Withdrawal Syndromes

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.[1] Resulting changes in the inhibitory and excitatory neurotransmitters disrupt the neurochemical balance in the brain, causing symptoms of withdrawal.

Ethanol binds to postsynaptic GABAA receptors (inhibitory neurons). Activation of these receptors enhances the effects of GABA. In response, the chloride channels open, causing chloride influx. This hyperpolarizes the cell, decreasing the firing rate of neurons, ultimately producing sedation. Long-term use of ethanol subsequently results in downregulation of GABAA 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.

Other GABAA receptor agonists, such as benzodiazepines, barbiturates, and volatile solvents, produce a withdrawal syndrome through some of the same mechanisms implicated in ethanol withdrawal. Modulatory changes in the GABAA receptor results in a decrease in GABA-ergic neurotransmission and decreased inhibitory control of excitatory neurotransmission.

Opioid withdrawal is mediated at both the receptor level and via downstream cellular and nerve network adaptations. At the receptor level, opioid tolerance induces receptor internalization with decreased receptor expression on the cell surface and receptor densensitization, whereby stimulation of the receptor is less efficiently coupled to second messenger activation.

At the cellular level, opioid tolerance and withdrawal is modulated by alterations in kinase cascades, which modulate the production and effects of second messengers such as cyclic adenosine monophosphate (cAMP). At the nerve network level, chronic opioid agonism results in homeostatic adaptations to other neurons throughout the neural network; alterations in neuronal, synaptic, and dendritic architecture; and changes in glial function. 

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. Binge drinkers may also be at risk.

According to the 2015 National Survey on Drug Use and Health, an estimated 17.3 million persons aged 12 or older were heavy alcohol users in the past month; this represents 6.5% of the population of that age. An estimated 66.7 million persons had been binge alcohol users in the past 30 days; this represents 24.9% of the population of that age.[2]

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 precisely and fluctuates with the supply of drugs and social trends. According to the 2015 National Survey on Drug Use and Health, 7.7 million people aged 12 or older had an illicit drug use disorder; this represents 2.9% of the population of that age.[2]

Sex- and age-related demographics

Chronic alcoholism and alcohol withdrawal syndrome are more common in men than women.

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.

The mortality rate from severe alcohol withdrawal and delirium tremens (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. Risk factors associated with increased mortality include the following[3] :

• Cirrhosis
• DT
• Underlying chronic pathology other than liver disease
• Need for endotracheal intubation

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.

Opioid withdrawal is uncomfortable but usually mild in terms of derangement of vital signs. Fatalities due to spontaneous opioid withdrawal is very rare, although precipitated opioid withdrawal is associated with acute lung injury or myocardial injury that may result in critical illnes or death.

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.

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.

Metabolic complications of alcohol withdrawal include the folllowing:

• Alcoholic ketoacidosis (AKA)
• Electrolyte disorders (eg,  hypomagnesemia,  hypokalemia,  hypernatremia)
• Vitamin deficiencies (eg, thiamine, phytonadione, cyanocobalamin, folic acid)

Cardiac complications include Takotsubo cardiomyopathy.[4]

Gastrointestinal complications of alcohol withdrawal include the folllowing:

• Pancreatitis
• Gastrointestinal bleeding (eg, peptic ulcer, esophageal varices, gastritis)
• Hepatic cirrhosis

Infectious complications of alcohol withdrawal include the folllowing:

• Pneumonia
• Meningitis
• Cellulitis

Neurologic complications of alcohol withdrawal include the folllowing:

• Wernicke-Korsakoff syndrome
• Cerebral atrophy
• Cerebellar degeneration
• Subdural or epidural hemorrhage
• Peripheral neuropathy

In addition to documenation of presenting complaints, essential elements of the history in withdrawal syndrome include the following:

• Type of drugs ingested over the long term
• Duration of addiction
• Time of last ingestion
• Reason for the patient's cessation of the drug
• Alternative treatments used to relieve withdrawal symptoms
• Previous withdrawal symptoms and their severity

Serious comorbid conditions can be inciting events for reasons for cessation of alcohol and should be thoroughly investigated. In patients admitted for reasons other than withdrawal (eg, myocardial infarction [MI], multiple trauma), obtaining a history of illicit drug and alcohol abuse is important, as it can assist with anticipating the need for treatment of withdrawal syndrome(s).

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 is most clinically useful.

