Case 8: Malcolm Lowry - Alcohol Use Disorder

Endogenous Reward System

Mesolimbic dopaminergic reward pathway

Motivation centre reinforcing behaviours causing satisfaction

Endogenous Reward System: Parts

Ventral tegmental area (VTA)

Nucleus accumbens (NAc)

Modulating areas

Endogenous Reward System: VTA

Region in midbrain

Contain dopamine

Endogenous Reward System: NAc

Region in forebrain

Contain GABAergic neurons

Part of limbic system

Endogenous Reward System: Modulating Areas

Prefrontal Cortex: Decision-making

Amygdala: Emotions/fear

Hippocampus: Memory

Thalamus

Endogenous Reward System: Normal Function

For survival

1. Stimulus perception = Dopamine relese from VTA → NAc = Increase motivation for action

2. Perform action/behaviour = NAc releases signals to

• VTA: Disinhibit dopamine neurons = Positive reinforcement

• Hypothalamus: Stimulate GABAergic neurons = Aversive response

3. Repeating behaviour = Long-term potentiation (association between stimulus + response) = Behaviour → Habit requiring less conscious effort

Alcohol: Description

CNS depressant

Alcohol: Absorption

Small intestine

Alcohol: Metabolism

Liver

1. Alcohol Dehydrogenase: Ethanol oxidation → Acetaldehyde

2. Acetaldehyde Dehydrogenase: Acetaldehyde oxidation → Acetate

• Rate-limiting step

  • Slower than alcohol dehydrogenase

3. Thiokinase: Acetate + coenzyme A → Acetyl-CoA

Substance Use Disorder (SUD): Description

Chronic condition with uncontrolled substance use patterns causing physical, psychological, and social impairment/distress

Types:

• Alcohol use disorder (AUD)

• OUD

• Tobacco use disorder (TUD)

• Cannabis use disorder (CUD)

AUD: Tolerance

Increasing alcohol amounts for same effect

AUD: Withdrawal

Signs + symptoms from reducing/stopping alcohol intake

AUD: Dependence

Dysregulated alcohol use from repeated/continuous use

SUD: Epidemiology

More common in men

Most common substance: Alcohol + nicotine

Risk Factors:

• Family history

• Psychiatric disorders

SUD: Etiology

Genetics

Neurobiological factors

Psychosocial factors

SUD Etiology: Neurobiological Factors

Dopamine receptor mutation = Increased density

Decreased dopamine metabolism efficacy

SUD Etiology: Psychosocial Factors

Childhood factors

• Observational Learning: Observing role models (parents, peers using drugs without perceiving negative consequences

• Social pressure to use from peers

• High ACEs

Low SES

Stress

SUD: Pathophysiology

Dysregulated endogenous reward system

Operant conditioning

SUD Pathophysiology: Dysregulated Endogenous Reward System

1. Hyperstimulation: Drugs cause increased/prolonged dopamine release from VTA → NAc

2. Perceptual Narrowing: Dopamine signals from drugs override natural rewards = Strong desire (craving)

3. Chronification: Repeated stimulus (drug) + response (high dopamine) = Positively reinforce neural pathway = Build habit

• Tolerance: Downregulate dopamine receptors = Same dose causes decreased pleasure = Increase craving (strong habit)

SUD Pathophysiology: Operant Conditioning

Positive Reinforcement: Drugs → Euphoria (increase dopamine) = Repeated use to feel better

Negative Reinforcement: Drugs → Remove withdrawal pain + anxiety = Repeated use to stop feeling bad

SUD: Diagnostic Criteria

DSM-5

≥2 within 1 year: CHEW REACH TW

• Impaired control

  • C: Craving

  • H: High amounts + longer time

  • E: Efforts to cut down fail

  • W: Wasting time on substance-related activities

• Social impairment

  • R: Relationship problems

  • E: External role problems

  • A: Activities reduced

• Risky use

  • C: Continuing despite awareness of problem

  • H: Hazardous situations

• Pharmacological indicators

  • Tolerance: Increasing dose to achieve desired effect

  • Withdrawal: Symptoms from stopping drug

    • Opposite of intoxication effects

    • NONE from hallucinogens + inhalants

SUD: Investigations

Neurological exam

Alcohol Misuse: Investigations

CAGE questionnaire

• Cut down

• Annoyed

• Guilty

• Eye-opener

AUDIT-C

Alcohol Dependence: Investigations

SADQ (Severity of Alcohol Dependence Questionnaire)

