Alcohol withdrawal syndrome | |
---|---|
Ethanol | |
Specialty | Toxicology, addiction medicine, intensive care medicine, psychiatry |
Symptoms | Anxiety, shakiness, sweating, vomiting, fast heart rate, mild fever [1] |
Complications | Seizures, delirium tremens, death |
Usual onset | Six hours following the last drink [2] |
Duration | Up to a week [2] |
Causes | Reduction or cessation of alcohol intake after a period of excessive use [1] |
Diagnostic method | Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) [3] |
Treatment | Benzodiazepines, thiamine [2] |
Frequency | ~50% of people with alcoholism upon reducing use [3] |
Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. [1] Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. [1] More severe symptoms may include seizures, and delirium tremens (DTs); which can be fatal in untreated patients. [1] Symptoms start at around 6 hours after the last drink. [2] Peak incidence of seizures occurs at 24-36 hours [5] and peak incidence of delirium tremens is at 48-72 hours. [6]
Alcohol withdrawal may occur in those who are alcohol dependent. [1] This may occur following a planned or unplanned decrease in alcohol intake. [1] The underlying mechanism involves a decreased responsiveness of GABA receptors in the brain. [3] The withdrawal process is typically followed using the Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). [3]
The typical treatment of alcohol withdrawal is with benzodiazepines such as chlordiazepoxide or diazepam. [2] Often the amounts given are based on a person's symptoms. [2] Thiamine is recommended routinely. [2] Electrolyte problems and low blood sugar should also be treated. [2] Early treatment improves outcomes. [2]
In the Western world about 15% of people have problems with alcoholism at some point in time. [3] Alcohol depresses the central nervous system, slowing cerebral messaging and altering the way signals are sent and received. Progressively larger amounts of alcohol are needed to achieve the same physical and emotional results. The drinker eventually must consume alcohol just to avoid the physical cravings and withdrawal symptoms. About half of people with alcoholism will develop withdrawal symptoms upon reducing their use, with four percent developing severe symptoms. [3] Among those with severe symptoms up to 15% die. [2] Symptoms of alcohol withdrawal have been described at least as early as 400 BC by Hippocrates. [7] [8] It is not believed to have become a widespread problem until the 1700s. [8]
Signs and symptoms of alcohol withdrawal occur primarily in the central nervous system. The severity of withdrawal can vary from mild symptoms such as insomnia, trembling, and anxiety to severe and life-threatening symptoms such as alcoholic hallucinosis, delirium tremens, and autonomic instability. [9] [10]
Withdrawal usually begins 6 to 24 hours after the last drink. [11] Symptoms are worst at 24 to 72 hours, and improve by seven days. [2] [3] To be classified as alcohol withdrawal syndrome, patients must exhibit at least two of the following symptoms: increased hand tremor, insomnia, nausea or vomiting, transient hallucinations (auditory, visual or tactile), psychomotor agitation, anxiety, generalized tonic–clonic seizures, and autonomic instability. [12]
The severity of symptoms is dictated by a number of factors, the most important of which are degree of alcohol intake, length of time the individual has been using alcohol, and previous history of alcohol withdrawal. [12] [13] Symptoms are also grouped together and classified:
Six to 12 hours after the ingestion of the last drink, withdrawal symptoms such as shaking, headache, sweating, anxiety, nausea or vomiting may occur. [15] Twelve to 24 hours after cessation, the condition may progress to such major symptoms as confusion, hallucinations [15] (with awareness of reality), while less severe symptoms may persist and develop including tremor, agitation, hyperactivity and insomnia. [13]
At 12 to 48 hours following the last ethanol ingestion, the possibility of generalized tonic–clonic seizures should be anticipated, occurring in 3–5% of cases. [13] Meanwhile, none of the earlier withdrawal symptoms will typically have abated. Seizures carry the risk of major complications and death for individuals with an alcohol use disorder. [16] [13]
Although the person's condition usually begins to improve after 48 hours, withdrawal symptoms sometimes continue to increase in severity and advance to the most severe stage of withdrawal, delirium tremens. This occurs in 5–20% of patients experiencing detoxification and one third of untreated cases, [14] [13] which is characterized by hallucinations that are indistinguishable from reality, severe confusion, seizures, high blood pressure, and fever that can persist anywhere from 4 to 12 days. [15]
A protracted alcohol withdrawal syndrome occurs in many alcoholics when 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 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 (known as anhedonia), clouding of sensorium, disorientation, nausea and vomiting or headache. [17]
Insomnia is a common protracted withdrawal symptom that 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 these individuals 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. [18] [19] [20] The acute phase of the alcohol withdrawal syndrome can occasionally be protracted. Protracted delirium tremens has been reported in the medical literature as a possible but unusual feature of alcohol withdrawal. [21]
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 downregulation 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 may gradually return towards normal. [22] [23] 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 excitotoxicity. [24] Alterations in ECG (in particular an increase in QT interval) and EEG abnormalities (including abnormal quantified EEG) may occur during early withdrawal. [24] 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. [25]
Kindling is a phenomenon where repeated alcohol detoxifications leads to an increased severity of the withdrawal syndrome. For example, binge drinkers may initially experience no withdrawal symptoms, but with each period of alcohol use followed by cessation, their withdrawal symptoms intensify in severity and may eventually result in full-blown delirium tremens with convulsive seizures. Alcoholics who experience seizures during detoxification are more likely to have had previous episodes of alcohol detoxification than patients who did not have seizures during withdrawal. In addition, people with previous withdrawal syndromes are more likely to have more medically complicated alcohol withdrawal symptoms. [26]
