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Ellen A. Ovson, M.D., F.A.S.A.M. Medical Director Bradford Health Services, Madison, Alabama “If the patient be in the prime of life and if from drinking he has trembling hands, it may be well to announce beforehand either delirium or convulsions” Hippocrates circa 400 BC BAC 20 mg% to 99 mg% Loss of muscular coordination Changes in mood, personality, and behavior BAC 100 mg% to 199 mg% Neurologic impairment Prolonged reaction time Ataxia Incoordination Mental impairment BAC 200 mg% to 299 mg% Marked ataxia Nausea and vomiting BAC 300 mg% to 399 mg% Hypothermia Severe dysarthria Amnesia Stage I anesthesia BAC 400 mg% to 799 mg% Alcoholic coma Progressive obtundation Decreased respiration Decreased blood pressure Decreased body temperature Urinary incontinence or retention Reflexes markedly decreased or absent BAC 600 mg% to 800 mg% Often fatal Death may occur from loss of airway protective reflexes (obstruction from flaccid tongue) Pulmonary aspiration of gastric contents Profound CNS depression Supportive Primary goals Prevent respiratiory depression Protect airway (prevent aspiration) Survival is probable with respiratory and cardiovascular support IV glucose and thiamine (alcohol impairs glucogenesis) Emesis / gastric lavage not indicated (EtOH rapidly absorbed) Charcoal does not absorb alcohol Enhancement of elimination has no role Hemodialysis is effective, but rarely indicated since treatment is supportive only No effective antagonist (flumazenil not effective) Agitation best managed non-pharmacologically Rate of metabolism follows zero order kinetics Independent of time and concentration of the drug Elimination occurs at a rate of 15 to 20 mg/dl/hr Begins 6 to 24 hrs after last drink Onset sometimes before BAC reaches 0 Early symptoms include anxiety, sleep disturbance, vivid dreams, anorexia, nausea, and headache Physical signs include tachycardia, elevation of blood pressure, hyperactive reflexes, sweating, and hyperthermia Tremor of hands/or tongue, 6 to 8 cycles/sec (exaggeration of normal physiologic tremor on EMG) Seizures may occur, typically within 48 hrs Delirium tremens may begin 48 to 72 hrs after last drink, preceded by symptoms of early withdrawal Profound sympathetic hyperactivity (tachycardia, hypertension, fever, diaphoresis) Mortality rate 1% to 5%, increases with delayed diagnosis, inadequate treatment, and concurrent medical illness Effect of alcohol exerted through GABA Sedation, muscle relaxation, increased seizure threshold Chronic alcohol exposure leads to adaptive suppression of GABA activity Abstinence produces sudden relative deficiency in GABA activity resulting in anxiety, increased psychomotor activity, and predisposition to seizures Alcohol inhibits sensitivity to autonomic adrenergic systems Chronic alcohol uptake results in upregulation Discontinuation of alcohol results in rebound overactivity of central and peripheral noradrenergic systems Increased sympathetic autonomic activity from the locus ceruleus contributes to tachycardia, hypertension, tremor, diaphoresis, and anxiety In mild withdrawal, may experience perceptual distortions of visual, auditory, or tactile nature (too bright, too loud, pins and needles) Frank hallucinations may develop in severe withdrawal Visual hallucinations are most common and frequently involve animals Auditory hallucinations begin as unformed sounds (clicks or buzzing) and may progress to voices Often friends and relatives, often accusatory Tactile hallucinations may involve bugs crawling on the skin In milder cases of withdrawal, the patient’s sensorium is otherwise clear and the patient retains insight that the hallucinations are not real In more severe withdrawal, this insight may be lost Generalized major motor seizures May occur singly or in a burst of several seizures over a few hours Onset is usually 8 to 24 hours after last drink and may occur before BAC zero Fewer than 3% progress to status epilepticus (but alcohol involved in 25% of status epilepticus) Seizures peak 24 hours after last drink, corresponding with EEG abnormalities (increased amplitude, photomyoclonic response, and spontaneous paroxysmal activity) EEG changes transient Risk of seizures appears to be genetically influenced Increased risk in those with prior history of withdrawal seizures Increased risk in those undergoing concurrent sedative-hypnotic withdrawal Kindling effect Increased risk of seizures as an individual undergoes repeated withdrawals Delirium tremens generally appears 72 to 96 hours after last drink Marked tachycardia, tremor, diaphoresis, fever Global confusion; disorientation to place and time; may become absorbed in a separate psychic reality Hallucinations frequent, may have no insight, and therefore may be very frightening Marked psychomotor activity may develop Severe agitation in some cases Persistent low level motor activity