AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Many illicit drugs and chemicals, including medications, produce withdrawal symptoms when their use is discontinued. This article primarily focuses on withdrawal from ethanol, sedative-hypnotics, opioids, stimulants, and gamma-hydroxybutyrate (GHB).

For related information, see Medscape's Addiction Resource Center.

Pathophysiology

The body, when exposed to any type of substance attempts to maintain homeostasis. When exposed, it produces counter-regulatory mechanisms and processes that attempt to keep the body in balance. When the substance is removed, the residual counter-regulatory mechanisms produce unopposed effects and withdrawal symptoms.

Tolerance occurs when long-term use of a substance produces adaptive changes so that increasing amounts of the substance are needed to produce an effect. Tolerance depends on the dose, duration, and frequency of use and is the result of pharmacokinetic (metabolic) or pharmacodynamic (cellular or functional) adaptation.

The mechanism of ethanol intoxication and withdrawal is complex. Most of the clinical effects can be explained by the interaction of ethanol with various neurotransmitters and neuroreceptors in the brain, including those interacting with gamma-aminobutyric acid (GABA), glutamate (NMDA), and opiates. Resulting changes in the inhibitory and excitatory neurotransmitters disrupt the neurochemical balance in the brain, causing symptoms of withdrawal.

Ethanol binds to postsynaptic GABA_A receptors (inhibitory neurons). Activation of these receptors enhances the effects of GABA. In response, the chloride channels open, causing chloride influx, which hyperpolarizes the cell, decreasing the firing rate of neurons, ultimately producing sedation. Long-term use of ethanol subsequently results in downregulation of GABA_A receptors. Due to the chronic suppression of excitatory neurotransmission, the brain increases synthesis of excitatory neurotransmitters, such as norepinephrine, serotonin, and dopamine, accounting for withdrawal symptoms. 

Ethanol inhibits excitatory neurons by decreasing the activity of N-methyl-D-aspartate (NMDA, glutamate subtype) receptors. Long-term use results in upregulation of NMDA receptors, an adaptation that causes tolerance. The unmasking of the increased neuroexcitatory tone contributes to withdrawal seizures and other symptoms when alcohol intake is decreased or stopped.

In the short-term, ethanol inhibits opioid binding to p-opioid receptors, and long-term use results in upregulation of opioid receptors. Opioid receptors in the nucleus accumbens and in the ventral tegmental area of the brain modulate ethanol-induced dopamine release, which produces alcohol craving and explains the use of opioid antagonists to prevent this craving.

In opioid or benzodiazepine addiction, chronic stimulation of specific receptors for these drugs suppresses endogenous production of neurotransmitters (endorphins or GABA, respectively). Removal of exogenous drug allows unopposed counter-regulatory effects to become clinically apparent. When the exogenous drug is precipitously removed, inadequate production of endogenous transmitters and the unopposed stimulation by counter-regulatory transmitters results in the characteristic clinical picture of withdrawal. The nature of the excess counter-regulatory transmitter dictates the characteristics of the withdrawal. The time it takes to restore homeostasis by synthesis of endogenous transmitters determines the time course of withdrawal.

Frequency

United States

An estimated 5-10% of the population has alcoholism. Although not all persons with chronic alcoholism have clinically apparent alcohol withdrawal on cessation of alcohol consumption, a substantial proportion is at risk for this syndrome. Approximately 15.2 million Americans are alcohol dependent. There are 1.2 million hospital admissions for problems related to alcohol abuse. As many as 5% of these patients may develop delirium tremens (DT).

The number of people addicted to opioids, sedative or hypnotic medications, and stimulants (eg, cocaine, amphetamines) is not known and fluctuates with the supply of drugs and social trends. In recent estimates, approximately 3.9 million Americans are dependent on illicit drugs.

Mortality/Morbidity

The mortality rate from severe alcohol withdrawal and DT historically has been as high as 20% if untreated. Early recognition and improved treatment has reduced the mortality rate from DT to approximately 1-5%. Many patients with alcohol withdrawal have additional medical or traumatic conditions that may increase their associated risk of morbidity and mortality.

• The mortality rate from less severe alcohol withdrawal is negligible and related to underlying conditions rather than alcohol withdrawal.
• Sedative or hypnotic withdrawal shares many of the features of alcohol withdrawal, namely, agitation, disorientation, seizures, sympathetic hyperactivity, hypertension, insomnia, anxiety, and anorexia.
• Opiate withdrawal is uncomfortable but usually mild in terms of derangement of vital signs. Fatalities are very rare.
• Because withdrawal from cocaine and amphetamine results in sedation and a state resembling adrenergic blockade, death occurs less often from this withdrawal than from acute intoxication.

Sex

Chronic alcoholism and withdrawal are more common among men than women.

Age

Alcohol withdrawal syndrome is less common in persons younger than 20 years because of their limited access to alcohol.

