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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 use 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. The withdrawal syndrome can include seizures and delirium tremens and may lead to excito-neurotoxicity.

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.

Alcohol withdrawal
As with similar substances with a sedative-hypnotic mechanism, such as barbiturates and benzodiazepines, withdrawal from alcohol dependence can be fatal if it is not properly managed. Alcohol's primary effect is the increase in stimulation of the GABAA receptor, promoting central nervous system depression. With repeated heavy consumption of alcohol, these receptors are desensitized and reduced in number, resulting in tolerance and physical dependence. When alcohol consumption is stopped too abruptly, the person's nervous system suffers from uncontrolled synapse firing. This can result in symptoms that include anxiety, life threatening seizures, delirium tremens, hallucinations, shakes and possible heart failure. Other neurotransmitter systems are also involved, especially dopamine, NMDA and glutamate.

Severe acute withdrawal symptoms such as delerium tremens and seizures rarely occur after 1 week post cessation of alcohol. The acute withdrawal phase can be defined as lasting between one and three weeks. In the period of 3 – 6 weeks following cessation increased anxiety, depression as well as sleep disturbance is common; fatigue and tension can persist for up to 5 weeks as part of the post-acute withdrawal syndrome; about a quarter of alcoholics experience anxiety and depression for up to 2 years. These post-acute withdrawal symptoms have also been demonstrated in animal models of alcohol dependence and withdrawal. A kindling effect also occurs in alcoholics whereby each subsequent withdrawal syndrome is more severe than the previous withdrawal episode; this is due to neuroadaptations which occur as a result of periods of abstinence followed by re-exposure to alcohol. Individuals who have had multiple withdrawal episodes are more likely to develop seizures and experience more severe anxiety during withdrawal from alcohol than alcohol dependent individuals without a history of past alcohol withdrawal episodes. The kindling effect leads to persistent functional changes in brain neural circuits as well as to gene expression. Kindling also results in psychological symptoms of alcohol withdrawal becoming more intensified.

Symptoms
Physical dependence can manifest itself in the appearance of both physical and psychological symptoms which are caused by physiological adaptions in the central nervous system and the brain due to chronic exposure to a substance. Symptoms which may be experienced during withdrawal or reduction in dosage include increased heart rate and/or blood pressure, sweating, and tremors. More serious withdrawal symptoms such as confusion, seizures, and visual hallucinations indicate a serious emergency and the need for immediate medical care. Sedative hypnotic drugs such as alcohol, benzodiazepines, and barbiturates are the only commonly available substances that can be fatal in withdrawal due to their propensity to induce withdrawal convulsions. Abrupt withdrawal from other drugs, such as opioids can cause an extremely physiologically and psychologically painful withdrawal that is very rarely fatal in patients of general good health and with medical treatment, but is more often fatal in patients with weakened cardiovascular systems; toxicity is generally caused by the often-extreme increases in heart rate and blood pressure (which can be treated with clonidine), or due to arrhythmia due to electrolyte imbalance caused by the inability to eat, and constant diarrhea and vomiting (which can be treated with loperamide and ondansetron respectively) associated with acute opioid withdrawal, especially in longer-acting substances where the diarrhea and emesis can continue unabated for weeks, although life-threatening complications are extremely rare, and nearly non-existent with proper medical management. Dependence itself and chronic intoxication on psychostimulants can cause mild-to-moderate neurotoxic effects due to hyperthermia and generation of free radicals.; this is treated with discontinuation; life-threatening complications are nonexistent.

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 initially 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 using alcohol and number of previous detoxifications.

• Agitation

• Alcoholic hallucinosis

• Anorexia

• Anxiety and panic attacks

• Catatonia

• Confusion

• Delirium tremens

• Depersonalization

• Depression

• Derealization

• Diaphoresis

• Diarrhea

• Euphoria

• Fear

• Gastrointestinal upset

• Hallucinations

• Headache

• Hypertension

• Hyperthermia (fever)

• Insomnia

• Irritability

• Migraines

• Nausea and vomiting

• Palpitations

• Psychosis

• Rebound REM sleep

• Restlessness

• Seizures and death

• Tachycardia

• Tremors

• Weakness

Progression of symptoms
Typically the severity of the symptoms experienced will depend on the amount and duration of prior alcohol consumption, as well as the number and severity of previous withdrawals. Even the most severe of these symptoms can occur in as little as 2 hours after cessation, therefore the overall unpredictability necessitates either pre-planned hospitalization, treatment coordinated with a doctor, or at the very least fast access to medical care and a supporting system of friends or family should be introduced prior to addressing detoxification. In many cases however, symptoms follow a reasonably predictable time frame as exampled below:

