Withdrawal Syndromes

Etiology

The human body attempts to maintain homeostasis. When a substance is removed from the body, the residual counterregulatory mechanisms produce unopposed effects, and withdrawal symptoms occur.[6][7][8][9] Physiologic dependence occurs when discontinuation of the substance leads to the development of a specific withdrawal syndrome. 

AlcoholAlcohol intoxication and withdrawal are complex. Most effects can be explained by the interaction of alcohol with neurotransmitters and neuroreceptors, including gamma-aminobutyric acid (GABA) and glutamate.[10][11] The changes in the inhibitory and excitation neurotransmitters disrupt the neurochemical balance in the brain, causing symptoms of withdrawal. Ethanol inhibits opioid binding to mu-opioid receptors and long-term use results in the upregulation of opioid receptors.[12][13] 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 the use of opioid antagonists to prevent this craving.[12][14] The "kindling" hypothesis of ethanol withdrawal describes the event where repeat and subsequent withdrawal in an individual becomes progressive and more severe.[15]

Benzodiazepines and Barbiturates

Benzodiazepines and barbiturates both bind to GABA_A receptors at different binding sites, leading to the inhibition of neuronal pathways. Without the neurotransmitter GABA, benzodiazepines have no functional effect, as opposed to barbiturates which can directly agonize the GABA_A reception in the absence of GABA. Sudden discontinuation of the inhibitory effect of these classes of drugs leads to an overall excitatory effect within the central nervous system, as endogenous production of GABA has been downregulated. Factors that determine the severity of withdrawal include the duration of use, the half-life of the particular drug, dosage use, rate of taper or sudden discontinuation, and the potency of the specific drug.[16] 

Opioids

Opioids exert their pain control effect via secondary messengers, specifically G proteins. After binding to the opioid receptor, the neuron is hyperpolarized and inhibited. With chronic opioid use, the opioid receptor has decreased effectiveness in its ability to open potassium channels, leading to decreased efficacy in hyperpolarization and inhibition of the neuron. In response, there is upregulation of cyclic adenosine monophosphate-mediated responses, which are responsible for neuronal excitability. Upon the discontinuation of an opioid, there is uninhibited activity within the locus ceruleus and decreased activity of inhibitory GABA activity, leading to unopposed counterregulatory excitability.[17][18] 

Both opioid and alpha-adrenergic receptors have the same effect on the potassium channel in the locus ceruleus. The medication clonidine has similar clinical findings in withdrawal, and this cross-tolerance explains why this medication can be used for the treatment of opioid withdrawal. Dexmedetomidine is a popular sedative utilized in the intensive care unit and is similar to clonidine as an alpha-adrenergic agonist but with more sedating properties; its withdrawal is similar to that of clonidine, with an unopposed excitatory effect. 

Caffeine 

Caffeine and other methylxanthines, such as theophylline, antagonize adenosine, which acts as an inhibitory neurotransmitter. Long-term caffeine intake leads to an increased affinity for adenosine at its receptor, which attempts to restore the balance.[19] 

Nicotine 

The nicotinic receptors are fast-response calcium channels that are not coupled to G protein second messengers. These receptors have inhibitory and excitatory effects and are upregulated in the setting of chronic nicotine use.[20]

Cocaine and Stimulants

Cocaine and other stimulants, such as methamphetamine, produce elevated levels of biologic amines, such as epinephrine and norepinephrine. These excitatory amines lead to an excitatory state. Upon discontinuation, these stimulants do not manifest with a withdrawal syndrome, as, by definition, no similar drug can be administered to avoid or treat the symptoms of withdrawal. A post-toxicity syndrome does occur after use, sometimes termed "crack crash" or "cocaine washout." Patients return to their baseline without intervention. 

Epidemiology

Withdrawal from drugs and alcohol is a common medical problem. The estimated global prevalence of withdrawal in adults for heavy episodic alcohol use is 18.4.%, for daily tobacco smoking is 15.2%, amphetamine 0.77%, opioids 0.37%, and cocaine 0.35%. North America was found to have the highest rates of opioid and cocaine dependence. Episodic alcohol use and daily tobacco use were highest in European regions.[21] The 2022 Annual Report of the National Poison Data System reported 19,635 calls for drug withdrawal, but this number is highly likely to be an underestimate as poison control centers are reliant on calls from healthcare professionals to generate their data. Therefore, unless the withdrawal is complicated, it will unlikely be called into the poison center. 