Sedative-hypnotic, opiate, cocaine, or amphetamine addiction occurs rapidly, and withdrawal may be seen from late adolescence through adulthood.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

In addition to documenting the presenting complaints, essential elements of history include type of drugs ingested over the long term, the duration of addiction, the time of last ingestion, the reason for the patient's cessation of the drug, alternative treatments used to relieve withdrawal symptoms, and previous withdrawal symptoms and their severity. 

Serious comorbid conditions can be inciting events for reasons for cessation of alcohol and should be thoroughly investigated.  

Obtaining a history of illicit drug and alcohol abuse is important and can assist with anticipation and treatment in patients admitted for reasons other than withdrawal (eg, myocardial infarction [MI], multiple trauma).

• Alcohol withdrawal
• • Patients have typically abused alcohol on a daily basis for at least 3 months, or they have consumed large quantities for at least 1 week (ie, binge drinking).
  • Withdrawal symptoms appear within 6-12 hours after individuals cease or decrease alcohol intake and are usually relieved by consuming additional alcohol.
  • The hallmark of alcohol withdrawal is a continuum of signs and symptoms ranging from simple tremulousness to DT. The spectrum varies greatly, and symptoms overlap in time and duration. Therefore, defining a constellation of manifestations ranging from mild to severe (as listed below) is most clinically useful.
  • • Mild withdrawal usually occurs within 24 hours of the last drink and is characterized by tremulousness (shakes), insomnia, anxiety, hyperreflexia, diaphoresis, mild autonomic hyperactivity, and GI upset.
    • Moderate withdrawal usually occurs 24-36 hours after the cessation of alcohol intake and includes intense anxiety, tremors, insomnia, and excessive adrenergic symptoms. 
    • Severe withdrawal usually occurs more than 48 hours after a cessation or decrease in alcohol consumption. It is characterized by profound alteration of sensorium including disorientation, agitation, and hallucinations; along with severe autonomic hyperactivity including tremulousness, tachycardia, tachypnea, hyperthermia, and diaphoresis.
  • As many as 25% of patients with a prolonged history of alcohol abuse have alcoholic hallucinosis.
  • • Alcoholic hallucinosis can occur 24 hours after the last drink and continues for about 24 hours.
    • Symptoms consist of persecutory, auditory, or (most commonly) visual and tactile hallucinations; however, the patient's sensorium is otherwise clear. In the early stage, the patient recognizes frank hallucinations. However, in the advanced stage, these hallucinations are perceived as real and may provoke extreme fear and anxiety. The patient can be seen pulling at imaginary objects, clothing, and sheets, for example.
    • Hallucinosis is not necessarily followed by DT.
  • Approximately 23-33% of patients with significant alcohol withdrawal have alcohol withdrawal seizures ("rum fits").
  • • Seizures are usually brief, generalized, tonic-clonic in nature, and without an aura. They occur in a cluster of 1-3 seizures with a short postictal period. Partial seizures are not uncommon. In 30-50% of patients, the seizures progress to DT.
    • The incidence peaks 24 hours after the most recent alcohol ingestion.
    • Most seizures typically terminate spontaneously or are easily controlled with benzodiazepines.
    • Status epilepticus may occur in 3% of alcohol withdrawal seizures and should prompt an investigation for other causes, as people with alcoholism are prone to head injuries, chronic idiopathic epilepsy, and meningitis.
  • DT, the most intense sign of alcohol withdrawal, occurs 48-72 hours after the last drink.
  • • DT includes all early and intermediate symptoms of alcohol withdrawal but with the additional feature of a profoundly altered sensorium (disorientation, agitation, and hallucination).
    • Severe autonomic derangements (including diaphoresis, tachycardia, tachypnea, and hyperthermia) are common.
    • DT may present without preceding seizures.
  • To blunt the effects of alcohol withdrawal, some patients may resort to ingesting other substances if they cannot obtain regular alcoholic beverages because of financial reasons.
  • • Ingestion of isopropyl alcohol is common.
    • Other alcohols (eg, methanol, ethylene glycol) are rarely ingested.
    • Ingesting cough syrup containing large amounts of alcohol may cause inadvertent acetaminophen toxicity.
    • The following substances have a sufficient alcohol concentration to mitigate the effects of withdrawal: isopropyl alcohol, cough syrup, hand sanitizer, mouthwash, methanol, and ethylene glycol.
• Sedative-hypnotic withdrawal syndrome
• • Chronic use of benzodiazepines, barbiturates, and other sedatives or hypnotics produce withdrawal symptoms on discontinuation resembling those of alcohol withdrawal syndrome.
  • The morbidity/mortality is closely related to that of alcohol withdrawal syndrome.
  • Sedative-hypnotic withdrawal syndrome is characterized by pronounced psychomotor and autonomic dysfunctions.
  • Symptoms usually occur 2-10 days after abrupt discontinuation of the drug, depending on its half-life.
• GHB withdrawal syndrome¹
• • GHB and its precursors (gamma-butyrolactone, 1,4'-butanediol) are reported to induce tolerance and produce dependence.
  • These drugs are most commonly abused by young adolescents in dance clubs and rave parties.
  • Many users have mild withdrawal symptoms on discontinuing the drug. The symptoms resemble those of sedative-hypnotic withdrawal syndrome and are characterized by mild and brief autonomic instability with prolonged psychotic symptoms.
  • Severe withdrawal is noted among people who use the drug chronically and heavily. Their symptoms are similar to those of alcohol withdrawal syndrome, but delirium occurs earlier and seizures rarely occur.
• Opioid withdrawal
• • Patients experiencing opioid withdrawal can usually provide an accurate history of their usual dose, of the timing of their last dose, and of any other current symptoms. The clinical problem is in differentiating symptoms associated with opiate withdrawal from symptoms that may reflect an underlying medical illness.
  • In general, opioid withdrawal does not directly cause life-threatening symptoms, seizures, or delirium.
  • Opioid withdrawal syndrome may resemble a severe flu-like illness. The syndrome is characterized by rhinorrhea, sneezing, yawning, lacrimation, abdominal cramping, leg cramping, piloerection (gooseflesh), nausea, vomiting, diarrhea, and dilated pupils.
  • Altered mental status, disorientation, hallucinations, and seizures, which are characteristic of DT, are not seen in opioid withdrawal.
  • The half-life of the opioid causing withdrawal syndrome determines the onset and duration of symptoms. For example, heroin and methadone withdrawal symptoms peak in 36-72 hours and 72-96 hours, respectively, and may last for 7-10 days and at least 14 days, respectively.
  • Persons with long-term intravenous (IV) drug abuse are susceptible to a host of infectious problems, including but not limited to the following; endocarditis, septic emboli, osteomyelitis, septic arthritis, abscesses (ie, psoas, brain, and epidural), and viral hepatitis. 
• Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome
• • In general, stimulant withdrawal does not directly cause life-threatening symptoms, seizures, or delirium.
  • This syndrome resembles severe depressive disorder.
  • • Manifestations include dysphoria, excessive sleep, hunger, and severe psychomotor retardation, whereas vital functions are well preserved.
    • The patient is typically in deep sleep with normal vital signs, and he or she may have a history of crack-cocaine binging and similar episodes ("crashes") in the past. Patients may be so motivated to do nothing but sleep deeply that another cause for the patient's lack of responsiveness is suspected. In this case, a gradual full recovery and a negative workup would be expected.
    • Severe depressive symptoms may last up to 2 days, though mild ones may persists for up to 2 weeks.

