eMedicine Specialties > Emergency Medicine > Toxicology

Withdrawal Syndromes

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

Introduction

Background

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 related information, see Medscape's Addiction Resource Center.

Pathophysiology

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 GABA_A 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 GABA_A 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.

In opioid or benzodiazepine addiction, chronic stimulation of specific receptors for these drugs suppresses endogenous production of neurotransmitters (endorphins or GABA, respectively). Removal of exogenous drug allows unopposed counter-regulatory effects to become clinically apparent. When the exogenous drug is precipitously removed, inadequate production of endogenous transmitters and the unopposed stimulation by counter-regulatory transmitters results in the characteristic clinical picture of withdrawal. The nature of the excess counter-regulatory transmitter dictates the characteristics of the withdrawal. The time it takes to restore homeostasis by synthesis of endogenous transmitters determines the time course of withdrawal.

Frequency

United States

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. Approximately 15.2 million Americans are alcohol dependent. 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 and fluctuates with the supply of drugs and social trends. In recent estimates, approximately 3.9 million Americans are dependent on illicit drugs.

Mortality/Morbidity

The mortality rate from severe alcohol withdrawal and 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.

• 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.
• Opiate withdrawal is uncomfortable but usually mild in terms of derangement of vital signs. Fatalities are very rare.
• 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.

Sex

Chronic alcoholism and withdrawal are more common among men than women.

Age

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.

Clinical

History

In addition to documenting the presenting complaints, essential elements of history include type of drugs ingested over the long term, the duration of addiction, the time of last ingestion, the reason for the patient's cessation of the drug, alternative treatments used to relieve withdrawal symptoms, and previous withdrawal symptoms and their severity.

Serious comorbid conditions can be inciting events for reasons for cessation of alcohol and should be thoroughly investigated.

Obtaining a history of illicit drug and alcohol abuse is important and can assist with anticipation and treatment in patients admitted for reasons other than withdrawal (eg, myocardial infarction [MI], multiple trauma).

