By Joshua L. Bacon, DO, and Brian Patrick Murray, DO

Executive Summary

• Withdrawal syndromes are common, high-acuity presentations in the emergency department (ED), arising after abrupt cessation or reduction of chronically used substances. They range from mild discomfort to life-threatening complications, such as seizures, delirium tremens, or severe autonomic instability.
• Alcohol, opioids, benzodiazepines/barbiturates, and antidepressants constitute the majority of withdrawal-related ED visits. Each syndrome has distinct pathophysiology and clinical trajectories but frequently overlaps with other medical, psychiatric, or toxicologic conditions.
• Early recognition is essential, since withdrawal can mimic sepsis, intracranial disease, metabolic derangements, psychiatric decompensation, or intoxication from other substances. Anchoring on withdrawal without ruling out critical alternative diagnoses can lead to missed pathology.
• Validated assessment tools support structured evaluation and guide treatment decisions. These tools help quantify severity, monitor progression, and reduce variability in management. Examples of these tools include:
  • Clinical Institute Withdrawal Assessment for Alcohol-Revised for alcohol withdrawal;
  • Clinical Opiate Withdrawal Scale for opioid withdrawal;
  • Clinical Institute Withdrawal Assessment-Benzodiazepines (limited utility) for benzodiazepine withdrawal;
  • Discontinuation Emergent Signs and Symptoms for antidepressant discontinuation.
• Pharmacologic management strategies differ by syndrome:
  • Alcohol and sedative-hypnotic withdrawal requires GABAergic therapy (benzodiazepines, phenobarbital) to prevent seizures and delirium tremens.
  • Opioid withdrawal typically benefits from early buprenorphine initiation once moderate withdrawal is present.
  • Antidepressant discontinuation generally is self-limited and responds to supportive care or reinstatement with gradual tapering.
• Complications arise when withdrawal treatment is delayed or is undertreated, including progression to seizures, delirium, autonomic instability, dehydration, electrolyte disturbances, or misdiagnosis of serious comorbid disease.
• Disposition decisions must account for symptom severity, comorbidities, polysubstance use, vital sign stability, and social supports.
• A persistent practice gap exists in emergency medicine. Variability remains in:
  • use of validated scoring systems;
  • evidence-based dosing strategies for alcohol and sedative withdrawal;
  • initiation of buprenorphine for opioid withdrawal;
  • linkage to addiction medicine and harm-reduction strategies.
• Closing this gap requires standardized ED protocols, early identification of high-risk patients, consistent application of validated tools, guideline-aligned pharmacologic management, and proactive connection to ongoing addiction care.

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Drug withdrawal syndromes are a frequent and challenging presentation in emergency departments, with a spectrum ranging from mild discomfort to severe, life-threatening complications. Emergency physicians must recognize and appropriately manage these syndromes, often with limited information and under acute clinical urgency. Despite established guidelines, inconsistencies remain in recognizing when withdrawal syndromes require inpatient stabilization vs. outpatient management. This article reviews the four most encountered withdrawal syndromes — alcohol, opioids, sedatives, and antidepressants — focusing on practical, evidence-based strategies for evaluation, treatment, and disposition in the emergency department.

— Daniel Migliaccio, MD, Editor

Introduction

Withdrawal syndromes represent a significant and growing burden on emergency departments (EDs) across the United States. The syndromes represent physiological and psychological responses that occur upon abrupt cessation or reduction in the intake of certain substances after a patient has developed physiologic dependence to the substance. Commonly encountered withdrawal in the ED involves alcohol, opioids, benzodiazepines, and antidepressants. The resulting symptoms range from mild discomfort to life-threatening complications, including seizures, delirium, severe autonomic instability, and cardiovascular collapse. Rapid recognition is essential, and emergency clinicians must be prepared to differentiate withdrawal from other medical or psychiatric conditions and to manage patients safely and effectively. This article provides an ED-centered, practical review of major withdrawal syndromes, emphasizing early recognition, structured evaluation, evidence-based management, and disposition planning. The goal is to equip emergency physicians with concise, high-yield strategies to improve patient outcomes, reduce complications, and address key practice gaps in ED care.

Relevance to Emergency Medicine

Emergency physicians frequently are the first clinicians to identify and manage patients experiencing acute withdrawal syndromes. These presentations are highly time sensitive. Delayed recognition or inadequate treatment may result in significant morbidity or mortality. Since substance use disorders (SUDs) are common among patients presenting for emergency care, withdrawal syndromes represent a recurrent and important clinical challenge. In addition to acute stabilization, the ED encounter offers a vital opportunity to engage in a discussion of treatment and initiate long-term treatment strategies, including medications for opioid use disorder, such as buprenorphine, and to coordinate psychiatric or addiction care follow-up. Thus, the ED serves as both a frontline setting for managing life-threatening withdrawal and a pivotal point of intervention for ongoing addiction care.

Epidemiology

Withdrawal syndromes represent a significant and growing burden on EDs across the United States. Alcohol, opioids, benzodiazepines, and other sedative-hypnotics account for the majority of the presentations, although the true incidence likely is underestimated as a result of underreporting, misdiagnosis, and overlap with medical or psychiatric conditions.

SUDs remain a significant public health concern in the United States. In 2021, an estimated 46.3 million individuals aged 12 years or older met the Diagnostic and Statistical Manual of Mental Disorders, 5th revision (DSM-5) criteria for an SUD, including 29.5 million with alcohol use disorder (AUD) and 6.7 million with opioid use disorder (OUD).¹ There were an estimated 13.6 million new cases and 137,278 deaths attributed to drug use disorders (DUDs) worldwide, with OUD accounting for the highest rates of incidence and mortality.² EDs serve as a frequent point of care for acute withdrawal and substance-related complications, including withdrawal, overdose, and injection-related infections.³

Alcohol withdrawal syndrome (AWS) is among the most common withdrawal syndromes encountered, contributing substantially to ED visits, hospitalizations, and intensive care use.⁴ Periods of forced abstinence, such as hospitalization, incarceration, detox attempts, or reduced access often precipitate withdrawal symptoms.

