Medication Summary
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.
Benzodiazepines
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.
Cardiovascular agents
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.
Vitamins
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.
Barbiturate
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.
Pharmacologic antidotes
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.
Electrolyte Replacement
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.
Anesthetics
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.
Psychiatry Agents, Other
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.
