Withdrawal syndrome, also known as discontinuation syndrome, occurs in individuals who have developed physiological dependence on drugs or alcohol and who discontinue or reduce their use of it.
Signs and symptoms of withdrawal vary depending on the substance discontinued.
The hallmark of alcohol withdrawal is a continuum of signs and symptoms ranging from simple tremulousness to delirium tremens (DT). The spectrum varies greatly, and symptoms overlap in time and duration.
Discontinuation of benzodiazepines, barbiturates, and other sedatives or hypnotics after long-term use results in withdrawal symptoms resembling those of alcohol withdrawal syndrome. Sedative-hypnotic withdrawal syndrome is characterized by pronounced psychomotor and autonomic dysfunctions.
Opioid withdrawal produces a characteristic syndrome that may resemble viral illness. The syndrome is characterized by rhinorrhea, sneezing, yawning, lacrimation, abdominal cramping, leg cramping, piloerection (gooseflesh), nausea, vomiting, diarrhea, mydriasis, myalgias and arthalgias.
Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome, resembles severe depressive disorder. Manifestations include dysphoria, excessive sleep, hunger, and severe psychomotor retardation, whereas vital functions are well preserved.
See Presentation for more detail.
The following laboratory tests may be indicated in cases of possible withdrawal, depending on the clinical scenario:
See Workup for more detail.
Patients presenting in mild alcohol withdrawal may be treated on an outpatient basis, provided that no underlying conditions require inpatient treatment. Patients presenting with moderate or severe alcohol withdrawal and DT require inpatient treatment and consideration of ICU admission.
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, dexmedetomidine, and (in rare cases) ethanol.
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, chloral hydrate, and baclofen.
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.
See Treatment and Medication for more detail.
Ethanol and 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 patient education resources, see the Substance Abuse Center, as well as Drug Dependence and Abuse and the Addiction Resource Center.
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.
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]
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] :
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.
Chronic alcoholism and withdrawal 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.
In addition to documenation of presenting complaints, essential elements of the history in withdrawal syndrome include the following:
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).
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:
Moderate withdrawal usually occurs 24-36 hours after the cessation of alcohol intake and includes the following:
Severe withdrawal usually occurs more than 48 hours after a cessation or decrease in alcohol consumption and is characterized by the following:
Predictors of severe alcohol withdrawal syndrome include the following[4] :
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:
DT, the most intense sign of alcohol withdrawal, occurs 48-72 hours after the last drink. Features of DT are as follows:
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:
Features include the following:
Gamma-hydroxybutyrate (GHB) withdrawal syndrome involves the following[6] :
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:
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:
Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome generally does not directly cause life-threatening symptoms, seizures, or delirium. Features include the following:
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:
Head and neck findings may include the following:
Chest findings in alcohol withdrawal may include the following:
Chest findings in opiate withdrawal may include the following:
Cardiac findings may include the following:
Abdominal findings may include the following:
Findings in the extremities include the following:
Neurologic examination findings may include the following:
Skin findings may include the following:
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:
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:
Urinalysis is indicated, as follows:
Cardiac markers may be indicated. Findings may include the following:
Measurement of prothrombin time (PT) may be indicated, as follows:
Toxicology screening may be indicated, as follows:
Imaging studies should be directed to the patient's clinical course.
Chest radiography findings may include the following:
Head computed tomography (CT) findings may include the following:
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:
Other tests may include the following:
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:
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 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 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. 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:
Treatment of other types of withdrawal may include the following:
The American Academy of Pediatrics has issued a guideline on the management of iatrogenically induced opioid dependence and withdrawal in children.[15, 16] Recommendations include the following:
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.[18, 19, 20]
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.[21] They are also effective in sedative-hypnotic and GHB withdrawal. Benzodiazepines 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 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.[22] The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification[23] 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.[24] Combination treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors.[25] 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.[21] Other agents used in combination therapy have included baclofen,[26] haloperidol, carbamazepine,[27] valproic acid,[27] clonidine,[28] and beta-blockers (atenolol).[29]
Dexmedetomidine is a newer 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.[28] Dexmedetomidine has proved useful for reducing hypertension and tachycardia and lowering benzodiazepine requirements.[30, 31] 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.[31, 32]
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.[33]
Research in treatment for alcohol withdrawal using less sedating medications have included gabapentin[34] and pregabalin.[35] However, evidence to date suggests that these agents are more effective for maintaining abstincence in recovering alcoholics.[36, 37]
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,[21] propofol, and ethanol,[38, 19] 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: Decreases blood pressure, pulse rate, and tremor. Does not decrease incidence or severity of seizures or delirium; does not affect craving for alcohol.
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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: 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.
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.
Clinical Context: 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.
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.
Clinical Context: 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.
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.
Clinical Context: Phenolic compound unrelated to other types of anticonvulsants. General anesthetic properties when administered IV.
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.
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).[29]
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:
Treatment considerations include the following:
See the list below:
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:
Cardiac complications include Takotsubo cardiomyopathy.[11]
Gastrointestinal complications of alcohol withdrawal include the folllowing:
Infectious complications of alcohol withdrawal include the folllowing:
Neurologic complications of alcohol withdrawal include the folllowing: