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Withdrawal Syndromes

Withdrawal Syndromes

Article Author:
Mohit Gupta
Article Author:
Srinivasa Gokarakonda
Article Editor:
Fibi Attia
7/2/2020 8:31:03 PM
For CME on this topic:
Withdrawal Syndromes CME
PubMed Link:
Withdrawal Syndromes


Withdrawal from drugs and alcohol is a common medical problem seen in most countries. The withdrawal response after discontinuation of a particular drug or alcohol can depend on how long it was used for. There is a tremendous variability in the withdrawal response. When people consume alcohol for at least 1 to 3 months or even consume large quantities for at least seven to ten days, the withdrawal response can occur within 6 to 24 hours after cessation of alcohol. The withdrawal response is relieved immediately by consuming additional alcohol.[1][2][3][4]


The body attempts to maintain homeostasis. When a substance is removed, the residual counter-regulatory mechanisms produce unopposed effects, and withdrawal symptoms occur.[5][6][7][8]

AlcoholEthanol intoxication and withdrawal is complex. Most effects can be explained by the interaction of ethanol with neurotransmitters and neuroreceptors including gamma-aminobutyric acid (GABA), glutamate (NMDA), and opiates which result in changes in the inhibitory and excitation neurotransmitters disrupting the neurochemical balance in the brain, causing symptoms of withdrawal. 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 the ventral tegmental area of the brain modulate ethanol-induced dopamine release, this, in turn, produces alcohol craving and use of opioid antagonists to prevent this craving.Opioids

In opioid or benzodiazepine addiction, chronic stimulation of specific receptors for these drugs suppresses endogenous production of neurotransmitters, endorphins or GABA. Removal of the exogenous drug allows unopposed counter-regulatory effects. When the exogenous drug is removed, inadequate production of endogenous transmitters and unopposed stimulation by counter-regulatory transmitters results in withdrawal symptoms. The time it takes to restore homeostasis by synthesis of endogenous transmitters determines the time course of withdrawal.


Withdrawal from drugs and alcohol is a common medical problem. Five to ten percent of the population has alcoholism. As many as 5% of these patients may develop delirium tremens (DT) when they withdraw from chronic alcohol use. The number of people addicted to opioids, sedatives, and stimulants is not known. The mortality rate from alcohol withdrawal and DT is high if untreated. Opiate withdrawal is uncomfortable, but fatalities are rare. Withdrawal from cocaine and amphetamine results in sedation and a state resembling adrenergic blockade, death is rare. Chronic alcoholism and withdrawal are more common in men than women.

History and Physical


The signs and symptoms of alcohol withdrawal may range from a simple tremor to a fully blown delirium tremens characterized by autonomic hyperactivity, tachypnea, hyperthermia, and diaphoresis. About 25% of patients may develop alcohol hallucinations which are commonly auditory. Some alcoholics may develop seizures which are brief.

On exam, the alcoholic withdrawal response signs may include hyperventilation, tachycardia, tremor, hypertension, diaphoresis or hypothermia. Signs of chronic alcoholism may include spider angiomata, flushed facies, paralysis of extraocular muscles (Wernicke encephalopathy), poor dentition, skull or facial trauma (as a result of falls) and tongue lacerations (biting tongue during seizures). Other features of chronic alcoholism include ascites, hepatosplenomegaly, and melena. Thinning of hair, spider angioma, and gynecomastia are all also seen in chronic alcoholics.

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, the presence of DTs at the time of diagnosis, the existence of underlying chronic pathology other than liver disease, and a need for endotracheal intubation. 

Barbiturates and Benzodiazepines

Use of sedatives like barbiturates and benzodiazepines can also produce withdrawal responses that resemble alcohol withdrawal syndrome. Autonomic and psychomotor dysfunction often characterize the withdrawal symptoms. The symptoms tend to develop 2 to 10 days after discontinuation of the agent. Gamma Hydroxybutyrate (GHB) is now a common club drug abused at nightclubs and all-night parties. The withdrawal response is mild, resembles a sedative withdrawal syndrome with psychotic symptoms. Severe withdrawal symptoms tend to occur in chronic users and can also present with seizures and rhabdomyolysis.


Opiate withdrawal response is usually mild and not life-threatening. It usually resembles a flu-like illness characterized by yawning, sneezing, rhinorrhea, nausea, diarrhea, vomiting, and dilated pupils. Depending on the half-life of the drug, the symptoms may last for three to ten days. Also, individuals who abuse IV drugs are prone to infections like endocarditis, osteomyelitis, cellulitis, hepatitis, and septic emboli.

Opiate addicts may have signs of a cough, hemoptysis, and tachypnea due to opportunistic infections as a result of acquiring HIV and PCP. IV drug users may have scars and needle marks.

Cocaine and Amphetamines

Central nervous system (CNS) stimulants like cocaine and amphetamine can also produce a withdrawal response. Like opiates, the withdrawal response is mild and not life-threatening. Often the individual will develop marked depression, excessive sleep, hunger, dysphoria, and severe psychomotor retardation but all vital functions are well preserved. These individuals are not motivated to do anything but sleep. Recovery is usually slow, and depression can last for several weeks.


