Medication Summary
Although thiamine has no effect on the symptoms or signs of alcohol withdrawal or on the incidence of seizures or delirium tremens (DTs), thiamine (100 mg PO/IV/IM qd for 3 d) is useful in preventing Wernicke encephalopathy and Korsakoff syndrome. Multivitamins (PO/IV qd) and folate (1 mg PO/IV qd) are frequently administered to these patients, but no evidence exists that vitamins, other than thiamine, have any benefit in the acute setting.
Many varying pharmacotherapeutic management recommendations exist for alcohol withdrawal and DTs. Even many authoritative textbooks and journal articles have made recommendations for use of pharmacotherapeutic agents that have never been tested in clinical trials for this condition.
Benzodiazepines are considered the drugs of choice for the management of all stages of alcohol withdrawal syndrome, including DTs. They act on the benzodiazepine-GABA-chloride receptor complex, having a similar GABA-potentiating effect as alcohol. Prospective, randomized clinical trials have demonstrated the effectiveness of benzodiazepines in treating the symptoms and signs of alcohol withdrawal and have also shown a protective benefit against seizures. [23] Although they are thought by many to have a high margin of safety, the heterogeneity of the trials in interventions and in assessment of outcomes prevent definitive conclusions about safety and harms.
For the treatment of minor or moderate alcohol withdrawal (in patients able to take oral therapy), symptom-triggered therapy (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy. [24] The dosage of benzodiazepine needs to be individualized for each patient. The successful use of symptom-triggered therapy requires motivated and attentive nursing.
Most experts recommend that intermittent intravenous bolus dosing of diazepam or lorazepam is the treatment of choice for drug therapy of DTs. In patients refractory to benzodiazepine therapy alone, barbiturates or other adjuncts may be added. [11] A review of four randomized controlled trials of front-loaded diazepam concluded that it produces a rapid calming effect with few untoward adverse effects in medically ill patients, required much less total dose of benzodiazepines, and resulted in a shorter duration of treatment, but may result in over sedation and respiratory depression in very elderly persons or those with severe liver disease. [25]
Phenobarbital, a long-acting barbiturate with a half-life of 50-140 hours and a duration of sedation of 4-10 hours, has been used successfully in the treatment of alcohol withdrawal and DTs. It has well-documented anticonvulsant activity, is inexpensive, and can be administered by the oral, intramuscular, or IV route. Although its mechanism of action is mediated by GABA at the GABA-A receptor, its mechanism of action is different from the benzodiazepines as well as the short-acting barbiturates. While benzodiazepines increase the frequency of chloride channel opening caused by GABA-A receptor activation requiring the presence of presynaptic GABA, phenobarbital enhances GABA-A chloride currents by increasing the duration of chloride channel opening. Therefore, phenobarbital and benzodiazepines may have synergistic clinical effects, supporting the use of phenobarbital as an adjunct to benzodiazepines. Phenobarbital can be used as a first-line agent to be given as an initial single large dose up to 10 mg/kg or preferably as repeated small doses (65, 130, or 260 mg IV per dose) for loading until the patient is calm, to be followed by use of benzodiazepines on an as-needed, symptom-triggered basis. [26]
A single dose of intravenous phenobarbital given in the emergency department may decrease the subsequent ICU admission rate and decrease the total dose of benzodiazepine and decrease the use of continuous lorazepam infusions required during the hospital course, without any increased adverse effects. [26]
Some patients are discharged from the emergency department (ED) or hospital to a setting where medical supervision of detoxification and withdrawal is not available. If this is the case, treatment with a sedative agent that has a long duration of action, such as phenobarbital or a long-acting benzodiazepine (eg, diazepam, chlordiazepoxide), in the ED or hospital may be preferable and safer. Because the effect of these drugs may persist for several days after the last dose, this avoids the less desirable option of prescribing sedative agents for patients to take at home in an unsupervised manner. A patient who is discharged home to a nonmedically supervised environment with a prescription for a benzodiazepine or other sedative-hypnotic agent may misuse the drug, will often resume alcohol at the same time, and may resell the drugs or share them with other persons.
For patients with refractory DTs, propofol has been described in case studies as effective in managing patients who are intubated. [13] It has effects on NMDA and GABA receptors. No clinical trial has demonstrated any superiority over benzodiazepines.