Mild withdrawal usually occurs within 24 hours of the last drink and is characterized by the following:

• Tremulousness (shakes)
• Insomnia
• Anxiety
• Hyperreflexia
• Diaphoresis
• Mild autonomic hyperactivity
• GI upset

Moderate withdrawal usually occurs 24-36 hours after the cessation of alcohol intake and includes the following:

• Intense anxiety
• Tremors
• Insomnia
• Excessive adrenergic symptoms

Severe withdrawal usually occurs more than 48 hours after a cessation or decrease in alcohol consumption and is characterized by the following:

• Profound alteration of sensorium, including disorientation, agitation, and hallucinations
• Severe autonomic hyperactivity, including tremulousness, tachycardia, tachypnea, hyperthermia, and diaphoresis

Predictors of severe alcohol withdrawal syndrome include the following[5] :

• Past history of severe withdrawal
• Thrombocytopenia
• Hypokalemia

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 delirium tremens (DT).

Approximately 23-33% of patients with significant alcohol withdrawal have alcohol withdrawal seizures ("rum fits"). Features of these seizures are as follows:

• Seizures are usually brief, generalized, tonic-clonic in nature, and without an aura. They occur in a cluster of  one to three 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.

• 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. Features of DT are as follows:

• 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, persons who cannot obtain regular alcoholic beverages because of financial reasons may resort to ingesting other substances, as follows:

• 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

Features include the following:

• Discontinuation of benzodiazepines, barbiturates, and other sedatives or hypnotics after long-term use produces withdrawal symptoms 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

• Catatonia may occur with benzodiazepine withdrawal, as well as clozapine withdrawal[6]

• Symptoms usually occur 2-10 days after abrupt discontinuation of the drug, depending on its half-life

Gamma-hydroxybutyrate withdrawal

Gamma-hydroxybutyrate (GHB) withdrawal syndrome involves the following[7] :

• 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 occurs following long-term heavy use; symptoms are similar to those of alcohol withdrawal syndrome, but delirium occurs earlier, while seizures (7%) and rhabdomyolysis (7%) rarely occur[8]

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 flulike illness. The syndrome is characterized by the following:

• Rhinorrhea
• Sneezing
• Yawning
• Lacrimation
• Abdominal and leg cramping
• Piloerection (gooseflesh)
• Nausea and vomiting
• Diarrhea
• Mydriasis
• Myalgias
• Arthralgias

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.

In addition to withdrawal syndrome, the differential diagnosis in patients with a history of long-term intravenous (IV) drug abuse must include the host of infectious problems to which these patients are susceptible, including but not limited to the following:

• Endocarditis
• Septic emboli
• Osteomyelitis
• Septic arthritis
• Abscesses (ie, psoas, brain, and epidural)
• Viral hepatitis

Stimulant withdrawal

Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome generally does not directly cause life-threatening symptoms, seizures, or delirium. Features include the following:

• 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

• Depression, mood, and anxiety symptoms improve over the first week but may persist for up to 2 weeks[9]

Thorough physical examination is important, 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 may include the following:

• The central adrenergic storm that occurs during alcohol withdrawal results in hyperventilation, tachycardia, hypertension, tremor, hyperthermia, and diaphoresis.

• Hyperthermia is common in severe alcohol withdrawal because of psychomotor agitation.

• Hypothermia can be seen with Wernicke encephalopathy.

Head and neck findings may include the following:

• 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 may include the following:

• Tachypnea is expected during moderate-to-severe 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. Potential causes in the setting of alcohol withdrawal include alcoholic ketoacidosis (AKA) and ingestion of toxic 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 may include the following:

• Patients with opiate addiction are at high risk for HIV infection and are susceptible to AIDS-related pneumonias, particularly those due to Pneumocystis jiroveci and Mycobacterium tuberculosis.

• Note symptoms and physical evidence of cough, hemoptysis, fever, and tachypnea

Cardiac findings may include the following:

• 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 may include the following:

• 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 may indicate 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 include the following:

• 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.

Neurologic examination findings may include the following:

• 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 may include the following:

• 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 is common during opioid withdrawal

A serum glucose or fingerstick 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 alcoholic ketoacidosis (AKA), volume-contraction alkalosis, and respiratory alkalosis. Hypoxia may occur due to aspiration pneumonitis.

A complete blood cell count (CBC) is recommended. Findings may include the following:

• Long-term alcohol ingestion leads to myelosuppression with a slight reduction in all cell lines; thrombocytopenia is common.

