signs of nystagmus, ataxia, drowsiness, dysarthria,

decreased blood pressure, and decreased pulse. If 2 or more signs are present, stop the procedure and convert to phenobarbital; if not, give pentobarbital (100 mg by mouth) every hour until 2 or more signs are present or a total of 600 mg pentobarbital has been given. Convert to phenobarbital, 30 mg for every 100 mg of pentobarbital given. Then, decrease phenobarbital by 10% of the initial dose per day.

Treatment with parenteral agents: Phenobarbital is recommended for most patients due to its long half-life, which allows less frequent dosing once the total daily dose needed to control withdrawal symptoms is determined. Infuse phenobarbital intravenously until the patient shows signs of mild intoxication (nystagmus, ataxia, drowsiness, dysarthria, decreased blood pressure, and decreased pulse). Once that dose is determined, it is the daily dose required to block withdrawal and may be given on subsequent days in divided doses.

Short-acting medications, instead of phenobarbital, are indicated for patients with severe hepatic failure and for hemodynamically unstable patients who require very rapid medication titration to control withdrawal symptoms. If a short-acting medication is to be used, choose among midazolam, diazepam, or lorazepam, depending on rapidity of reversal of effects required. Intravenous medication should be given until signs of intoxication or reduction of withdrawal signs occurs. For the short-acting intravenous medications, adjust frequency of administration to duration of action of the medication and reduce the total daily dose 10% per day.

Treatment of mild-moderate sedative-hypnotic withdrawal

Many patients who have mild dependence on benzodiazepines can be managed by a slow taper of the drug in an outpatient setting. The first step is to objectively determine an approximate level of drug to which the patient is tolerant; patients tend to overestimate or underestimate the amount of drug they have been taking.

A patient can be slowly weaned off the medication; however, this is often unsuccessful if the patient cannot cope with mild withdrawal effects. An alternative is to replace short-acting benzodiazepines (eg, alprazolam) with equivalent dosing of a longer-acting drug (eg, clonazepam), which may provide for a milder withdrawal syndrome during the taper.[7]

The following is a commonly used benzodiazepine equivalence schedule. Diazepam 10 mg is approximately equivalent to the following drugs and doses:[2]

Alprazolam - 1 mg Chlordiazepoxide - 25 mg Clonazepam- 0.5-1 mg Lorazepam - 2 mg Oxazepam - 30 mg Temazepam - 20 mg Zolpidem- 10 mg

The weekly tapering dose can be calculated by dividing the total dose by 5 and reducing the dose by this amount weekly. The dose for most patients can be reduced to zero in 4-8 weeks.

Anticonvulsant agents that do not demonstrate cross-dependence with sedative-hypnotics (ie, carbamazepine) have been used successfully in the treatment of mild sedative-hypnotic withdrawal. The main rationales for using anticonvulsants in substance-abuse patients are their lack of addiction potential, evidence supporting a role of kindling mechanisms in withdrawal syndromes, and their efficacy in comorbid psychiatric disorders. The available data currently support the utilization of carbamazepine as a treatment for detoxification from benzodiazepines and use of gabapentin and topiramate in the treatment of benzodiazepine detoxification.[9]

Consultations

Neurologist: Consultation is indicated if seizures are unresponsive to usual treatment of the withdrawal symptoms or when neurologic symptoms not explained by the usual symptoms of intoxication or withdrawal are present.

Psychiatrist: Consultation is indicated in the context of suicidal risk, aggressive behavior, or comorbid psychiatric disorders (eg, mood or psychotic disorders).

Poison centers: Poison centers may be contacted to obtain information about other possible unknown substances being used, especially in overdose situations.

DietKeep nothing by mouth if patient is unconscious.

Medication SummaryA variety of drugs are used both in the acute and the long-term setting for the treatment of sedative, hypnotic, and anxiolytic use disorders. Drug selection depends upon whether toxicity or withdrawal symptoms are being targeted.

