DESCRIPTION

• Withdrawal is characterized by physical or psychological signs and symptoms that occur following discontinuation of a drug.
• This discussion covers withdrawal from alcohol, benzodiazepine, opioid, stimulant, and sedative-hypnotic classes of drugs.

PATHOPHYSIOLOGY

Alcohol and Sedative-Hypnotic Withdrawal

Chronic ethanol or sedative-hypnotic use produces downward regulation of inhibitory CNS receptors and a suppression of gamma-aminobutyric acid (GABA) production; withdrawal states are characterized by a relative GABA deficiency. Sedative-hypnotic withdrawal is caused by cessation of any of numerous compounds, including benzodiazepines (diazepam, chlordiazepoxide, clonazepam, lorazepam, and many others), intermediate-acting barbiturates (phenobarbital, pentobarbital, and many others), chloral hydrate, ethchlorvynol, glutethimide, meprobamate, and methaqualone and gammahydroxybutyric acid (GHB).

Opioid Withdrawal

Chronic opioid use produces downward regulation of CNS opioid receptors. Substances capable of producing opioid withdrawal upon cessation include codeine, alphaprodine, buprenorphine, butorphanol, diamorphine, diphenoxylate, fentanyl, sufentanil, remifentanil, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, opium, oxycodone, oxymorphone, pentazocine, and propoxyphene.

Stimulant Withdrawal

Chronic stimulant use produces CNS dopaminergic excess; withdrawal states are characterized by a relative dopamine deficiency. Substances capable of producing stimulant withdrawal upon cessation include caffeine, nicotine, cocaine, amphetamines, methamphetamine, and phenylpropanolamine.

PREGNANCY AND LACTATION

• Neonatal withdrawal syndromes have been reported in infants born to mothers addicted to opioids, stimulants, ethanol, or sedative hypnotic agents.

CAUSES

• Withdrawal syndrome may result from abrupt cessation or from decreasing the dosage of a drug.
• Administration of an antagonist or partial antagonist may precipitate withdrawal symptoms in addicted patients.

Section Outline:

• DESCRIPTION
• PATHOPHYSIOLOGY
  • Alcohol and Sedative-Hypnotic Withdrawal
  • Opioid Withdrawal
  • Stimulant Withdrawal
• PREGNANCY AND LACTATION
• CAUSES

DIFFERENTIAL DIAGNOSIS

Further information on each poison is available in SECTION IV, Chemical and Biological Agents.

Alcohol or Sedative-Hypnotic Withdrawal

• Toxicologic causes of symptoms that resemble alcohol or sedative-hypnotic withdrawal include neuroleptic malignant syndrome, malignant hyperthermia, serotonin syndrome, monoamine oxidase inhibitor toxicity, sympathomimetic toxicity, anticholinergic toxicity, clonidine withdrawal, theophylline toxicity, thyroid hormone toxicity, and nicotine toxicity.
• Nontoxicologic causes of symptoms that resemble alcohol or sedative-hypnotic withdrawal include hyperthyroidism, pheochromocytoma, heat stroke, intracranial hemorrhage, cerebral vascular accident, intracranial infection, seizures, and acute or chronic psychosis.
• Withdrawal from sedative-hypnotic agents may be life threatening in elderly patients.

Stimulant Withdrawal

• Toxicologic causes of symptoms that resemble stimulant withdrawal include opioid toxicity, sedative-hypnotic toxicity, and toxicity caused by agents capable of producing CNS depression.
• Nontoxicologic causes of symptoms that resemble stimulant withdrawal include intracranial infection, cerebral vascular accident, intracranial hemorrhage, acute depression, and seizure with postictal period.

SIGNS AND SYMPTOMS

Withdrawal syndromes generally result in findings that are the opposite of the usual drug effects.

Vital Signs

Alcohol or sedative-hypnotic withdrawal produces low-grade fever, tachycardia, and hypertension.

HEENT

• Sneezing, yawning, rhinorrhea, and lacrimation are common in cases of opioid withdrawal.
• Dilated pupils are common in cases of alcohol or sedative-hypnotic, opioid, or stimulant withdrawal.

Dermatologic

• Diaphoresis is common in cases of alcohol or sedative-hypnotic withdrawal.
• Piloerection is common in cases of opioid withdrawal.

Cardiovascular

• Tachycardia and hypertension are the hallmarks of both alcohol and sedative-hypnotic withdrawal.
• Tachycardia related to agitation and dehydration may accompany opioid withdrawal.
• Cocaine withdrawal may produce ST segment elevation.

Gastrointestinal

• Nausea, vomiting, abdominal cramping, increased bowel sounds, and diarrhea are common in cases of opioid withdrawal
• Nausea and vomiting also may accompany ethanol and sedative-hypnotic withdrawal.

Fluids and Electrolytes

• Dehydration with hypokalemic metabolic alkalosis may accompany severe opioid withdrawal.
• In cases of alcohol or sedative-hypnotic withdrawal, seizures may cause lactic acidosis.

Musculoskeletal

• In cases of alcohol or sedative-hypnotic withdrawal, seizures can cause rhabdomyolysis.
• Opioid withdrawal commonly produces myalgias.

Neurologic

• Seizures are common in cases of alcohol or sedative-hypnotic withdrawal.
• Seizures may be associated with opioid withdrawal in neonates born to mothers addicted to opioids, but such seizures are not associated with isolated opioid withdrawal in adults.
• Delirium tremens is the most severe form of alcohol withdrawal and is characterized by hyperthermia, tachycardia, hypertension, altered mental status, persistent hallucinations, and seizures.
• Stimulant withdrawal may produce generalized fatigue, dysphoria, irritability, and depression.
• Although stimulant withdrawal can cause extreme sleepiness that responds to verbal and tactile stimulation, it does not produce true alteration of mental status.