in others Severe disruption in sleep-wake cycle is common; absence of clear sleep for days Duration is variable, 2 to 3 days in most studies May last few hours May last several days (report of confusion lasting 50 days before clearing) Amount of daily intake and duration of heavy drinking have not been correlated consistently to the risk of severe withdrawal BAC >300 mg% on presentation at higher risk of DT’s Withdrawal seizure at presentation increases risk of DT’s Older patients at higher risk of confusion and delirium, may not involve severe autonomic manifestations of classic DT’s CIWA, and shortened version CIWA-Ar are most extensively studied Documented reliability, reproducibility, and validity <9 indicates mild withdrawal, 10 to 18 indicates moderate withdrawal, and >18 suggests severe withdrawal High scores are predictive of seizures and delirium ASAM Clinical Practice Guidelines (1997) reviewed literature on pharmacologic management of withdrawal Evidence indicated that the cornerstone of pharmacologic management of withdrawal is the use of benzodiazepines Pharmacologically cross tolerant with alcohol Produce the similar effect of enhancing GABAinduced sedation Administration of benzodiazepines alleviates the acute deficiency of GABA activity that occurs with sudden cessation of alcohol All are similarly efficatious in reducing signs and symptoms of withdrawal Longer acting agents (diazepam and chlordiazepoxide) may be more effective in preventing seizures Longer acting agents may provide a smoother withdrawal course Longer acting agents may pose a risk for oversedation in the elderly and those with liver disease (shorter acting agents, lorazepam or oxazepam may be preferable). Rapid acting agents (diazepam, lorazepam, and alprazolam) offer more prompt control of symptoms Rapid acting agents demonstrate greater abuse potential Not as extensively studied Size of studies not adequate to draw conclusions regarding efficacy in reduction of seizures and delirium Benzodiazepines offer greater margin of safety with lower risk of respiratory depression as well as overall lower risk of abuse “Phenobarbital, a long acting barbiturate, still is used by some programs, as it is long-acting, has well-documented anticonvulsant activity, is inexpensive, and has low abuse potential.” Fixed Schedule Medication administered in fixed amounts at scheduled times for five to seven days However, many patients can go through withdrawal with only minor symptoms and need little or no medication Symptom-triggered therapy Patient is monitored with structured assessment scale and given medication only when symptoms cross a threshold of severity Studies demonstrate as effective as fixed-dose regimen, but significantly less medication used and significantly shorter duration of detox Facilitates delivery of large amounts of medication to patients with rapidly escalating symptoms, thus reducing undertreatment with fixed-dose schedule In certain patients, such as those with severe coronary artery disease, fixed-dose may be used to prevent development of even minor withdrawal symptoms In patients with a history of alcohol withdrawal seizures, fixed-dose may be used since seizures usually occur early in the course of withdrawal Any detox regimen should allow for individualization with a mechanism to provide for large amounts of medication rapidly if needed. Benzodiazepines should be administered orally or intravenously Lorazepam provides good intramuscular and sublingual absorption Beta blockers and alpha adrenergic agonists are effective in ameliorating symptoms by reducing autonomic manifestations of withdrawal No demonstrated efficacy in reducing seizures or delirium Delirium is a rare side effect of beta blockers Reduction in autonomic symptoms may mask progression of withdrawal and hinder reliability of withdrawal scales Carbamazepine used in Europe for alcohol withdrawal Equal efficacy to benzos for patients with mild to moderate withdrawal Without toxicity over 7 day course of tx, less psychiatric distress, faster return to work, no impairment of learning, no abuse potential Prevents withdrawal seizure in animal studies Studies of adequate size to demonstrate efficacy in preventing withdrawal seizures or delirium not yet available Antipsychotics are less effective than benzodiazepines to prevent delirium Actually lead to increase rate of seizure Widely used for agitation in withdrawal Should never be used except in conjunction with benzodiazepines Magnesium generally normal at onset of withdrawal, drops as withdrawal progresses, normalizes as symptoms subside Only one randomized trial of magnesium during alcohol withdrawal documented No difference in severity of withdrawal or rate of seizures, regardless of magnesium correction Oral magnesium supplementation is without risk Routine magnesium administration no longer recommended Alcohol No controlled trials