eMedicine Specialties > Emergency Medicine > Toxicology

Withdrawal Syndromes: Treatment & Medication

Author: Nathanael J McKeown, DO, Assistant Professor, Oregon Health and Science University; Medical Toxicologist, Oregon Poison Center; Attending Physician, Emergency Medicine, Portland Veteran Affairs Medical Center, Oregon Health and Science University
Coauthor(s): Patrick L West, MD, Clinical Instructor, Medical Toxicology Fellow, Department of Emergency Medicine, Oregon Health and Sciences University; Staff Physician, Department of Emergency Medicine, Portland Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Oct 27, 2009

Treatment

Prehospital Care

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

Emergency Department Care

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

• Treatment goals for ethanol or sedative-hypnotic withdrawal are as follows:
  • Stabilization of the patient's condition and prevention of syndrome progression
  • Treatment of withdrawal by substituting sedative medications
  • Determination of underlying medical problems and initiation of appropriate treatments
  • Appropriate disposition for ongoing care and addiction treatment
• If bedside glucose testing reveals hypoglycemia, glucose given as dextrose 50% in water (D50W) 25-50 mL is indicated. Concurrent administration of thiamine 100 mg IV is also indicated.
• Alcohol withdrawal seizures are typically brief and followed by a brief postictal period. The occurrence of more than 3 seizures or status epilepticus is rare and mandates further investigation.
  • Most alcohol withdrawal seizures are self-terminating; however, if prolonged, they are usually quickly terminated with benzodiazepines (eg, diazepam, lorazepam). Lorazepam is preferred because it has a long redistribution time that enables it to have prolonged effectiveness, protecting the patient from recurrent seizures. Lorazepam is less dependent on hepatic metabolism than other benzodiazepines, and hepatic function may be impaired in chronic alcoholics.
  • Occurrence of seizures should prompt bedside glucose determination.
• Patients presenting in mild alcohol withdrawal may be treated on an outpatient basis, provided that no underlying conditions require inpatient treatment.
  • Various regimens are described for outpatient management of alcohol withdrawal syndrome, but the simplest involve administering benzodiazepines with a short half-life and few metabolites (eg, oxazepam) to prevent the accumulation of sedating compounds. This drug is initially administered frequently and in higher doses, with gradual lengthening of the dosing interval and reduction of the dose over 1 week.
  • Patients must be reliable enough to adjust their own medications, and they must be able to tolerate oral medications.
  • Low doses of clonidine (eg, 0.1-0.2 mg PO tid) can help reverse central adrenergic discharge, thus relieving tachycardia, hypertension, tachypnea, tremor, and (possibly) some craving for alcohol.
  • The use of beta-blockers to diminish tachycardia, hypertension, and perhaps anxiety has been described and are occasionally useful; however, their effects mask the warning signs of autonomic hyperactivity if the patient develops DT.
• Patients presenting with moderate or severe alcohol withdrawal and DT require inpatient treatment and consideration of ICU admission. Initial emergency care includes the following steps:
  • The patient should be placed in a quiet room with low lighting.
  • Physical restraints may be applied to prevent physical injury pending adequate sedation.
  • In severe withdrawal, abnormalities of fluid, electrolytes, and nutrition are common. The patient's blood chemistry guides appropriate and adequate fluid replacement.
  • Compared with mild withdrawal, larger doses of substitute medications, as outlined below, are required to treat withdrawal.
• Sedative-hypnotic drugs are the primary agents for treatment of alcohol withdrawal syndrome because they are cross-tolerant drugs that modulate GABA functions. These medications commonly include benzodiazepines, barbiturates, propofol, and (in rare cases) ethanol.⁵ Clomethiazole and GHB are used in Europe as substitute medications for alcohol withdrawal syndrome. They are currently not available in the United States for the treatment of alcohol-withdrawal syndrome.
  • No evidence suggests that one sedative-hypnotic is more effective than another, but benzodiazepines have fewer adverse effects.
  • Benzodiazepines are the mainstay of therapy in the United States and are the primary agents used as substitutes and cross-tolerant medications for alcohol, sedative-hypnotic, or GHB withdrawal. They substitute for the GABA-modulating effects of alcohol and other drugs and are extremely safe and effective.
  • Benzodiazepines can be administered by using fixed-schedule or symptom-triggered regimens with or without loading. The efficacy profile is better with symptom-triggered therapy than with fixed-schedule dosing in patients admitted for detoxification but not necessarily for the treatment of DT.
  • The use of intravenous drugs allows immediate assessment of treatment adequacy compared with the lag time associated with absorption of oral medications. This is a particularly useful factor when using symptom-triggered therapy.
  • The Clinical Institute Withdrawal of Alcohol Scale, Revised (CIWA-Ar) has been validated and is used for medication administration in symptom-triggered therapy.
