INTRODUCTION	Section 2 of 10
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Background: Many illicit drugs and chemicals, including medications, produce withdrawal symptoms when their use is discontinued. This article primarily focuses on withdrawal from ethanol, opioids, other sedatives or hypnotics, stimulants, and gamma-hydroxybutyrate (GHB).

Pathophysiology: 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.

Withdrawal occurs when drug use is decreased or discontinued, though adaptive changes persist. The mechanism of ethanol intoxication and withdrawal is complex. It may involve interaction with membrane proteins, but most of the clinical effects can be explained by interaction of ethanol with various neurotransmitters and neuroreceptors in the brain, including those interacting with gamma-aminobutyric acid (GABA), glutamate (NMDA), and opiates. 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), and activation of these receptors enhances the effects of GABA. In response, the chloride channels open, causing chloride influx, which hyperpolarizes the cell. The decrease in the firing rate of neurons produces sedation. Long-term use of ethanol subsequently results in downregulation of GABA(A) receptor function, that is, a compensatory decrease of the GABA-A receptor response to GABA, an adaptation that causes tolerance. Because of the chronic suppression of excitatory neurotransmission, the brain increases synthesis of excitatory neurotransmitters, such as norepinephrine, serotonin, and dopamine. This response accounts for withdrawal symptoms, such as delirium tremens (DT), seizures, hallucinations, tachycardia, hypertension, hyperventilation, and fever.

Ethanol also inhibits excitatory neurons. It inhibits 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 or sensitivity 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.

Direct measurements of central norepinephrine and its metabolites (eg, methoxyhydroxyphenylglycol [MHPG]) during alcohol withdrawal show that levels are uniformly elevated in proportion to the severity of withdrawal. Likewise, 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 counterregulatory effects to become clinically apparent. When the exogenous drug is precipitously removed, inadequate production of endogenous transmitters and the unopposed stimulation by counterregulatory transmitters results in the characteristic clinical picture of withdrawal. The nature of the excess counterregulatory 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:

• In the US: An estimated 5-10% of the population has alcoholism. Although not all persons with chronic alcoholism have clinically apparent alcohol withdrawal on their cessation of alcohol consumption, a substantial proportion is at risk for this syndrome. In recent reports, investigators estimate that approximately 8.2 million Americans are alcohol dependent, and approximately 1.2 million hospital admissions are for problems related to alcohol abuse. As many as 5% of these patients develop 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 3.5 million Americans are dependent on illicit drugs.

• Internationally: Alcohol and drug abuse are worldwide problems. Demographic information varies, though data suggest an increased prevalence in developed nations.

Mortality/Morbidity: The mortality rate from pure, full-blown alcohol withdrawal and DT historically reached 20%. However, in the last 30 years, early recognition and improved treatments have 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 (short of full-blown DT) is negligible and related to underlying conditions rather than alcohol withdrawal.

• Opiate withdrawal is uncomfortable but usually mild in terms of derangement of vital signs. Fatalities are 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. However, the asynchronous nature of cocaine withdrawal may result in cardiac ischemia several days after the last ingestion, when sedation and drug craving manifest.

• Sedative or hypnotic withdrawal shares many of the features of alcohol withdrawal, namely, agitation, disorientation, seizures, sympathetic hyperactivity, hypertension, insomnia, anxiety, and anorexia.

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

Age:

• Alcohol-withdrawal syndrome is rare in persons younger than 20 years because of their limited access to alcohol and because of the duration of alcohol abuse required to produce tolerance and potential withdrawal. DT is rare in persons younger than 30 years.

• Cocaine or amphetamine addiction and tolerance occur quickly, and these drugs are available to adolescents. As a consequence, withdrawal from these drugs may be seen in adolescents as well as adults.

• As with cocaine addiction, opiate addiction occurs rapidly, and withdrawal may be seen from late adolescence through adulthood.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: If patients are in an advanced stage of alcohol withdrawal, their history may be unobtainable, and their friends or family may be the only sources of background information.

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, alternative treatments used to relieve withdrawal symptoms, the reason for the patient's stopping the drug, previous withdrawal symptoms, other associated symptoms, coexisting medical conditions, and current therapeutic medications.