• Alcohol withdrawal
  • 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 (as listed below) is most clinically useful.
    • Mild withdrawal usually occurs within 24 hours of the last drink and is characterized by tremulousness (shakes), insomnia, anxiety, hyperreflexia, diaphoresis, mild autonomic hyperactivity, and GI upset.
    • Moderate withdrawal usually occurs 24-36 hours after the cessation of alcohol intake and includes intense anxiety, tremors, insomnia, and excessive adrenergic symptoms.
    • Severe withdrawal usually occurs more than 48 hours after a cessation or decrease in alcohol consumption. It is characterized by profound alteration of sensorium including disorientation, agitation, and hallucinations; along with severe autonomic hyperactivity including tremulousness, tachycardia, tachypnea, hyperthermia, and diaphoresis.
  • 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 DT.
  • Approximately 23-33% of patients with significant alcohol withdrawal have alcohol withdrawal seizures ("rum fits").
    • Seizures are usually brief, generalized, tonic-clonic in nature, and without an aura. They occur in a cluster of 1-3 seizures with a short postictal period. Partial seizures are not uncommon. In 30-50% of patients, the seizures progress to DT.
    • The incidence peaks 24 hours after the most recent alcohol ingestion.
    • Most seizures typically terminate spontaneously or are easily controlled with benzodiazepines.
    • Status epilepticus may occur in 3% of alcohol withdrawal seizures and should prompt an investigation for other causes, as people with alcoholism are prone to head injuries, chronic idiopathic epilepsy, and meningitis.
  • DT, the most intense sign of alcohol withdrawal, occurs 48-72 hours after the last drink.
    • DT includes all early and intermediate symptoms of alcohol withdrawal but with the additional feature of a profoundly altered sensorium (disorientation, agitation, and hallucination).
    • Severe autonomic derangements (including diaphoresis, tachycardia, tachypnea, and hyperthermia) are common.
    • DT may present without preceding seizures.
  • To blunt the effects of alcohol withdrawal, some patients may resort to ingesting other substances if they cannot obtain regular alcoholic beverages because of financial reasons.
    • Ingestion of isopropyl alcohol is common.
    • Other alcohols (eg, methanol, ethylene glycol) are rarely ingested.
    • Ingesting cough syrup containing large amounts of alcohol may cause inadvertent acetaminophen toxicity.
    • The following substances have a sufficient alcohol concentration to mitigate the effects of withdrawal: isopropyl alcohol, cough syrup, hand sanitizer, mouthwash, methanol, and ethylene glycol.
• Sedative-hypnotic withdrawal syndrome
  • Chronic use of benzodiazepines, barbiturates, and other sedatives or hypnotics produce withdrawal symptoms on discontinuation resembling those of alcohol withdrawal syndrome.
  • The morbidity/mortality is closely related to that of alcohol withdrawal syndrome.
  • Sedative-hypnotic withdrawal syndrome is characterized by pronounced psychomotor and autonomic dysfunctions.
  • Symptoms usually occur 2-10 days after abrupt discontinuation of the drug, depending on its half-life.
• GHB withdrawal syndrome²
  • GHB and its precursors (gamma-butyrolactone, 1,4'-butanediol) are reported to induce tolerance and produce dependence.
  • These drugs are most commonly abused by young adolescents in dance clubs and rave parties.
  • Many users have mild withdrawal symptoms on discontinuing the drug. The symptoms resemble those of sedative-hypnotic withdrawal syndrome and are characterized by mild and brief autonomic instability with prolonged psychotic symptoms.
  • Severe withdrawal is noted among people who use the drug chronically and heavily. Their symptoms are similar to those of alcohol withdrawal syndrome, but delirium occurs earlier, seizures (7%) and rhabdomyolysis (7%) rarely occur.³
• Opioid withdrawal
  • 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 flu-like illness. The syndrome is characterized by rhinorrhea, sneezing, yawning, lacrimation, abdominal cramping, leg cramping, piloerection (gooseflesh), nausea, vomiting, diarrhea, and dilated pupils.
  • 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.
  • Persons with long-term intravenous (IV) drug abuse are susceptible to a host of infectious problems, including but not limited to the following; endocarditis, septic emboli, osteomyelitis, septic arthritis, abscesses (ie, psoas, brain, and epidural), and viral hepatitis.
• Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome
  • In general, stimulant withdrawal does not directly cause life-threatening symptoms, seizures, or delirium.
  • This syndrome resembles severe depressive disorder.
    • Manifestations include dysphoria, excessive sleep, hunger, and severe psychomotor retardation, whereas vital functions are well preserved.
    • The patient is typically in deep sleep with normal vital signs, and he or she may have a history of crack-cocaine binging and similar episodes ("crashes") in the past. Patients may be so motivated to do nothing but sleep deeply that another cause for the patient's lack of responsiveness is suspected. In this case, a gradual full recovery and a negative workup would be expected.
    • Severe depressive symptoms may last up to 2 days, though mild ones may persists for up to 2 weeks.