Physical

Increased reliance on physical examination is inevitable given the multisystemic effects of alcohol withdrawal, the wide variety of potential medical diseases associated with alcoholism, and the patient's often limited ability to provide an accurate history. Although a complete physical examination may have to be deferred until after resuscitation, the treatment of seizures, and/or sedation for severe agitation, this examination must be completed as soon as possible with the goal of detecting end-organ damage resulting from the effects of withdrawal as well as other underlying conditions.

• Vital signs
• • The central adrenergic storm that occurs during alcohol withdrawal results in hyperventilation, tachycardia, hypertension, tremor, hyperthermia, and diaphoresis.
  • Low-grade fever is common because of increased motor activity.
  • Hypothermia can be seen with Wernicke encephalopathy.
• Head and neck findings
• • Stigmata of chronic alcoholism (eg, flushed facies, vascular spider angiomata) may be present.
  • Paralysis of extraocular muscles and nystagmus may indicate Wernicke encephalopathy or other intracerebral processes. These findings are important because they represent an opportunity to diagnose a readily treatable condition.
  • Dentition is often neglected and may be a source of infection.
  • Tongue lacerations may indicate previous seizures or other trauma. The tongue is also a reliable place to look for withdrawal tremors.
  • Determine if evidence of head and facial trauma (eg, signs of basilar skull fracture) is present as this represents a common opportunity for critical intervention.
• Chest findings in alcohol withdrawal
• • Tachypnea is expected during alcohol withdrawal, but dyspnea is not expected.
  • Rib fractures are common in people with chronic alcoholism; recent rib fractures may be associated with pneumothorax.
  • Note signs of pneumonia (eg, cough, sputum production, fever, localized wheezing, consolidation, respiratory distress).
  • Kussmaul respiration may represent underlying metabolic acidosis. Common causes in the setting of alcohol withdrawal include alcoholic ketoacidosis (AKA) and ingestion of alcohols or medications that result in metabolic acidosis (eg, methanol, ethylene glycol, salicylate). Consumption of rubbing alcohol (isopropyl alcohol) does not cause metabolic acidosis or Kussmaul respiration.
• Chest findings in opiate withdrawal
• • Patients with opiate addiction are at high risk for HIV infection and are susceptible to AIDS-related pneumonias, particularly those due to Pneumocystis carinii and Mycobacterium tuberculosis.
  • Note symptoms and physical evidence of cough, hemoptysis, fever, and tachypnea.
• Cardiac findings
• • Tachycardia and hypertension are common and expected during alcohol withdrawal.
  • A murmur (particularly a right-sided tricuspid or pulmonic murmur) and fever in a patient with a history of intravenous drug abuse is worrisome because of the possibility of endocarditis. Blood cultures and an echocardiography are indicated in this circumstance to determine if infective endocarditis is present.
• Abdominal findings
• • Stigmata of chronic alcoholism include caput medusae, ascites, and hepatomegaly. Splenomegaly may be detected in patients with cirrhosis.
  • Diffuse abdominal tenderness in a patient with ascites may indicate spontaneous bacterial peritonitis, but other causes of peritonitis (eg, ruptured appendicitis) can occur as well. Peritoneal findings should not be ascribed to opiate withdrawal, though significant gastrointestinal distress with cramping and vomiting are common.  
  • Rectal examination is indicated to look for evidence of GI bleeding.
  • Opiate use suppresses peristalsis and commonly produces chronic constipation. During withdrawal, increased bowel sounds, abdominal cramping, vomiting, and diarrhea can be seen. 
• Findings in the extremities
• • Examine the limbs and joints for evidence of trauma or joint infection. 
  • Unexplained painful and limited hip movements in a patient with intravenous drug abuse and fever suggests psoas abscess.
• CNS findings
• • Alcohol withdrawal results in a progressive sequence of increasing anxiety, agitation, confusion, disorientation, visual and auditory hallucinations, seizures, dysphoria, panic, and potentially violent attacks on others.
  • Dysphoria due to opioid withdrawal may also promote negative reactions and possible violence in affected patients but are not associated with delirium.
  • Cranial-nerve deficits may indicate Wernicke encephalopathy (ocular nerve palsies), intracranial trauma, or bleeding.