Alcohol

According to data from the National Epidemiologic Survey on alcohol and related conditions, the estimated lifetime prevalence of alcohol use disorder was 12.8%.[22] Approximately 20% of adults in the emergency room may have alcohol use disorder, and about 4% to 40% of patients admitted to the intensive care unit will have alcohol withdrawal symptoms (AWS).[23][24] Patients hospitalized with AWS have an increased length of hospital stay and increased mortality compared to patients without AWS.[25] Chronic alcoholism and withdrawal are more common in men than in women.[23] The mortality rate from alcohol withdrawal and delirium tremens is high if untreated, with as many as 5% of these patients developing delirium tremens when they withdraw from chronic alcohol use. 

Benzodiazepines

Benzodiazepines are one of the most prescribed classes of medications in the United States. In 2007, there were approximately 85 million prescriptions written for benzodiazepines. More prescriptions were written for women, but the diagnosis of substance use disorder appears not to have a sex difference.[16] Due to an increased safety profile, benzodiazepines have largely replaced barbiturates for sedation in inpatient and outpatient settings. Despite their increased safety compared to barbiturates, benzodiazepines carry a high risk of abuse and dependence. There is an estimation that of the individuals who have taken a benzodiazepine longer than 6 months, 40% will experience moderate to severe withdrawal symptoms.[26] 

Opioids

In 2017, an estimated 11.4 million people in the United States misused opioids, including prescription pain medication and illicit heroin, and opioid overdose is now the leading cause of unintentional death. Opioid withdrawal symptoms, known as becoming "dope sick," were estimated to occur in 85% of people who used these substances.[27] The economic cost of substance use is estimated at over 72 billion dollars, with the majority being due to healthcare costs.[28] Many individuals enter healthcare due to withdrawal, where there is an opportunity to begin treatment for their addiction.

Caffeine 

Caffeine is considered to be the most commonly used psychoactive substance in the world. In the United States, over 80% of adults consume caffeine, with an average per capita intake of 170 mg/day.[29] Due to advancing knowledge of its addictive properties and problematic withdrawal syndrome, caffeine use disorder was added to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) in 2017.[30]

Nicotine and Tobacco

Nicotine and tobacco are the second most commonly used psychoactive substances in the world, behind caffeine. Over an estimated billion people use tobacco globally. In higher-income countries, there has been a decrease in the prevalence of use, but this is not the case in middle and lower-income countries.[31] Cigarette smoking is a leading cause of preventable morbidity and mortality, with about 480,000 deaths due to smoking-related illnesses in 2012.[32] One study's results showed that 61.3% of smokers who attempted to quit experienced withdrawal symptoms. The most common symptoms experienced were cravings, restlessness, and anxiety. For those who experienced withdrawal, it was found that they were less likely to quit successfully.[33] Although public health initiatives have led to a decrease in tobacco use via cigarette smoking in high-income countries, the introduction of electronic cigarettes and vaping has led to a new delivery system for nicotine, which has attracted a younger population.[34] 

Cocaine and Stimulants

Cocaine and stimulant use is rising globally, with an estimated 18.1 million cocaine users worldwide. The highest incidence of cocaine and methamphetamine use is found in North America.[35] In the United States, between the years 2008 and 2018, there has been an increase in cocaine and psychostimulant use presentations to the emergency department. Of the visits for cocaine use, 49% were in the southern United States, whereas 60% of psychostimulant use visits were in the western United States. Psychiatric and cardiovascular concerns were seen most often.[36] Statistical data on the prevalence of drug discontinuation syndrome is limited and likely underrepresented.

History and Physical

Alcohol

The alcohol withdrawal syndrome is a spectrum and ranges from anxiety and mild tremors to potentially life-threatening delirium tremens characterized by autonomic hyperactivity, tachypnea, hyperthermia, and diaphoresis. Symptoms of insomnia, anxiety, and mild tremors can occur while there is still a detectable alcohol level in the patient's blood work. Alcoholic hallucinosis is characterized by visual and tactile hallucinations, with an otherwise clear sensorium, and one can understand that the hallucinations are not real. Due to the kindling effect of alcohol withdrawal, more severe and progressive symptoms occur with subsequent withdrawal episodes.