Benzodiazepine antagonistClass Summary

These agents are used in reversing the CNS depressant effects of benzodiazepine overdose. Its ability to reverse the benzodiazepine-induced respiratory depression is difficult to predict.

View full drug informationFlumazenil (Romazicon) 

Benzodiazepine antagonist has a high affinity for the benzodiazepine receptor, making it a competitive antagonist. Flumazenil is short-acting, with a half-life of 0.7-1.3 h. Because most benzodiazepines have longer half-lives, multiple doses of flumazenil may be required to avoid relapse back into a sedative state.

BarbituratesClass Summary

These agents are used in some cases to facilitate smooth withdrawals in patients with benzodiazepines and barbiturate dependence.

View full drug informationPhenobarbital (Barbita, Luminal, Solfoton) 

Chosen for withdrawal because of long half-life and wide therapeutic index. General principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Arbitrary doses are given, and treatment is individualized to respect variable effects in different patients.

BenzodiazepinesClass Summary

In dependent patients, these are used in a manner similar to phenobarbital to wean patients from short-acting benzodiazepines. The general principle is that sedatives with longer half-lives have less severe withdrawal symptoms. Various patient-specific dosing strategies are used. If symptoms are severe enough to require inpatient treatment, IV lorazepam or diazepam is used.

After stabilizing the patient, the tapering dose is calculated by dividing the total dose by 5 and reducing by this amount weekly.

View full drug informationDiazepam (Valium) 

Depresses all levels of CNS (eg, limbic, reticular formation), possibly by increasing activity of GABA. Individualize the dosage and increase cautiously to avoid adverse effects.

View full drug informationLorazepam (Ativan) 

Sedative-hypnotic with short onset of effects and relatively long half-life.

By increasing the action of GABA, which is the major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Important to monitor patient's blood pressure after administering dose. Adjust dose as necessary.

View full drug informationClonazepam (Klonopin) 

Suppresses muscle contractions by facilitating neurotransmission of GABA and other inhibitory transmitters.

Further Inpatient Care Definitive treatment is a lengthy process, taking months or years. A return to drug use should

not be considered a treatment failure, but rather a time to intensify treatment. After successful medical treatment of sedative/hypnotic withdrawal/intoxication, the patient

may be transferred to the psychiatric unit, if he or she meets criteria for inpatient psychiatric treatment.

Effective treatment requires a thorough evaluation of the patient's psychiatric problems and development of long-term treatment plans.

Urine drug screens should be performed periodically to monitor illicit drug use. Family counseling should be completed to focus on the family's role in helping the patient

develop a successful long-term treatment plan.[7]

Referrals for long-term outpatient or residential treatment for sedative-hypnotic addiction should be made early in the treatment process to prevent relapse.

Further Outpatient Care Patients with sedative-hypnotic use disorders are frequently treated in the outpatient setting, as

most are stable and require minimal monitoring. Inpatient hospitalization is reserved for the most severely impaired patients requiring complicated withdrawals, patients who have been unsuccessful as outpatients, or patients with medical and/or psychiatric comorbidity.

A recent study confirms the efficacy of cognitive behavior therapy (CBT) in both hypnotic-abusing and nonabusing patients with chronic insomnia. The results of this study suggest that tapered withdrawal of third-generation hypnotics during CBT therapy for chronic insomnia could be associated with improvement rather than worsening of sleep continuity.[10]

Some may benefit from enrollment in support groups, such as Pills Anonymous, and attending drug-free outpatient counseling.

Prognosis

Some individuals respond to treatment and stay in remission, while others experience periods of relapse, in which they begin SHA use/abuse after a period of remission, and again meet the criteria for substance dependence. Some individuals are never able to abstain from use and do not experience any periods of remission.

Only a handful of studies have looked into long-term success of benzodiazepine discontinuation programs. Most studies indicate a high relapse state; however, outcome is more favorable in those individuals who manage to complete a discontinuation program.[11] A 4- to 6-year post discharge follow-up study of patients primarily admitted for primary sedative-hypnotic dependence showed that 84% of the patients had resumed using sedative-hypnotics, 52% were abusing drugs at follow-up, and 42% had been readmitted for drug abuse.[12]

Outcome is better in individuals with good social support, absence of psychiatric co-morbidity or remission of preexisting psychiatric symptoms, and absence of dependence on other drugs.