  • Ataxia can be seen in Wernicke-Korsakoff syndrome.
  • Peripheral neuropathy is common in chronic alcoholism, but it is difficult to confirm in a minimally cooperative patient.
  • Focal neurologic deficits, other than those listed above, meningeal signs, and coma are not a part of the clinical picture of alcohol withdrawal and require further investigation.
• Skin findings
• • Spider angiomas, gynecomastia, and sparse pubic hair are common in persons with chronic alcoholism.
  • Patients with intravenous drug abuse have evidence of injections, such as tract marks, and they often have tattoos to mask these marks.
  • Piloerection and cutis anserina (goose bumps) are common during opiate withdrawal.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Serum glucose or finger-stick glucose test is indicated.
• • Patients with liver disease due to alcoholism have reduced glycogen stores, and ethanol impairs gluconeogenesis. As a consequence, these patients are susceptible to hypoglycemia.
  • Patients in alcohol withdrawal develop anxiety, agitation, tremor, seizure, and diaphoresis, all of which can occur with hypoglycemia.
• Analysis of arterial blood gases may be indicated.
• • Mixed acid-base disorders are common and usually result from AKA, volume-contraction alkalosis, and respiratory alkalosis.
  • Patients with these disorders may have hypoxia due to aspiration pneumonitis.
• Chemistry panel analysis is indicated.
• • A CHEM-7 analysis or its equivalent is indicated to look for acidosis, dehydration, concurrent renal disease, and other abnormalities that can occur in patients with chronic alcoholism. It also provides data needed to calculate anion and delta gaps, which are helpful in differentiating mixed acid-base disorders.
  • A low BUN value is expected in alcoholic liver disease. Obtain lipase levels if pancreatitis is suspected. Obtain the blood ammonia level if hepatic encephalopathy is suspected.
  • Determination of magnesium and calcium levels and liver function tests (LFTs) may be indicated because patients with chronic alcoholism usually have dietary magnesium deficiency and possibly concurrent alcoholic hepatitis. Alcoholic pancreatitis may cause hypocalcemia.
• Urinalysis is indicated.
• • Routinely check for ketones, as patients may have associated AKA.
  • Ketonuria without glycosuria must be investigated further to exclude AKA and the ingestion of isopropyl alcohol.
  • Myoglobinuria from rhabdomyolysis may first be suspected when hematuria is noted on urinalysis.
• CBC determination is recommended.
• • Long-term alcohol ingestion leads to myelosuppression with a slight reduction in all cell lines. Thrombocytopenia is common.
  • Blood loss from the GI tract and nutritional deficiencies producing anemia are common in alcohol withdrawal.
  • Many patients have dehydration, and hemoconcentration and anemia may become apparent only when rehydration is accomplished.
  • Megaloblastic anemia is observed in people with alcoholism and based on a dietary deficiency of vitamin B-12 and folate. Increased mean corpuscular volume suggests this condition.
• Cardiac markers may be indicated.
• • Elevated CK and cardiac troponin levels may indicate myocardial infarction resulting from increased demands placed on the heart from hypertension associated with alcohol withdrawal or from hypertension produced by cocaine intoxication prior to the patient's presentation.
  • Elevated CK level can also be from rhabdomyolysis, which may be associated with significant adrenergic hyperactivity from alcohol withdrawal or from myonecrosis in immobile patients.
• Measurement of prothrombin time may be indicated.
• • The prothrombin time (PT) is a useful index of liver function; patients with cirrhosis are at risk for coagulopathy.
  • PT should be considered in a patient with active bleeding in the GI tract or CNS.
• Toxicology screening may be indicated.
• • Consider measuring serum osmolality and screening for toxic alcohols if the patient is severely acidemic.
  • The ethanol concentration is frequently zero. However, some patients that are habituated to alcohol can be in severe alcohol withdrawal even if ethanol levels are clinically significant.
  • Send urine samples for drug toxicology screening because co-ingestion of other medications (eg, psychiatric medications) and use of other recreational drugs are common.
  • GHB, ketamine, fentanyl, and many other drugs of abuse are not included in routine urine drug screening, and a special request may be required if use of these drugs is suspected.