Concomitantly, the opioid epidemic continues to escalate. Since 2013, overdose deaths involving synthetic opioids have increased dramatically, by more than 1,000% from 2013 to 2019, with fentanyl now implicated in nearly 70% of all U.S. drug overdose deaths as of 2022.^5,6 Fentanyl’s extreme potency, approximately 50 to 100 times greater than morphine, combined with its low production cost, ease of synthesis, and rapid infiltration into the illicit drug supply, has led to widespread distribution across the United States. It frequently is mixed into heroin, cocaine, methamphetamine, and counterfeit pills, resulting in substantial risk for unintentional exposure and overdose. ED visits for suspected opioid overdoses increased nearly 30% from 2016 to 2017, reflecting the early impact of these shifts in the drug landscape.⁷ More recent national surveillance data demonstrate continued increases in fentanyl-involved nonfatal overdoses from 2019 through 2023, highlighting the ongoing expansion of synthetic opioid-related harm.⁸

Benzodiazepine misuse also has risen, particularly when combined with opioids, substantially increasing overdose risk. National ED surveillance reports show benzodiazepine-related ED visits increased during the mid-2010s, driven largely by co-use with opioids.⁹ Specifically, between 1996 and 2013, benzodiazepine-related overdose deaths in the United States increased more than four-fold, and ED adverse-event visits involving benzodiazepines have continued to rise into the mid-2010s.^10,11

Finally, antidepressant discontinuation syndromes, particularly from abrupt cessation of short half-life selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, often go underrecognized in the ED, where patients may present with nonspecific dizziness, anxiety, and flu-like symptoms.^12,13

Overall, the rising incidence of withdrawal syndromes reflects broader national trends in substance use, highlighting the ED’s key role in early recognition, stabilization, and linkage to ongoing care.

Etiology and Risk Factors

Patients most at risk for severe or complicated withdrawal often share common clinical and social characteristics. High-dose or prolonged substance use is strongly associated with increased severity of withdrawal syndromes, particularly if those individuals also have physiologic dependence.¹⁴ Concomitant use of multiple substances, such as alcohol with benzodiazepines or opioids with stimulants, further increases both the severity and unpredictability of withdrawal presentations.¹⁴

Underlying psychiatric comorbidities, including depression, anxiety disorders, and post-traumatic stress disorder, are highly prevalent among individuals with SUDs and can exacerbate withdrawal-related agitation, insomnia, and suicidality.^15,16 Limited social support and unstable housing reduce patients’ ability to manage early withdrawal safely and increase the likelihood of ED presentation or relapse.¹⁷

A history of prior complicated withdrawal (e.g., seizures, delirium tremens, hallucinosis, alcohol withdrawal psychosis, or severe autonomic instability) is one of the strongest predictors of future severe episodes.¹⁴ In addition, external circumstances such as hospitalization, incarceration, or abrupt loss of access to substances, whether due to prescription interruption, financial strain, or supply disruption, commonly precipitate acute withdrawal crises.¹⁸ Recognition of these risk factors is essential for early identification, risk stratification in the ED, and proactive initiation of appropriate monitoring and treatment strategies.

Pathophysiology

Alcohol, benzodiazepines, and barbiturates all enhance inhibitory signaling through the neurotransmitter gamma-aminobutyric acid-A (GABA-A) receptor, a ligand-gated chloride channel, while concurrently suppressing excitatory glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors.¹⁹ However, they all bind at different allosteric sites on the receptor. Because of this similar activity, overdose is exacerbated through synergy, and withdrawal can be equally amplified. Barbiturates and benzodiazepines modulate GABA-A receptors via distinct mechanisms, and at higher doses, barbiturates can directly activate or even block the receptor, while benzodiazepines exhibit a ceiling effect because of their reliance on endogenous GABA. Barbiturates act by prolonging and potentiating GABA action at GABA-A receptors, and at higher concentrations, they can directly activate the receptor even in the absence of GABA. At very high concentrations, barbiturates also may block the channel, leading to toxicity.^19-21 This dose-dependent shift in mechanism explains why barbiturates can cause profound central nervous system (CNS) depression and have a narrow therapeutic window.

In contrast, benzodiazepines only enhance the effect of GABA by increasing the frequency of channel opening, but they do not directly activate the receptor. Their effect is limited by the amount of endogenous GABA present, resulting in a ceiling effect. Even at high doses, benzodiazepines cannot produce maximal receptor activation or fatal CNS depression unless combined with other CNS depressants.^22,23 This ceiling effect is a key reason for the improved safety profile of benzodiazepines compared to barbiturates. Structurally, both drug classes bind to distinct sites on the GABA-A receptor and induce different conformational changes, further supporting their differential dose-dependent effects.^23,24

Chronic exposure to drugs that modulate GABA-A and NMDA receptors leads to compensatory neuroadaptations in the CNS that shift the balance toward excitation. This occurs through downregulation of GABA-A receptor expression and sensitivity, while also upregulating NMDA receptor activity. At the GABA-A receptor level, chronic benzodiazepine exposure induces several adaptive changes. There is transcriptional downregulation of key subunits (e.g., α1), mediated by increased calcium influx and signaling pathways, resulting in reduced receptor expression and altered subunit composition.^25,26 Chronic exposure also leads to uncoupling of GABA and benzodiazepine binding sites, receptor desensitization, and increased receptor internalization and degradation, further diminishing inhibitory signaling.²⁶ Synaptic reorganization occurs, with gephyrin scaffold destabilization and redistribution of γ2-GABA-A receptors to synaptic sites, reducing synaptic inhibitory efficacy despite unchanged total receptor levels.²⁷ At the NMDA receptor level, compensatory upregulation is observed. Chronic benzodiazepine treatment increases NMDA receptor-mediated excitatory postsynaptic currents and enhances the surface expression and synaptic localization of GluN2A- and GluN2B-containing NMDA receptors, particularly at silent synapses, thereby augmenting excitatory potential.^28,29 There also is evidence of increased glutamate release and NMDA-stimulated signaling in the hippocampus after prolonged benzodiazepine exposure, further promoting excitation.²⁹ Similar adaptive responses are seen with chronic NMDA antagonist exposure, which can alter GABA-A receptor subunit expression and function, highlighting bidirectional regulation between these systems.^30,31 Abrupt discontinuation removes the exogenous GABAergic drive while leaving heightened unopposed excitatory activity, leading to widespread neuronal hyperexcitability. Additional contributors to this excitatory activity include noradrenergic overactivation from the locus coeruleus, driving sympathetic surge, and dopaminergic dysregulation, which may underlie perceptual disturbances.^32,33

