Alcohol withdrawal syndrome

Alcohol withdrawal syndrome is the set of symptoms seen when an individual reduces or stops alcohol consumption after prolonged periods of excessive alcohol intake. Excessive abuse of alcohol leads to tolerance, physical dependence, and an alcohol withdrawal syndrome. The withdrawal syndrome is largely due to the central nervous system being in a hyper-excitable state. Unlike most withdrawals from other drugs, alcohol withdrawal can be fatal. The withdrawal syndrome can include seizures and delirium tremens and may lead to excito-neurotoxicity.

Background
Sedative-hypnotics such as alcohol are well known for their propensity to induce physiological dependence. Alcohol withdrawal occurs as a result of neuro-adaptation resulting from chronic exposure to alcohol. A withdrawal syndrome occurs upon declining blood levels of alcohol which can be alleviated by reintroduction of alcohol or a cross-tolerant agent. Alcohol withdrawal is characterized by neuropsychiatric excitability and autonomic disturbances similar to other sedative-hypnotic drugs. Dependence on other sedative-hypnotics increases the severity of the withdrawal syndrome.

Signs and symptoms
The severity of the alcohol withdrawal syndrome can vary from mild symptoms such as mild sleep disturbances and mild anxiety to very severe and life threatening including delirium, particularly visual hallucinations in severe cases and convulsions (which may result in death). These symptoms appear characteristically on waking, due to the fall in the blood alcohol concentration during sleep. The severity of alcohol withdrawal depends on various factors including age, genetics, and, most importantly, degree of alcohol intake and length of time the individual has been misusing alcohol and number of previous detoxifications.

• 2

Protracted withdrawal
A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to as the post acute withdrawal syndrome. Some withdrawal symptoms can linger for at least a year after discontinuation of alcohol. Symptoms can include a craving for alcohol, inability to feel pleasure from normally pleasurable things (also known as anhedonia), clouding of sensorium, disorientation, nausea and vomiting or headache. Insomnia is also a common protracted withdrawal symptom which persists after the acute withdrawal phase of alcohol. Insomnia has also been found to influence relapse rate. Studies have found that magnesium or trazodone can help treat the persisting withdrawal symptom of insomnia in recovering alcoholics. Insomnia can be difficult to treat in alcoholics because many of the traditional sleep aids (e.g. benzodiazepine receptor agonists and barbiturate receptor agonists) work via a GABAA receptor mechanism and are cross tolerant with alcohol. However, trazodone is not cross tolerant with alcohol. The acute phase of the alcohol withdrawal syndrome can also occasionally be protracted. Protracted delirium tremens has been reported in the medical literature as a possible but unusual feature of alcohol withdrawal.

Pathophysiology
Chronic use of alcohol leads to changes in brain chemistry especially in the GABAergic system. Various adaptations occur such as changes in gene expression and down regulation of GABAA receptors. During acute alcohol withdrawal, changes also occur such as upregulation of alpha4 containing GABAA receptors and down regulation of alpha1 and alpha3 containing GABAA receptors. Neurochemical changes occurring during alcohol withdrawal can be minimized with drugs which are used for acute detoxification. With abstinence from alcohol and cross tolerant drugs these changes in neurochemistry gradually return towards normal. Adaptations to the NMDA system also occur as a result of repeated alcohol intoxication and are involved in the hyper-excitability of the central nervous system during the alcohol withdrawal syndrome. Homocysteine levels which are elevated during chronic drinking increase even further during the withdrawal state and may result in excito-neurotoxicity. Alterations in ECG, in particular an increase in QT interval, and EEG abnormalities including may occur during early withdrawal.