Imaging Studies

Imaging studies should be directed to the patient's clinical course.

• Chest radiography
• • Aspiration pneumonia is common among patients with alcohol withdrawal syndrome.
  • People with chronic alcoholism may have cardiomyopathy and CHF.
  • Patients using intravenous drugs are at increased risk for immunosuppression and consequently prone to pneumonia.
• Head CT scanning
• • Patients with alcohol withdrawal syndrome are at risk for intracranial bleeding because of cortical atrophy and coagulopathy.
  • Consider obtaining a head CT in patients with an inappropriate level of consciousness, in those with multiple seizures, in those with signs of head trauma, and in those with an unexpected failure to respond to treatment.
  • Cocaine can cause intracerebral bleeding due to hypertension. The symptoms may closely resemble those of the cocaine wash-out syndrome.
• Abdominal CT scanning: Patients with a history of intravenous drug abuse and unexplained hip pain may have intra-abdominal pathology, including psoas abscess, which may be seen on abdominal CT scan or ultrasonography.
• Spinal MRI: In patients with unexplained back pain, intravenous drug abuse, and fever, spinal MRI may be required to rule out epidural abscess, particularly if focal neurologic deficits are also present.
• Other imaging may be indicated if trauma or other associated conditions are suspected.

Other Tests

• Electrocardiography
• • Adrenergic storm produced by alcohol withdrawal increases demands on the heart and may precipitate infarction in susceptible individuals.
  • A prolonged QTc interval has been described in patients with alcohol withdrawal syndrome. The interval gradually reverts to normal as withdrawal symptoms remit.
• Lumbar puncture: One should have a low threshold for lumbar puncture and spinal-fluid analysis to rule out meningitis or subarachnoid hemorrhage because individuals in withdrawal are at increased risk.
• Blood cultures may also be indicated if sepsis or endocarditis is suspected in this group of often immunosuppressed patients.
• Additional tests may be indicated based on a patient's presentation.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Prehospital Care

• Patients in alcohol withdrawal may have a number of medical problems (eg, cardiac or respiratory arrest, multiple trauma) that may take priority in terms of management. Manage these presentations according to existing prehospital protocols.
• Patients withdrawing from alcohol sometimes present to the prehospital system as a result of a withdrawal seizure requiring their transport to the ED. Established prehospital protocols for seizures are generally appropriate for these patients.
• Administration of intravenous glucose to patients with seizures is controversial because this is thought to precipitate acute Wernicke encephalopathy in patients with chronic alcoholism unless thiamine is also administered. How soon thiamine must be administered after a glucose load to prevent Wernicke encephalopathy is unknown. The time to transport a patient to the ED seems insufficient to result in this complication. In general, withholding glucose until after thiamine is administered is not necessary and potentially life threatening. Thiamine takes several hours to enter into cells, whereas the effects of glucose are almost immediate.
• On occasion, patients in advanced alcohol withdrawal may be too combative to safely transport them or to apply physical restraints. In these cases, administer a sedative, such as lorazepam, before transport is attempted.

Emergency Department Care

As in the prehospital setting, immediately life-threatening conditions must be treated first.