• Blood loss from the gastrointestinal (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 patients with alcoholism, due to dietary deficiency of vitamin B-12 and folate; increased mean corpuscular volume suggests this condition

A comprehensive metabolic panel 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. Other findings may include the following:

• A low blood urea nitrogen (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.

• An article in the Journal of Trauma reported that a mean corpuscular volume (MCV) and aspartate aminotransferase (AST) level in an intoxicated trauma patient admitted to the hospital predicated a low risk for developing delirium tremens.[10] However, this has not been studied in nontrauma patients.

Urinalysis is indicated, as follows:

• 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.

Cardiac markers may be indicated. Findings may include the following:

• Elevated creatine kinase (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.

• An elevated CK level can also be from rhabdomyolysis, which may be secondary to psychomotor agitation in alcohol and sedative-hypnotic withdrawal or due to limb compression with skeletal muscle injury in patients with depressed mental status. 

Measurement of prothrombin time (PT) may be indicated, as follows:

• The PT is a useful index of liver function; patients with cirrhosis are at risk for coagulopathy.

• PT testing should be considered in a patient with active bleeding in the gastrointestinal tract or central nervous system.

Toxicology screening may be indicated, as follows:

• Consider measuring serum osmolality and testing for toxic alcohols if the history is suspicious for toxic alcohol ingestion or if the patient has a widened anion gap metabolic acidosis.

• The ethanol concentration is frequently zero. However, some patients that are habituated to alcohol can be in severe alcohol withdrawal even with a positive serum ethanol concentration.

• Urine drug immunoassay is of limited utility but may be considered to assess for co-ingestion of other medications (eg, benzodiazepines) and other recreational drugs. 

• Gamma hydroxybutyrate (GHB), fentanyl, and many other drugs of abuse are not targeted in routine urine drug immunoassays. Send-out testing to a reference laboratory is typically unnecessary from a clinical perspective.

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

Chest radiography findings may include the following:

• Aspiration pneumonia is common in patients with alcohol withdrawal syndrome.

• Patients with chronic alcoholism may have cardiomyopathy and chronic heart failure

• Patients using intravenous drugs are prone to pneumonia due to non-sterile injection practices and immunosuppression (eg, HIV infection).

Head computed tomography (CT) findings may include the following:

• 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 or ultrasonography in patients with a history of intravenous drug abuse and unexplained hip pain may reveal intra-abdominal pathology, including psoas abscess.

Spinal MRI may be required to rule out epidural abscess in patients with unexplained back pain, intravenous drug abuse, and fever, particularly if focal neurologic deficits are also present.

Other imaging may be indicated if trauma or other associated conditions are suspected.

Electrocardiography findings may include the following:

• Adrenergic storm produced by alcohol withdrawal increases demands on the heart and may precipitate infarction or fatal ventricular dysrhythmia in susceptible individuals[11]

• Takotsubo cardiomyopathy with resulting CHF has also been reported[4]

• A prolonged QTc interval has been described in patients with alcohol withdrawal syndrome[12] ; the interval gradually reverts to normal as withdrawal symptoms remit

Other tests may include the following:

• 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 considerations include the following:

• Symptoms of alcohol withdrawal are often mild or absent in the emergency department (ED) and may manifest only after the patient is admitted to the hospital for other reasons (eg, multiple trauma).

• Patients may require admission for associated conditions (eg, gastrointestinal 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, the sedative can be tapered by decreasing the dose or lengthening the dosing interval over 3-4 days.

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 emergency department (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 is 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.

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.

Ethanol Withdrawal

Alcohol withdrawal seizures are typically brief and followed by a brief postictal period. The occurrence of more than three 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 provides 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 patients with chronic alcoholism.

Phenobarbital is sometimes used as an adjunctive or alternative treatment for alcohol withdrawal syndrome. The benefit of phenobarbital as a first-line treatment is that its longer half-life could eliminate the need for addition medications at discharge.[13]   

In patients receiving symptom-triggered lorazepam for the acute management of alcohol withdrawal syndrome, Ibarra reported that more patients were discharged within 3 days if they received a single parenteral dose of phenobarbital on hospital day one. Of patients receiving lorazepam and phenobarbital, 9 of 40 were discharged within 3 days, compared with only 2 of 38 who received lorazepam only (P < 0.05).[14]  

Hawa, et al conducted a retrospective study comparing 543 patients given lorazepam for alcohol withdrawal syndrome to 63 patients who received phenobarbital. In this cohort, the group receiving phenobarbital had significantly shorter hospital stays than the group receiving lorazepam (2.8 versus 3.6 days, P < 0.001). In addition, the phenobarbital group had lower rates of all-cause 30-day readmission (11.11% versus 14.18%, P = 0.020) and 30-day emergency department (ED)_ visits after discharge (11.11% versus 18.6%, P = 0.015).[15]

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. See Follow-up/Further Outpatient Care.