Opioids are mu-opioid receptor agonists, suppressing GABAergic interneurons and thereby inhibiting noradrenergic neurons in the locus coeruleus. This reduces sympathetic outflow and contributes to euphoria, analgesia, and sedation. With chronic use, adaptive upregulation of cAMP signaling in the locus coeruleus restores sympathetic tone despite the presence of opioids. When opioids are withdrawn, the inhibitory effect is lost while the compensatory mechanisms remain active, causing a surge in noradrenergic firing and widespread autonomic activation.³² This mechanism drives the hyperadrenergic state seen in opioid withdrawal, producing sympathetic overactivity that manifests as nausea, vomiting, diarrhea, tachycardia, and mydriasis.

SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) chronically increase extracellular serotonin and norepinephrine, respectively. Over time, this leads to downregulation of postsynaptic receptors and adaptive changes in intracellular signaling pathways.^12,13 Abrupt discontinuation creates a mismatch between neurotransmitter availability and receptor sensitivity, disrupting serotonergic and noradrenergic tone. This neurochemical disequilibrium explains the constellation of discontinuation symptoms often seen in clinical practice.¹² During chronic reuptake blockade, extracellular serotonin and norepinephrine levels remain elevated, causing downregulation of postsynaptic receptors (e.g., 5-HT and adrenergic receptors) and desensitization of presynaptic autoreceptors (such as 5-HT1A and α2-adrenergic receptors).^34,35 This adaptation reduces receptor sensitivity and alters feedback inhibition, so the system becomes reliant on continued reuptake inhibition for homeostasis. When an SSRI or SNRI is stopped abruptly, synaptic serotonin and norepinephrine levels rapidly fall, but the postsynaptic receptors remain downregulated and presynaptic autoreceptors desensitize, leading to a period of neurotransmitter imbalance and hyperexcitability.^36,37 Recent evidence shows that SSRI discontinuation triggers rebound activation of 5-HT neurons, with increased neuronal excitability and neurotransmitter release, which correlates with anxiety-like and other discontinuation symptoms.^38,39 This rebound is thought to result from the loss of inhibitory feedback as a result of autoreceptor desensitization and the lag in postsynaptic receptor re-sensitization. However, these findings are based on emerging preclinical and early translational research, and the precise mechanisms remain an area of ongoing investigation.

For SNRIs, similar mechanisms apply, with norepinephrine system adaptations contributing to withdrawal symptoms, such as agitation, autonomic instability, and sensory disturbances.⁴⁰ The neurochemical dysregulation leads to the clinical features seen in the ED and is more pronounced with short half-life agents due to the abruptness of neurotransmitter changes.^41,42

Across all substance classes, the unifying mechanism of withdrawal involves adaptive receptor and signaling changes that restore homeostasis in the presence of chronic drug exposure but become maladaptive when the drug is abruptly removed. Recognition of these processes provides the mechanistic foundation for understanding withdrawal severity and informs targeted treatment strategies in the ED.

Clinical Features

Alcohol withdrawal develops due to the loss of GABAergic inhibition and unopposed glutamatergic excitation. Symptoms typically begin within six to 12 hours of cessation, with tremors, diaphoresis, tachycardia, and anxiety, reflecting early autonomic hyperactivity. Progression may include visual, auditory, or tactile hallucinations, driven by dopaminergic dysregulation. Seizures often occur within 12-48 hours, resulting from neuronal hyperexcitability, and in profoundly dependent patients, may even occur with an elevated blood alcohol concentration. The most severe form, delirium tremens (DT), typically develops after 48-72 hours, with confusion, agitation, and profound autonomic instability due to catecholaminergic surge.⁴³

Benzodiazepine and barbiturate withdrawal closely mimic alcohol withdrawal because of their shared GABA-A receptor mechanism. Chronic use downregulates GABA receptor sensitivity via functional uncoupling of modulatory sites, downregulation of key receptor subunits, and synaptic reorganization. Sudden cessation elicits excess excitatory activity.⁴⁴ Clinically, patients present with anxiety, tremors, insomnia, and agitation. In more severe cases, seizures and psychosis occur, reflecting loss of inhibitory tone and unchecked cortical excitation. Short half-life benzodiazepines, such as alprazolam, are particularly prone to causing abrupt, severe withdrawal.⁴⁵

Opioid withdrawal arises from noradrenergic overactivity in the locus coeruleus following abrupt loss of mu-opioid receptor-mediated suppression.³² Onset typically occurs within six to 24 hours of last use. Patients experience rhinorrhea, lacrimation, yawning, piloerection, and diaphoresis, all explained by sympathetic overactivation. Myalgias and abdominal cramping result from increased noradrenergic signaling to skeletal and smooth muscle. Gastrointestinal hypermotility produces nausea, vomiting, and diarrhea. While intensely uncomfortable, opioid withdrawal rarely is life-threatening. However, because of vomiting, diarrhea, and lack of appetite, opioid withdrawal can result in significant fluid loss and risk of dehydration if not adequately managed.^46-48 These symptoms are common across age groups and can be particularly severe in debilitated patients, potentially leading to life-threatening complications, such as electrolyte imbalances and cardiac arrhythmias.⁴⁸

SSRI and SNRI discontinuation syndromes stem from receptor and intracellular adaptations to chronic reuptake blockade. Abrupt cessation produces a mismatch between low neurotransmitter availability and this adapted receptor state.³⁶ Clinically, patients develop dizziness and disequilibrium due to serotonergic disruption of vestibular pathways, irritability and anxiety from serotonergic and noradrenergic imbalance, insomnia from loss of serotonergic modulation of sleep centers, and characteristic “electric shock” sensations reflecting abnormal cortical excitability.^36,37 Symptoms are more common with agents that have short half-lives, such as paroxetine and venlafaxine.