  • The various benzodiazepines have similar efficacies in treating alcohol withdrawal syndrome, though one may choose one drug over another on the basis of the route of administration, onset of effects on agitation, elimination half-life, active metabolites, and/or duration of effects. Typically, a loading dose is given to achieve light sedation, followed by maintenance medication. The amount of medication required to achieve an adequate loading dose varies with the severity of withdrawal.
    • Lorazepam can be administered intravenously, intramuscularly, or orally. Lorazepam provides a long duration of seizure control because of its slow redistribution. It may have decreased risk of sedation among those with liver disease because of its short half-life and absence of active metabolites. The dosing is 1-4 mg every 5-15 minutes until adequate control of agitation is achieved. Large and rapid doses of lorazepam may cause cardiovascular toxicity due to propylene glycol, the diluent.
    • Diazepam can be administered intravenously, orally, or PR. Diazepam rapidly controls agitation because of its rapid distribution secondary to its high lipid solubility. However, it has a long duration of action. Its active metabolites help smooth the course of withdrawal and limit breakthrough symptoms; however, prolonged sedation is a risk. Diazepam is initially given at a dose of 5 mg IV. The drug is repeated at 5-20 mg per dose every 5-15 minutes until adequate control of agitation is achieved. After agitation is controlled, an hourly dose is given as needed to maintain light somnolence.
    • Total dosing of intravenous diazepam should not routinely exceed 100 mg/h or 250 mg in 8 hours. Total dosing of intravenous lorazepam should not routinely exceed 20 mg/h or 50 mg in 8 hours.
    • Short-acting agents have a higher incidence of rebound symptoms. Short-acting benzodiazepines, such as oxazepam and midazolam, must be tapered carefully to avoid breakthrough symptoms and seizures.
    • Intermittent intravenous administration of long-acting benzodiazepines and continuous intravenous infusion of short-acting benzodiazepines is effective and acceptable.
  • In cases not responding to massive doses of benzodiazepines, intravenous infusion of propofol or intravenous boluses of barbiturates (phenobarbital and pentobarbital) should be added as second-line GABA modulators.⁶ This treatment is typically effective as the drugs act on different sets of GABA receptors. Propofol also modulates glutamate (NMDA) receptors.
  • Neuroleptics are not used as primary agents because studies have demonstrated the superior efficacy of sedative-hypnotics in reducing duration of alcohol withdrawal syndrome and associated mortality.
  • In a severely agitated patient, neuroleptics such as haloperidol 5 mg IV or IM may be added to sedative-hypnotic agents as an adjunctive therapy and repeated with caution in 30-60 minutes if needed to control agitation. Caution must be taken because haloperidol has been known to decrease the seizure threshold as well as prolong the QT interval.
  • Several medications are reported to be helpful adjuncts to benzodiazepines and other GABA modulators (barbiturates⁷ and propofol⁸ ) in the treatment of refractory alcohol-withdrawal syndrome, but they should never be used as a monotherapy. These include haloperidol, carbamazepine, valproic acid, gabapentin, clonidine, and beta-blockers (atenolol).⁹
• 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.¹⁰
• Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone 20-35 mg/d or buprenorphine 4-16 mg/d, and then tapered over days to weeks. Clonidine 0.1-0.2 mg every 4-8 hours also decreases the severity of symptoms. Long-acting benzodiazepines can be added to control insomnia and muscle cramps.
• Stimulant-withdrawal syndrome is treated by observation alone and does not require any specific medications.

Medication

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

Many regimens for treating withdrawal involve cross-tolerant medications titrated to the severity of the withdrawal by gradually decreasing the dose and by increasing the dosing interval to wean the patient from the original substance. For alcohol withdrawal syndrome, these regimens include benzodiazepines, barbiturates,⁷ propofol, and ethanol,^11,5 and clomethiazole (in Europe). Tegretol, valproic acid, gabapentin, gamma-hydroxybutyrate, propranolol (Inderal), and clonidine all have been used as an adjunctive therapy and are effective, though they should not be used as monotherapy.

Benzodiazepines

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

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 (Serax)

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 (Librium)

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.

Midazolam (Versed)

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

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)

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)

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

Vitamins

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

Thiamine (Vitamin B-1; Thiamilate)

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, AquaMEPHYTON)

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

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 (Barbita, Luminal)

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

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

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

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

Propofol

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

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