Use of intravenous dexmedetomidine, an alpha-2 receptor antagonist with sedative and sympatholytic properties, is also an option for refractory DTs. It alleviates agitation, causes less respiratory depression, and may be given without mechanical ventilation, unlike propofol. It has been used with benzodiazepines as adjunctive therapy and may reduce total benzodiazepine dosage, but with the risk of producing bradycardia and hypotension. [27] A 2015 review of English-language studies of dexmedetomidine for alcohol withdrawal, none of which was of high quality, found that dexmedetomidine appears to reduce benzodiazepine requirements and decreases sympathomimetic responses, but without convincing evidence that it improves clinical endpoints, including need for mechanical ventilation or length of stay. [28]
Ketamine is another NMDA antagonist with less potential for respiratory depression. Two small studies found that ketamine as an adjunct reduced benzodiazepine requirements in patients with DTs. Another retrospective study found that the adjunctive use of ketamine resulted in decreased length of ICU stay and mechanical ventilation. [12, 29, 30]
Clonidine and beta-blockers may control some of the autonomic symptoms but do not treat or prevent the DTs. As they can mask the severity of alcohol withdrawal syndrome, they should not be used.
Carbamazepine has been shown in some clinical trials to be effective in treating patients with minor symptoms of alcohol withdrawal and has been used extensively in Europe as monotherapy. There is insufficient evidence indicating that carbamazepine or other anticonvulsants are effective in the prevention or treatment of more severe manifestations of alcohol withdrawal, including DTs, but they appear to have limited side effects in this population. [31]
Drugs such as esmolol and midazolam, which have a short half-life and rapid onset of action, can be administered by continuous IV infusion and have been used in critically ill patients with DTs. Clinical studies have not shown them to be superior, or even equal, in overall effectiveness compared with longer-acting agents.
Neuroleptic drug therapy is inferior to sedative-hypnotic drug therapy in reducing mortality or the duration of severe alcohol withdrawal. [32] Neuroleptic drugs are associated with more adverse effects, including lowering of seizure threshold, hypotension, prolonged QT interval, and neuroleptic malignant syndrome. These precautions apply to the older neuroleptics. Little experience with the newer neuroleptics (atypical antipsychotics) exists in the treatment of alcohol withdrawal.
As the extreme hyperglutamatergic and hyperdopaminergic states that occur in severe alcohol withdrawal are thought to be responsible for paranoia, hallucinations, and agitated delirium, there may be a role for small titrated doses of dopamine antagonists (eg, haloperidol) in highly agitated patients, provided that adequate treatment with GABA coverage (benzodiazepines, phenobarbital) has been administered. Some authorities recommend haloperidol at a dose of 0.5-5 mg intravenously or intramuscularly every 30-60 minutes or the same dose orally every 4 hours for severe agitation, perceptual disturbances, or disturbed thinking not adequately controlled by high-dose benzodiazepines.
Benzodiazepines
Class Summary
By acting on the GABA receptor, benzodiazepines produce a cross-tolerance to alcohol, thus reducing the hemodynamic and peripheral symptoms of alcohol withdrawal. The dose of benzodiazepine used should be based on the patient's symptoms and signs of alcohol withdrawal, including vital signs and amount of agitation. The longer-acting agents appear to be superior to the short-acting agents and may result in a smoother withdrawal course, with less breakthrough and rebound symptoms, although a risk of excessive sedation exists in certain patient groups (elderly patients, patients with liver failure) with the longer-acting agents.
For the treatment of minor or moderate alcohol withdrawal (in patients able to take oral therapy), symptom-triggered therapy (also known as prn therapy) has been shown in prospective, randomized, controlled trials to be superior to fixed-dose drug therapy, with less medication use and a shorter duration of therapy. The dosage of benzodiazepine needs to be individualized for each patient. The successful use of symptom-triggered therapy requires motivated and attentive nursing.
Drug regimens and doses recommended for minor withdrawal are not appropriate for patients with delirium tremens (DTs), who often require very high doses of these agents. For the treatment of DTs, benzodiazepines should be administered only parenterally.
