Antacids may reduce the rate of absorption of benzodiazepines from the intestine. Fatal cases of overdose have been reported with the use of benzodiazepines. Benzodiazepines have the best evidence base in the treatment of alcohol withdrawal, followed by anticonvulsants. Minor alcohol withdrawal syndrome may not need pharmacotherapy in all cases. Online Started by Rabramas , Feb 26 For these reasons, barbiturates have fallen out of favor.
Supportive care and use of vitamins is also discussed. Alcohol dependence is a severe form of alcohol use disorder and it may first manifest when a person develops withdrawal symptoms after stopping alcohol - either due to family pressure, self-motivation, physical ill health or difficulty in procuring alcohol. It is a common misconception among regular drinkers that stopping alcohol causes more problems than continuing it.
This may be partly true in those who have developed dependence as they may experience withdrawal symptoms including autonomic arousal, hallucinations, seizures and delirium tremens DT. Since many people underplay or minimize their drinking behavior, they tend to develop withdrawal symptoms when hospitalized for other physical problems and not for alcoholism forming a substantial part of consultation-liaison psychiatry. Our aim was to review the evidence base for the appropriate management of the alcohol withdrawal syndrome using pharmacotherapy.
This review informs readers about medications to be used for treating alcohol withdrawal, their dosing strategies to be used and managing specific complications arising during alcohol withdrawal such delirum trements DT and alcohol withdrawal seizures. We specifically sought articles relating to medications commonly used in India and those that can be recommended based on strong evidence.
We searched Pubmed for articles published in English on pharmacological management of alcohol withdrawal in humans without any restriction on the publication date. We used the following medical subject heading MeSH terms: Articles not relevant to the topic were excluded based on the titles and abstract available. Full text articles were obtained for the 24 articles relevant to clinical practice at this stage. Cross-references mentioned in the full text articles were checked for other relevant articles.
Further search for books, monographs and articles relating to thiamine supplementation, neurobiology of alcohol withdrawal state were done by hand-search and other convenient means. A total of full text-articles, books and monographs were identified. There were four meta-analyses, nine systematic reviews and 26 review articles. Other publications were randomized controlled trials, observational studies, case reports, manuals and monographs.
By exclusion of articles relating to drugs with poor quality of evidence and inclusion of the latest version of Cochrane reviews, we were left with 35 published studies for our review focused on the clinical management and the rest are reports, books and monographs. The literature was reviewed independently by the two authors. We tabulated the major recommendations from each source as regards the management of alcohol withdrawal with respect to severity of withdrawal, doses and regimen used in each study and the outcomes.
Ordinarily, the excitatory glutamate and inhibitory GABA neurotransmitters are in a state of homeostasis [ Figure 1a ]. In the long-term, it causes a decrease in the number of GABA receptors down regulation. This results in the requirement of increasingly larger doses of ethanol to achieve the same euphoric effect, a phenomenon known as tolerance. Chronic use of alcohol leads to an increase in the number of NMDA receptors up regulation and production of more glutamate to maintain CNS homeostasis [ Figure 1c ].
With the sudden cessation of alcohol in the chronic user, the alcohol mediated CNS inhibition is reduced and the glutamate mediated CNS excitation is left unopposed, resulting in a net CNS excitation [ Figure 1d ]. This CNS excitation results in the clinical symptoms of alcohol withdrawal in the form of autonomic over activity such as tachycardia, tremors, sweating and neuropsychiatric complications such as delirium and seizures. Dopamine is another neurotransmitter involved in alcohol withdrawal states.
During alcohol use and withdrawal the increase in CNS dopamine levels contribute to the clinical manifestations of autonomic hyper arousal and hallucinations. Repeated episodes of withdrawal and neuroexcitation results in a lowered seizure threshold as a result of kindling[ 2 ] predisposing to withdrawal seizures. The alcohol withdrawal syndrome is diagnosed when the following two conditions are met. The diagnosis requires adequate history of the amount and frequency of alcohol intake, the temporal relation between cessation or reduction of alcohol intake and the onset of symptoms that may resemble a withdrawal state.
