Substance disorders and alcohol withdrawal

Substance Use Disorders & Acute Withdrawal Syndromes

Substance misuse and acute withdrawal syndromes account for a substantial burden of acute admissions across Australian emergency departments, general medical units, and addiction medicine services. Sound clinical knowledge of the neurobiological adaptations underlying drug dependence, the chronological progression of alcohol withdrawal states, and the pharmacology of detoxification and substitution therapies is vital for candidate success on the AMC examination.

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Diagnostic Framework: DSM-5 Substance Use Disorders

The DSM-5 provides a unified diagnostic construct for Substance Use Disorders (SUD), replacing earlier distinctions between substance abuse and dependence with an 11-item criterion matrix categorized across four functional domains:

Important Clinical Caveat: Criteria 10 (tolerance) and 11 (withdrawal) are not counted toward a substance use disorder diagnosis if the medication is taken strictly under appropriate medical supervision (e.g., prescribed opioids for chronic cancer pain).

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Alcohol Withdrawal: Neurobiology, Chronology & Management

Neurobiology and Pathophysiology

Alcohol is a potent central nervous system depressant. Its neurochemical effects involve two primary receptor systems:

• GABA-A Receptors: Ethanol acts as a positive allosteric modulator of inhibitory GABA-A receptors, facilitating chloride influx and hyperpolarizing neuronal membranes. Chronic exposure results in compensatory downregulation and conformational desensitization of GABA-A receptors.
• NMDA Glutamate Receptors: Ethanol acts as a negative allosteric modulator of excitatory NMDA (N-methyl-D-aspartate) glutamate receptors, suppressing excitatory neurotransmission. Chronic exposure induces compensatory upregulation and hypersensitization of NMDA receptors to preserve basal neuroexcitation.

Upon abrupt alcohol cessation, the inhibitory dampening is suddenly removed while the upregulated NMDA receptors are exposed to endogenous glutamate. The resulting neurochemical imbalance—GABA hypofunction coupled with glutamate excitotoxicity—leads to unrestrained neuronal firing, profound central sympathetic hyperarousal, autonomic hyperactivity, seizures, and excitotoxic neuronal death.

Clinical Phases of Alcohol Withdrawal

1. Minor Autonomic Hyperactivity (6 to 12 Hours): Fine resting and postural tremor, profuse diaphoresis, tachycardia ($> 100\text{ bpm}$), systolic hypertension, anorexia, nausea, vomiting, insomnia, and psychomotor agitation.
2. Alcoholic Hallucinosis (12 to 48 Hours): Perceptual abnormalities that may be auditory (voices, clicking), visual, or tactile (formication, sensation of insects under skin). Crucial AMC Diagnostic Distinction: Alcoholic hallucinosis occurs in a clear sensorium. The patient is alert, oriented to time, place, and person, and recognizes that their environment is real, differentiating this state from delirium.
3. Withdrawal Seizures ("Rum Fits") (24 to 48 Hours): Generalized tonic-clonic seizures occurring as a solitary event or a brief cluster of 2 to 3 discrete seizures within hours. Electroencephalography is normal between episodes. Status epilepticus is rare ($< 3\%$) and should prompt urgent search for concurrent intracranial pathology (subdural haematoma) or infection.
4. Delirium Tremens (DTs) (48 to 72+ Hours, peaking at 72-96 hours): The most severe manifestation of withdrawal, carrying an untreated mortality rate of $5-15\%$. Characterized by:
   • Global clouding of consciousness and delirium: Severe disorientation, fluctuating alertness, and profound agitation.
   • Autonomic instability: Severe hyperpyrexia (temperature $> 38.5^\circ\text{C}$), marked resting tachycardia ($> 120-140\text{ bpm}$), labile severe hypertension, and drenching diaphoresis.
   • Coarse gross tremor and polymorphic visual/tactile hallucinations.
   • Medical Complications: Cardiovascular collapse, severe electrolyte derangements (hypokalaemia, hypomagnesaemia, hypophosphataemia), aspiration pneumonia, and cardiac arrhythmias.

Clinical Assessment: The CIWA-Ar Protocol

• Withdrawal assessment: CIWA-Ar can guide symptom-triggered therapy in a communicative suitable patient. It is unreliable in delirium, intubation or major symptom confounding. High-risk cases can need fixed/loading regimens and higher-acuity monitoring; use the local addiction pathway and treat competing illness.
• Score $< 10$: Mild withdrawal; supportive care, quiet environment, oral hydration.
• Score $10-19$: Moderate withdrawal; triggers medical pharmacotherapy with benzodiazepines.
• Score $\ge 20$: Severe withdrawal; aggressive benzodiazepine titration, high-acuity nursing observation.

Pharmacotherapy of Alcohol Withdrawal

• Symptom-Triggered Benzodiazepine Regimen: Rather than fixed-dose schedules, Australian guidelines recommend symptom-triggered therapy, administering benzodiazepines only when the CIWA-Ar score is $\ge 10$. This approach reduces the total duration of treatment and cumulative drug exposure.
• Diazepam: The drug of choice in standard patients due to its rapid oral absorption and long-acting active metabolites (nordiazepam / desmethyldiazepam), which provide a smooth, "self-tapering" clinical effect. Typical regimen: diazepam $10-20\text{ mg}$ orally every 1 to 2 hours until the patient is calm and CIWA-Ar is $< 10$.
• Hepatic Impairment and the Elderly: In patients with decompensated chronic liver disease (cirrhosis, elevated INR, jaundice) or frail elderly patients, long-acting benzodiazepines accumulate, risking prolonged sedation and hepatic encephalopathy. In this cohort, short-acting agents directly metabolized by glucuronidation without active metabolites are mandatory: oxazepam $15-30\text{ mg}$ orally or lorazepam $1-2\text{ mg}$ orally/IV.

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Wernicke's Encephalopathy and Korsakoff Syndrome

Wernicke's encephalopathy (WE) is an acute, life-threatening neuropsychiatric syndrome resulting from thiamine (vitamin B1) deficiency. Thiamine pyrophosphate is an obligatory cofactor for key enzymes in cerebral energy metabolism (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase). Thiamine deficiency leads to selective neuronal death in the mammillary bodies, thalamus, periaqueductal grey matter, and cerebellar vermis.

Primary references (checked 7 October 2026): Australian alcohol treatment guidance.