Withdrawal Syndromes

Updated: Aug 15, 2018
  • Author: Nathanael J McKeown, DO; Chief Editor: David Vearrier, MD, MPH  more...
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Overview

Practice Essentials

Withdrawal syndrome, also known as discontinuation syndrome, occurs in individuals who have developed physiological dependence on drugs or alcohol and who discontinue or reduce their use of it.

Signs and symptoms

Signs and symptoms of withdrawal vary depending on the substance discontinued.

The hallmark of alcohol withdrawal is a continuum of signs and symptoms ranging from simple tremulousness to delirium tremens (DT). The spectrum varies greatly, and symptoms overlap in time and duration.

Discontinuation of benzodiazepines, barbiturates, and other sedatives or hypnotics after long-term use results in withdrawal symptoms resembling those of alcohol withdrawal syndrome. Sedative-hypnotic withdrawal syndrome is characterized by pronounced psychomotor and autonomic dysfunctions.

Opioid withdrawal produces a characteristic syndrome that may resemble viral illness. The syndrome is characterized by rhinorrhea, sneezing, yawning, lacrimation, abdominal cramping, leg cramping, piloerection (gooseflesh), nausea, vomiting, diarrhea, mydriasis, myalgias and arthalgias.

Stimulant (cocaine and amphetamine) withdrawal, or wash-out syndrome, resembles severe depressive disorder. Manifestations include dysphoria, excessive sleep, hunger, and severe psychomotor retardation, whereas vital functions are well preserved.

See Presentation for more detail.

Diagnosis

The following laboratory tests may be indicated in cases of possible withdrawal, depending on the clinical scenario:

  • Serum glucose
  • Arterial blood gas analysis
  • CBC
  • Comprehensive metabolic panel
  • Urinalysis
  • Cardiac biomarker measurements
  • Prothrombin time
  • Toxicology screening

See Workup for more detail.

Management

Patients presenting in mild alcohol withdrawal may be treated on an outpatient basis, provided that no underlying conditions require inpatient treatment. Patients presenting with moderate or severe alcohol withdrawal and DT require inpatient treatment and consideration of ICU admission.

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, dexmedetomidine, and (in rare cases) ethanol.

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.

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.

See Treatment and Medication for more detail.

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Background

Ethanol and 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 patient education resources, see the Substance Abuse Center, as well as Drug Dependence and Abuse and the Addiction Resource Center.

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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 GABAA 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 GABAA 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.

Other GABAA receptor agonists, such as benzodiazepines, barbiturates, and volatile solvents, produce a withdrawal syndrome through some of the same mechanisms implicated in ethanol withdrawal. Modulatory changes in the GABAA receptor results in a decrease in GABA-ergic neurotransmission and decreased inhibitory control of excitatory neurotransmission.

Opioid withdrawal is mediated at both the receptor level and via downstream cellular and nerve network adaptations. At the receptor level, opioid tolerance induces receptor internalization with decreased receptor expression on the cell surface and receptor densensitization, whereby stimulation of the receptor is less efficiently coupled to second messenger activation.

At the cellular level, opioid tolerance and withdrawal is modulated by alterations in kinase cascades, which modulate the production and effects of second messengers such as cyclic adenosine monophosphate (cAMP). At the nerve network level, chronic opioid agonism results in homeostatic adaptations to other neurons throughout the neural network; alterations in neuronal, synaptic, and dendritic architecture; and changes in glial function. 

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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. Binge drinkers may also be at risk.

According to the 2015 National Survey on Drug Use and Health, an estimated 17.3 million persons aged 12 or older were heavy alcohol users in the past month; this represents 6.5% of the population of that age. An estimated 66.7 million persons had been binge alcohol users in the past 30 days; this represents 24.9% of the population of that age. [2]

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 precisely and fluctuates with the supply of drugs and social trends. According to the 2015 National Survey on Drug Use and Health, 7.7 million people aged 12 or older had an illicit drug use disorder; this represents 2.9% of the population of that age. [2]

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Mortality/Morbidity

The mortality rate from severe alcohol withdrawal and delirium tremens (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. Risk factors associated with increased mortality include the following [3] :

  • Cirrhosis
  • DT
  • Underlying chronic pathology other than liver disease
  • Need for endotracheal intubation

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.

Opioid withdrawal is uncomfortable but usually mild in terms of derangement of vital signs. Fatalities due to spontaneous opioid withdrawal is very rare, although precipitated opioid withdrawal is associated with acute lung injury or myocardial injury that may result in critical illnes or death.

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- and Age-related Demographics

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

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.

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