comparing ethyl alcohol to benzos or placebo IV administration requires very close monitoring Numerous adverse effects Use is discouraged by addiction specialists Phenytoin Recent studies failed to demonstrate efficacy of preventing recurrent withdrawal seizures Benzos are extremely effective in preventing withdrawal seizures, and the addition of phenytoin does not lead to improved outcomes Use of phenytoin in withdrawal has been largely abandoned Thiamine Thiamine deficiency may lead to Wernicke’s disease and the Wernicke-Korsakoff syndrome Acute onset Triad: Mental disturbance Global confusion, apathetic state, memory impairment Paralysis of ocular movements Sixth nerve palsy: weakness or paralysis of abduction, invariably bilateral, rarely symmetric Ataxia Gait and stance Neurologic emergency Treated with immediate administration of thiamine, 50 mg IV and 50 mg IM Delay in thiamine administration increases risk of permanent memory impairment Administration of IV glucose may exhaust reserve of B vitamins resulting in acute precipitation of Wernicke’s disease IV solutions containing glucose should always be accompanied with administration of thiamine in the alcoholic patient Ocular palsy responds to thiamine administration within hours Gait and cognition improve more slowly As apathy, drowsiness, and confusion recede, a permanent defect in retentive memory and learning known as Korsakoff’s psychosis may persist Patients with symptoms of Wernicke’s disease, those to receive IV glucose solution, and those at high risk of malnutrition should receive initial dose of thiamine parenterally Not all seizures in alcoholics are due to withdrawal Alcoholics are at higher risk for seizures unrelated to withdrawal Careful history of temporal relationship of alcohol use to the seizure should be taken, diagnosis of withdrawal seizure should be assumed only is there is a clear history of marked reduction or cessation of drinking 24 to 48 hours preceding the seizure All patients with first seizure should be admitted for observation and evaluation Neurologic exam and brain imaging as a minimum; EEG and lumbar puncture may be appropriate Previous history of withdrawal seizures with clear history of withdrawal seizure may not require full evaluation If seizure is generalized If no focal deficit on exam If no history of head trauma If no suspicion of meningitis Then, additional testing has a very low yield and may be safely omitted Increased risk of seizures for 6 to 12 hours post seizure Second seizure occurs in 1 of 4 Parenteral rapidly acting benzodiazepine indicated, followed by oral detox regimen Phenytoin no more effective than placebo at preventing recurrent seizures Since seizure increases risk for DT’s, admission for treatment with benzos is safe and reasonable approach Older studies indicated mortality ~30% Current studies reflect ~1% mortality Adequate sedation and meticulous medical care often necessitate ICU admit Management of fluid / electrolytes in midst of marked autonomic hyperactivity Often delirium arises in medically ill patient in whom alcohol dependence was unrecognized High index of suspicion for infection; may be masked by fever, tachycardia, and confusion Cross tolerant sedative-hypnotics reduce mortality, but have not been shown to reverse the delirium or reduce its duration Goal is to sedate to a point of light sleep, thus controlling agitation and preventing behavior risking harm to self or staff, and allowing staff to provide supportive medical care IV benzodiazepines provide rapid control Massive doses (hundreds, even thousands mg of diazepam) may be required to control agitation Respiratory support must be available Reports of continuous infusion of short-acting agents, but existing evidence suggests no more effective than bolus dosing of longer-acting agents Benzodiazepines may be supplemented with neuroleptic to manage agitation, but neuroleptics must never be used alone due to effect on seizure threshold Management of withdrawal is only the first- and at times most easily achieved- step toward the primary goal of treating the patient’s underlying addiction to alcohol Development of a plan to engage the patient in treatment is a critical component of withdrawal Medical detoxification first, if applicable Group therapy Individual therapy Experiential therapy Twelve Step facilitation Length of stay, regardless of level of care, correlates directly with rate of sobriety. Monitoring and accountability enhance that rate. Sedative-hypnotic medications decrease excitement, exert a calming effect, and facilitate sleep. Among the most widely prescribed drugs in the U.S. Sedative-hypnotics stimulate the inhibitory neurotransmitters in the GABA receptors. Although all sedative-hypnotics are stimulating at low doses, their primary effect is to decrease CNS function. Those associated with severe withdrawal states include: methaqualone, glutethimide, phenobarbital, and short-acting benzodiazepines such as alprazolam and triazolam. Those with less severe clinical withdrawal include: meprobamate, diazepam, chlordiazepoxide, and lorazepam. Mild to Moderate toxicity: slurred speech, ataxia, and incoordination In older adults, there may be a paradoxical agitated confusion and even delirium. Severe toxicity: stupor and coma With older non-BZD agents, toxicity may progress leading to respiratory arrest or cardiovascular collapse. Overdose on the older agents may be associated with a variety of agent-specific manifestations, such as the bullous lesions (barb blisters) with barbiturates. With the older sedative-hypnotic agents, tolerance may develop to the therapeutic effects, but not their lethal effects; therefore, the therapeutic index decreases. Toxicity and overdose thus occur with only small increases over the individual’s regular intake. On the other hand, benzodiazepines virtually never lead to death when ingested by themselves. A lethal dose has not been established for any of the benzodiazepines. The few reported deaths involved short-acting, high potency BZDs such as alprazolam and triazolam, or administration of BZDs IV. Inappropriate administration of chlordiazepoxide by the IM route can lead to erratic absorption, producing respiratory compromise. Despite their safety, BZDs continue to be a major cause of overdose when ingested with other agents. Mixed overdoses – such as those in combination with alcohol, major tranquilizers, antidepressants, or opiates – can be fatal. Assessment and maintenance of the airway and, when required, ventilatory support are the cornerstone in managing overdose. Many BZDs slow gut motility and some – such as phenobarbital, meprobamate, glutethimide, and ethchlorvinyl – can form concretions in the stomach. Therefore, gastric lavage is effective, provided that the patient has an active gag reflex or is mechanically ventilated. Gastric lavage with 1.0 g/kg of activated charcoal, alongwith a dose of cathartic, should be given, followed by repeated doses of activated charcoal at 0.5-1.0 g/kg every 2-4 hours; alternatively, the charcoal may be administered by slow continuous nasogastric infusion. Some agents have extensive enterohepatic circulation and repeated doses of charcoal have been shown to speed their elimination. Alkalinization of the urine may be helpful in eliminating phenobarbital, but forced diuresis has not been shown to be helpful with any of the agents. Flumazenil is a competitive antagonist with very weak agonist properties at the BZD receptor; thus it can reverse the effects of BZDs, but not alcohol or other sedative-hypnotic agents. Flumazenil’s primary indication is the reversal of short-acting BZDs, such as midazolam, after medical procedures. It may also be used when BZDs have been ingested alone in overdose. Flumazenil is administered by slow IV titration, not exceeding 1 mg, with monitoring for the recurrence of sedation. Flumazenil is very short-acting; therefore signs of sedation may return in 50-60 minutes. The use of flumazenil has been associated with seizures and cardiac arrhythmias, especially when it is administered rapidly in large amounts and in patients who have ingested a sedativehypnotic in combination with a substance capable of causing seizures (i.e., tricyclics). Patients who are physiologically dependent on BZDs are at high risk of seizures when given flumazenil. Thus, flumazenil is not part of the standard “coma cocktail” (thiamine, glucose, and naloxone) because it causes rapid BZD withdrawal. Sedative-hypnotic withdrawal can occur with both high- and low-dose use. The withdrawal syndrome resembles that of acute alcohol withdrawal syndrome in many ways due to both binding to the GABA receptor. The withdrawal syndrome is most likely to occur following discontinuation of a low dose of at least 4-6 months or a high dose for 2-3 months. Time course and severity of withdrawal of determined by (1) dose, (2) duration of use, and (3) duration of drug action. Vital Signs Tachcardia Hypertension Fever Central Nervous System Agitation Anxiety Delirium Hallucinations Insomnia Irritability Nightmares Sensory disturbances Tremor Ears Tinnitus Gastrointestinal Anorexia Diarrhea Nausea High-Dose (Severe) Withdrawal Seizures Delirium Death Withdrawal severity has been related to dose and duration of treatment. Latency to onset of withdrawal is related to the elimination half-life. Most frequents signs of W/D: anxiety, insomnia, restlessness, agitation, irritability, and muscle tension Less frequent: nausea, diaphoresis, lethargy, aches and pains, coryza, hyperacusis, blurred vision, nightmares, depression, hyperreflexia, and ataxia Uncommon: psychosis, seizures, confusion, paranoid delusions, hallucinations, and persistent tinnitus Four different etiologies of signs and symptoms of discontinuation: (1) symptom recurrence or