Aetiology

Alcohol withdrawal syndrome (AWS) is caused by abstinence from alcohol in a person with alcohol dependence.[16] It is characterised by signs of overactivity of the sympathetic nervous system.[17]

Chronic alcohol use results in up-regulation of post-synaptic N-methyl-D-aspartate (NMDA) receptors and down-regulation of post-synaptic gamma-aminobutyric acid (GABA) receptors. A decrease in blood ethanol concentration due to abrupt cessation in alcohol consumption results in an imbalance between stimulatory (NMDA) and inhibitory (GABA) systems in the central nervous system. Excessive stimulatory effect leads to the development of the clinical signs and symptoms of AWS.[13][18][19][20][21]

Pathophysiology

Ethanol interacts with two major receptors in the central nervous system (CNS) that are essential for normal CNS function: gamma-aminobutyric acid (GABA) type A receptors and N-methyl-D-aspartate (NMDA) receptors.

Ethanol predominantly targets the GABA type A receptor, where the persistent stimulation of inhibitory receptors results in downregulation of the GABA type A receptor/Cl- channel complex.[18][19][20][21] The adaptive downregulation of GABA type A receptors also contributes to the development of tolerance by allowing alcohol users to maintain a level of consciousness despite the presence of a sedative ethanol concentration.​[20][21]

Among numerous different excitatory amino acid receptor systems, the presence of a persistent blood ethanol concentration primarily affects the expression of the post-synaptic NMDA receptor-Ca+2 channel complex. In contrast to GABA type A receptor agonism, ethanol inhibits the NMDA receptor function by competitively binding to the glycine binding site on the NMDA receptor. This inhibitory effect causes a compensatory upregulation of NMDA receptors on the post-synaptic membrane.

At the pre-synaptic level, chronic alcohol use increases excitatory glutamate release while re-uptake of glutamate is inhibited.[19][21][22][23] There is evidence to suggest that acute alcohol use increases pre-synaptic GABA release.[19][21][24][25] However, the relationship between chronic alcohol use and alteration of pre-synaptic release of GABA is currently not well understood.

Adaptive mechanisms in neurotransmitter-receptor interaction maintain homeostasis between excitatory (NMDA) and inhibitory (GABA) receptor systems and mediate the development of alcohol tolerance. Abstinence from alcohol in the alcohol-dependent patient leads to a disequilibrium between NMDA and GABA type A receptor function due to decreased blood ethanol concentration from the previously maintained steady-state level. As a result, excessive glutamatergic stimulation with diminished inhibitory (GABA) activity leads to the development of clinical symptoms of alcohol withdrawal syndrome (AWS), including autonomic hyperactivity, tremors, hallucinations, and seizures.[21]

Multiple episodes of AWS increase the severity of subsequent AWS due to kindling phenomena. Kindling is a process where low chemical or electrical stimulus, which does not normally produce a behavioural response, results in behavioural effects, such as seizure, from repetitive administration.[26][27] There is a growing body of evidence that kindling phenomena contribute to the exacerbation of withdrawal symptoms.[26] Clinically, a significant proportion of patients with AWS who suffer seizures have a history of multiple episodes of AWS compared with patients with AWS who do not have associated seizures.[28][29][30]

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