6 to 12 hours after the ingestion of the last drink, withdrawal symptoms such as shaking, headache, sweating, anxiety, nausea or vomiting occur. Other comparable symptoms may also exist in this period. 12 to 24 hours after cessation, the condition may progress to such major symptoms as confusion, hallucinations, (with awareness of reality) tremor, agitation, and similar ailments. It's between the 24 and 48 hour period that seizures typically may begin to emerge among the previous symptoms in the period, and this is where the serious risk of mortality begins. Although most often, the condition begins to improve past the 48 hour mark, it can sometimes continue to increase in severity to delirium tremens, characterized by hallucinations that are indistinguishable from reality, severe confusion, more seizures, high blood pressure and fever which can persist anywhere from 4 to 12 days.

Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as misuse of recreational drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months, and protracted withdrawal syndrome, also known as "post-acute withdrawal syndrome" or "PAWS" - a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, that often results in relapse in to active addiction and prolonged disability of a degree to preclude the possibility of lawful employment - can last for months, years, or, in relatively common to extremely rare cases, depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines, but is also present in a majority of cases of alcohol and opioid addiction, especially that of a long-term, high-dose, adolescent-beginning, or chronic-relapsing nature (viz. a second or third addiction after withdrawal from the self-same substance of dependence). Withdrawal response will vary according to the dose used, the type of drug used, the duration of use, the age of the patient, the age of first use, and the individual person.

Treatment
Treatment for physical dependence depends upon the drug being withdrawn and often includes administration of another drug, especially for substances that can be dangerous when abruptly discontinued. Physical dependence is usually managed by a slow dose reduction over a period of weeks, months or sometimes longer depending on the drug, dose and the individual. A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.

Drugs that cause physical dependence

 * All µ-opioids with any (even slight) agonist effect, such as (partial list) morphine, heroin, codeine, oxycodone, buprenorphine, nalbuphine, methadone, and fentanil, but not agonists specific to non-µ opioid receptors, such as salvinorin A (a k-opioid agonist), nor opioid antagonists or inverse agonists, such as naltrexone (a universal opioid inverse agonist)
 * All GABA agonists and positive allosteric modulators of both the GABA-A ionotropic receptor and GABA-B metabotropic receptor subunits, of which the following drugs are examples (partial list):
 * barbiturates such as phenobarbital, sodium thiopental and secobarbital
 * benzodiazepines such as diazepam (Valium), lorazepam (Ativan), and alprazolam (Xanax) (see benzodiazepine dependence and benzodiazepine withdrawal syndrome)
 * nonbenzodiazepines (z-drugs) such as zopiclone and zolpidem.
 * ethyl alcohol (alcoholic beverage) (cf. alcohol dependence, alcohol withdrawal, delirium tremens)
 * gamma-hydroxybutyric acid (GHB) and 1,4-butanediol
 * carisoprodol (Soma) and related carbamates (tybamate and meprobamate)
 * baclofen (Lioresal) and its non-chlorinated analogue phenibut
 * chloral hydrate
 * glutethimide
 * clomethiazole
 * methaqualone (Quaalude)
 * gabapentin (Neurontin) and pregabalin (Lyrica), calcium channel modifiers that affect GABA
 * antiepileptic drugs such as valproate, lamotrigine, tiagabine, vigabatrin, carbamazepine and oxcarbazepine, and topiramate
 * possibly neuroleptic drugs such as clozapine, risperidone, olanzapine, haloperidol, thioridazine, etc.
 * commonly prescribed antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (cf. SSRI/SNRI withdrawal syndrome)
 * Nicotine
 * blood pressure medications, including beta blockers such as propanolol and alpha-adrenergic agonists such as clonidine
 * androgenic-anabolic steroids
 * glucocorticoids
 * Cocaine

Drugs such as amphetamines (including methamphetamine and methylenedioxymethylamphetamine (MDMA)), cathinone, hallucinogens (such as LSD, psilocin, and mescaline), cannabis (tetrahydrocannabinol) do not cause physical dependency/physical addiction,

Rebound syndrome
A wide range of drugs whilst not causing a true physical dependence can still cause withdrawal symptoms or rebound effects during dosage reduction or especially abrupt or rapid withdrawal. These can include caffeine, stimulants,   steroidal drugs and antiparkinsonian drugs. It is debated if the entire antipsychotic drug class causes true physical dependency, if only a subset do, or if none do, but all, if discontinued too rapidly, cause an acute withdrawal syndrome. Drugs like cocaine, marijuana, amphetamines, and hallucinogens can be associated with minimal physical dependence but can still cause withdrawal or rebound symptoms. However, with sustained and heavy cocaine abuse signs of physiological dependence may occur. When talking about illicit drugs rebound withdrawal is, especially with stimulants, sometimes referred to as "coming down" or "crashing".