For patients with severe withdrawal symptoms, including DTs, the benzodiazepine dose should be front loaded. That is, large doses should be administered intravenously at short intervals until the patient is calm but easily aroused. Then additional doses are administered only as needed. Most authorities recommend intravenous diazepam as the first choice for front-loading treatment of severe alcohol withdrawal. Because of its long serum half-life, and the even longer half-life of its active metabolite (desmethyldiazepam), additional doses may not be required once the patient is calm.
Longer-acting benzodiazepines (especially those with active metabolites) provide less fluctuation in blood levels and allow a more gradual physiologic taper. A review of 4 randomized controlled trials of front-loaded diazepam concluded that it produces a rapid calming effect with few untoward adverse effects in medically ill patients, required much less total dose of benzodiazepines, and resulted in a shorter duration of treatment, but may result in over sedation and respiratory depression in very elderly persons or those with severe liver disease. Aggressive treatment of severe alcohol withdrawal syndrome with diazepam may decrease the need for intubation.
Intravenous lorazepam, which has an intermediate serum half-life and no active metabolites, has been successfully used and may be preferable in elderly persons or in those with severe liver disease. Reports describe a higher incidence of late-onset alcohol withdrawal seizures with use of shorter-acting benzodiazepines such as oxazepam or lorazepam.
No controlled studies show superiority of shorter-acting agents (propofol, pentobarbital, lorazepam, and midazolam) over diazepam or other long-acting benzodiazepines.
If the IV route is not available, then intramuscular lorazepam (or midazolam as an alternative) is recommended. Diazepam and chlordiazepoxide should not be administered intramuscularly, because absorption is erratic.
The use of continuous IV infusions of short-acting benzodiazepines (lorazepam, midazolam) has been reported, but these infusions have required very large amounts of drug and are very expensive. No evidence indicates that continuous infusion therapy with short-acting agents leads to better outcomes than does oral or intravenous intermittent bolus therapy with long-acting agents.
Patients with DTs who do not respond to high doses of benzodiazepines may respond to the addition of phenobarbital, propofol, or possibly dexmedetomidine to the treatment regimen.
Chlordiazepoxide
Chlordiazepoxide depresses all levels of the central nervous system, including the limbic and reticular formations, possibly by increasing the activity of GABA, a major inhibitory neurotransmitter. The parenteral form is usually used initially. Because of limited experience with IV chlordiazepoxide for severe alcohol withdrawal and DTs, the use of IV diazepam or lorazepam is preferred.
Diazepam (Valium, Diastat)
Diazepam depresses all levels of central nervous system (eg, the limbic and reticular formations), possibly by increasing the activity of GABA. Individualize the dosage and increase cautiously to avoid adverse effects.
Because of its rapid onset, prolonged duration of effects, and high therapeutic index, diazepam is the drug of choice. Volumes of literature exist regarding the use of diazepam for ethanol withdrawal. The onset of action is within 5 minutes after IV administration. It has an active metabolite (desmethyldiazepam) that has a longer duration of action than that of diazepam.
Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a rapid onset of action and a medium duration of effect. By increasing the action of GABA, which is major inhibitory neurotransmitter in brain, it may depress all levels of the central nervous system, including the limbic and reticular formations. When the patient must be sedated for more than 24 hours, this medication is excellent, although it may require frequent redosing. Although diazepam is the preferred benzodiazepine, lorazepam is an excellent alternative and is especially useful in elderly persons and in those with severe hepatic dysfunction. It is commonly used prophylactically to prevent DTs. It can be given intramuscularly in patients lacking intravenous access.
General Anesthetics, Systemic
Ketamine (Ketalar)
Ketamine is an NMDA antagonist with less potential for respiratory depression. Two small studies have found that ketamine as an adjunct can reduce benzodiazepine requirements in patients with DTs.
Propofol (Diprivan)
Propofol, an IV anesthetic agent, is active on the glutamate and GABA-A receptors, similar to alcohol itself, whereas benzodiazepines are active only against the GABA receptors. Due to its rapid onset of hypnosis and anticonvulsant properties, propofol is an alternative treatment for intubated patients with delirium tremens (DTs) who are refractory to high-dose benzodiazepines. Advantages to its use are that it is easily titratable, with predictable effects, and has a rapid metabolic clearance.
Propofol is a phenolic compound unrelated to other types of anticonvulsants. It has general anesthetic properties when administered intravenously. Propofol IV produces rapid hypnosis, usually within 40 seconds. The effects are reversed within 30 minutes, following the discontinuation of infusion. Propofol has also been shown to have anticonvulsant properties.