Patient Education Excellent patient education resources are available at eMedicine's Substance Abuse

Center and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Benzodiazepine Abuse, Barbiturate Abuse, andSubstance Abuse.

Family education: Sedative-hypnotic abuse/dependence can affect the entire family, it is necessary to inform them of the pertinent issues. In certain cases, family members can be enablers.

Physician education: It is important for the prescribing physician to know about the harmful effects and complications related to sedative-hypnotic use. Often, the patient will seek supply of these drugs from many practitioners. Physicians may also benefit from feedback on their prescribing practices.

Perawatan Medis

Pengobatan sedatif-hipnotik overdosis

• Awalnya, mengobati pasien yang telah mengambil overdosis obat penenang-hipnotik seperti pasien lain dengan intoksikasi obat.

• Memberikan jalan napas dan ventilasi yang memadai.

• Menstabilkan dan mempertahankan status hemodinamik.

• Setelah langkah-langkah awal telah dilakukan, mempertimbangkan emesis merangsang, melakukan lavage, dan pemberian arang aktif kepada pasien yang telah secara lisan tertelan obat, tergantung pada waktu konsumsi dan tingkat kesadaran.

• Emesis, lavage, dan / atau arang aktif mencegah penyerapan obat ke dalam sistem dan penyerapan obat atau metabolit aktif melalui resirkulasi enterohepatik.

• Obat pencahar dapat digunakan untuk menginduksi katarsis.

• Benzodiazepin yang paling sering diresepkan dan disalahgunakan sedatif-hipnotik, tetapi mereka menghasilkan depresi pernafasan kurang dari barbiturat. Long-acting metabolit sering menyebabkan keracunan yang berlangsung selama beberapa hari. Overdosis benzodiazepin yang paling berbahaya dalam kombinasi dengan obat penenang-hipnotik.

• antagonis Clobazam, flumazenil, tersedia untuk pengobatan keracunan benzodiazepine [7] Hal ini harus digunakan dengan hati-hati,. Dalam beberapa kasus, hal itu belum benar-benar terbalik depresi pernafasan, dan dapat menyebabkan kejang pada pasien dengan ketergantungan benzodiazepine. (Weinbroum A et al, 1993; Wiviott SD, Sumber buku penyalahgunaan zat dan kecanduan, 1996).

• Flumazenil merupakan kontraindikasi pada pasien dengan peningkatan tekanan intrakranial (ICP) atau tertutup-cedera kepala (CHI), mereka yang memiliki riwayat epilepsi, atau mereka diketahui telah menelan antidepresan trisiklik (TCA) agen [8].

• Flumazenil harus diberikan dalam dosis IV awal 0,2 mg diberikan selama 30 detik, diikuti dengan dosis 0,2 mg IV detik jika tidak ada respon setelah 45 detik. Prosedur ini dapat diulang pada interval 1 menit sampai dosis kumulatif dari 5 mg. Pada pasien yang secara fisik tergantung pada benzodiazepine, perlahan-lahan mengatur dosis berulang flumazenil. (Lihat Flumazenil).

• Flumazenil adalah obat short-acting, karena itu, sedasi setelah kebangkitan awal bisa kambuh. Amati pasien dengan toksisitas benzodiazepin selama minimal 2 jam setelah pemulihan dari flumazenil untuk depresi pernafasan terlambat atau resedation.

• Jika pasien overdosis barbiturat, mengelola natrium bikarbonat intravena untuk membasakan urin, yang meningkatkan laju ekskresi barbiturat. Dosis bikarbonat bervariasi tergantung pada keadaan

metabolik pasien. PH urine harus dipantau dan dipertahankan pada 7,5. Dialisis mungkin diperlukan, tergantung pada tingkat keparahan kondisi pasien.