The workup required depends on the severity of the patient's condition. [9][10][11] Tests to be considered include:

  • Glucose - liver disease due to alcoholism may reduce glycogen stores, and ethanol impairs gluconeogenesis. As a consequence, patients in alcohol withdrawal develop anxiety, agitation, tremor, seizures, and diaphoresis, all of which can occur with hypoglycemia.
  • Arterial blood gas (ABG) - mixed acid-base disorders are common and often result from alcoholic ketoacidosis (AKA), volume-contraction alkalosis, and respiratory alkalosis.
  • Complete blood count (CBC) - long-term alcohol ingestion causes myelosuppression, thrombocytopenia, and anemia. Megaloblastic anemia occurs with dietary deficiency of vitamin B-12 and folate; increased mean corpuscular volume suggests this condition
  • Metabolic panel - look for acidosis, dehydration, concurrent renal disease, and other abnormalities that can occur in chronic alcoholism. Calculate anion and delta gaps, which are helpful in differentiating mixed acid-base disorders. A low BUN value is expected in alcoholic liver disease. Expect an elevated lipase level if pancreatitis is suspected. Obtain the blood ammonia level if hepatic encephalopathy is suspected.
  • Magnesium, calcium, and liver function tests (LFTs) - may be indicated because patients with chronic alcoholism usually have a dietary magnesium deficiency and concurrent alcoholic hepatitis. Alcoholic pancreatitis may cause hypocalcemia.
  • Urinalysis - check for ketones, as patients may have associated alcoholic ketoacidosis (AKA). Ketonuria without glycosuria to exclude alcoholic ketoacidosis and the ingestion of isopropyl alcohol. Myoglobinuria from rhabdomyolysis may be suspected when hematuria is noted on urinalysis.
  • Cardiac markers - elevated creatine kinase (CK) and cardiac troponin levels may indicate myocardial infarction. Elevated CK level may be from rhabdomyolysis, which may be associated with adrenergic hyperactivity from alcohol withdrawal or myonecrosis if immobile.
  • Prothrombin time - useful index of liver function; patients with cirrhosis are at risk for coagulopathy.
  • Toxicology screening - consider measuring serum osmolality and screening for toxic alcohols if severely acidaemic. Other recreational drugs may be present as well.
  • Imaging - chest radiography to evaluate for aspiration pneumonia, cardiomyopathy, and chronic heart failure.
  • Head computed tomography (CT) - risk for intracranial bleeding because of cortical atrophy and coagulopathy.
  • ECG - a prolonged QTc interval has been described in patients with alcohol withdrawal syndrome.
  • Lumbar puncture - to rule out meningitis or subarachnoid hemorrhage.
  • Blood cultures may also be indicated if sepsis or endocarditis is suspected.

Treatment / Management


Patients in alcohol withdrawal may have numerous potentially life-threatening medical problems. Administration of intravenous glucose to patients with seizures is controversial because this is thought to precipitate acute Wernicke encephalopathy in chronic alcoholism unless thiamine is also administered. Lorazepam can be administered to control seizures. If glucose testing reveals hypoglycemia, dextrose 50% in water (D50W) 25 mL to 50 mL and Thiamine 100 mg intravenously (IV) is also indicated. Low doses of clonidine can help reverse central adrenergic discharge, relieving tachypnea, tachycardia, hypertension, tremor, and craving for alcohol. In an agitated patient, neuroleptics such as haloperidol 5 mg IV or intramuscularly (IM) may be added to sedative-hypnotic agents as an adjunctive therapy. Caution must be taken because haloperidol may decrease the seizure threshold as well as prolong the QT interval.


Patients exposed to opioids for longer than 14 days usually need to be weaned over time. Withdrawal symptoms should be assessed with the Sophia Observation Withdrawal Symptoms Scale. Weaning protocols should consider the length of opioid exposure and total daily opioid dose. Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone or buprenorphine. Clonidine may also decrease the severity of symptoms. Long-acting benzodiazepines may be used to control insomnia and muscle cramps.Sedative-Hypnotic

Sedative-hypnotic withdrawal is treated with substituting drugs that have a long duration of action, benzodiazepine or phenobarbital for a few days followed by a decreasing dose over 2 to 3 weeks.


GHB withdrawal can initially be treated with high doses of benzodiazepines, refractory cases have responded to pentobarbital, chloral hydrate, and baclofen.


Stimulant-withdrawal syndrome is treated with observation.

Pearls and Other Issues

Patients with DTs or other severe withdrawal symptoms may require admission to the intensive care unit due to the risk of mortality.

Patients with chronic alcoholism or intravenous drug use should be evaluated for inpatient and outpatient treatment programs. Treatment programs are only successful if the patient is motivated. Often individuals addicted to opiates will be placed on methadone or buprenorphine.

  • Methadone, a long-acting opiate that prevents somatic withdrawal symptoms but does not cause euphoria equivalent to heroin, may be prescribed.
  • Buprenorphine is a Mu-opioid agonist/antagonist prescribed similarly to methadone.

Psychiatric evaluation is strongly recommended to rule out mental health concerns such as suicidal ideation, major depression, and poly-substance abuse.

Enhancing Healthcare Team Outcomes

The management of patients undergoing withdrawal symptoms is interprofessional. The severity of the withdrawal symptoms depends on the type of agent and duration of use. Some patients with mild withdrawal symptoms can be managed as outpatients but those with alcohol withdrawal may require admission. Besides the psychiatrist, other healthcare professionals that should be involved in the management of these patients include the internist, neurologist, pain specialist, intensivist, mental health nurse, pharmacist, and sometimes a cardiologist. The nurse should assist in patient monitoring and education. The pharmacist should evaluate for drug-drug interactions and assist in selection and dosing of drugs used to control withdrawal symptoms. The outcomes depend on the agent ingested. For most patients relapses and remissions are very common following addiction to drugs and alcohol. (Level V)


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