PROCEDURES AND LABORATORY TESTS

• No test may be needed in asymptomatic patients.
• Serum electrolytes, BUN, creatinine, and glucose levels should be obtained to evaluate other causes of seizures and altered mental status.
• Serum liver enzymes, coagulation studies, and creatine kinase may be elevated in patients with hyperthermia or agitation, or in patients with liver injury from previous ethanol abuse.
• Head CT, lumbar puncture, and toxicology studies should be performed as needed to evaluate other causes of seizure or altered mental status.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
  • Alcohol or Sedative-Hypnotic Withdrawal
  • Stimulant Withdrawal
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Gastrointestinal
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS

Supportive care with appropriate airway management is vital, with specific treatment initiated while supportive care continues.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Cause or management of withdrawal is unclear.
• Drug interaction or underlying disease presents unusual problems.

Admission Considerations

Patients in withdrawal from ethanol or sedative-hypnotics should be admitted.

DECONTAMINATION

Decontamination is usually unnecessary for a patient experiencing withdrawal, unless the patient has self-medicated in an attempt to prevent or treat withdrawal.

ADJUNCTIVE TREATMENT

• Because patients experiencing any type of withdrawal are at risk for dehydration, intravenous fluids should be administered to maintain a urine output of 1 to 2 ml/kg/h.
• Patients experiencing withdrawal may be a danger to themselves or others and should be placed in a protected, monitored setting.

Alcohol or Sedative-Hypnotic Withdrawal

• A long-acting sedative that will be eliminated slowly should be provided in the treatment of tachycardia, hypertension, hyperthermia, agitation, tremor, altered mental status, or seizure.
• A long-acting benzodiazepine is the drug of choice; although any benzodiazepine will be effective in large doses, short-acting agents should be avoided.
  • Diazepam. Adult dosage is 5 to 10 mg by intravenous push, repeated every 5 to 10 minutes as needed; pediatric dosage is 0.2 to 0.5 mg/kg, up to 5 to 10 mg by intravenous push, repeated every 5 to 10 minutes as needed.
  • Lorazepam. Adult dosage is 1 to 2 mg by intravenous push, repeated every 5 to 10 minutes as needed; pediatric dose is 0.05 mg/kg by intravenous push, repeated every 5 to 10 minutes as needed.
• Phenobarbital is also effective in cases of alcohol or sedative-hypnotic withdrawal.

Opioid Withdrawal

• Clonidine has been used to ameliorate the symptoms of narcotic withdrawal; the adult dose of 0.1 to 0.2 mg orally every 4 to 6 hours until withdrawal symptoms resolve, usually in 7 to 10 days.
• Paregoric is the drug of choice for symptoms of neonatal opioid withdrawal, which can be life threatening
  • Dosage is 0.2 ml orally every 3 to 4 hours, increased by 0.05 ml every dose until symptoms are controlled and tapered over 7 to 10 days.
  • Side effects include sedation and respiratory depression.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
• ADJUNCTIVE TREATMENT
  • Alcohol or Sedative-Hypnotic Withdrawal
  • Opioid Withdrawal

• Ethanol withdrawal begins 8 to 36 hours following discontinuation or decrease of ethanol intake, peaks within 36 to 72 hours, and subsides over 1 week. Death occurs occasionally and is usually associated with significant comorbid states.
• The course of sedative-hypnotic withdrawal varies substantially with the specific agent, but usually begins within 1 to 2 days following cessation of drug or decrease in dosage, peaks within 36 to 72 hours, and subsides over 1 week; withdrawal may, however, occur up to 1 to 2 weeks following discontinuation or decreasing drug administration. Death occurs occasionally and is usually associated with significant comorbid states.
• The course of opioid withdrawal varies substantially with the specific agent, but usually begins within 8 to 48 hours following discontinuation or decrease of drug administration, peaks within 36 to 72 hours, and subsides over 1 week. Opiate withdrawal is not considered life threatening in adults. Neonatal withdrawal seizures have resulted in fatalities.
• Stimulant withdrawal usually begins within 1 to 5 days following discontinuation or decrease of drug administration, peaks within the first 1 to 3 days, and subsides gradually over 1 to 3 weeks. Stimulant withdrawal is not life threatening.

• It is important to determine whether drug toxicity rather than withdrawal may be the cause of symptoms. For example, the toxic effects of a stimulant may be similar to ethanol withdrawal.
• In chronic alcoholic patients, alcohol withdrawal symptoms may occur at declining blood ethanol levels that are still in the referenced range for intoxication.
• Withdrawal does not require abstinence but may occur after decreasing the dose.
• Discontinuation of long-acting sedative hypnotic agents may produce signs and symptoms of withdrawal as late as 1 to 2 weeks following the last use.
• Neuroleptic agents, clonidine, and beta-blockers may be used as adjunctive therapy, but they are not useful for primary treatment of ethanol or sedative-hypnotic withdrawal.
• Phenytoin is not useful in treating withdrawal seizures.
• Patients may claim to be in withdrawal in an effort to gain access to drugs for abuse; this claim is especially common for opioid abusers.

Poisoning by analgesics, antipyretics, and antirheumatics: opiates and related narcotics.

See Also: SECTION IV, Cocaine Coma chapter.

RECOMMENDED READING

Mayo-Smith MF, et al. The pharmacologic management of alcohol withdrawal. JAMA 1997;278:144-151.

Author: Edwin K. Kuffner

Reviewers: Kennon Heard and Richard C. Dart