Some drugs, like anticonvulsants and antidepressants, describe the drug category and not the mechanism. The individual agents and drug classes in the anticonvulsant drug category act at many different receptors and it is not possible to generalize their potential for physical dependence or incidence or severity of rebound syndrome as a group so need to be looked at individually. Anticonvulsants as a group however are known to cause tolerance to the anti-seizure effect. SSRI drugs, which have an important use as antidepressants, are considered to cause physical dependence, although it is considered mild compared to drugs like opioids and GABA modulators, but they engender a discontinuation syndrome, which was originally called "SSRI withdrawal" until a 1997 symposium sponsored by Pfizer and Eli Lilly (the producers of several anti-depressants including Prozac and Effexor) was held, with the drug representative attendees concluding that "discontinuation syndrome" sounded less threatening than "withdrawal"; however, "SSRI discontinuation syndrome" is a withdrawal syndrome upon discontinuation of SSRI/SNRI drugs, just as "heroin discontinuation syndrome" is a synonym for "heroin withdrawal". Due to this, in Europe these drugs cannot be advertised as "non-habit forming". There have been case reports of dependence with venlafaxine (Effexor).

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.

Post-acute-withdrawal syndrome (PAWS), or the terms post-withdrawal syndrome, protracted withdrawal syndrome,proloned withdrawal syndromes describe a set of persistent impairments that occur after withdrawal from alcohol, opiates, benzodiazepines, antidepressants and other substances. Infants born to mothers who used substances of dependence during pregnancy may also experience a post acute withdrawal syndrome. Post acute withdrawal syndrome affects many aspects of recovery and everyday life, including the ability to keep a job and interact with family and friends. Symptoms occur in over 90% of people withdrawing from a long-term opioid (such as heroin habit), three-quarters of persons recovering from long-term use of alcohol, methamphetamine, or benzodiazepines and to a lesser degree other psychotropic drugs. Post-acute withdrawal syndrome as a result of GABA-agonist (benzodiazepine, barbiturate, ethanol) dependence and opioid dependence can last from a year to several decades, or indefinitely, with the symptoms entering in to periods of relative remission between periods of instability. Symptoms include mood swings resembling an affective disorder, anhedonia (the inability to feel pleasure from anything beyond use of the drug) insomnia, extreme drug craving and obsession, anxiety and panic attacks, depression, suicidal ideation and suicide and general cognitive impairment.

Background
Drug abuse, including alcohol and prescription drugs can induce symptomatology which resembles mental illness. This can occur both in the intoxicated state and also during the withdrawal state. In some cases these substance induced psychiatric disorders can persist long after detoxification, such as prolonged psychosis or depression after amphetamine or cocaine abuse. A protracted withdrawal syndrome can also occur with symptoms persisting for months after cessation of use. Benzodiazepines are the most notable drug for inducing prolonged withdrawal effects with symptoms sometimes persisting for years after cessation of use. Severe anxiety and depression are commonly induced by sustained alcohol abuse which in most cases abates with prolonged abstinence. Even moderate alcohol sustained use may increase anxiety and depression levels in some individuals. In most cases these drug induced psychiatric disorders fade away with prolonged abstinence.

Cause
The syndrome may be in part due to persisting physiological adaptions in the central nervous system manifested in the form of continuing but slowly reversible tolerance, disturbances in neurotransmitters and resultant hyperexcitability of neuronal pathways. The symptoms of post acute withdrawal syndrome occur because the brain's ability to react to stress has been weakened by long-term substance use. Stressful situations arise in early recovery, and the symptoms of post acute withdrawal syndrome produce further distress. It is important to avoid or to deal with the triggers that make post acute withdrawal syndrome worse. The types of symptomology and impairments in severity, frequency, and duration associated with the condition vary depending on the drug of use.

Symptoms
Symptoms can sometimes come and go with wave-like reoccurrences or fluctuations in severity of symptoms. Common symptoms include impaired cognition, irritability, depressed mood, and anxiety; all of which may reach severe levels which can lead to relapse.