Diagnostic Evaluation

The general evaluation for undifferentiated withdrawal syndromes should begin with a thorough clinical history, physical examination, and targeted laboratory testing, alongside the use of validated symptom rating scales and screening for polysubstance use.

Initial assessment should focus on identifying the substance(s) involved, the timing and pattern of cessation or dose reduction, prior withdrawal episodes, and risk factors for severe or complicated withdrawal (e.g., history of seizures, delirium, and comorbid medical or psychiatric conditions).^14,43,49 Collateral information from family or caregivers may be necessary if the patient cannot provide a clear history.

Physical examination should evaluate for autonomic hyperactivity (tachycardia, hypertension, diaphoresis), tremor, agitation, and signs of delirium or psychosis.^42,43,49 Symptom rating scales such as the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) for alcohol, Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) for benzodiazepines, Clinical Opiate Withdrawal Scale (COWS) for opioids, and Discontinuation Emergent Signs and Symptoms (DESS) for antidepressants can help quantify severity and guide management.^43,50

The laboratory workup should include a comprehensive metabolic panel, hepatic panel, and complete blood count to assess for electrolyte disturbances, liver and renal function, and infection. Additional tests may be indicated based on history and risk factors. Creatine kinase (for rhabdomyolysis), troponin (for stimulant- or withdrawal-related demand ischemia), and lactate should be considered based on the clinical context. An electrocardiogram (ECG) should be performed in patients with moderate to severe withdrawal or altered mental status. Measurement of blood alcohol concentration, serum osmolality, and ammonia may assist in differentiating altered mental status due to intoxication, metabolic derangements, or hepatic encephalopathy. However, relying on ethanol levels to evaluate intoxication is not recommended because blood alcohol concentrations correlate poorly with observed impairment, vary based on individual tolerance, and cannot reliably distinguish acute intoxication from withdrawal, co-ingestion, or other causes of altered mental status.¹⁴ Screening for concurrent substance use is essential, and the addition of a urine toxicology screen may be beneficial, since polysubstance withdrawal can alter presentation and management. Tools like the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) can be used to assist in performing a comprehensive assessment.¹⁴

Alcohol, stimulant, and antidepressant withdrawal all may manifest with tachyarrhythmias due to autonomic hyperactivity. QT prolongation is a particular concern, especially in withdrawal from methadone, tricyclic antidepressants (TCAs), SSRIs, and antipsychotics, all of which can prolong the QT interval.⁵¹ These effects often are exacerbated by electrolyte abnormalities, such as hypokalemia and hypomagnesemia, which are common in patients with chronic alcohol use or with vomiting and diarrhea.^14,43 Additionally, clinicians should evaluate for QRS widening, sinus tachycardia, atrial fibrillation, or premature ventricular complexes as signs of sympathetic overdrive. Continuous cardiac monitoring is recommended for patients with severe withdrawal (e.g., CIWA-Ar score > 15), those requiring high benzodiazepine or barbiturate doses, patients with significant tachycardia, and those with underlying cardiac disease.^14,43 Chest radiography or noncontrast head computed tomography (CT) should be considered in cases involving trauma, seizures, or unexplained altered mentation and should be considered as part of the initial workup for clinically complex cases. In hyperthermia or encephalopathic patients, lumbar puncture may be necessary to exclude CNS infection.

Importantly, the diagnostic evaluation should be tailored to the clinical context, but treatment should not be delayed for pending results if there is a suspicion for substance withdrawal.

Severity Assessment Tools

Diagnosis remains primarily clinical, but structured assessment instruments enhance objectivity and reproducibility. The CIWA-Ar, CIWA-B, and COWS are validated tools for quantifying symptom severity, titrating pharmacologic therapy, and determining disposition. Serial assessments improve dynamic monitoring and inter-provider consistency.

The CIWA-Ar is a validated, 10-item clinician-administered scale used to quantify the severity of alcohol withdrawal symptoms and guide management decisions in patients with suspected or confirmed AWS.^14,52 (See Tables 1 and 2.) It assesses symptoms such as nausea/vomiting, tremor, sweats, anxiety, agitation, perceptual disturbances, headache, and orientation, with a total score ranging from 0 to 67. The score helps determine the need for pharmacologic intervention and the appropriate level of care. Scores less than 8 are considered mild withdrawal, usually managed with supportive care and monitoring. Scores 8-15 are considered moderate withdrawal and may require benzodiazepines or other pharmacologic agents (e.g., clonidine, carbamazepine). Scores > 15 indicate severe withdrawal with higher risk for complications (e.g., seizures, DT) and typically warrant inpatient management.^53–55 The CIWA-Ar is most useful for serial monitoring, allowing clinicians to track symptom progression and adjust treatment accordingly. Symptom-triggered therapy, where benzodiazepines are administered based on CIWA-Ar scores rather than a fixed schedule, has been shown to reduce medication exposure and duration of treatment.⁵⁶

The CIWA-B is a symptom rating scale designed to quantify benzodiazepine withdrawal severity, but it is not widely used or validated in clinical practice. The CIWA-B consists of 22 items assessing symptoms such as anxiety, tremor, perceptual disturbances, and autonomic instability. While it provides a structured approach to monitoring withdrawal, major guidelines, including those from the American College of Medical Toxicology and the American Society of Addiction Medicine, note that the CIWA-B was developed in small patient samples and lacks robust validation or reliability data. As a result, it is infrequently used in routine clinical care, and no validated scales for benzodiazepine withdrawal currently are recommended for standard practice.^48,57 In the context of evaluating withdrawal syndromes, clinicians are advised to prioritize regular monitoring of vital signs and patient-reported symptoms, with particular attention to seizure risk and delirium. Structured symptom collection can improve objectivity and consistency, but the absence of a validated, widely accepted scale means that clinical judgment remains paramount.^48,57 The CIWA-B may be used as a supplemental tool in research or highly structured settings, but its results should be interpreted cautiously.