• Treatment goals for ethanol or sedative-hypnotic withdrawal are as follows:
• • Stabilization of the patient's condition and prevention of syndrome progression
  • Treatment of withdrawal by substituting sedative medications
  • Determination of underlying medical problems and initiation of appropriate treatments
  • Appropriate disposition for ongoing care and addiction treatment
• If bedside glucose testing reveals hypoglycemia, glucose given as dextrose 50% in water (D50W) 25-50 mL is indicated. Concurrent administration of thiamine 100 mg IV is also indicated.
• Alcohol withdrawal seizures are typically brief and followed by a brief postictal period. The occurrence of more than 3 seizures or status epilepticus is rare and mandates further investigation.
• • Most alcohol withdrawal seizures are self-terminating; however, if prolonged, they are usually quickly terminated with benzodiazepines (eg, diazepam, lorazepam). Lorazepam is preferred because it has a long redistribution time that enables it to have prolonged effectiveness, protecting the patient from recurrent seizures. Lorazepam is less dependent on hepatic metabolism than other benzodiazepines, and hepatic function may be impaired in chronic alcoholics.
  • Occurrence of seizures should prompt bedside glucose determination.
• Patients presenting in mild alcohol withdrawal may be treated on an outpatient basis, provided that no underlying conditions require inpatient treatment.
• • Various regimens are described for outpatient management of alcohol withdrawal syndrome, but the simplest involve administering benzodiazepines with a short half-life and few metabolites (eg, oxazepam) to prevent the accumulation of sedating compounds. This drug is initially administered frequently and in higher doses, with gradual lengthening of the dosing interval and reduction of the dose over 1 week.
  • Patients must be reliable enough to adjust their own medications, and they must be able to tolerate oral medications.
  • Low doses of clonidine (eg, 0.1-0.2 mg PO tid) can help reverse central adrenergic discharge, thus relieving tachycardia, hypertension, tachypnea, tremor, and (possibly) some craving for alcohol.
  • The use of beta-blockers to diminish tachycardia, hypertension, and perhaps anxiety has been described and are occasionally useful; however, their effects mask the warning signs of autonomic hyperactivity if the patient develops DT.
• Patients presenting with moderate or severe alcohol withdrawal and DT require inpatient treatment and consideration of ICU admission. Initial emergency care includes the following steps:
• • The patient should be placed in a quiet room with low lighting.
  • Physical restraints may be applied to prevent physical injury pending adequate sedation.
  • In severe withdrawal, abnormalities of fluid, electrolytes, and nutrition are common. The patient's blood chemistry guides appropriate and adequate fluid replacement.
  • Compared with mild withdrawal, larger doses of substitute medications, as outlined below, are required to treat withdrawal.
• Sedative-hypnotic drugs are the primary agents for treatment of alcohol withdrawal syndrome because they are cross-tolerant drugs that modulate GABA functions. These medications commonly include benzodiazepines, barbiturates, propofol, and (in rare cases) ethanol. Clomethiazole and GHB are used in Europe as substitute medications for alcohol withdrawal syndrome. They are currently not available in the United States for the treatment of alcohol-withdrawal syndrome.  
• • No evidence suggests that one sedative-hypnotic is more effective than another, but benzodiazepines have fewer adverse effects.
  • Benzodiazepines are the mainstay of therapy in the United States and are the primary agents used as substitutes and cross-tolerant medications for alcohol, sedative-hypnotic, or GHB withdrawal. They substitute for the GABA-modulating effects of alcohol and other drugs and are extremely safe and effective.
  • Benzodiazepines can be administered by using fixed-schedule or symptom-triggered regimens with or without loading. The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification but not necessarily for the treatment of DT.
  • The use of intravenous drugs allows immediate assessment of treatment adequacy compared with the lag time associated with absorption of oral medications. This is a particularly useful factor when using symptom-triggered therapy.
  • The Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) has been validated and is used for medication administration in symptom-triggered therapy (see Media file 1).
  • The various benzodiazepines have similar efficacies in treating alcohol withdrawal syndrome, though one may choose one drug over another on the basis of the route of administration, onset of effects on agitation, elimination half-life, active metabolites, and/or duration of effects. Typically, a loading dose is given to achieve light sedation, followed by maintenance medication. The amount of medication required to achieve an adequate loading dose varies with the severity of withdrawal.
  • • Lorazepam can be administered intravenously, intramuscularly, or orally. Lorazepam provides a long duration of seizure control because of its slow redistribution. It may have decreased risk of sedation among those with liver disease because of its short half-life and absence of active metabolites. The dosing is 1-4 mg every 5-15 minutes until adequate control of agitation is achieved. Large and rapid doses of lorazepam may cause cardiovascular toxicity due to propylene glycol, the diluent.
    • Diazepam can be administered intravenously, orally, or PR. Diazepam rapidly controls agitation because of its rapid distribution secondary to its high lipid solubility. However, it has a long duration of action. Its active metabolites help smooth the course of withdrawal and limit breakthrough symptoms; however, prolonged sedation is a risk. Diazepam is initially given at a dose of 5 mg IV. The drug is repeated at 5-20 mg per dose every 5-15 minutes until adequate control of agitation is achieved. After agitation is controlled, an hourly dose is given as needed to maintain light somnolence.
    • Total dosing of intravenous diazepam should not routinely exceed 100 mg/h or 250 mg in 8 hours. Total dosing of intravenous lorazepam should not routinely exceed 20 mg/h or 50 mg in 8 hours.
    • Short-acting agents have a higher incidence of rebound symptoms. Short-acting benzodiazepines, such as oxazepam and midazolam, must be tapered carefully to avoid breakthrough symptoms and seizures.
    • Intermittent intravenous administration of long-acting benzodiazepines and continuous intravenous infusion of short-acting benzodiazepines is effective and acceptable.
  • In cases not responding to massive doses of benzodiazepines, intravenous infusion of propofol or intravenous boluses of barbiturates (phenobarbital and pentobarbital) should be added as second-line GABA modulators.² This treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors.
  • Neuroleptics are not used as primary agents because studies have demonstrated the superior efficacy of sedative-hypnotics in reducing duration of alcohol withdrawal syndrome and associated mortality.
  • In a severely agitated patient, neuroleptics such as haloperidol 5 mg IV or IM may be added to sedative-hypnotic agents as an adjunctive therapy and repeated with caution in 30-60 minutes if needed to control agitation. Caution must be taken because haloperidol has been known to decrease the seizure threshold as well as prolong the QT interval.
  • Several medications are reported to be helpful adjuncts to benzodiazepines and other GABA modulators (barbiturates and propofol) in the treatment of refractory alcohol-withdrawal syndrome, but they should never be used as a monotherapy. These include haloperidol, carbamazepine, valproic acid, gabapentin, clonidine, and beta-blockers (atenolol).³
• Sedative-hypnotic withdrawal is treated with substituting drugs that have a long duration of action, either a benzodiazepine or phenobarbital, in a maintenance dose for a few days followed by a gradually decreasing dose over 2-3 weeks.
• GHB withdrawal can initially be treated with high doses of benzodiazepines, though anecdotally, refractory cases have responded to other sedative agents, such as pentobarbital and chloral hydrate.
• Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone 20-35 mg/d or buprenorphine 4-16 mg/d, and then tapered over days to weeks. Clonidine 0.1-0.2 mg every 4-8 hours also decreases the severity of symptoms. Long-acting benzodiazepines can be added to control insomnia and muscle cramps.
• Stimulant-withdrawal syndrome is treated by observation alone and does not require any specific medications.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Treatment involves administering a substitute medication that has cross-tolerance with the chronically ingested substance. These medications either interact at specific receptors (eg, methadone in opiate withdrawal) or have generalized effects that reduce withdrawal symptoms (eg, barbiturates in alcohol withdrawal). Probably the most common treatment of withdrawal symptoms from alcohol or illicit drugs is the self-administration of more alcohol or drugs.