Patients presenting with moderate or severe alcohol withdrawal and delirium tremens (DT) require inpatient treatment and consideration of intensive care unit (ICU) admission. Initial emergency care includes the following steps:

• Place the patient 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, severe withdrawal mandates larger doses of substitute medications (see Alcohol Withdrawal Drug Therapy).

Other Withdrawal Syndromes

Sedative-hypnotic withdrawal is treated by 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.

Gamma hydroxybutyrate (GHB) withdrawal can initially be treated with high doses of benzodiazepines, although anecdotally, refractory cases have responded to other sedative agents, such as pentobarbital, chloral hydrate, and baclofen.[16, 17]

Treatment of opioid withdrawal in the ED is typically limited to supportive measures such as antiemetics (eg, ondansetron), antispasmodics (eg, octreotide, dicyclomine), and non-opioid analgesics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen); clonidine 0.1-0.2 mg every 4-6 hours or lofexidine 0.54–0.72 mg every 6 hours may be useful in treating autonomic components of opioid withdrawal; clonazepam, 0.5–2.0 mg every 4–8 hours, may reduce anxiety.[18] Patients who are able to tolerate oral fluids and who are clinically stable may be discharged with appropriate prescriptions. Patients with intractable vomiting and those with clinically significant metabolic derangements from gastrointestinal fluid/electrolyte loss may require admission.

Emergency providers may administer but not prescribe methadone or buprenorphine to a patient for acute opioid withdrawal symptoms while arranging the patient's referral for treatment. According to US federal law, such treatment is limited to a maximum of 72 hours and only 1 day's medication may administered at one time. Due to logistical considerations in arranging referral to an opioid treatment program, it is uncommon for emergency providers to undertake treatment with methadone or buprenorphine in the ED. 

Stimulant-withdrawal syndrome is treated with observation alone and does not require any specific medications. Patients may be discharged once their mental status has normalized. Patients with persistent depressed mental status may require admission. In such patients, diagnostic testing for other causes of altered mental status should be undertaken. 

Pediatric Opioid Withdrawal

The American Academy of Pediatrics has issued a guideline on the management of iatrogenically induced opioid dependence and withdrawal in children.[19] Recommendations include the following:

• Children exposed to opioids for longer than 14 days usually need to be weaned with a gradual reduction in dose over time.

• Pain status should be assessed at the time of weaning.

• Withdrawal symptoms should be assessed with the Sophia Observation Withdrawal Symptoms Scale,[20] which is validated in children, or another validated scale.

• Weaning protocols should account for the length of opioid exposure and total daily opioid dose.

• Biofeedback and other behavioral strategies might help with sleep, anxiety/mood symptoms, and pain-related symptoms.

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 myocardial infarction).  

Patients in opiate withdrawal are generally stable for transfer unless underlying conditions render them unstable.

For patients who are admitted to the hospital for alcohol or sedative-hypnotic withdrawal, see Alcohol Withdrawal Drug Therapy section below.

Patients who are admitted to the hospital for complications of opioid withdrawal (eg, electrolyte disturbances, intractable vomiting, or end-organ damage) may be treated with the supportive medications discussed in the section Emergency Department Care, above. Federal law allows inpatient providers to administer opioid agonist medications such as methadone and buprenorphine to prevent opioid withdrawal that would complicate the patient's hospital course.

Should such therapy be undertaken, patients should be referred to appropriate outpatient treatment programs at the time of discharge to avoid interruption of detoxification or maintenance treatment regimens. 

Methadone may be started at a dose of 10-20 mg and titrated to relief of a patient's withdrawal syndrome. Use of a validated opioid withdrawal metric such as the Clinical Opiate Withdrawal Scale (COWS) may be helpful in quantifying the severity of opioid withdrawal and titrating opioid agonist medication. Due to its long half-life, serum and tissue methadone concentrations rise over the first several days of scheduled daily methdone dosing and patients should be monitored for signs of opioid toxicity. 

