Withdrawal Syndromes 

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.

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. 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

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.