• Alamat semua potensi komplikasi, seperti aspirasi, edema paru, dan kegagalan pernafasan karena sedatif-hipnotik overdosis narkoba. Jika usaha bunuh diri diduga, kemudian menempatkan pasien pada tindakan pencegahan bunuh diri dan memesan evaluasi psikiatri.

Prinsip-prinsip umum untuk pengobatan sedatif-hipnotik sindrom penarikan

• Pengobatan sindrom penarikan identik untuk penarikan dari semua sedatif hipnotik-karena semua obat dalam kategori ini, termasuk barbiturat, obat tidur, benzodiazepines, dan alkohol, menunjukkan silang-ketergantungan. Prinsip dasarnya adalah untuk menarik agen addicting perlahan untuk menghindari kejang-kejang.

• Langkah pertama dalam pengobatan adalah untuk menentukan obyektif obat perkiraan pasien tingkat toleransi karena pasien sering tidak akurat memperkirakan jumlah obat yang mereka telah mengambil. Pengamatan langsung sangat ideal dan mungkin paling baik dilakukan dalam pengaturan diawasi.

• Penggunaan barbiturat long-acting mengurangi keparahan gejala penarikan, dan fenobarbital dipilih dalam preferensi untuk obat penenang lain karena memiliki lagi setengah-hidup.

• Sebuah dosis awal diberikan, biasanya 30-60 mg fenobarbital atau setara. Obat penarikan diulang pada interval per jam atau 2 jam seperti yang diperlukan untuk 2-7 hari. [7] Pasien harus dipantau ketat untuk perubahan akut pada tanda-tanda vital atau delirium memburuk, serta untuk gejala penarikan lainnya.

• Setelah pasien telah menerima sama 24-jam dosis selama 2 hari berturut-turut, dosis pemantapan 24 jam diberikan dalam dosis terbagi tiap 3-6 jam. Dosis ini indeks kemudian meruncing, mengurangi dosis harian berikutnya oleh 30-60 mg / hari [7].

Pengobatan parah sedatif-hipnotik penarikan

• Jika seorang pasien yang telah menggunakan obat penenang-hipnotik pada basis jangka panjang menyajikan dengan penarikan canggih (misalnya, tanda-tanda vital ditinggikan, delirium), penting untuk mengobati cepat dan dalam dosis yang cukup untuk menekan gejala penarikan.

• penarikan Advanced paling aman dikelola dalam lingkungan perawatan intensif, terutama jika pasien telah menggunakan dosis tinggi obat penenang-hipnotik, memiliki riwayat kejang penarikan atau tremens delirium, atau memiliki penyakit medis yang bersamaan.

• Pengobatan dengan obat oral: Tentukan tingkat toleransi dengan memberikan pentobarbital, 200 mg melalui mulut dan menunggu 1 jam. Carilah tanda-tanda nystagmus, ataksia, mengantuk, dysarthria, penurunan tekanan darah, dan penurunan denyut nadi. Jika 2 atau lebih tanda-tanda yang hadir, hentikan prosedur dan mengkonversi ke fenobarbital, jika tidak, berikan pentobarbital (100 mg melalui mulut) setiap jam sampai 2 atau lebih tanda-tanda hadir atau total 600 mg pentobarbital telah

diberikan. Konversikan ke fenobarbital, mg 30 mg untuk setiap 100 dari pentobarbital diberikan. Kemudian, menurunkan fenobarbital sebesar 10% dari dosis awal per hari.

• Pengobatan dengan agen parenteral: Phenobarbital direkomendasikan untuk sebagian besar pasien karena panjang paruh, yang memungkinkan dosis kurang sering sekali dosis harian total yang dibutuhkan untuk mengendalikan gejala penarikan ditentukan. Infus intravena fenobarbital sampai pasien menunjukkan tanda-tanda keracunan ringan (nystagmus, ataksia, mengantuk, dysarthria, penurunan tekanan darah, dan penurunan denyut nadi). Setelah dosis yang ditentukan, itu adalah dosis harian yang diperlukan untuk memblokir penarikan dan dapat diberikan pada hari-hari berikutnya dalam dosis terbagi.