When the onset of withdrawal like symptoms or delirium is after 2 weeks of complete cessation of alcohol, the diagnosis of alcohol withdrawal syndrome or DT becomes untenable, regardless of frequent or heavy use of alcohol. Table 2 gives a clinical description of alcohol withdrawal syndrome by severity and syndromes. Once a clinical diagnosis of alcohol withdrawal is made, we must review the patient's condition from time to time for the appearance of signs of medical or neurological illness which may not have been evident at admission but may develop subsequently.
In a patient diagnosed to have alcohol withdrawal syndrome, the CIWA-Ar[ 8 ] can be used to measure its severity. The scale is not a diagnostic tool as it has not been found to be useful in differentiating between DT and delirium due to medical illnesses. It has also been found useful in Indian setting. Scores of indicate absent to minimal withdrawal, scores of indicate mild to moderate withdrawal marked autonomic arousal and scores of 20 or more indicate severe withdrawal impending DT.
Delirium is a clinical syndrome of acute onset, characterized by altered sensorium with disorientation, perceptual abnormalities in the form of illusions and hallucinations and confused or disordered thinking, psychomotor agitation or retardation with disturbed usually reversed sleep-wake cycle. In most cases, it is secondary to a general medical condition causing disturbance in the basic functions of the brain.
It could be due to infection, toxic, metabolic, traumatic or endocrine disturbances. DT is a specific type of delirium occurring in patients who are in alcohol withdrawal states. Alcohol withdrawal delirium is typically associated with psychomotor agitation hyperactive delirium and in cases of hypoactive delirium comorbid hepatic encephalopathy, hyponatremia or other medical illnesses [ Table 3 ] must be ruled out.
This is especially important in a patient who has not had previous history of DT. Hence, it is important for clinicians to be able to predict it. The risk factors for DT were analyzed by Ferguson et al. Detoxification is the process of weaning a person from a psychoactive substance in a safe and effective manner by gradually tapering the dependence producing substance or by substituting it with a cross-tolerant pharmacological agent and tapering it. Patients in alcohol withdrawal should preferably be treated in a quiet room with low lighting and minimal stimulation.
All patients with seizures or DT should have immediate intravenous access for administration of drugs and fluids. Intramuscular lorazepam may be given to prevent further seizures. Adequate sedation should be provided to calm the patient as early as possible and physical restraints may be used as required in order to prevent injuries due to agitation. Fluid and electrolyte imbalances must be promptly corrected.
Adequate nutrition must be ensured with care to prevent aspiration in over-sedated patients. Vitamin B supplementation helps to prevent Wernicke's encephalopathy WE. In , a landmark study by Kaim et al. They may be considered in mild withdrawal states due to their advantages of lower sedation and lower chances of dependence or abuse potential. However, they may not have the expected advantage of preventing seizures or DT in alcohol withdrawal states[ 18 ] and their use is not recommended in severe withdrawal states.
The dose of benzodiazepine required per day is calculated according to the average daily alcohol intake. An estimate of the amount of alcohol consumption is given by the following formula: The percentage of alcohol in various liquors[ 20 ] is: One standard drink contains about 10 g of absolute alcohol or ethanol. A fixed daily dose of benzodiazepines is administered in four divided doses.
The daily dose is calculated by using the aforementioned formula. Approximately 5 mg of diazepam equivalents [ Table 5 ] is prescribed for every standard drink consumed. However, it needs to be based upon the severity of withdrawals and time since last drink. For example, a person presenting after 5 days of abstinence, whose peak of withdrawal symptoms have passed, may need a lower dose of benzodiazepines than a patient who has come on the second day of his withdrawal syndrome.