Kindling
Kindling is the phenomenon where repeated alcohol detoxifications lead to an increased severity of the withdrawal syndrome. For example, binge drinkers may initially experience no withdrawal symptoms but with each period of resumption of drinking followed by abstinence their withdrawal symptoms intensify in severity and may eventually result in full blown delirium tremens with convulsive seizures. Alcoholics who experience seizures during hospital detoxification have been found to be much more likely to have experienced more previous alcohol detoxification episodes than alcoholics who did not have seizures. Those experiencing previous detoxification are more likely to have more medically complicated alcohol withdrawal symptoms. Kindling can cause complications and may increase the risk of relapse, alcohol related brain damage and cognitive deficits. Chronic alcohol misuse and kindling via multiple alcohol withdrawals may lead to permanent alterations in the GABAA receptors.

The mechanism behind kindling is sensitization of some neuronal systems and desensitization of other neuronal systems which leads to increasingly gross neurochemical imbalances. This in turn leads to more profound withdrawal symptoms including anxiety, convulsions and neurotoxicity.

Binge drinking is associated with increased impulsivity, impairments in spatial working memory and impaired emotional learning. These adverse effects are believed to be due to the neurotoxic effects of repeated withdrawal from alcohol on aberrant neuronal plasticity and cortical damage. Repeated periods of acute intoxication followed by acute detoxification has profound effects on the brain and is associated with an increased risk of seizures as well as cognitive deficits. The effects on the brain are similar to those seen in alcoholics who have been detoxified multiple times but not as severe as in alcoholics who have no history of prior detox. Thus the acute withdrawal syndrome appears to be the most important factor in causing damage or impairment to brain function. The brain regions most sensitive to harm from binge drinking are the amygdala and prefrontal cortex.

People in adolescence who experience multiple withdrawals from binge drinking show impairments of long-term nonverbal memory. Alcoholics who have had two or more alcohol withdrawals show more frontal lobe cognitive dysfunction than alcoholics who have experienced one or no prior withdrawals. Kindling of neurons is the proposed cause of withdrawal related cognitive damage. Kindling from multiple withdrawals leads to accumulating neuroadaptational changes. Kindling may also be the reason for cognitive damage seen in binge drinkers.

Diagnosis
Many hospitals use the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol in order to assess the level of withdrawal present and therefore the amount medication needed. When overuse of alcohol is suspected but drinking history is unclear, testing for elevated values of carbohydrate-deficient transferrin and/or gammaglutamyl transferase can help make the diagnosis of alcohol overuse and dependence more clear.

Treatment
Benzodiazepines are effective for the management of symptoms as well as the prevention of seizures.

Treatment of alcohol withdrawal syndrome can be managed with various pharmaceutical medications including barbiturates and clonidine. Certain vitamins are also an important part of the management of alcohol withdrawal syndrome.


 * Benzodiazepines

Benzodiazepines such as diazepam or lorazepam, are the most commonly used drug for the treatment of alcohol withdrawal and are generally safe and effective in suppressing alcohol withdrawal signs. Chlordiazepoxide and diazepam are the benzodiazepines most commonly used in alcohol detoxification. Benzodiazepines can be life saving, particularly if delirium tremens appears during alcohol withdrawal. Benzodiazepines should only be used short term in alcoholics who aren't already dependent on benzodiazepines as benzodiazepines share cross tolerance with ethanol and there is a risk of replacing the addiction with a benzodiazepine dependence or worse still adding an additional addiction. Furthermore, disrupted GABA benzodiazepine receptor function is part of alcohol dependence and chronic benzodiazepines may prevent full recovery from alcohol induced mental effects. Benzodiazepines have the problem of increasing cravings for alcohol in problem alcohol consumers and they also increase the volume of alcohol consumed by problem drinkers. The combination of benzodiazepines and alcohol can amplify the adverse psychological effects of each other causing enhanced depressive effects on mood and increase suicidal actions and are generally contraindicated except for alcohol withdrawal.


 * Antipsychotics

Antipsychotic agents such as haloperidol are sometimes used for alcohol withdrawal as an add-on to first-line measures such as benzodiazepines to control agitation or psychosis. Antipsychotics may potentially worsen alcohol withdrawal effects (or other CNS depressant withdrawal states) as they lower the seizure threshold and can worsen withdrawal effects. Clozapine, olanzapine or low potency phenothiazines (e.g. chlorpromazine) are particularly risky; if used, extreme caution is required. There is also concern for this class of drugs prolonging the QT interval, sometimes leading to fatal heart dysrhthmias.