Many regimens for treating withdrawal involve cross-tolerant medications titrated to the severity of the withdrawal by gradually decreasing the dose and by increasing the dosing interval to wean the patient from the original substance. For alcohol withdrawal syndrome, these regimens include benzodiazepines, barbiturates, propofol, and ethanol,⁴ and clomethiazole (in Europe). Tegretol, valproic acid, gabapentin, gamma-hydroxybutyrate, propranolol (Inderal), and clonidine all have been used as an adjunctive therapy and are effective, though they should not be used as monotherapy.

Drug Category: Benzodiazepines

These drugs produce sedative effects by enhancing GABA neurotransmission from binding to GABA_A receptors. All benzodiazepines appear similarly effective in the treatment of alcohol withdrawal syndrome. In moderate-to-severe withdrawal, long-acting agents are preferred over short-acting drugs. Symptom-triggered therapy is preferred over fixed-schedule therapy because it decreases the duration and total dose of treatment to resolve symptoms. Fixed-dose therapy is appropriate in mild-to-moderate withdrawal.

Drug Category: Cardiovascular agents

Clonidine has been used in alcohol withdrawal because its central alpha₂-agonist activity reduces central output of adrenergic neurotransmitters. Because excessive adrenergic neurotransmission may be the basis for withdrawal symptoms, clonidine is a logical choice and has been effective. It is most commonly used in opioid withdrawal.

Drug Category: Vitamins

Thiamine (vitamin B-1), folic acid (folate), cyanocobalamin (vitamin B-12), and other water-soluble vitamins are often depleted in persons with chronic alcoholism, who are also frequently malnourished. Replenishing these vitamins can prevent or treat Wernicke-Korsakoff syndrome (with thiamine), correct megaloblastic anemia (with folic acid and cyanocobalamin), correct high-output CHF (with thiamine), and halt peripheral neuropathy (with cyanocobalamin). Although the effects of these treatments are typically not apparent in the ED, vitamins are commonly administered in the ED because deficiencies are common in this population and because the manifestations are often subtle.

Drug Category: Barbiturate

These drugs are acceptable alternative to benzodiazepines. GABA agonists are similar to benzodiazepines but directly open chloride channels in large doses. In contrast to benzodiazepines, barbiturates prolong GABA response by delaying closure of the GABA channels. Benzodiazepines increase the frequency of opening events in GABA chloride channels, whereas barbiturates maintain the channel open longer. Use barbiturates as the second-line drug in patients not responding to an adequate trial of benzodiazepines.

Drug Category: Pharmacologic antidotes

As with other withdrawal syndromes, replacement of the chronically ingested substance is an effective means of terminating the withdrawal. In rare cases that do not respond to cross-tolerant sedatives, an infusion of ethanol may be used as a last resort in achieving sedation.

Drug Category: Electrolyte Replacement

At pharmacologic doses, magnesium sulfate has many effects, including anticonvulsant action, decreased nerve-conduction velocity, relaxation of smooth muscle, and antidysrhythmic actions. In addition, it appears to act as a sedating agent. Patients with chronic alcoholism have a total body deficit of magnesium that may exacerbate symptoms of alcohol withdrawal. Replacement of magnesium appears to decrease the total dose of benzodiazepines required to achieve sedation.