Chlordiazepoxide and diazepam remain the agents of choice. However, in the presence of co-morbidities shorter acting drugs such as oxazepam and lorazepam are used. A ceiling dose of 60 mg of diazepam or mg of chlordiazepoxide is advised per day. This is best suited for out-patient setting. Patients need to be advised about the risks and to reduce the dose, in case of excessive drowsiness. In in-patient settings where intense monitoring is not possible due to lack of trained staff, a fixed dose regimen is preferred.
In studies by Sellers et al. This has been shown to reduce the risk of complications, reduces the total dose of benzodiazepines needed and the duration of withdrawal symptoms. Loading dose strategies use long acting benzodiazepines as they provide a self-tapering effect due to their pharmacokinetic properties. The STT was proposed by Saitz et al. The STT requires close monitoring as in-patient. Patients who are non-verbal e.
This protocol is not safe in patients with a past history of withdrawal seizures because they can occur even in a patient without overt autonomic arousal or symptoms of alcohol withdrawal. We recommend that clinicians take into account the past history of seizures or DT as well as the current clinical status while deciding upon medications for a patient. In the presence of an acute medical illness at present or a past history of severe withdrawals, a single loading dose of 20 mg diazepam should preferably be given immediately and the patient be monitored for further signs of alcohol withdrawal.
Up to three doses are required in most patients,[ 23 ] which helps in reliably preventing the occurrence of withdrawal seizures. This method is recommended only in patients with DT. Frequent boluses of diazepam are given intravenously until the patient is calm and sedated. It is described under management of DT below. Minor alcohol withdrawal syndrome may not need pharmacotherapy in all cases. The patient needs supportive care in a calm and quiet environment and observation for a period of up to 36 h, after which he is unlikely to develop withdrawal symptoms.
In the presence of risk factors like an acute medical illness or a past history of severe withdrawals, a single dose of 20 mg of diazepam should be given immediately as a loading dose and the patient be monitored for further signs of alcohol withdrawal,[ 13 ] further doses being guided by the appearance of withdrawal symptoms. Out-patient treatment can be started for patients without these risk factors and is based on the clinical withdrawal signs. Pharmacotherapy is started when the systolic blood pressure exceeds mmHg, diastolic blood pressure exceeds 90 mmHg, body temperature greater than In these cases, we recommend that patients should be started immediately on a SML dose regimen, while monitoring the withdrawal severity CIWA-Ar ratings and clinical signs of tachycardia and hypertension.
A fixed dose regimen can be safely used in such patients in case adequate trained personnel are not available or if outpatient treatment is advised. Regardless of the CIWA-Ar score, the occurrence of seizures during the alcohol withdrawal period is indicative of severe alcohol withdrawal. Although, a single lorazepam dose given is likely to prevent further seizure recurrences, it may still be required to give SML dose of diazepam of at least 20[ 13 ] mg[ 27 ] or at times even 80 mg diazepam[ 7 ] in such patients.
This strategy helps to prevent the development of DT. All patients who presenting with seizures after cessation of alcohol, regardless of previous episodes, must ideally be monitored as inpatients for at least h to watch for further seizures or DT. In patients who present with seizures, a thorough neurological and general medical evaluation is a must to detect alternative cause of seizures. Patients with new onset seizures should preferably undergo brain imaging.
Treatment of alcohol withdrawal delirium DT is defined by the goal of achieving a calm, but awake state[ 13 ] or light somnolence defined as a sleep from which the patient is easily aroused. Intravenous or intramuscular lorazepam may be used in patients with hepatic disease, pulmonary disease or in the elderly where there is risk of over-sedation and respiratory depression with diazepam.
An initial dose of 10 mg diazepam is given intravenously. Further doses of 10 mg can be repeated every min interval. Though experts advice the use of rapid loading doses of diazepam for management of DT, no trials of rapid loading with diazepam has been conducted in patients with DT. There have been trials comparing loading doses of barbiturates versus diazepam loading , where the drug is given at 2 h intervals[ 30 ] and a trial of diazepam loading dose versus fixed doses [ 31 ] for the management of DT.