COWS is an 11-item, clinician-administered tool used to quantify the severity of opioid withdrawal symptoms. It assesses both objective signs (e.g., resting pulse rate, pupil size, tremor, gooseflesh skin) and subjective symptoms (e.g., anxiety, bone/joint aches, gastrointestinal [GI] upset) observed over a short interval. (See Tables 3 and 4.) Each item is scored, and the total score guides clinical decision-making. COWS is widely used to determine the timing and appropriateness of initiating medications for OUD, such as buprenorphine. For example, a score of ≥ 8-12 typically is required before starting buprenorphine to minimize the risk of precipitated withdrawal.^58-60 The scale also is used to monitor withdrawal progression and response to treatment, including symptomatic management with agents like lofexidine or clonidine.^48,61 COWS has demonstrated good reliability and validity compared to other withdrawal scales, such as the Clinical Institute Narcotic Assessment (CINA).⁶¹ It is recommended by the American Society of Addiction Medicine and other major guidelines for routine monitoring in both inpatient and outpatient settings.⁶¹

Differential Diagnosis

Each withdrawal syndrome may present with signs and symptoms that mimic other serious medical or psychiatric disorders. A careful and systematic differential diagnosis is critical to avoid misattributing potentially life-threatening pathology to withdrawal alone.

In alcohol withdrawal, autonomic hyperactivity, tremor, and altered sensorium can mimic sepsis, hepatic encephalopathy, traumatic brain injury, hypoglycemia, or sympathomimetic intoxication. Wernicke encephalopathy always should be considered in patients with confusion or ataxia, since it frequently coexists with withdrawal and requires urgent recognition. Seizures must be differentiated from other conditions, such as epilepsy, electrolyte abnormalities, hypoglycemia, trauma/intracranial hemorrhage, and CNS malignancies or infection.

Similarly, sedative-hypnotic withdrawal, including that from benzodiazepines or barbiturates, may be indistinguishable from delirium caused by sepsis, endocrine emergencies like thyroid storm, metabolic derangements, or alcohol withdrawal. Tremor, agitation, perceptual disturbances, and seizures are common across these entities, highlighting the need for careful evaluation of concurrent infection or intracranial pathology.

Opioid withdrawal typically manifests with mydriasis, piloerection, yawning, rhinorrhea, lacrimation, and diffuse abdominal cramping. These features may mimic viral gastroenteritis, influenza, or acute abdominal pathology such as appendicitis or pancreatitis.

Antidepressant discontinuation syndrome may present with dizziness, disequilibrium, anxiety, insomnia, and sensory disturbances, including “electric shock” sensations. These symptoms often are mistaken for neurological disorders, vestibular disorders, viral illness, or panic attacks. Symptom onset within days of missed doses or abrupt cessation and the absence of focal neurologic deficits help differentiate this syndrome from cerebrovascular or demyelinating disease.

In all suspected withdrawal presentations, clinicians should maintain a broad differential for metabolic, endocrine, infectious, structural, traumatic, and toxicologic causes, particularly in patients with fever, focal neurologic findings, or refractory altered mental status.

Management

The management of withdrawal syndromes in the ED centers on symptom control, prevention of complications, and identification of comorbid medical or psychiatric illness. Treatment should begin promptly based on clinical suspicion rather than laboratory confirmation, since delayed intervention can increase morbidity. Supportive care, including correction of dehydration, electrolyte abnormalities, and nutritional deficiencies, is foundational across all withdrawal presentations. (See Table 5.)

Alcohol Withdrawal

Benzodiazepines

Benzodiazepines remain the mainstay of therapy for alcohol withdrawal, targeting hyperexcitability of the CNS through enhancement of GABAergic activity. Either symptom-triggered or fixed-schedule approaches can be used, guided by the CIWA-Ar scale. Long-acting agents such as diazepam or chlordiazepoxide often are preferred for smoother coverage, while lorazepam is preferred in patients with hepatic dysfunction or hemodynamic instability, since it is not metabolized by the liver.

The American Society of Addiction Medicine recommends symptom-triggered dosing as the preferred approach, where diazepam 10 mg to 20 mg is administered orally (PO) every one to two hours as needed when CIWA-Ar scores are ≥ 10. A symptom-triggered approach allows individualized dosing based on real-time symptom severity and has been shown to reduce treatment duration and total benzodiazepine exposure compared to fixed schedules.¹⁴ Other oral dosing strategies include chlordiazepoxide 50 mg PO every one to two hours as needed or lorazepam 2 mg PO every one to two hours as needed may be administered until symptoms are controlled. Front-loading (e.g., 20 mg diazepam PO every two hours for three doses) is indicated for severe withdrawal (CIWA-Ar ≥ 19-21).^14,48,62 Front-loading can help obtain rapid symptom control and has been shown to reduce withdrawal seizure incidence and delirium duration.¹⁴