Seizures are often seen in those who have had multiple past episodes of withdrawal and attempts to detoxify. An alternative diagnosis should be considered if a seizure occurs in the absence of an alcohol use history, there is evidence of trauma or fever, the seizure is focal, or the patient's last drink was over 48 hours prior. Alcohol withdrawal delirium, commonly known as delirium tremens, is life-threatening and carries a mortality risk of 1% to 5%.[37] Risk factors for the development of delirium tremens include a coexisting medical illness, heavy and prolonged alcohol use, previous history of severe withdrawal, older age, and abnormal life function testing.[38][39] 

The physical examination of a patient with the signs and symptoms of alcohol withdrawal may reveal hyperventilation, tachycardia, tremor, hypertension, and diaphoresis. 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 due to biting the tongue during seizures. Other features of chronic alcohol use disorder include ascites, hepatosplenomegaly, and melena. Thinning of hair and gynecomastia are also seen in patients with chronic alcohol use disorder.

The Clinical Institute Withdrawal Assessment for Alcohol-Revised is a scoring tool that can be used to assess for alcohol withdrawal syndrome. This tool assigns a numerical value to the patient based on nausea and vomiting, tremors, diaphoresis, anxiety, agitation, tactile, visual and auditory disturbances, headache, and orientation.[38][40] 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 delirium tremens at the time of diagnosis, the existence of underlying chronic pathology other than liver disease, and a need for endotracheal intubation. 

Barbiturates and Benzodiazepines

The chronic use of sedatives like barbiturates and benzodiazepines can also produce withdrawal responses that resemble alcohol withdrawal syndrome due to their similar effect on GABA receptors. Autonomic and psychomotor dysfunction often characterize the withdrawal symptoms. The symptoms tend to develop 2 to 10 days after discontinuation of the agent and can last for weeks. The onset and length of withdrawal depend on the particular agent's pharmacokinetics, elimination half-life, and duration of use.

Symptoms include agitation, poor memory, insomnia, anxiety, panic attacks, irritability, social phobia, and psychosis. Physical symptoms and signs include headache, gastrointestinal distress, muscle fatigue, weakness, tremor, and seizures. Autonomic instability with tachycardia, hypertension, and tachypnea occur in severe withdrawal.[16][41]

Gamma hydroxybutyrate is a GABA_B receptor agonist now commonly abused at nightclubs and all-night parties. The withdrawal response is mild and 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. As with alcohol withdrawal, benzodiazepine and barbiturate withdrawal are potentially life-threatening and require aggressive management. 

Opiates

When compared to the withdrawal syndrome of GABA agonists, such as alcohol and benzodiazepine, the opiate withdrawal response is usually mild and less severe. Although the experience is exceptionally distressing for the patient, it is not life-threatening when drug discontinuation occurs naturally. The withdrawal 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 3 to 10 days.

The Clinical Opiate Withdrawal Score can help categorize the withdrawal state and assist in medication-assisted management.[42] The score takes into consideration the patient's heart rate, amount of diaphoresis, restlessness, pupil size, body aches, lacrimation, gastrointestinal upset, tremors, yawning, anxiety, and gooseflesh and provides a numeric score to the withdrawal. If withdrawal is precipitated by opioid antagonists, such as naloxone, a more severe syndrome can occur. Extreme agitation, agitated delirium, gastrointestinal distress with profuse vomiting and diarrhea, as well as flash pulmonary edema and cardiopulmonary compromise, can be seen.[43][44]

Caffeine

Due to the upregulation of adenosine receptors with habitual caffeine intake, sudden discontinuation leads to a well-documented withdrawal syndrome. Symptoms initially present 12 to 24 hours after cessation of caffeine, peak in the first 24 to 48 hours, and can last over a week.[45] Symptoms include fatigue with decreased energy and alertness, depression, difficulty concentrating, brain fog, and, most commonly, headache. Flu-like symptoms, including nausea, vomiting, and muscle aches, can also be present.[46][47] Although uncomfortable and distressing to the patient, caffeine withdrawal is not life-threatening. But, as caffeine withdrawal can impair functionality, there are concerns with work safety, academic achievement, and driving.[47]

Nicotine 

Symptoms of nicotine withdrawal can occur rapidly, within 4 to 24 hours after cessation of habitual use, peak around day 3, and can persist for 3 to 4 weeks. Symptoms are variable between patients but can include irritability, anxiety, depressed mood, trouble with concentration, insomnia, anhedonia, and restlessness. Symptoms are similar to other withdrawal syndromes, but specific to nicotine withdrawal are weight gain and a decrease in heart rate.[48][49] The severity of withdrawal is also variable and dependent on the method of use. 

Cocaine and Amphetamines

Central nervous system stimulants like cocaine and amphetamine do not produce withdrawal symptoms by definition but can manifest with post-use toxicity. The post-use symptoms are mild and not life-threatening, but unlike alcohol, benzodiazepines, and opioids, a specific syndrome is not classic.[50] Often the individual will develop marked depression, excessive sleep, hunger, dysphoria, and severe psychomotor retardation, but all vital functions are well preserved. Recovery is generally slow, and depression can last for several weeks.[51]

Evaluation

The evaluation needed to assess withdrawal syndromes fully depends on the substance of concern and the severity of the patient's condition.[52][53][54] No specific laboratory or imaging studies confirm withdrawal, but diagnostic studies to be considered include:

• Glucose: Liver disease due to alcoholism may reduce glycogen stores, and ethanol impairs gluconeogenesis. As a consequence, patients with alcohol withdrawal develop anxiety, agitation, tremors, seizures, and diaphoresis, all of which can also occur with hypoglycemia.
• Arterial blood gas: Mixed acid-base disorders are common and often result from alcoholic ketoacidosis, volume-contraction alkalosis, and respiratory alkalosis.
• Complete blood count: Long-term alcohol ingestion causes myelosuppression, thrombocytopenia, and anemia. Megaloblastic anemia occurs with dietary deficiency of vitamin B12 and folate; increased mean corpuscular volume suggests this condition.
• Metabolic panel: Clinicians should look for acidosis, dehydration, concurrent renal disease, and other abnormalities that can occur in chronic alcoholism. Calculate anion and delta gaps, which help differentiate mixed acid-base disorders. A low blood urea nitrogen 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: These tests may be indicated because patients with chronic alcoholism usually have a dietary magnesium deficiency and concurrent alcoholic hepatitis. Alcoholic pancreatitis may cause hypocalcemia.
• Urinalysis: Urinalysis is utilized to check for ketones, as patients may have associated alcoholic ketoacidosis. Ketonuria without glycosuria can 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 and cardiac troponin levels may indicate myocardial infarction. Elevated creatine kinase level may be from rhabdomyolysis, which may be associated with adrenergic hyperactivity from alcohol withdrawal or myonecrosis if immobile.
• Prothrombin time: This can be a valuable index of liver function; patients with cirrhosis are at risk for coagulopathy.
• Toxicology screening: Clinicians should consider measuring serum osmolality and screening for toxic alcohols if severely acidaemic. Other recreational drugs may be present as well, although this should be used with caution due to the potential for both false positive and false negative results.
• Plain radiographs: Chest radiography may be considered to evaluate for aspiration pneumonia, pulmonary edema, cardiomyopathy, and chronic heart failure. 
• Head computed tomography: There is a risk for intracranial bleeding because of cortical atrophy and coagulopathy.
• Electrocardiogram: A prolonged QTc interval has been described in patients with an alcohol withdrawal syndrome and should be monitored for those on methadone maintenance therapy.
• Lumbar puncture: This procedure is primarily used to rule out meningitis or subarachnoid hemorrhage.
• Blood cultures: Bliid cultures may also be indicated if sepsis or endocarditis is suspected.

Treatment / Management

Alcohol

Patients undergoing alcohol withdrawal may have numerous potentially life-threatening medical problems, which should be identified and treated along with their withdrawal. The administration of intravenous glucose empiricly to patients with seizures is controversial because this is thought to precipitate acute Wernicke encephalopathy in chronic alcoholism unless thiamine is also administered. If the patient is hypoglycemic, glucose should not be withheld, and dextrose 50% in water (25 mL to 50 mL) and thiamine (100 mg intravenously) should be provided. Although low doses of clonidine can help reverse central adrenergic discharge, relieving tachypnea, tachycardia, hypertension, tremor, and craving for alcohol, it has a minimal role in the treatment of acute alcohol withdrawal and should never be used as monotherapy.[55] The drugs of choice for the treatment of alcohol withdrawal in the inpatient setting are benzodiazepines. Due to its preferable pharmacokinetics, Diazepam is the benzodiazepine of choice, especially with a history of prior delirium tremens and severe withdrawal symptoms.[56] Lorazepam may be preferable in patients with preexisting liver disease.(A1)