The protracted withdrawal syndrome from benzodiazepines can produce symptoms identical to generalised anxiety disorder as well as panic disorder. Due to the sometimes prolonged nature and severity of benzodiazepine withdrawal, abrupt withdrawal is not advised.

Common symptoms of post acute withdrawal syndrome are:
 * Psychosocial dysfunction
 * Anhedonia
 * Depression
 * Impaired interpersonal skills
 * Obsessive-compulsive behaviour
 * Feelings of guilt
 * Autonomic disturbances
 * Pessimistic thoughts
 * Impaired concentration
 * Lack of initiative
 * Craving
 * Inability to think clearly
 * Memory problems
 * Emotional overreactions or numbness
 * Sleep disturbances
 * Physical coordination problems
 * Stress sensitivity
 * Increased sensitivity to pain
 * Panic disorder
 * Generalised anxiety disorder
 * Sleep distubance (dreams of using, behaviors associated with the life style)

Symptoms occur intermittently, but are not always present. They are made worse by stress or other triggers and may arise at unexpected times and for no apparent reason. They may last for a short while or longer. Any of the following may trigger a temporary return or worsening of the symptoms of post acute withdrawal syndrome:


 * Stressful and/or frustrating situations
 * Multitasking
 * Feelings of anxiety, fearfulness or anger
 * Social Conflicts
 * Unrealistic expectations of oneself

Post-acute benzodiazepine withdrawal
Disturbances in mental function can persist for several months or years after withdrawal from benzodiazepines. Psychotic depression persisting for more than a year following benzodiazepine withdrawal has been documented in the medical literature. The patient had no prior psychiatric history. The symptoms reported in the patient included, major depressive disorder with psychotic features, including persistent depressed mood, poor concentration, decreased appetite, insomnia, anhedonia, anergia and psychomotor retardation. The patient also experienced paranoid ideation (believing she was being poisoned and persecuted by co-employees), accompanied by sensory hallucinations. Symptoms developed after abrupt withdrawal of chlordiazepoxide and persisted for 14 months. Various psychiatric medications were trialed which were unsuccessful in alleviating the symptomatology. Symptoms were completely relieved by recommending chlordiazepoxide for irritable bowel syndrome 14 months later. Another case report, reported similar phenomenon in a female patient who abruptly reduced her diazepam dosage from 30 mg to 5 mg per day. She developed electric shock sensations, depersonalisation, anxiety, dizziness, left temporal lobe EEG spiking activity, hallucinations, visual perceptual and sensory distortions which persisted for years.

A clinical trial of patients taking the benzodiazepine alprazolam (Xanax) for as little as 8 weeks triggered protracted symptoms of memory deficits which were still present after up to 8 weeks post cessation of alprazolam.

Treatment
The condition gradually improves over a period of time which can range from six months to several years in more severe cases. Acamprosate has been found to be effective in alleviating some of the post acute withdrawal symptoms of alcohol withdrawal. Carbamazepine or trazodone may also be effective in the treatment of post acute withdrawal syndrome. Cognitive behavioural therapy can also help the post acute withdrawal syndrome especially when cravings are a prominent feature.

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. Dysfunction of the hypothalamic–pituitary–adrenal axis and increased release of corticotropin-releasing hormone occur during both acute as well as protracted abstinence from alcohol and contribute to both acute and protracted withdrawal symptoms. Anhedonia/dysphoria symptoms, which can persist as part of a protracted withdrawal may be due to dopamine underactivity.

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, but only when given intravenously by medical personnel, 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.

Nitrous Oxide
Nitrous oxide has been shown to be an effective and safe treatment for alcohol withdrawal. Over 20,000 cases of the alcoholic withdrawal state have been successfully treated with PAN in South Africa and Finland. In 1992 it was officially approved for the treatment of addictive withdrawal states by the medical authorities in South Africa. Consequently, patients receiving it can claim a refund from their medical insurance. The gas therapy reduces the use of highly addictive sedative medications (like benzopdiazepines and barbiturates) by over 90%. The technique thus reduces the danger of secondary addiction to benzodiazepines, which can be a real problem amongst alcoholics who have been treated with these agents. 

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
Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. 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. A cheaper, non prescription substance would be dextromethorphan, with is metabolized into dextrothrophan, which has calcium channel and NMDA blocking effects. Any NMDA antagonist is likely to be of benefit in alcohol withdrawal, due to the upregulated nature of ligand gated calcium channels due to the downregulated GABAA Cl- channel.

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.