Obtaining a history of illicit-drug and alcohol abuse is important in patients admitted for reasons other than withdrawal (eg, myocardial infarction [MI], multiple trauma), namely, those in whom withdrawal then can be anticipated and promptly treated in the inpatient setting. Failure to obtain this history can lead to confusion and incorrect treatment if unexpected alcohol or drug withdrawal develops several days into the patient's hospital course.

• 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 classic hangover is likely an early and mild form of alcohol withdrawal, as the symptoms are promptly relieved by ingesting additional alcohol known as an "eye-opener" drink.

• The hallmark of alcohol withdrawal is a continuum of signs and symptoms ranging from simple shakes to DT. The spectrum varies greatly, and symptoms overlap in time and duration. Therefore, defining a constellation of manifestations ranging from mild or minor to severe or major (as listed below) is most clinically useful.
  • Mild or minor alcohol withdrawal usually occurs within 24 hours of the last drink and is characterized by tremulousness (shakes), insomnia, anxiety, hyperreflexia, diaphoresis, minor autonomic hyperactivity, and GI upset.

  • Moderate or intermediate alcohol withdrawal usually occurs 24-36 hours after the cessation of alcohol intake. This is an intermediate stage along the continuum. Its manifestations include intense anxiety, tremors, insomnia, and excessive adrenergic symptoms. Patients maintain a clear sensorium even during hallucinations.

  • Severe or major alcohol 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 usually occurs 24 hours after the last drink and may last for about 24 hours.

  • Symptoms consists of persecutory, auditory, or (most commonly) visual and tactile hallucinations; however, the patient's sensorium is otherwise clear. In the early stage, the patients recognize 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 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 terminate spontaneously or are easily controlled with benzodiazepine.

• Status epilepticus may occur in 3% of alcohol-withdrawal seizures.
  • This occurrence should prompt an investigation for other causes, as people with alcoholism are prone to head injuries, chronic idiopathic epilepsy, and meningitis.

  • Indications for investigation of the seizure by means of CT and lumbar puncture or EEG include seizures that occur after the onset of delirium, focal seizures, multiple seizures, high temperature or meningismus, focal neurologic deficits, or associated head trauma.

• 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).

  • Tonic-clonic seizure may precede DT. However, most of the time, DT develops without seizures.

  • Severe autonomic derangements (including diaphoresis, tachycardia, tachypnea, and hyperthermia) are common.

  • Physical and chemical restraints may be required to protect the patient and his or her caregivers.

  • Clinically significant dehydration is possible because of intense diaphoresis, hyperventilation, and restricted oral intake.

• If the patient can provide a clear history, determine why he or she chose to stop drinking alcohol at this time.
  • Patients often report symptoms suggestive of pancreatitis, peptic ulcer, gastritis, GI hemorrhage, or a wide variety of other complaints that require further investigation.

  • Because people with chronic alcoholism are relatively immunocompromised and malnourished and because they are more commonly exposed to infectious agents (eg, tuberculosis) than others, they may have symptoms of pneumonia, meningitis, bacterial peritonitis, or other diseases.

  • People with chronic alcoholism have an incidence of trauma higher than that of the general population. Overlooking chronic subdural hematoma (SDH) in this population is common, as these patients have relative coagulopathy, they have increased cerebral atrophy for their age, and their conditions are difficult to assess because of inebriation. Progression of or rebleeding from a chronic SDH may cause cessation of alcohol intake.

  • People with chronic alcoholism frequently stop drinking because they simply are too ill to continue obtaining and ingesting alcohol. Physicians must consider and discover their underlying medical illnesses, which ultimately may prove to be more serious than the alcohol withdrawal itself.

• 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) are rarely ingested.

  • Acetaminophen toxicity is possible with the ingestion of cough syrups containing large quantities of alcohol.

  • Toothpaste does not contain alcohol. The following substances have a sufficient alcohol concentration to mitigate the effects of withdrawal: isopropyl alcohol, cough syrup (may have associated acetaminophen toxicity), mouthwash, methanol, and ethylene glycol.

• Determine what self-treatment occurred before the patient's visit to the ED.

• 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.
  • Opioid withdrawal syndrome may resemble severe flu. 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 symptoms reach peak concentrations within 36-72 and 72-96 h, respectively, and have durations of action of 7-10 and at least 14 d, respectively.