Drug Category: Anesthetics

Consider propofol as a last-resort drug in refractory DT and status epilepticus that does not respond to adequate trial of benzodiazepines and barbiturates. It not only directly activates GABA_A receptors but also inhibits NMDA receptors. It causes rapid recovery from sedation after it is discontinued, as it is highly lipophilic. The emulsion containing propofol causes a high lipid load and may result in hyperlipidemia if its use is prolonged. Propofol-induced hypertriglyceridemia has been causally associated with pancreatitis. Propofol infusions have been titrated up to 90 mcg/kg/min in case series describing the treatment of alcohol withdrawal syndrome refractory to other medications.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Symptoms of alcohol withdrawal are often mild or absent in the ED and may manifest only after the patient is admitted to the hospital for other reasons (eg, multiple trauma).
• Patients already manifesting advanced stages of withdrawal in the ED (eg, seizure, DT) require admission.
• Patients with DT require admission to the ICU because their hemodynamic picture can change rapidly and because appreciable mortality is associated with DT.
• Patients may require admission for associated conditions (eg, GI bleed, pancreatitis). In these cases, use of sedatives may be more complex if the patient is hypotensive from blood or third-space fluid losses. 
• In uncomplicated cases of withdrawal, the sedative regimen can be continued until the patient is calm and vital signs are normalized. At that point, decreasing the dose or increasing the dosing interval over 3-4 days can taper the administration of sedatives.

Further Outpatient Care

• Referral of patients with chronic alcoholism or intravenous drug use to ongoing treatment programs is worthwhile, even if a minority of these patients maintain sobriety for long periods. Numerous agencies offer inpatient and outpatient treatment programs; the most successful groups appear to be Alcoholics Anonymous and Narcotics Anonymous.
• The following options are available for people addicted to heroin:
• • Methadone is a long-acting opiate that prevents occurrence of somatic withdrawal symptoms but does not produce sedation or euphoria equivalent to heroin.
  • Buprenorphine is a μ-opioid agonist/antagonist and is prescribed in a manner that is similar to methadone.
  • Both treatment programs require patient compliance and motivation. This appears to be the limiting factor in their success rates.
• Patients withdrawing from chronic stimulant abuse are best cared for under medical supervision; refer these patients to appropriate institutions or agencies.

Transfer

• Because of the risk of seizures, patients in active withdrawal from alcohol are unstable for transfer until they have received adequate sedation.
• Decisions about when to transfer largely depend on underlying associated conditions that may have stabilization requirements of their own (eg, pancreatitis, acute MI).
• Patients in opiate withdrawal are generally stable for transfer unless underlying conditions render them unstable.

Complications

• Numerous complications are associated with long-term alcohol and intravenous drug abuse. Complications are more common and more serious in alcohol withdrawal than in opiate or stimulant withdrawal.
• Alcohol withdrawal
• • Metabolic complications
  • • Alcoholic ketoacidosis (AKA)
    • Electrolyte disorders (eg, hypomagnesemia, hypokalemia, hypernatremia)
    • Vitamin deficiencies (eg, thiamine, phytonadione, cyanocobalamin, folic acid)
  • GI complications
  • • Pancreatitis
    • Gastrointestinal bleeding (eg, peptic ulcer, esophageal varices, gastritis)
    • Hepatic cirrhosis
  • Infectious complications
  • • Pneumonia
    • Meningitis
    • Cellulitis
  • Neurologic complications
  • • Wernicke-Korsakoff syndrome
    • Cerebral atrophy
    • Cerebellar degeneration
    • Subdural or epidural hemorrhage
    • Peripheral neuropathy

Patient Education

• For excellent patient education resources, visit eMedicine's Substance Abuse Center. Also, see eMedicine's patient education article Drug Dependence and Abuse.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to report patients who have seizures and who are likely to experience repeated loss of consciousness in the future is a pitfall. State laws commonly require reporting of these patients to the state vehicular agencies.
• Failure to recognize and treat Wernicke-Korsakoff syndrome is a pitfall.
• Failure to recognize and adequately treat patients in alcohol withdrawal is a pitfall.
• Failure to recognize and treat associated medical conditions (eg, gastrointestinal bleeding in an alcoholic, sepsis in someone who is opioid dependent) that may have precipitated withdrawal by making a patient unable or unwilling to continue further substance abuse.
• Failure to recognize a patient's use of ethanol alternatives (eg, methanol, ethylene glycol, cough syrup containing significant amounts of acetaminophen) that may cause significant morbidity or mortality if untreated.
• Attributing an altered mental status, hyperthermia, or seizures to opioid withdrawal is a pitfall. Patients in opioid withdrawal, though dysphoric, should have a clear sensorium without signs of delirium. An appropriate workup should be initiated if an altered mental status is present. Hyperthermia is not part of the clinical picture of opioid withdrawal, and its presence should prompt an investigation for the cause of the fever. Seizures are also not a part of the clinical picture of opioid withdrawal, except in neonates, in whom seizures may occur. Again, an appropriate workup is indicated if seizures occur in this setting.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Ashok Jain, MD, and Edward Newton, MD, to the development and writing of this article.

The authors and editors of eMedicine gratefully acknowledge the medical review of this article by Lada Kokan, MD.

MULTIMEDIA

Section 11 of 12