Dexmedetomidine (Precedex)
Dexmedetomidine is an alpha-2-agonist that is used for sedation and anesthesia. It has been evaluated for use in alcohol withdrawal syndrome. Specifically, studies have shown that it can reduce the short-term benzodiazepine requirement and can provide sedation without respiratory depression. However, it can cause hypotension and bradycardia. Keep in mind, it does not target the underlying mechanism of alcohol withdrawal (GABA receptors), so it does not prevent the progression of alcohol withdrawal syndrome.
Barbiturates
Class Summary
These agents have direct effects on the benzodiazepine ̶ GABA-A ̶ chloride receptor complex in enhancing chloride flux. Barbiturates may be useful in patients refractory to benzodiazepines. Respiratory depression is common at large doses. Ventilatory support may be required.
Phenobarbital
Phenobarbital has direct effects on the benzodiazepine-GABA-A-chloride receptor complex in enhancing chloride flux. It may be useful in patients refractory to benzodiazepines. The drug exhibits anticonvulsant properties in anesthetic doses. Because a barbiturate-induced respiratory depression may occur, especially after previous benzodiazepine therapy, early mechanical ventilation should be considered.
Pentobarbital (Nembutal)
Pentobarbital is a short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties and can produce all levels of central nervous system mood alteration.
Vitamins and Nutrients
Class Summary
These agents are used to treat the hypoglycemia and nutrient and electrolyte deficiencies associated with delirium tremens (DTs). Alcoholics usually are deficient in thiamine, which functions as a cofactor for a number of important enzymes, such as pyruvate dehydrogenase, transketolase, and alpha-ketoglutarate dehydrogenase. Deficiency leads to Wernicke encephalopathy, peripheral neuropathy, cardiomyopathy, and metabolic acidosis.
Alcoholics often are also magnesium deficient, due to poor nutritional status and malabsorption. Magnesium stabilizes membranes, helps in the maintenance of potassium and calcium homeostasis, and may protect against seizures and arrhythmias.
Patients suffering from alcoholism may also develop hypoglycemia, due to malnutrition and poor glycogen stores. Additionally, gluconeogenesis is impaired because of a relative reduced redox state resulting from alcohol metabolism, which uses NAD+ as a cofactor for alcohol dehydrogenase and aldehyde dehydrogenase. The relative excess of NADH shifts the pyruvate-to-lactate ratio toward lactate, decreasing the substrate for gluconeogenesis.
Dextrose (D-Glucose)
Dextrose is a monosaccharide absorbed from the intestine and distributed, stored, and used by tissues. Parenterally injected dextrose is used in patients who are unable to obtain adequate oral intake. Direct oral absorption results in a rapid increase of blood glucose concentrations. Dextrose is effective in small doses; there is no evidence of toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake, with minimal fluid volume. Use 1 ampule of 50 mL of a 50% glucose solution (25 g).
Thiamine (Vitamin B-1)
This is used to treat thiamine deficiency, including Wernicke encephalopathy.
Folic acid (Folacin-800)
Dietary deficiency of folic acid is common in alcoholics. Folic acid is an important cofactor for enzymes used in the production of red blood cells.
Magnesium sulfate
Magnesium sulfate is used to treat and prevent seizures. It decreases the amount of acetylcholine liberated at the endplate by the motor nerve impulse. The drug blocks neuromuscular transmission associated with seizure activity. Magnesium also exercises central nervous system depressant effects by blocking the NMDA receptor. Monitor patients carefully; large doses of magnesium sulfate may cause respiratory depression, hyporeflexia, and bradycardia. Infusion should be discontinued if reflexes are absent or if magnesium levels exceed 6-8 mEq/L. Calcium chloride, 10 mL IV of a 10% solution, can be given as an antidote for clinically significant hypermagnesemia.
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Average annual deaths from alcohol.
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Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar). The CIWA-Ar is not copyrighted and may be reproduced freely. This assessment for monitoring withdrawal symptoms requires approximately 5 minutes to administer. The maximum score is 67 (see instrument). Patients scoring less than 10 do not usually need additional medication for withdrawal. From Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). British Journal of Addiction 1989;84:1353-1357.