relapse, (2) rebound, (3) pseudowithdrawal, and (4) true withdrawal. Symptom recurrence or relapse is characterized by recurrence of symptoms for which the BZD was prescribed and can occur over days or months after discontinuation. Rebound is marked by the development of symptoms within hours to days of discontinuation that are qualitatively similar to the disorder for which the drug was precribed but more intense. Symptoms are of short duration and self-limited. Pseudowithdrawal (over-interpretation of symptoms) may occur when expectations of withdrawal lead to the experiencing of abstinence symptoms. True withdrawal is marked by emergence of symptoms in an individual who is physically dependent on the drug. It can only be suppressed by reinstitution of the discontinued drug or another cross-tolerant sedativehypnotic. Considerable individual variation and variability exist among patients who discontinue BZDs. Any combination of sgs and sxs may be experienced with varying severity throughout the initial one to four weeks of abstinence. The clinical picture can consist primarily of subjective symptoms with few concurrently observable hyperadrenergic signs or vital sign fluctuations. Discontinuation syndromes commonly occur in combination. For example, recurrence of anxiety and insomnia and the sgs and sxs of rebound and withdrawal overlap. Therefore, sorting out rebound from withdrawal is unnecessary (if not impossible!). Prolonged withdrawal has been reported in a small proportion of patients following long-term BZD use. Sgs and sxs may persist for weeks to months following discontinuation and is characterized by its irregular and unpredictable course. Patients experience slowly abating, waxing and waning symptoms of insomnia, perceptual disturbances, tremor, sensory hypersensitivity, and anxiety. BZD action in the CNS is mediated by the GABABenzodiazepine-Receptor Complex. GABA is the primary CNS inhibitory neurotransmitter. Activation of the GABA receptor induces the opening of a neuronal membrane-bound chloride channel, causing hyperpolarization. Chronic lorazepam use resulting in tolerance to the ataxia-inducing effects causes down-regulation (decreased receptor number, decreased GABAreceptor function, and diminished protein synthesis for GABA receptors). With abrupt discontinuation, GABA receptors are upregulated with GABA-receptor complex function enhanced. BZD pharmacokinetics determine the onset of discontinuation symptoms following chronic use, with the elimination half-life dictating the rate of decline of blood levels. Onset of action of W/D from short-acting BZDs (lorazepam, oxazepam, triazolam, alprazolam, and temazepam) occurs within 24 hours of cessation, with peak severity within 1 to 5 days. With long-acting BZDs (diazepam, chlordiazepoxide, and clonazepam), onset occurs within 5 days and withdrawal peaks at 1 to 9 days. Duration of acute withdrawal can be as long as 7-21 days for short-acting and 10-28 days for long-acting BZDs. Withdrawal symptoms from short-acting BZDs are experienced as being more intense than those with long-acting drugs, and are of more rapid onset. Higher dose and longer duration place patients are greater risk for severe withdrawal. Beyond one year of continuous use, duration of use becomes a less important factor. Tolerance develops more rapidly to short-acting BZDs and withdrawal requires more aggressive medical attention. Patients with chronic psychiatric disorders maintained on BZDs for more than 3-6 months will be physically dependent on the BZD. Numerous BZD discontinuation studies highlight the high (40-100%) prevalence of active concurrent psychiatric disorders. Most demonstrate a correlation between the patients’ degree of psychopathology and their withdrawal symptom severity and difficulty in discontinuing use. Concurrent use/abuse of other substances complicates the clinical presentation in withdrawal. The percentage of alcoholics who regularly use BZDs ranges from 29-33%. Comorbid alcohol abuse and anxiety disorders occurs in 18-19%. Moderate alcohol use (>1 beer/day) is a more significant predictor of BZD withdrawal severity than half-life of the drug. Patients with high-dose BZD use who present for inpatient addiction treatment exhibit a high rate (7096%) of concurrent dependence on other substances. >20% of patients newly admitted to inpatient treatment reported using BZDs at least weekly; 73% of heroin users reported greater than weekly use; >15% of heroin users used BZDs daily. There is also a high rate of BZD use in methadone clinics. Studies of adult sons and daughters of alcoholics have shown increased propensity to develop dependence when exposed to alprazolam and diazepam. There also appears to be a linkage of paternal hx of alcoholism and severity of withdrawal from alprazolam. BZD withdrawal should be avoided during acute medical and surgical conditions; continued BZD use rarely has a