Intravenous (IV) benzodiazepine regimens may be appropriate when patients cannot tolerate oral medications or when rapid titration is needed for severe, life-threatening withdrawal. In IV administration in these cases, the dosing must be individualized based on symptom severity and response. The goal is to achieve light somnolence and a calm, cooperative state, which may require very large doses, much higher than typically seen in other patient populations. Once symptoms are controlled, transitioning from IV to oral symptom-triggered treatment is recommended.¹⁴ An example for IV diazepam in acute alcohol withdrawal is the initial dose of 10 mg IV, followed by 5 mg to 10 mg every three to four hours as necessary.¹⁴

Clinicians should consider tachyphylaxis when initially treating alcohol withdrawal. Tachyphylaxis is a rapid decrease in response to a drug after repeated or continuous administration, typically occurring over a short time frame (hours to days) rather than the prolonged period associated with tolerance.⁶³ Inadequate initial dosing or slow titration can lead to tachyphylaxis, requiring higher subsequent doses for symptom control and risking loss of efficacy.¹⁴ Rapid, adequate dosing early in severe withdrawal is essential to prevent tachyphylaxis and maintain benzodiazepine effectiveness.^14,56

For management of outpatient alcohol withdrawal, chlordiazepoxide (Librium) is an effective first-line agent in patients with mild-to-moderate symptoms, a stable social situation, and no history of severe withdrawal, seizures, or significant comorbidities. Candidates should be carefully screened using the CIWA-Ar scale to assess withdrawal severity and appropriateness for outpatient care.¹⁴ Benefits of chlordiazepoxide include its long half-life, which provides smoother withdrawal, reduces the risk of withdrawal seizures and DT, and allows for less frequent dosing compared to shorter-acting benzodiazepines. A typical starting dose is 25 mg to 50 mg every four to six hours on day 1, with the dose tapered by 15% to 20% daily over five to seven days. Doses should be adjusted based on symptom control, and additional take-home doses may be provided for breakthrough symptoms.¹⁴ Chlordiazepoxide should be avoided in patients with advanced liver disease because of the risk of accumulation and encephalopathy. All patients should be monitored for oversedation and respiratory depression, and benzodiazepines should be tapered and discontinued after withdrawal is complete.¹⁴ Daily follow-up is recommended to reassess symptoms and adjust dosing as needed. Long-term management of AUD should be initiated concurrently with withdrawal treatment.

Phenobarbital

The Society for Academic Emergency Medicine notes that phenobarbital is increasingly used for AWS, either as monotherapy or adjunctively with benzodiazepines, and may offer certain clinical benefits compared to benzodiazepines alone. Multiple retrospective studies cited by the society demonstrate that phenobarbital use is associated with a reduction in hospital length of stay (LOS). For example, phenobarbital monotherapy was associated with a shorter LOS compared to benzodiazepine-only therapy (2.8 vs. 3.6 days, P < 0.001), and adjunctive phenobarbital also reduced LOS (4.3 vs. 6.9 days, P = 0.004). Additionally, patients receiving phenobarbital were more likely to be discharged within three days of presentation.⁶⁴

The society highlights that benzodiazepines remain the criterion standard for AWS, with phenobarbital traditionally reserved for severe or benzodiazepine-resistant cases due to safety concerns. However, recent interest in phenobarbital is driven by its pharmacologic profile — direct GABA-A agonism and glutamate inhibition — which may provide advantages over benzodiazepines. However, the evidence supporting phenobarbital is of mixed quality and high heterogeneity, especially regarding dosing strategies and whether it is used alone or in combination with benzodiazepines.⁶⁴

The risks of phenobarbital include a narrow therapeutic window, potential for oversedation, respiratory depression, hypotension, and rare but serious adverse effects, such as Stevens-Johnson syndrome and acute renal failure. The society notes that while phenobarbital may be more effective in some settings, safety concerns and variability in evidence quality mean that its use should be individualized and carefully monitored.⁶⁴ Although phenobarbital may reduce LOS and is increasingly incorporated into ED protocols, it should not be used without continuous cardiorespiratory monitoring and ready access to airway management. Institutions using phenobarbital for alcohol withdrawal typically restrict its use to settings where clinicians are trained in its pharmacology, where standardized dosing pathways exist, and where escalation to higher levels of care is readily available.

Propofol/Barbiturate Therapy

In cases of benzodiazepine-refractory withdrawal, defined as persistent withdrawal symptoms despite high-dose benzodiazepines (e.g., > 200 mg diazepam in four hours), barbiturates or propofol may be required and usually require admission to an intensive care setting. In severe or refractory alcohol withdrawal, GABAergic tone is profoundly reduced and glutamatergic excitation is increased, sometimes rendering benzodiazepines insufficient even at high doses. Barbiturates increase the duration of chloride channel opening at the GABA-A receptor, and at higher concentrations, can directly activate the receptor even in the absence of GABA. Additionally, barbiturates inhibit excitatory neurotransmission by blocking AMPA/kainate glutamate receptors and reducing presynaptic glutamate release.^14,64-69 This dual action, potentiating GABA and suppressing glutamate, provides a broader spectrum of CNS depression, which is particularly useful in benzodiazepine-resistant cases.^14,70

Propofol also acts as a positive allosteric modulator of GABA-A receptors, but at a different binding site than benzodiazepines, and can directly activate the receptor. Propofol additionally inhibits NMDA-type glutamate receptors, further suppressing excitatory neurotransmission.⁶⁹ These properties make propofol effective in controlling agitation, seizures, and delirium in refractory alcohol withdrawal, especially in patients who require mechanical ventilation because of its risk of respiratory depression.^14,69

Adjunctive Therapies

Adjunctive measures include thiamine administration to prevent Wernicke encephalopathy, glucose repletion when indicated, and correction of magnesium and potassium. Thiamine supplementation is critical in patients presenting with alcohol withdrawal to prevent Wernicke encephalopathy, a neurologic emergency that can rapidly progress to irreversible Korsakoff syndrome if untreated. Parenteral thiamine is preferred in hospitalized or high-risk patients due to poor gastrointestinal absorption and the urgency of repletion, especially in those with malnutrition, severe withdrawal, or suspected Wernicke’s symptoms.¹⁴ Routine thiamine supplementation is recommended for all patients with AUD or withdrawal, regardless of laboratory confirmation, because deficiency is common and treatment is safe and inexpensive.¹⁴