The most common regimens in use for the treatment of alcohol withdrawal with benzodiazepine are fixed-dose scheduling and the symptoms-triggered approach. The fixed-dose regimen followed a scheduled administration of a benzodiazepine with a taping of the dosing over time. The symptom-triggered regimen utilizes a scoring system, most commonly the Clinical Institute Withdrawal Assessment Alcohol Scale-Revised, and administers dosing of the benzodiazepine dependent on the signs and symptoms present. Although more time and labor-intensive, the symptom-triggered approach has been noted to lead to a decrease in total benzodiazepine use and duration of treatment. Although there has been no reported benefit in regards to mortality or the development of seizures and delirium tremens.[56][57] (A1)

For patients who cannot receive benzodiazepines, carbamazepine or gabapentin are appropriate alternatives. Gabapentin can also be utilized to treat the patient's alcohol use disorder in the outpatient setting. For patients with severe alcohol withdrawal and unresponsive to benzodiazepine therapy, there can be an escalation to phenobarbital. Due to this drug's narrow therapeutic window and risk for respiratory depression, these patients require a higher level of care and should be monitored in an intensive care unit setting. Mechanical intubation and the utilization of propofol and dexmeatomidine may be needed for severe and resistant withdrawal.[55] (A1)

Benzodiazepines and barbiturates 

The treatment of benzodiazepine and barbiturate withdrawal is similar to that of alcohol withdrawal, with instituting medication to restore GABA agonism with a slow taper off the medication. A long-acting benzodiazepine (eg, clonazepam) with a slow taper has been utilized in the outpatient setting. Alternative medications, including alpha-blockers (eg, propranolol and clonidine), anticonvulsants (eg, valproic acid, lamotrigine, carbamazepine, and phenobarbital), progesterone, baclofen, and trazodone have been attempted, but none have been proven superior to benzodiazepine use.[16] Multiple taper regimens are documented in the literature. One recommendation is to decrease the dose by 25% every 2 weeks until reduced by 50%. This is followed by a maintenance dose for 1 to 2 months, followed by resuming the tapering of 25% for every 2 weeks. Alternatively, a dose reduction of 10% to 25% every 4 weeks has also been recommended.[58] (B3)

Patients requiring inpatient treatment due to seizures, delirium, or other medical diagnoses follow the same treatment regimen. Seizures should be treated with benzodiazepines. As with alcohol withdrawal, supportive care and evaluation and treatment of comorbid conditions are equally crucial to the treatment of the patient's withdrawal syndrome. 

Gamma Hydroxybutyrate

Gamma hydroxybutyrate is a GABA_B agonist, and withdrawal can initially be treated with high doses of benzodiazepines; refractory cases have responded to pentobarbital, chloral hydrate, and baclofen.

Opioids

Opioid use disorder is treated outpatient with a long-acting opioid agonist, such as methadone or buprenorphine, and buprenorphine can be utilized in the acute withdrawal stage. As there is the potential for buprenorphine to exacerbate withdrawal due to its partial antagonist effect, clinical guideline pathways have been developed to assist in determining the proper candidate for initiation of this therapy. For those unable to receive buprenorphine, intravenous fluids, antiemetics, nonsteroidal anti-inflammatory drugs, benzodiazepines, and clonidine can be administered. The same treatment strategy applies to patients undergoing withdrawal naturally from the inability to obtain opioids and to those with precipitated withdrawal from antagonists such as naloxone.[59][60][61] 

Caffeine

Similar to the treatment of other withdrawal syndromes, reinstitution of caffeine with a slow taper is the treatment of choice for caffeine withdrawal. Headaches can also be treated with supportive care, hydration, and pain control medication such as acetaminophen and nonsteroidal anti-inflammatory medications. No specific medication is recommended in the treatment of caffeine use disorder and withdrawal. 

Nicotine

Treatment for acute nicotine withdrawal is supportive, and there has been more research on treatment for nicotine use disorder rather than the treatment of acute withdrawal. Many proposed treatments have been investigated, including bupropion and varenicline, a partial agonist at the nicotinic receptor. Behavioral modifications and cognitive behavioral therapies have also been investigated. Despite these treatment modalities, nicotine dependence is exceptionally difficult to treat, with a low success rate of cessation.[62][63] (B3)

Stimulants

The drug withdrawal syndrome from stimulants such as cocaine and methamphetamine is treated with observation and supportive care, as no specific medications can abate symptoms or restore hemostasis. Multiple behavioral management strategies, as well as pharmacologic interventions, have been investigated for the treatment of stimulant use disorder, but the evidence does not support their use during the acute drug discontinuation syndrome phase.[35] (A1)