• Short-acting obat, bukan fenobarbital, diindikasikan untuk pasien dengan gagal hati yang parah dan untuk pasien hemodinamik tidak stabil yang memerlukan titrasi obat yang sangat cepat untuk mengontrol gejala penarikan. Jika obat short-acting yang akan digunakan, memilih di antara midazolam, diazepam, lorazepam atau, tergantung pada kecepatan dari pembalikan efek yang diperlukan. Obat intravena harus diberikan sampai tanda-tanda keracunan atau pengurangan tanda-tanda penarikan terjadi. Untuk short-acting obat intravena, menyesuaikan frekuensi administrasi untuk durasi aksi obat dan mengurangi dosis harian total 10% per hari.

Pengobatan ringan-sedang sedatif-hipnotik penarikan

• Banyak pasien yang memiliki ketergantungan ringan pada benzodiazepin dapat dikelola oleh lancip lambat dari obat dalam pengaturan rawat jalan. Langkah pertama adalah untuk menentukan tingkat obyektif perkiraan obat yang pasien toleran, pasien cenderung untuk melebih-lebihkan atau meremehkan jumlah obat yang mereka telah mengambil.

• Seorang pasien dapat perlahan-lahan disapih dari obat, namun, hal ini sering tidak berhasil jika pasien tidak dapat mengatasi dengan efek penarikan ringan. Alternatif adalah untuk menggantikan short-acting benzodiazepin (misalnya, alprazolam) dengan dosis setara dengan obat lama-acting (misalnya, clonazepam), yang dapat memberikan untuk sindrom penarikan ringan selama lancip. [7]

• Berikut ini adalah jadwal umum digunakan kesetaraan benzodiazepine. Diazepam 10 mg kurang lebih setara dengan obat berikut dan dosis: [2]

• Alprazolam - 1 mg

• chlordiazepoxide - 25 mg

• Clonazepam-0,5-1 mg

• Lorazepam - 2 mg

• oxazepam - 30 mg

• Temazepam - 20 mg

• Zolpidem-10 mg

• Dosis meruncing mingguan dapat dihitung dengan membagi dosis total 5 dan mengurangi dosis dengan jumlah ini mingguan. Dosis untuk sebagian besar pasien dapat dikurangi menjadi nol dalam 4-8 minggu.

• agen Anticonvulsant yang tidak menunjukkan silang-ketergantungan dengan sedatif hipnotik-(yaitu, carbamazepine) telah berhasil digunakan dalam pengobatan obat penenang ringan-hipnotis penarikan. Dasar pemikiran utama untuk menggunakan antikonvulsan di penyalahgunaan zat-pasien kurangnya potensi kecanduan, bukti yang mendukung peran dari ranting mekanisme dalam sindrom penarikan, dan keberhasilan mereka dalam gangguan kejiwaan komorbid. Data yang tersedia saat ini mendukung pemanfaatan karbamazepin sebagai pengobatan untuk detoksifikasi dari benzodiazepin dan penggunaan gabapentin dan topiramate dalam pengobatan detoksifikasi benzodiazepine. [9]

Konsultasi

• Neurolog: Konsultasi diindikasikan jika kejang tidak responsif terhadap pengobatan biasa gejala penarikan atau bila gejala neurologis tidak dijelaskan oleh gejala yang biasa keracunan atau penarikan yang hadir.

• Psikiater: Konsultasi diindikasikan dalam konteks risiko bunuh diri, perilaku agresif, atau gangguan kejiwaan komorbid (misalnya, suasana hati atau gangguan psikotik).

Pusat Poison •: pusat Racun dapat dihubungi untuk memperoleh informasi tentang zat lain yang tidak diketahui yang mungkin digunakan, terutama dalam situasi overdosis.

Diet

Jauhkan apa-apa melalui mulut jika pasien tidak sadar.