Alcohol Withdrawal: Investigations

CIWA (Clinical Institute of Withdrawal Assessment)

• Score symptom severity

AUD: Investigations

Blood tests

LFTs

AUD: Blood Tests

CBC + differentials

• Thrombocytopenia

• Increased MCV

  • Disrupted erythropoiesis

  • Decreased folate cycling

PT/INR

• Increased: Alcohol-associated hepatitis

Electrolytes

• Decreased

• Acid-base disturbances

  • Alkolosis

  • Alcoholic ketoacidosis

Blood alcohol level + ethanol metabolites

Creatinine

• Increased: Alcohol-induced kidney damage

AUD: LFTs

AST/ALT ≥ 1-1.5

• Alcohol-associated hepatitis

• AST ≤ 400 U/L

GGT: Increased

• Normal: 5-85 IU/L

SUD: Treatment/Management

Acute

Nonpharmacological

Pharmacological

SUD Management: Acute

5As

Counselling

Withdrawal

• Benzodiazepines: First-line

  • Ex: Lorazepam, oxazepam, diazepam

• Anticonvulsants: Second-line

  • Ex: Valproic acid, lamotrigine

SUD Management: Nonpharmacological

Lifestyle changes

• Healthy eating

• Vit supplements (B1, B6, folic acid)

Smoking cessation

Reduce relapse triggers

Psychotherapy

• CBT

• AA

SUD Management: Pharmacological

GABA analog

Opioid agonists

Opioid antagonists

Nicotinic receptor agonists

Atypical antidepressants

SUD Management: GABA Analog

Ex: Acamprosate

MOA: Decrease CNS glutamate receptor activity

Indications: AUD maintenance

SUD Management: Opioid Agonists

Ex: Methadone, buprenorphine + naloxone

MOA:

• μ-opioid receptor agonist

• N-methyl-D-aspartate (NMDA) receptor antagonist

Indications: OUD induction + maintenance

SUD Management: Opioid Antagonists

Ex: Naltrexone

MOA: CNS μ-opioid receptor antagonist = Decrease craving

Indications: AUD, OUD maintenance

SUD Management: Nicotinic Receptor Agonists

Varenicline

• MOA: Partial nicotine receptor agonist = Decrease cravings + withdrawal

Nicotine Replacement Therapy

• MOA: Short-acting nicotine receptor agonist = Decrease withdrawal

Indications: TUD

SUD Management: Atypical Antidepressants

Ex: Bupropion

MOA: Inhibit norepinephrine + dopamine reuptake inhibitors = Decrease cravings + withdrawal

Indications: TUD

AUD: Complications

Alcoholic ketoacidosis

Wernicke encephalopathy

Increased infections

Alcoholic Ketoacidosis: Pathophysiology

Alcohol disrupt glucose metabolism + starvation = Increase ketone bodies + normal/low glucose = HAGMA

Alcoholic Ketoacidosis: Treatment

Acute

• Thiamine: Prevent Wernicke encephalopathy

• IV dextrose

• Correct electrolyte imbalances

Wernicke Encephalopathy: Pathophysiology

Severe thiamine/B1 deficiency = Decreased cerebral glucose metabolism + mitochondrial dysfunction = Neuronal injury

• Prolonged = Korsakoff syndrome (irreversible)

Wernicke Encephalopathy: Clinical Presentation

Confusion

Oculomotor dysfunction

Gait ataxia: Wide base + small steps

Korsakoff Syndrome: Clinical Presentation

Amnesia + Confabulation

• Producing false memories to fill in gaps

Personality changes

Disorientation

Wernicke Encephalopathy: Treatment

Acute: IV thiamine

• BEFORE IV dextrose/glucose (worsen encephalopathy)

AUD Complications: Increased Infections

Aspiration pneumonia

Cellulitis

Sepsis

TB