Differential Diagnosis

Differential diagnoses of withdrawal syndromes include:

• Acute coronary syndromes
• Acute hypoglycemia
• Addison disease
• Adrenal crisis 
• Amphetamine toxicity
• Anticholinergic toxicity
• Anxiety disorder
• Central nervous disorder
• Cocaine toxicity
• Delirium tremens
• Dementia
• Depression
• Suicide
• Diabetic ketoacidosis
• Pancreatitis 
• Hallucinogen toxicity
• Hyperthyroidism and thyroid storm
• Hyperventilation syndrome
• 3,4-methylenedioxymethamphetamine toxicity
• Panic disorder
• Phencyclidine toxicity
• Salicylate toxicity
• Status epilepticus 
• Wernicke encephalopathy 

Prognosis

Alcohol

Patients who require hospitalization for alcohol withdrawal have a high risk of mortality, with one study estimating a 30% mortality rate at 4 years.[64] The leading causes of mortality included malignancy, cardiovascular disease, and liver disease.[65] 

Benzodiazepines

Morbidity and mortality rates appear to be lower for those who experience withdrawal from benzodiazepines when compared to alcohol.[66] 

Opioids

Opioid withdrawal can be a bridge to long-term treatment.[67] The most common medications used are methadone and buprenorphine. Each has its strengths and limitations, but both can aid in long-term abstinence and decrease mortality from a subsequent opioid overdose.[68]

Caffeine

Caffeine withdrawal carries no mortality rate. 

Nicotine

Nicotine dependency has a high relapse rate, even with medication management. Patients more likely to achieve abstinence include those older than 50, those with over 6 months of abstinence in a previous attempt, those who smoke more than 20 cigarettes a day, and patients with low nicotine dependence.[69] 

Cocaine and stimulants 

Although no mortality is associated with stimulant withdrawal, depression and sleep disturbance can lead to poor prognosis and act as barriers to abstinence.[70] 

Complications

Alcohol 

Complications of alcohol withdrawal include anxiety, depression, sleep disturbances, and hallucinations with disturbances of perception. More serious complications include seizures, delirium tremens, Wernicke-Korsakoff syndrome, and death. Although not a true complication of withdrawal, the Wernicke-Korsakoff syndrome is a nutritional deficiency of thiamine that often coincides with alcohol use and withdrawal; this syndrome is characterized by confusion with delirium, gait disturbances with ataxia, and paralysis of the eye muscles, termed ophthalmoplegia. Long-term memory impairment can occur in up to 80% of patients with alcohol use disorder who experience this syndrome.[71][72] A protracted withdrawal syndrome can occur, with symptoms of anhedonia, irritability, insomnia, and craving, which occur past the expected course of standard withdrawal and potentially can be a reason for relapse.[73]

Benzodiazepines and Barbiturates 

Complications of benzodiazepine and barbiturate withdrawal are similar to those of alcohol withdrawal, including seizures and death. A protracted withdrawal syndrome can also be seen and can potentially last for many months.[74]

Opioids

Although opioid withdrawal is considered non-life-threatening, significant complications can occur. Dehydration and electrolyte disturbances can develop in the setting of vomiting and diarrhea. The emotional and physical discomfort from withdrawal is a barrier to treatment and often the cause of relapse.[75] Withdrawal induced by opioid antagonists has the potential to be very serious and complicated by extreme discomfort as well as delirium. Ultra-rapid opioid detoxification done under general anesthesia has been fatal.[76] A protracted withdrawal syndrome can be seen, especially with longer-acting opioids (eg, methadone), with hypotension, bradycardia, and hypothermia occurring weeks after the original cessation of the drug.

Caffeine

Potential complications from caffeine withdrawal include loss of productivity due to headaches, inability to concentrate, and insomnia. As with other substances, avoidance of the discomfort of withdrawal is often a barrier to abstinence. 

Nicotine

The complications of nicotine use are well known, including significant morbidity and mortality from cigarette smoking. The main complication of withdrawal is the somatic and behavioral complaints that lead to relapse and continued nicotine use. 

Cocaine and stimulants 

Although without a true withdrawal syndrome, complications of abstinence from stimulants include anxiety, anhedonia, and depression. Loss of productivity is possible due to fatigue and hypersomnia. A protracted withdrawal syndrome, sometimes termed the extinction phase, with the manifestation of behavior disturbances, including depression with suicidal thoughts, may also occur.