Obat Ringkasan

Berbagai obat yang digunakan baik dalam akut dan pengaturan jangka panjang untuk pengobatan gangguan penggunaan obat penenang, hipnotik, dan anxiolytic. Pemilihan obat tergantung pada apakah racun atau penarikan gejala yang menjadi sasaran.

Benzodiazepine antagonis

Kelas Ringkasan

Agen-agen ini digunakan dalam membalikkan efek depresan SSP dari overdosis benzodiazepine. Kemampuannya untuk membalikkan depresi pernafasan benzodiazepine-induced sulit untuk memprediksi.

Lihat informasi obat penuh

Flumazenil (Romazicon)

Antagonis benzodiazepin memiliki afinitas tinggi untuk reseptor benzodiazepine, membuatnya menjadi antagonis kompetitif. Flumazenil adalah short-acting, dengan waktu paruh dari 0,7-1,3 jam. Karena benzodiazepin sebagian besar lagi setengah-hidup, beberapa dosis flumazenil mungkin diperlukan untuk menghindari kambuh kembali menjadi negara penenang.

Barbiturat

Kelas Ringkasan

Agen-agen ini digunakan dalam beberapa kasus untuk memfasilitasi penarikan halus pada pasien dengan benzodiazepin dan ketergantungan barbiturat.

Lihat informasi obat penuh

Fenobarbital (Barbita, Luminal, Solfoton)

Dipilih untuk penarikan karena panjang setengah-hidup dan indeks terapeutik yang luas. Prinsip umum adalah bahwa obat penenang dengan panjang setengah-hidup memiliki gejala penarikan kurang parah. Sewenang-wenang dosis yang diberikan, dan pengobatan individual untuk menghormati efek variabel pada pasien yang berbeda.

Benzodiazepin

Kelas Ringkasan

Pada pasien tergantung, ini digunakan dalam cara yang mirip dengan fenobarbital dengan pasien menyapih dari short-acting benzodiazepin. Prinsip umum adalah bahwa obat penenang dengan panjang setengah-hidup memiliki gejala penarikan kurang parah. Berbagai pasien-spesifik strategi dosis yang digunakan. Jika gejalanya cukup parah memerlukan rawat inap, IV lorazepam atau diazepam digunakan.

Setelah menstabilkan pasien, dosis meruncing dihitung dengan membagi dosis total 5 dan mengurangi jumlah ini oleh mingguan.

Lihat informasi obat penuh

Diazepam (valium)

Menekan semua tingkat SSP (misalnya, limbik, formasi reticular), mungkin dengan meningkatkan aktivitas GABA. Individualize dosis dan meningkatkan hati-hati untuk menghindari efek samping.

Lihat informasi obat penuh

Lorazepam (Ativan)

Sedatif-hipnotik dengan onset pendek efek dan relatif lama paruh.

Dengan meningkatkan aksi GABA, yang merupakan neurotransmitter inhibisi utama dalam otak, dapat menekan semua tingkat SSP, termasuk pembentukan limbik dan reticular.

Penting untuk memonitor tekanan darah pasien setelah pemberian dosis. Menyesuaikan dosis yang diperlukan.

Lihat informasi obat penuh

Clonazepam (Klonopin)

Menekan kontraksi otot dengan memfasilitasi neurotransmisi pemancar hambat GABA dan lainnya.

Selanjutnya Rawat Inap

• Terapi definitif adalah proses yang panjang, mengambil bulan atau tahun. A kembali ke penggunaan narkoba seharusnya tidak dianggap sebagai kegagalan pengobatan, melainkan waktu untuk mengintensifkan pengobatan.

• Setelah pengobatan berhasil penenang / hipnotik penarikan / keracunan, pasien dapat dipindahkan ke unit psikiatri, jika ia memenuhi kriteria untuk pengobatan rawat inap psikiatri.

• Pengobatan yang efektif memerlukan evaluasi menyeluruh dari masalah kejiwaan pasien dan pengembangan rencana jangka panjang pengobatan.