Buprenorphine may be started at a dose of 2-4 mg and titrated to relief of the withdrawal syndrome. Buprenorphine is a partial opioid agonist and administration of buprenorphine to patient with opioid tolerance who is not in withdrawal may result in a severe precipitated opioid withdrawal syndrome. Therefore patients must be in moderate-to-severe opioid withdrawal (eg, COWS > 12) before being given buprenorphine.

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, dexmedetomidine, ketamine, propofol, and (in rare cases) ethanol.[21, 22, 23]

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.

Benzodiazepines are the mainstay of therapy in the United States and are the primary agents used as substitutes and cross-tolerant medications for alcohol withdrawal syndrome.[24] They are also effective in sedative-hypnotic and GHB withdrawal. Benzodiazepines substitute for the gamma aminobutyric acid (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 Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) has been validated and is used for medication administration in symptom-triggered therapy. In this approach, medication is given only when the CIWA-Ar score is higher than 8 points.[25] The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification[26] but not necessarily for the treatment of DT.

Intravenous administration of 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 various benzodiazepines have similar efficacies in treating alcohol withdrawal syndrome, though one drug may be chosen 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 per rectum. 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.[27, 28] Combination treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors.[29] A meta-analysis suggested that barbiturates, alone or in combination with benzodiazepines, are at least as effective as benzodiazepines in the treatment of alcohol withdrawal syndrome, with acceptable tolerability and safety profiles similar to those of benzodiazepines in this setting.[24] Other agents used in combination therapy have included the following:

• Baclofen ^[30]
• Haloperidol
• Carbamazepine ^[31]
• Valproic acid ^[31]
• Clonidine ^[32]
• Beta-blockers (atenolol) ^[33]

Dexmedetomidine is an intravenous α-2 agonist (similar to clonidine but more selective) that is approved by the US Food and Drug Administration (FDA) for ICU and procedural sedation. A continuous infusion produces sedation, anxiolysis, and sympatholysis with no activity at the GABA or opioid receptors and is without respiratory compromise.[32] Dexmedetomidine has proved useful for reducing hypertension and tachycardia and lowering benzodiazepine requirements.[34, 35] However, it has not been convincingly shown to improve clinical endpoints such as need for mechanical ventilation or length of stay in the intensive care unit or hospital.[35, 36]

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. However, in a severely agitated patient, a neuroleptic 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.

Adjunctive ketamine reduced benzodiazepine requirements and was well tolerated at low doses in a retrospective study of 23 adult patients with alcohol withdrawal syndrome. Mean initial infusion dose was 0.21 mg/kg/h; median total infusion rate was 0.20 mg/kg/h. Median change in benzodiazepine requirements at 12 and 24 hours after initiating ketamine were -40.0 and -13.3 mg, respectively.[37]

Less-sedating medications that have been studied for treatment of alcohol withdrawal have included gabapentin[38, 39] and pregabalin.[40] However, evidence to date suggests that these agents are more effective for maintaining abstinence in recovering alcoholics.[41, 42]

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. These drugs are occasionally useful, but their effects mask the warning signs of autonomic hyperactivity if the patient develops delirium tremens (DT).[33]

Addiction treatment programs

Referral of patients with chronic alcoholism or intravenous drug use to ongoing treatment programs is worthwhile, even if only 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.

The following guidelines on withdrawal are available:

• World Health Organization: Withdrawal Management and Treatment of Drug Dependence in Closed Settings - Covers standard care and provides specific recommendations on opioid, benzodizepine, stimulant, alcohol, inhalant, and cannabis withdrawal ^[43]
• American Society of Addiction Medicine: Identification and management of alcohol withdrawal in adults - Addresses varying degrees of syndrome severity and provides recommendations on both ambulatory and inpatient care ^[44]
• American Society of Addiction Medicine: Use of medications in the treatment of addiction involving opioid use ^{[45, 46]}
• American Academy of Pediatrics: Management of iatrogenically induced opioid dependence and withdrawal in children ^[19]

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). 

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,[24] propofol, and ethanol,[47, 22] and clomethiazole (in Europe). Carbamazepine, valproic acid, gabapentin, gamma-hydroxybutyrate, propranolol, and clonidine all have been used as an adjunctive therapy and are effective, but should not be used as monotherapy.