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. [27] 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. [26]
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 detoxified repeatedly 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. [28]
People in adolescence who experience repeated 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 those who have experienced one or no prior withdrawals. Kindling of neurons is the proposed cause of withdrawal-related cognitive damage. Kindling from repeated withdrawals leads to accumulating neuroadaptive changes. Kindling may also be the reason for cognitive damage seen in binge drinkers. [29]
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 of medication needed. [12] When overuse of alcohol is suspected but drinking history is unclear, testing for elevated values of carbohydrate-deficient transferrin or gammaglutamyl transferase can help make the diagnosis of alcohol overuse and dependence more clear. The CIWA has also been shortened (now called the CIWA-Ar), while retaining its validity and reliability, to help assess patients more efficiently due to the life-threatening nature of alcohol withdrawal. [30]
Benzodiazepines are effective for the management of symptoms as well as the prevention of seizures. [31] Certain vitamins are also an important part of the management of alcohol withdrawal syndrome. In those with severe symptoms inpatient care is often required. [11] In those with lesser symptoms treatment at home may be possible with daily visits with a health care provider. [11]
Cohort studies have demonstrated that the combination of anticonvulsants and benzodiazepines is more effective than other treatments in reducing alcohol withdrawal scores and shortening the duration of intensive care unit stays. [32]
Benzodiazepines are the most commonly used medication for the treatment of alcohol withdrawal and are generally safe and effective in suppressing symptoms of alcohol withdrawal. [33] This class of medication is generally effective in symptoms control, but needs to be used carefully. Although benzodiazepines have a long history of successfully treating and preventing withdrawal, there is no consensus on the ideal one to use. The most commonly used agents are long-acting benzodiazepines, such as chlordiazepoxide and diazepam. These are believed to be superior to other benzodiazepines for treatment of delirium and allow for longer periods between doses. However, benzodiazepines with intermediate half-lives like lorazepam may be safer in people with liver problems. [34] Benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizure, compared to other common methods of treatment. [35]
The primary debate between use of long-acting benzodiazepines and short-acting is that of ease of use. Longer-acting drugs, such as diazepam, can be administered less frequently. However, evidence does exist that "symptom-triggered regimens" such as those used when treating with lorazepam, are as safe and effective, but have decreased treatment duration and medication quantity used. [34]
Although benzodiazepines are very effective at treating alcohol withdrawal, they should be carefully used. Benzodiazepines should only be used for brief periods in alcoholics who are not already dependent on them, as they share cross tolerance with alcohol. There is a risk of replacing an alcohol addiction with benzodiazepine dependence or adding another addiction. Furthermore, disrupted GABA benzodiazepine receptor function is part of alcohol dependence and chronic benzodiazepines may prevent full recovery from alcohol induced mental effects. [36] [37] 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. [38]
Alcoholics are often deficient in various nutrients, which can cause severe complications during alcohol withdrawal, such as the development of Wernicke syndrome. To help to prevent Wernicke syndrome, these individuals should be administered a multivitamin preparation with sufficient quantities of thiamine and folic acid. During alcohol withdrawal, the prophylactic administration of thiamine, folic acid, and pyridoxine intravenously is recommended before starting any carbohydrate-containing fluids or food. These vitamins are often combined into a banana bag for intravenous administration. [39]
Very limited evidence indicates that topiramate or pregabalin may be useful in the treatment of alcohol withdrawal syndrome. [40] Limited evidence supports the use of gabapentin or carbamazepine for the treatment of mild or moderate alcohol withdrawal as the sole treatment or as combination therapy with other medications; however, gabapentin does not appear to be effective for treatment of severe alcohol withdrawal and is therefore not recommended for use in this setting. [40] [41] A 2010 Cochrane review similarly reported that the evidence to support the role of anticonvulsants over benzodiazepines in the treatment of alcohol withdrawal is not supported. [42] Paraldehyde combined with chloral hydrate showed superiority over chlordiazepoxide with regard to life-threatening side effects and carbamazepine may have advantages for certain symptoms. [42] Long term anticonvulsant medications are not usually recommended in those who have had prior seizures due to withdrawal. [43]
There are three medications used to help prevent a return to drinking: naltrexone, acamprosate, and disulfiram. They are used after withdrawal has occurred. [44]
Clonidine may be used in combination with benzodiazepines to help some of the symptoms. [12] No conclusions can be drawn concerning the efficacy or safety of baclofen for alcohol withdrawal syndrome due to the insufficiency and low quality of the evidence. [45]
Antipsychotics, such as haloperidol, are sometimes used in addition to benzodiazepines to control agitation or psychosis. [12] Antipsychotics may potentially worsen alcohol withdrawal as they lower the seizure threshold. Clozapine, olanzapine, or low-potency phenothiazines (such as chlorpromazine) are particularly risky; if used, extreme caution is required. [46]
While intravenous ethanol could theoretically be used, evidence to support this use, at least in those who are very sick, is insufficient. [47]
Hypertension is common, and some doctors also prescribe beta blockers during withdrawal.
Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. [48] 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. [49]
Continued use of benzodiazepines may impair recovery from psychomotor and cognitive impairments from alcohol. [50] Cigarette smoking may slow down or interfere with recovery of brain pathways in recovering alcoholics. [51]
Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Health Organization (WHO) estimated there were 283 million people with alcohol use disorders worldwide as of 2016. The term alcoholism was first coined in 1852, but alcoholism and alcoholic are sometimes considered stigmatizing and to discourage seeking treatment, so diagnostic terms such as alcohol use disorder or alcohol dependence are often used instead in a clinical context.
Benzodiazepines, colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.
Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given orally, transdermally, intravenously (IV), or intramuscularly When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.
Depressants, colloquially known as "downers" or central nervous system (CNS) depressants, are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.
Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.
Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.
Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of 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. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.
Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.
Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.
Acamprosate, sold under the brand name Campral, is a medication which reduces alcoholism cravings. It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals, as it only addresses withdrawal symptoms and not psychological dependence. It facilitates a reduction in alcohol consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior.
Organic brain syndrome, also known as organic brain disease, organic brain damage, organic brain disorder (OBD), organic mental syndrome, or organic mental disorder, refers to any syndrome or disorder of mental function whose cause is alleged to be known as organic (physiologic) rather than purely of the mind. These names are older and nearly obsolete general terms from psychiatry, referring to many physical disorders that cause impaired mental function. They are meant to exclude psychiatric disorders. Originally, the term was created to distinguish physical causes of mental impairment from psychiatric disorders, but during the era when this distinction was drawn, not enough was known about brain science for this cause-based classification to be more than educated guesswork labeled with misplaced certainty, which is why it has been deemphasized in current medicine. While mental or behavioural abnormalities related to the dysfunction can be permanent, treating the disease early may prevent permanent damage in addition to fully restoring mental functions. An organic cause to brain dysfunction is suspected when there is no indication of a clearly defined psychiatric or "inorganic" cause, such as a mood disorder.
Delirium tremens is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shivering, irregular heart rate, and sweating. People may also hallucinate. Occasionally, a very high body temperature or seizures may result in death.
Chlordiazepoxide, sold under the brand name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class. It is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.
Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.
Alcohol detoxification is the abrupt cessation of alcohol intake in individuals that have alcohol use disorder. This process is often coupled with substitution of drugs that have effects similar to the effects of alcohol in order to lessen the symptoms of alcohol withdrawal. When withdrawal does occur, it results in symptoms of varying severity.
Post-acute withdrawal syndrome (PAWS) is a hypothesized 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 PAWS. While PAWS has been frequently reported by those withdrawing from opiate and alcohol dependence, the research has limitations. Protracted benzodiazepine withdrawal has been observed to occur in some individuals prescribed benzodiazepines.
Alcoholic hallucinosis is a complication of alcohol misuse in people with alcohol use disorder. It can occur during acute intoxication or withdrawal with the potential of having delirium tremens. Alcohol hallucinosis is a rather uncommon alcohol-induced psychotic disorder almost exclusively seen in chronic alcoholics who have many consecutive years of severe and heavy drinking during their lifetime. Alcoholic hallucinosis develops about 12 to 24 hours after the heavy drinking stops suddenly, and can last for days. It involves auditory and visual hallucinations, most commonly accusatory or threatening voices. The risk of developing alcoholic hallucinosis is increased by long-term heavy alcohol abuse and the use of other drugs. Descriptions of the condition date back to at least 1907.
Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.
Kindling due to substance withdrawal is the neurological condition which results from repeated withdrawal episodes from sedative–hypnotic drugs such as alcohol and benzodiazepines.
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