Benzodiazepine/Barbiturate Withdrawal

Withdrawal from benzodiazepines or barbiturates can result in severe agitation, tremor, autonomic instability, or seizures. Because abrupt cessation of these agents can be life-threatening, treatment focuses on controlled re-administration and gradual tapering using long-acting benzodiazepines. Phenobarbital may be considered in patients with prior heavy barbiturate or benzodiazepine use or in those with an incomplete response to standard benzodiazepine therapy. Close observation and supportive care are essential, and severe cases may require admission for titrated therapy and continuous monitoring. Immediate priorities in the ED include stabilizing the patient, assessing seizure risk, and determining the need for inpatient admission. Patients with severe symptoms, such as autonomic instability, agitation, or seizures, should be admitted to a medically managed setting for continuous monitoring and titrated therapy.

Opioid Withdrawal

The objectives of opioid withdrawal management in the ED are to mitigate autonomic and gastrointestinal distress while facilitating linkage to ongoing addiction treatment. Buprenorphine remains the preferred agent for withdrawal management, with robust data showing that ED-initiated buprenorphine significantly increases short- and medium-term engagement in treatment for OUD, reduces illicit opioid use, and lowers relapse rates compared to referral alone. Studies demonstrate that most patients stabilize at 8 mg to 16 mg on the first day, and precipitated withdrawal is rare when buprenorphine is initiated at moderate withdrawal (COWS score ≥ 8-13).⁷¹ Initial dosing commonly begins with buprenorphine/naloxone 2 mg to 4 mg sublingual (SL), with reassessment in 30-45 minutes and additional 2-mg to 8-mg doses titrated to symptom control.⁷²

Non-opioid adjuncts, such as clonidine or lofexidine, which are centrally acting α2-agonists, can be used when buprenorphine is contraindicated or declined, or as supportive therapy for adrenergic excess. Clonidine typically is dosed at 0.1 mg to 0.2 mg PO every six to eight hours as needed (maximum ~1.2 mg/day), with heart rate and blood pressure monitoring because of the risk of hypotension and bradycardia. Lofexidine may be given as 0.54 mg (three
0.18-mg tablets) PO four times daily, up to a daily maximum of 2.88 mg. Additional symptomatic therapy includes ondansetron 4 mg to 8 mg PO/IV every six hours for nausea, loperamide 2 mg to 4 mg PO for diarrhea, nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for myalgias, and oral or IV fluids for dehydration.⁴⁷ Early initiation of medication-assisted treatment in the ED is consistently associated with improved engagement in care, reduced illicit opioid use, and lower relapse rates.⁷¹

Antidepressant Withdrawal

Discontinuation of serotonergic antidepressants, particularly agents with shorter half-lives such as paroxetine or venlafaxine, can lead to sensory disturbances, dizziness, insomnia, and anxiety. Management primarily is supportive, with patient reassurance and reinstatement of the original agent at the prior dose when symptoms are severe. Gradual tapering over several weeks generally is sufficient to prevent recurrence. Benzodiazepines or antihistamines may provide short-term symptomatic relief for anxiety or insomnia.^36,37

Complications and Pitfalls

Complications and common pitfalls vary across withdrawal syndromes, and failure to recognize early markers of severity can lead to preventable morbidity.

Alcohol Withdrawal

Alcohol withdrawal is the most common and clinically significant, since inadequate benzodiazepine dosing may allow progression to withdrawal seizures or DT, each of which carries distinct clinical implications and requires nuanced assessment and escalation strategies.

Seizures

Withdrawal-related seizures most commonly occur within six to 48 hours after abrupt cessation or significant reduction of alcohol or benzodiazepine use, with peak risk around 24 hours. Seizures may occur even in the absence of other prominent withdrawal symptoms, and their occurrence signals increased risk for progression to delirium and further seizures. Recurrent withdrawal episodes increase the risk and severity of seizures due to the “kindling” phenomenon, where repeated withdrawals lower the threshold for future seizures.¹⁴

Withdrawal seizures typically are generalized tonic-clonic and often occur as single events but can present in clusters. In alcohol withdrawal, seizures usually are not associated with underlying epilepsy and do not require long-term antiseizure therapy if abstinence is maintained.⁷³

Management centers on rapid, adequate benzodiazepine administration. Underdosing benzodiazepines during withdrawal management increases the risk of recurrent withdrawal seizures and progression to DT due to inadequate suppression of CNS hyperexcitability. Insufficient dosing fails to control withdrawal symptoms, allowing escalation to severe complications, particularly in patients with a history of withdrawal seizures or high physical dependence.¹⁴

Symptom-triggered regimens may be insufficient during the seizure-prone period, and many patients require front-loaded or escalating dosing strategies. Patients with recurrent seizures, marked autonomic instability, or significant comorbidities warrant close monitoring and/or intensive care unit (ICU) admission. Persistent agitation or seizures despite adequate benzodiazepine therapy should raise concern for evolving DT or the need for phenobarbital-based escalation.

Delirium Tremens

DT warrants similar elaboration, since early identification of patients at risk for DT can meaningfully influence disposition decisions and the need for higher-intensity monitoring. Progression of DT is marked by severe confusion, autonomic instability, and agitation. Clinical progression of AWS is monitored using symptom rating scales such as the CIWA-Ar, although these are not validated for diagnosis in the presence of coexisting medical conditions. CIWA-Ar is unreliable in delirious patients because of its reliance on patient-reported symptoms.¹⁴ Therefore, frequent monitoring of vital signs and cardiac and respiratory status is critical, with intubation and resuscitative equipment readily available when high-dose benzodiazepines or continuous infusions are required.¹⁴ Escalation to ICU often is warranted for severe DT because of the risk of respiratory depression, arrhythmias, and the need for intensive monitoring and rapid intervention. Early identification and aggressive management are crucial to reduce morbidity and mortality associated with DT.