Class Summary

These drugs produce sedative effects by enhancing GABA neurotransmission from binding to GABAA 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.

Lorazepam (Ativan)

Has advantages of non–liver-dependent metabolism, intermediate half-life, and ease of administration (PO/IV/IM), making it ideal medication for alcohol withdrawal; may be drug of choice. After some sedation achieved, can start 2 mg IV q8h on day 1. Can decrease to 1 mg tid on day 2 and gradually eliminate over next 2 d if patient responding well.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic, reticular formation), possibly by increasing GABA activity. Individualize dosage and increase cautiously to avoid adverse effects. Idiosyncratic apnea can occur in addition to progressive depression of respiratory drive and hypotension with accumulating doses. After stabilization, oral diazepam can be started at 10 mg tid/qid.

Oxazepam

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Half-life is relatively brief compared with that of diazepam. Titrated to treat mild alcohol withdrawal in outpatients and in those who can tolerate PO medications.

Chlordiazepoxide

Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing GABA activity, major inhibitory neurotransmitter. Long considered standard therapy for alcohol withdrawal; has relatively long half-life and inexpensive and effective. Parenteral chlordiazepoxide is currently not available commercially in the United States.

Midazolam

As with other benzodiazepines, can sedate patients in alcohol withdrawal. However, brief half-life requires constant infusion to maintain sedation. More expensive than many alternatives, requires more nursing attention for constant infusion than other drugs, and no more effective than other benzodiazepines. Not recommended for routine use in DT. Because of its relatively rapid effects and clinically significant bioavailability when given IM, may be of special use when IV access unavailable.

Class Summary

Clonidine has been used in alcohol withdrawal because its central alpha 2 -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.Many of the aberrant vital signs associated with alcohol withdrawal improve with beta-adrenergic blockade. Blockade can mask the development of adrenergic symptoms and blunts warning signs of DT. It does not prevent delirium, seizures, or hallucinations.

Clonidine (Catapres, Kapvay)

Not to be used as monotherapy. Reduces central adrenergic discharge and decreases blood pressure and pulse, though effect on pulse less predictable than other effect. Also useful in opiate withdrawal; decreases some symptoms (eg, lacrimation, diarrhea, tachycardia). Transdermal patches deliver 0.1, 0.2, or 0.3 mg/d for 7 d.

Propranolol (Inderal, Innopran XL, Hemangeol)

Decreases blood pressure, pulse rate, and tremor. Does not decrease incidence or severity of seizures or delirium; does not affect craving for alcohol.

Class Summary

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.

Thiamine (Vitamin B-1)

Essential cofactor in multiple metabolic processes. Deficiency can occur relatively quickly in starvation states, as body stores are limited. Manifestations of deficiency include wet beriberi and Wernicke-Korsakoff syndrome, which glucose administration in chronic thiamine deficiency can precipitate.

Phytonadione (Vitamin K-1, Mephyton)

Correction of vitamin K deficiency may increase synthesis of liver-dependent clotting factors and correct prolonged PT common in chronic alcoholism and cirrhosis. Use only in patients with hypoprothrombinemia.

Class Summary

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.

Phenobarbital

Effectively reduces signs and symptoms of alcohol withdrawal by producing a generalized decrease in neurotransmission. Can produce sedation in almost all patients in alcohol withdrawal, but the hypotension and respiratory depression it produces limit its use.

Class Summary

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.

Ethanol

IV administration may cause thrombophlebitis; PO administration may cause severe gastritis. Low doses may effectively prevent alcohol withdrawal syndrome in surgical patients. Use in established alcohol withdrawal syndrome not studied.

Class Summary

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.

Magnesium sulfate

Many patients with chronic alcoholism have clinically significant magnesium deficiency due to malnutrition and chronic diuresis from alcohol ingestion. Symptoms are similar to those of alcohol withdrawal and include tachycardia, seizures, tremor, and hyperreflexia. Magnesium replacement decreases total sedation required and decreases incidence of seizures, but a recent study shows that deficiencies are self-limited and treatment might not be required.

Class Summary

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 GABAA 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.

Propofol (Diprivan)

Phenolic compound unrelated to other types of anticonvulsants. General anesthetic properties when administered IV.

Lofexidine (Lucemyra)

Centrally acting alpha2-agonist that binds to receptors on adrenergic neurons; this reduces the release of norepinephrine and decreases sympathetic tone. Indicated for short-term mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.