Urine layar • obat harus dilakukan secara berkala untuk memantau penggunaan narkoba.

• Konseling keluarga harus diselesaikan untuk fokus pada peran keluarga dalam membantu pasien mengembangkan rencana pengobatan jangka panjang yang sukses [7].

• Referal untuk jangka panjang rawat jalan atau perawatan perumahan untuk sedatif-hipnotik kecanduan harus dilakukan pada awal proses pengobatan untuk mencegah kekambuhan.

Selanjutnya Rawat Jalan Perawatan

• Pasien dengan sedatif-hipnotik gangguan penggunaan sering diperlakukan dalam pengaturan rawat jalan, karena kebanyakan stabil dan memerlukan pemantauan minimal. Rawat inap Rawat Inap dicadangkan untuk sebagian besar pasien sangat terganggu memerlukan penarikan rumit, pasien yang telah gagal sebagai pasien rawat jalan, atau pasien dengan komorbiditas medis dan / atau kejiwaan.

• Sebuah studi baru-baru ini menegaskan kemanjuran terapi perilaku kognitif (CBT) di kedua hipnotis-menyalahgunakan dan nonabusing pasien dengan insomnia kronis. Hasil penelitian ini menunjukkan bahwa penarikan meruncing generasi ketiga hipnotik selama terapi CBT untuk insomnia kronis dapat dikaitkan dengan peningkatan ketimbang memburuknya kontinuitas tidur. [10]

• Beberapa dapat mengambil manfaat dari partisipasi dalam kelompok pendukung, seperti Pil Anonymous, dan menghadiri bebas narkoba konseling rawat jalan.

Prognosa

• Beberapa individu merespon pengobatan dan tinggal di remisi, sementara periode pengalaman orang lain kambuh, di mana mereka mulai menggunakan SHA / pelecehan setelah periode remisi, dan lagi memenuhi kriteria untuk ketergantungan zat. Beberapa orang tidak pernah mampu untuk menjauhkan diri dari penggunaan dan tidak mengalami periode remisi.

• Hanya sedikit studi telah melihat ke keberhasilan jangka panjang dari program penghentian benzodiazepine. Kebanyakan penelitian menunjukkan keadaan kekambuhan tinggi, namun, hasil yang lebih menguntungkan dalam orang-orang yang berhasil menyelesaikan program penghentian [11] A 4 - sampai 6 tahun pasca-discharge tindak lanjut studi pasien terutama mengakui untuk SD sedatif-hipnotik. ketergantungan menunjukkan bahwa 84% dari pasien telah kembali dengan menggunakan sedatif hipnotik-, 52% yang menyalahgunakan narkoba di follow-up, dan 42% telah diterima kembali untuk penyalahgunaan narkoba [12].

• Hasil lebih baik pada individu dengan dukungan sosial yang baik, tidak adanya kejiwaan co-morbiditas atau remisi gejala kejiwaan yang sudah ada sebelumnya, dan tidak adanya ketergantungan pada obat lain.

Pasien Pendidikan

• sumber daya pendidikan pasien sangat baik tersedia di Pusat Penyalahgunaan Zat eMedicine dan Mental Pusat Kesehatan dan Perilaku. Juga, melihat pendidikan pasien eMedicine ini Pelanggaran artikel Clobazam, barbiturat Abuse, Pelanggaran andSubstance.

• Pendidikan Keluarga: ketergantungan Sedative-hipnotis pelecehan / dapat mempengaruhi seluruh keluarga, maka perlu untuk memberitahu mereka tentang isu-isu terkait. Dalam kasus-kasus tertentu, anggota keluarga dapat menjadi enabler.

• Pendidikan Dokter: Penting bagi dokter meresepkan tahu tentang efek berbahaya dan komplikasi yang berhubungan dengan sedatif-hipnotik digunakan. Seringkali, pasien akan mencari pasokan obat-obatan dari banyak praktisi. Dokter juga dapat mengambil manfaat dari umpan balik pada praktek-praktek mereka resep.