Sedative-Hypnotic Withdrawal

Although less common, sedative-hypnotic withdrawal carries the highest mortality risk because of the potential for refractory seizures and severe autonomic instability. Unrecognized dependence on benzodiazepines or barbiturates can lead to rapid deterioration once GABAergic suppression is lifted.

Opioid Withdrawal

Opioid withdrawal rarely is life-threatening. However, dismissing these patients as “drug-seeking” may contribute to missed or delayed diagnoses of serious comorbid conditions, such as endocarditis, epidural or psoas abscess, osteomyelitis, human immunodeficiency virus (HIV), hepatitis C, or untreated soft-tissue infections. Inadequate evaluation also can overlook dehydration, electrolyte disturbances, or precipitating withdrawal from mixed substance use. Additionally, failing to initiate buprenorphine is associated with higher rates of persistent withdrawal, relapse to illicit opioid use, overdose events, and poor linkage to outpatient treatment.^74,75

Antidepressant Discontinuation

Discontinuation of antidepressants typically causes mild symptoms but may mimic neurologic or vestibular disease, leading to unnecessary diagnostic testing or consultation. Antidepressant discontinuation carries significant risk for suicide attempt with an odds ratio of 1.61, with rates remaining elevated in the first 28 days after stopping treatment.⁷⁶

Across all withdrawal syndromes, anchoring on a withdrawal diagnosis without excluding other medical or toxicologic causes of altered mental status can be a critical error. Patients with severe symptoms, polysubstance use, significant comorbidities, and/or limited follow-up warrant close observation or admission to prevent deterioration after apparent stabilization.

Disposition

Disposition decisions for withdrawal syndromes depend on symptom severity, comorbid medical or psychiatric illness, polysubstance use, vital sign stability, and the patient’s social supports. Patients with mild, uncomplicated alcohol withdrawal who have stable vitals, no history of withdrawal seizures or DT, no significant comorbidities, and reliable follow-up may be discharged with a brief, structured home benzodiazepine taper. Those with moderate to severe symptoms, autonomic instability, or escalating benzodiazepine requirements should be admitted for monitored withdrawal, while patients with DT, recurrent seizures, or refractory agitation require ICU-level care.¹⁴ Opioid withdrawal rarely is life-threatening, and most patients may be safely discharged after successful buprenorphine initiation if symptoms improve and they have reliable follow-up. Admission is appropriate for patients with severe dehydration, intractable vomiting, electrolyte abnormalities, and/or active infections (e.g., endocarditis, epidural abscess, osteomyelitis), polysubstance withdrawal, psychiatric instability, or for pregnant patients who require monitored initiation of opioid agonist therapy. Hospitalization also is warranted when outpatient care is not feasible because of medical, psychiatric, or social instability.^47,48

Sedative-hypnotic withdrawal, by contrast, carries a substantial risk of seizures and delirium and typically warrants admission for patients with moderate to severe symptoms, long-term high-dose use, comorbid alcohol or GABAergic withdrawal, unstable vitals, or inability to ensure a safe taper at home. Only reliable patients with mild symptoms and strong outpatient support may be considered for discharge with a supervised, gradual taper.⁵⁷ Antidepressant discontinuation syndromes generally are mild, self-limited, and most patients can be discharged with education, reassurance, and re-initiation of the prior dose if symptoms are severe. Admission rarely is required except when symptoms overlap with severe psychiatric decompensation, suicidality, or diagnostic uncertainty. When disposition remains unclear, early involvement of toxicology, psychiatry, or addiction medicine can assist in ensuring safe, appropriate management and follow-up.

Summary

Withdrawal syndromes represent a diverse group of time-sensitive emergencies frequently encountered in the ED. They range from mild discomfort to life-threatening complications, such as seizures, DT, and autonomic instability. Early recognition is essential, since clinical features often overlap with other critical illnesses. Alcohol and sedative-hypnotic withdrawal require prompt GABAergic support to prevent progression to severe manifestations, while opioid withdrawal management emphasizes symptom control and linkage to addiction treatment. Antidepressant discontinuation symptoms typically are self-limited but may mimic psychiatric or neurologic disease. Across all categories, comprehensive evaluation for coexisting medical conditions, correction of metabolic derangements, and vigilant monitoring are crucial. Emergency physicians play a central role not only in stabilizing acute withdrawal but also in initiating long-term recovery pathways through medication-assisted treatment and coordinated follow-up.

Practice Gap

Despite well-established guidelines for managing common withdrawal syndromes, significant variability persists in how emergency physicians recognize, risk-stratify, and treat these conditions. Best practice involves early identification of patients at risk, use of validated assessment tools (e.g., CIWA-Ar, COWS), symptom-triggered pharmacologic management, and initiation of evidence-based treatments such as buprenorphine for OUD. However, current practice remains inconsistent. Many patients either are under-treated (leading to seizures, DT, or autonomic instability) or discharged without linkage to ongoing addiction treatment. This gap is driven by time constraints, diagnostic uncertainty, and limited familiarity with withdrawal protocols, particularly for less common syndromes such as benzodiazepine or antidepressant withdrawal. As well, outpatient resources may be limited for certain areas of practice. This article aims to reduce that gap by synthesizing current evidence into practical, ED-focused strategies that emphasize early recognition, standardized management, and safe disposition planning.

Joshua L. Bacon, DO, is an emergency medicine resident, PGY-3, Wellness and Medical Student Chief, Wright State University, Dayton, OH.

Brian Patrick Murray, DO, is Associate Professor, Emergency Medicine, Wright State University, Dayton, OH.

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