In practice, loading dose strategy 20 mg diazepam every 2 h can be safely administered in DT. A review by Hack et al. Such patients can be diagnosed to have refractory DT after a review of the clinical condition to rule out medical or neurological causes of delirium. There is no antidote to barbiturate toxicity. For these reasons, barbiturates have fallen out of favor. An alternative adjunctive medication useful in patients with refractory DT is haloperidol given in doses of 0.
In patients who do not respond to benzodiazepines and haloperidol, propofol infusion 0. This is a unique form of withdrawal related psychosis which can begin even while the person is continuing to use alcohol or begins after he stops alcohol. Hallucinations occurring in clear sensorium are the hallmark of this disorder. A cluster analysis of alcohol withdrawal symptoms by Driessen et al. However, it is one of the conditions that may cause apparent failure of the loading dose regimen[ 11 ] and we recommend a fixed dose strategy to cover the period of alcoholic hallucinosis.
The hallucinations last about a week in most cases, but may last up to 1 month in some patients after which the antipsychotic can be stopped. Abrupt cessation of chronic BZD use is also associated with a withdrawal syndrome, characterized by CNS hyperexcitability, and symptoms such as anxiety, restlessness, agitation, hallucinations, delirium, and seizures. For this reason, chronic BZD use should be discontinued gradually over a period of weeks .
Use in Status Epilepticus BZDs are first-line agents for termination of seizures in status epilepticus. If IV access is available, lorazepam 4 mg IV 0. Onset of action is within 2 minutes, and duration is hours. Efficacy of lorazepam and diazepam at terminating seizures is similar, though studies show a trend toward improved efficacy in lorazepam .
A unique benefit of diazepam is that it remains stable in pre-mixed liquid form, unlike lorazepam and midazolam. This makes it more convenient for pre-hospital settings. Diazepam is also available in a rectal gel, and many families use this at home to terminate seizures in children with epilepsy . Midazolam is also effective in status epilepticus, but is second-line after lorazepam and diazepam due to its short half-life and risk of recurrent seizure.
However, if IV access is unavailable, IM midazolam is the drug of choice . Doses may be repeated after minutes. Midazolam also has the advantage of administration via buccal and intranasal routes. One study showed that buccal midazolam was more effective in terminating seizures in children than rectal diazepam . A buccal formulation of midazolam is not currently available in the United States, but some trials have used the intravenous formulation of midazolam for buccal use.
The dose of midazolam for buccal administration is 0. The dose of intranasal midazolam is 0. Use in Alcohol Withdrawal BZDs are commonly used to treat the psychomotor agitation experienced by patients withdrawing from alcohol, and to prevent development of serious complications, such as delirium, hallucinations, and seizures. While all BZDs could theoretically work, long-acting BZDs with active metabolites such as diazepam and chlordiazepoxide are preferred due to more consistent drug levels and decreased chance of symptom recurrence .
On the other hand, for patients with advanced liver disease, which is true of many alcoholics, a BZD with a moderate duration of action may be preferred, like lorazepam, because it may help avoid oversedation in a patient with impaired hepatic clearance . Use in Procedural Sedation and Anxiolysis Midazolam is the BZD of choice for procedural sedation, due to its rapid onset and short duration of action. Onset is typically within minutes, with duration lasting minutes .
Lorazepam and diazepam are less commonly used because they have a longer duration of action, and produce less amnesia compared to midazolam . The dose of midazolam for procedural sedation is 0. In children, the dose is 0. Lower doses should be used in the obese, the elderly, and those with renal or hepatic disease who are at greater risk of respiratory depression and prolonged sedation. Midazolam is often given for anxiolysis prior to having children.
The dose is 0. However, use of flumazenil is controversial, because it can precipitate withdrawal seizures in patients who take chronic BZDs, and then since the receptor is blocked, BZDs would be ineffective in terminating the seizures.