negative effect on the acute medical condition. Special consideration should be given to discontinuing BZDs in patients in whom the medical condition could be worsened by adrenergic and psychological stress factors. In general, patients with chronic medical conditions experience BZD withdrawal more severely than others. The use of anxiolytics peaks between the ages of 50 and 65, with hypnotics most frequent in the oldest age range. Hepatic microsomal enzyme oxidase system (MEOs) efficiency decreases with age. Elderly patients’ elimination half-lives are two to five times slower than younger adults. Therefore, withdrawal in the elderly may be quite prolonged, especially with the long-acting BZDs. Women are prescribed BZDs twice as often as men; hence, twice as many women as men are likely to become dependent. Female gender is also associated with increased withdrawal severity in patients undergoing tapered cessation of longterm, therapeutic BZD use. However, gender is not a factor in abrupt cessation. Determine the reason the patient or referent is seeking evaluation of sedative-hypnotic use and/or discontinuation. Take a sedative-hypnotic history. Elicit a history of other alcohol or psychoactive drug use. Take a psychiatric history. Take a family history of substance use, psychiatric, and medical disorders. Take a current and past medical history. Take a psychosocial history. Perform a physical and mental status exam. Conduct a UDS. Complete an individualized assessment with differential diagnoses. Determine level of care for Detox and method. Obtain patient consent and initiate Detox. Benzodiazepines alprazolam chlordiazepoxide clonazepam clorazepate diazepam flurazepam lorazepam oxazepam temazepam triazolam Barbiturates pentobarbital secobarbital butalbital phenobarbital Non-barbiturates Placidyl Doriden Quaalude Dose Equivalent to 30 mg of Phenobarbital 0.5-1 25 1-2 7.5 10 15 2 10-15 15 15 100 100 100 30 500 250 300 For dependent patients, there are two options for detoxification: tapering or substitution. Tapering is indicated for use in: (1) outpatient ambulatory setting, (2) patient with therapeutic-dose BZD dependence, (3) patients who are dependent only on BZDs, and (4) patients who can reliably present for regular clinical follow-up during and after detoxification. Tapering is done by decreasing the BZD dose on a weekly to every-other-week schedule. The rate should not exceed 5 mg diazepam (12.5 mg chlordiazepoxide or 15 mg phenobarb) or 10% of the starting dose per week, whichever is smaller. The first 50% of the taper is usually smoother, quicker, and less symptomatic. For the final 25-35%, the rate and dose should be cut in half. Substitution and taper is indicated for those who are unable to tolerate the taper and those previously excluded from taper. Substitution is accomplished with a cross-tolerant longacting BZD or Phenobarbital, with Phenobarbital having the advantage of less disinhibition and broad clinical efficacy. If hepatomegaly or elevated liver enzymes are a problem, then oxazepam may be substituted. Lorazepam could be used, but has higher abuse liability. Calculate the equivalent dose of chlordiazepoxide, clonazepam, or phenobarbital using the Substitution Dose Conversion Table and divide into three to four daily doses. Provide prn doses of BZD until substituted drug reaches steady state. Gradually reduce the dose. Sedative-hypnotic tolerance testing may be performed when the tolerance level is difficult to determine. Pentobarbital 200 mg is given PO q2 hours for up to 24-48 hours or until signs of intoxication appear; then total dose administered in divided by number of days to arrive at daily dose. Phenobarbital is then substituted with gradual taper. Signs and symptoms of withdrawal are treated as needed with 30-60 mg phenobarbital every 1-4 hours. When the patient has received similar 24-hour phenobarbital doses for two consecutive days, the total is divided by 2 to arrive at the stabilizing dose. This dose is divided over the next 24 hours and then is tapered. Carbamazepine has been studied as an adjunct to traditional detoxification. In one study, significantly more patients treated with carbamazepine were BZDfree at 5 weeks with less withdrawal severity reported. Sodium valproate also is effective in attenuating withdrawal. Propranol diminishes the severity of adrenergic symptoms, but should not be used alone. Clonidine is ineffective in treating BZD W/D. Buspirone is ineffective as well. Trazodone decreases anxiety in BZD-tapered patients. CBT has been shown to improve the rate of successful alprazolam discontinuation. Prolonged BZD W/D is associated with sgs and sxs lasting weeks to months following discontinuation, probably as a result of long-term receptor site adaptation. Propranolol 10-20 mg qid is helpful in attenuating anxiety or tremors, as are sedating antidepressants for insomnia. [email protected]