• Persons with long-term intravenous (IV) drug abuse are susceptible to a host of infectious problems, including the following:
  • Endocarditis

  • Septic emboli

  • Osteomyelitis

  • Septic arthritis

  • Psoas abscess

  • Brain and epidural abscess

  • Viral hepatitis

  • Skin infections including that due to methicillin-resistant Staphylococcus aureus (MRSA)

  • All infections commonly associated with HIV, including tuberculosis

  • Uncommon infections transmitted by means of IV drug use (tetanus, malaria, syphilis)

• Given the multitude of infectious complications that can occur in this population, universal precautions are indicated.

• Elicit a history of the following symptoms:
  • Fever

  • Night sweats

  • Weight loss

  • Headache

  • Back or joint pain, particularly hip pain

  • Numbness or weakness

  • Visual changes

  • Cough

  • Dyspnea

  • Chest or abdominal pain

• 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.

  • Severe depressive symptoms may last up to 2 d, though mild ones may persists for up to 2 wk.

  • Watch for symptoms of sedative or hypnotic, opioid or alcohol withdrawal during the observation period, as many patients may also be dependent on these drugs ("downers").

• GHB-withdrawal syndrome

• GHB and its precursors (gamma-butyrolactone, 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 but 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 early and seizures do not occur.

• 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.

• 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.

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 complete physical examination may have to be performed after immediate resuscitation, after the treatment of seizures, and/or after sedation for severe agitation, it must be completed as soon as possible to detect end-organ damage and underlying conditions.

• Head and neck findings

• Stigmata of chronic alcoholism (eg, parotid swelling, flushed facies, vascular spider angiomata) may be present.

• Dentition is often neglected and may be a source of infection.

• Paralysis of extraocular muscles and nystagmus may indicate Wernicke encephalopathy or other intracerebral processes.

• Evidence of recent hematemesis with blood in the pharynx or nares may be present.

• Note meningismus.

• Tongue lacerations may indicate previous seizures or other trauma.

• Determine if evidence of head and facial trauma (eg, signs of basilar skull fracture) is present.

• 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.

• Many people with chronic alcoholism also smoke heavily. Findings suggestive of chronic obstructive pulmonary disease (eg, barrel chest, diminished air entry, wheezing, cough, cyanosis) are common.

• Note signs of pneumonia (eg, cough, sputum production, fever, localized wheezing, consolidation, respiratory distress).

• Rales may result from ischemic heart disease and cardiogenic congestive heart failure (CHF), or they may result from high-output failure. Wet beriberi is associated with chronic thiamine deficiency— an entity, according to some evidence, that is often missed on clinical examination.

• 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 and 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 that due to Pneumocystis carinii and Mycobacterium tuberculosis.

• Note symptoms and physical evidence of cough, hemoptysis, fever, and tachypnea.

• Cardiac findings

• Tachycardia is common and expected during alcohol withdrawal.

• Any murmurs, rubs, and gallops should be noted, as usual.

• A murmur (particularly a right-sided tricuspid or pulmonic murmur) and fever in a patient with a history of IV 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 (acute fatty liver, an early sign, and small cirrhotic liver, a late sign). 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. Epigastric tenderness may reflect pancreatitis or peptic ulcer disease and gastritis.

• Rectal examination is indicated to look for evidence of GI bleeding. Testicular atrophy is common in people with chronic alcoholism.

• Opiate use suppresses peristalsis and commonly produces chronic constipation. During withdrawal, signs of increased peristalsis (eg, increased bowel sounds, abdominal cramping, vomiting, diarrhea) result. Do not ascribe peritoneal findings to opiate withdrawal.

• Findings in the extremities

• Examine the limbs and joints for evidence of trauma, joint infection, and osteomyelitis.

• Dupuytren contractures of the digits can be common in people with alcoholism.

• Unexplained painful and limited hip movements in a patient with IV 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.

• The central adrenergic storm that occurs during alcohol withdrawal results in hyperventilation, tachycardia, tremor, hyperthermia, and diaphoresis. Low-grade fever is common because of increased motor activity. Reflexes are hyperactive, and clonus may occur.

• Cranial-nerve deficits may indicate Wernicke encephalopathy, intracranial trauma, or bleeding. Complete cranial-nerve examination may need to be delayed until the patient's condition responds to therapy.

• Peripheral neuropathy is common in chronic alcoholism, but it is difficult to confirm in a minimally cooperative patient.

• Focal neurologic deficits, 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.

• Palmar erythema may be seen.

• Patients with IV 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.