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Withdrawal Syndromes

  • Author: Nathanael J McKeown, DO; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Sep 21, 2015
 

Practice Essentials

Withdrawal syndrome, also known as discontinuation syndrome, occurs in drug and alcohol addicted individuals who discontinue or reduce the use of their drug of choice.

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. The spectrum varies greatly, and symptoms overlap in time and duration.

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.

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.

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 Clinical Presentation for more detail.

Diagnosis

The following laboratory tests are indicated in cases of possible withdrawal:

  • 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, 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

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.

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.

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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. 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.

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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. Risk factors associated with increased mortality include cirrhosis, presenting in DTs at time of diagnosis, existence of underlying chronic pathology other than liver disease, and need for endotracheal intubation.[2]

  • 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- 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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Contributor Information and Disclosures
Author

Nathanael J McKeown, DO Assistant Professor, Department of Emergency Medicine, Oregon Health and Science University School of Medicine; Medical Toxicologist, Oregon Poison Center; Attending Physician, Emergency Medicine, Portland Veteran Affairs Medical Center

Nathanael J McKeown, DO is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine

Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: American College of Emergency Physicians, New York Academy of Medicine, Society for Academic Emergency Medicine, Council of Emergency Medicine Residency Directors, Clerkship Directors in Emergency Medicine, Alliance for Clinical Education

Disclosure: Nothing to disclose.

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