Physical

Increased reliance on physical examination is inevitable 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
  • The central adrenergic storm that occurs during alcohol withdrawal results in hyperventilation, tachycardia, hypertension, tremor, hyperthermia, and diaphoresis.
  • Low-grade fever is common because of increased motor activity.
  • Hypothermia can be seen with Wernicke encephalopathy.
• Head and neck findings
  • Stigmata of chronic alcoholism (eg, flushed facies, vascular spider angiomata) may be present.
  • Paralysis of extraocular muscles and nystagmus may indicate Wernicke encephalopathy or other intracerebral processes. These findings are important because they represent an opportunity to diagnose a readily treatable condition.
  • Dentition is often neglected and may be a source of infection.
  • Tongue lacerations may indicate previous seizures or other trauma. The tongue is also a reliable place to look for withdrawal tremors.
  • Determine if evidence of head and facial trauma (eg, signs of basilar skull fracture) is present as this represents a common opportunity for critical intervention.
• Chest findings in alcohol withdrawal
  • Tachypnea is expected during alcohol withdrawal, but dyspnea is not expected.
  • Rib fractures are common in people with chronic alcoholism; recent rib fractures may be associated with pneumothorax.
  • Note signs of pneumonia (eg, cough, sputum production, fever, localized wheezing, consolidation, respiratory distress).
  • Kussmaul respiration may represent underlying metabolic acidosis. Common causes in the setting of alcohol withdrawal include alcoholic ketoacidosis (AKA) and ingestion of alcohols or medications that result in metabolic acidosis (eg, methanol, ethylene glycol, salicylate). Consumption of rubbing alcohol (isopropyl alcohol) does not cause metabolic acidosis or Kussmaul respiration.
• Chest findings in opiate withdrawal
  • Patients with opiate addiction are at high risk for HIV infection and are susceptible to AIDS-related pneumonias, particularly those due to Pneumocystis carinii and Mycobacterium tuberculosis.
  • Note symptoms and physical evidence of cough, hemoptysis, fever, and tachypnea.
• Cardiac findings
  • Tachycardia and hypertension are common and expected during alcohol withdrawal.
  • A murmur (particularly a right-sided tricuspid or pulmonic murmur) and fever in a patient with a history of intravenous drug abuse is worrisome because of the possibility of endocarditis. Blood cultures and an echocardiography are indicated in this circumstance to determine if infective endocarditis is present.
• Abdominal findings
  • Stigmata of chronic alcoholism include caput medusae, ascites, and hepatomegaly. Splenomegaly may be detected in patients with cirrhosis.
  • Diffuse abdominal tenderness in a patient with ascites may indicate spontaneous bacterial peritonitis, but other causes of peritonitis (eg, ruptured appendicitis) can occur as well. Peritoneal findings should not be ascribed to opiate withdrawal, though significant gastrointestinal distress with cramping and vomiting are common.
  • Rectal examination is indicated to look for evidence of GI bleeding.
  • Opiate use suppresses peristalsis and commonly produces chronic constipation. During withdrawal, increased bowel sounds, abdominal cramping, vomiting, and diarrhea can be seen.
• Findings in the extremities
  • Examine the limbs and joints for evidence of trauma or joint infection.
  • Unexplained painful and limited hip movements in a patient with intravenous drug abuse and fever suggests psoas abscess.
• CNS findings
  • Alcohol withdrawal results in a progressive sequence of increasing anxiety, agitation, confusion, disorientation, visual and auditory hallucinations, seizures, dysphoria, panic, and potentially violent attacks on others.
  • Dysphoria due to opioid withdrawal may also promote negative reactions and possible violence in affected patients but are not associated with delirium.
  • Cranial-nerve deficits may indicate Wernicke encephalopathy (ocular nerve palsies), intracranial trauma, or bleeding.
  • Ataxia can be seen in Wernicke-Korsakoff syndrome.
  • Peripheral neuropathy is common in chronic alcoholism, but it is difficult to confirm in a minimally cooperative patient.
  • Focal neurologic deficits, other than those listed above, meningeal signs, and coma are not a part of the clinical picture of alcohol withdrawal and require further investigation.
• Skin findings
  • Spider angiomas, gynecomastia, and sparse pubic hair are common in persons with chronic alcoholism.
  • Patients with intravenous drug abuse have evidence of injections, such as tract marks, and they often have tattoos to mask these marks.
  • Piloerection and cutis anserina (goose bumps) are common during opiate withdrawal.

• Search for CME/CE on This Topic »

• Substance Abuse Center
• Drug Dependence and Abuse Overview
• Drug Dependence and Abuse Causes
• Drug Dependence and Abuse Symptoms
• Drug Dependence and Abuse Treatment

• Contemporary Considerations in Cranial-Base Surgery
• Information About ADRs Explored By Pharmacovigilance Approaches: A Qualitative Review of Studies on Antibiotics, SSRIs and NSAIDs
• A Qualitative Investigation of Long-term Zopiclone Use and Sleep Quality among Vietnam War Veterans with PTSD