 * Anticonvulsants

Some evidence indicates that topiramate carbamazepine and other anticonvulsants are effective in the treatment of alcohol withdrawal however, research is limited. A Cochrane review similarly reported that the evidence to support the role of anticonvulsants over benzodiazepines in the treatment of alcohol withdrawal is not statistically significant and noted significant weaknesses in the studies available and recommended further research. The Cochrane Review did note however, that paraldehyde combined with chloral hydrate showed superiority over chlordiazepoxide with regard to incidence of life threatening side effects and also noted that carbamazapine may have advantages for certain symptoms. The advantages of carbamazapine demonstrated in one trial are less rebound withdrawal symptoms and appears to have a higher success rate for abstinence from alcohol post detoxification compared to benzodiazepines.


 * Baclofen

Baclofen has been shown to be as effective as diazepam in uncomplicated alcohol withdrawal syndrome.


 * Barbiturates

Barbiturates are superior to diazepam in the treatment of severe alcohol withdrawal syndromes such as delirium tremens but equally effective in milder cases of alcohol withdrawal.


 * Clomethiazole

Clomethiazole (Heminevrin) is a non-benzodiazepine sedative-hypnotic with anticonvulsant effects which is active on the barbiturate site of the GABA-A receptor. Clomethiazole also inhibits the enzyme alcohol dehydrogenase, which is responsible for breaking down alcohol in the body. This slows the rate of elimination of alcohol from the body, which helps to relieve the sudden effects of alcohol withdrawal in alcoholics.


 * Clonidine

Clonidine has demonstrated superior clinical effects in the suppression of alcohol withdrawal symptoms in a head to head comparison study with the benzodiazepine drug chlordiazepoxide.


 * Ethanol

Alcohol (ethanol) itself at low doses has been found to be superior to chlordiazepoxide in the detoxification of alcohol dependent patients. Low dose ethanol as a means of weaning alcoholics off of alcohol was found to produce less profound sleep disturbances during withdrawal. Low dose ethanol has been found to reduce treatment time, improve the failure rate from 20% down to 7% and increase retention in treatment centers with an increased rate of alcoholics attending substance misuse clinics after detoxification.


 * Flumazenil

Flumazenil, which has shown some promise in the management of the benzodiazepine withdrawal syndrome has also demonstrated benefit in a research study in reducing anxiety withdrawal related symptomatology during alcohol withdrawal.


 * Trazodone

Trazodone has demonstrated efficacy in the treatment of the alcohol withdrawal syndrome. It may have particular use in withdrawal symptoms, especially insomnia, persisting beyond the acute withdrawal phase.


 * Magnesium

Magnesium appears to be effective in the treatment of alcohol withdrawal related cardiac arrhythmias. It is ineffective in controlling other symptoms of alcohol withdrawal.


 * Vitamins

The prophylactic administration of thiamine intravenously is recommended before starting any carbohydrate containing fluids or food. Alcoholics are often deficient in various nutrients which can cause severe complications during alcohol withdrawal such as the development of Wernicke syndrome. The vitamins of most importance in alcohol withdrawal are thiamine and folic acid. To help to prevent Wernicke syndrome alcoholics should be administered a multivitamin preparation with sufficient quantities of thiamine and folic acid. Vitamins should always be administered before any glucose is administered otherwise Wernicke syndrome can be precipitated.

Prevention of brain damage
It has been proposed that brain damage due to alcohol withdrawal may be prevented by the administration of NMDA antagonists, calcium antagonists, and glucocorticoid antagonists. The NMDA antagonist acamprosate reduces excessive glutamate rebound thereby suppressing excitotoxicity and potential withdrawal related neurotoxicity.

Substances impairing recovery
Continued use of benzodiazepines may impair recovery from psychomotor and cognitive impairments from alcohol. Cigarette smoking may slow down or interfere with recovery of brain pathways in recovering alcoholics.