Compared with outpatient facilities, inpatient clinic may provide better continuity of care for patients who begin treatment while in the hospital. In addition, inpatient detoxification separates the patient from alcohol-related social and environmental stimuli that might increase the risk of relapse 30. During alcohol use and the increase in the dopamine levels in CNS contribute to the autonomic hyper arousal and hallucinations.
Receptors/Hormones and Biomarkers
This suggests that increasing adaptive coping strategies in a person is likely to lead to a decrease in the severity of alcohol dependence which may, in turn, reduce the chances of a relapse. In their research with improved methods and a general hospital sample of problem drinkers, Johnson et al.,14 determined that the age of onset is a more reliable indicator of the extent of alcoholism than a family history of alcoholism alone; the average age of commencement of alcohol drinking was reported as 21.39 ± 5.34 years. Among the individuals serving in the Indian Armed Forces, Chatterjee et al.,15 observed no link between the age at first consumption and severity of alcohol dependence at detection. Similar to these reports, we observed that participants up to the age of 30 had statistically non-significant higher scores on the SADQ. Three-fourths of our study participants had their first use of Alcohol before 25 years of age.
Sociodemographic Factors
In postsynaptic neurons, GABA generally makes it more difficult to generate an electrical signal, thereby interfering with further signal transmission. To exert these effects, GABA acts via presynaptic and postsynaptic ionotropic (GABAA) and metabotropic (GABAB) receptors. The GABAA receptor, which is expressed widely in the central nervous system, is a protein complex that is linked to a chloride channel. When activated by GABA, the channel opens to allow chloride ions to pass through the cell membrane, thereby increasing the difference in electrical charge between the inside and outside the cell (Mohler 2006; Sieghart and Sperk 2002) (see figure 5A). Through this mechanism, GABAA receptor-coupled chloride channels mediate fast synaptic inhibition in the brain.
GABA Systems and Alcohol Dependence
- Alcohol and stress also have been reported to produce elevations in plasma concentrations of neuroactive steroids in humans, but the effects are not entirely consistent (Holdstock et al. 2006; Pierucci-Lagha et al. 2006; Torres and Ortega 2003, 2004).
- Our findings should be interpreted as preliminary because they are limited by several factors like the study sample being hospital-based, lack of a control group, small sample size, shorter duration of follow-up period, and the presence of confounding factors.
- When these GABA neurons are activated, their signals decrease the firing of dopamin-ergic neurons.
- Empowering individuals with better coping strategies can help improve outcomes in persons suffering from alcohol-related problems.
- Given the diverse and widespread neuroadaptive changes that are set in motion as a consequence of chronic alcohol exposure and withdrawal, it perhaps is not surprising that no single pharmacological agent has proven to be fully successful in the treatment of alcoholism.
The primary limitation is the high heterogeneity between studies owing to the nebulous nature of PAWS, the lack of a shared consensus definition, the variable durations of symptoms presented as components of PAWS and the small sample sizes of the component studies. In addition, much of the literature on PAWS is dated, and there is a shortage of robust, randomized, controlled trials. Furthermore, there is a lack of standardization of PAWS across studies, and the extent of post-withdrawal abstinence was highly variable. In addition, because of a lack of pertinent studies, it remains unclear whether all the symptoms described here are manifested equally in both sexes or in individuals with comorbid substance use disorders. Finally, for a systematic review, ideally, two individuals should review articles for eligibility. However, in this article, only one author (A.B.) reviewed and identified the articles for inclusion and the second reviewer only reviewed the excluded articles.
This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on ‘Alcohol withdrawal syndrome’ in humans during the last 10 years. Articles not relevant to clinical utility and management were excluded based on the titles and abstract available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were considered for review. The GABAB agonist, baclofen, also can reduce alcohol consumption in dependent rats and block cue-induced reinstatement of alcohol-seeking behavior in alcohol-preferring rats (Maccioni et al. 2008; Walker and Koob 2007).
More specifically, increased cycles of chronic intermittent alcohol exposure appeared to blunt HPA axis activation, as measured by reduced levels of plasma corticosterone (Lopez et al. 2010). This reduced HPA response was observed just prior to withdrawal and at peak withdrawal in a mouse model of alcohol dependence. Recent studies suggest that this dampening of HPA axis activity may relate to enhanced activity of receptors for the neurotransmitter γ-aminobutyric acid (i.e., increased GABAA receptor function) (Li et al. 2011) and/or reduced number of CRF-releasing neurons (Silva et al. 2009) in the paraventricular nucleus of the hypothalamus.
Repeated Alcohol Withdrawals
These changes depend on the treatment regimen, the time after withdrawal at which measurements are taken, and the brain area examined (Cagetti et al. 2003). The most consistent effects appear to be a decrease in the production of α1 subunits and an increase in the production of α4 subunits (see Biggio et al. 2007; Follesa et al. 2006; Krystal et al. 2006; Kumar et al. 2004; Olsen et al. 2005). Thus, one study (Follesa et al. 2006) reported that production of this subunit after alcohol withdrawal was decreased in cells from the cerebellum and increased in neurons from the hippocampus. In contrast, a study using chronic intermittent alcohol exposure found that production of the δ subunit was decreased in the hippocampus (Olsen et al. 2005).
One hundred and twenty-seven consecutive individuals were recruited over 14 months from April 2019 to June 2020. The majority of our study participants had completed their six-month follow-up period well before the Covid lockdown on 25 March 2020. Only a few participants who resided in areas near our hospital were followed up during the strict Covid lockdown period, from April 2020 to June 2020. We included individuals above 18 years attending our outpatient de-addiction services, who qualified for a diagnosis of Alcohol Dependence and were also abstinent from alcohol for one month.
These drugs commonly are used to treat acute symptoms of alcohol withdrawal (Schuckit and Tapert 2004). Alcohol has anxiety-reducing properties and can relieve stress, while at the same time acting as a stressor and activating the body’s stress response systems. In particular, chronic alcohol exposure and withdrawal can profoundly disturb the function of the body’s neuroendocrine stress response system, the hypothalamic–pituitary–adrenocortical (HPA) axis. A hormone, corticotropin-releasing factor (CRF), which is produced and released from the hypothalamus and activates the pituitary in response to stress, plays a central role in the relationship between stress and alcohol dependence and withdrawal. Chronic alcohol exposure and withdrawal lead to changes in CRF activity both within the HPA axis and in extrahypothalamic brain sites.
- Cross-references from selected studies were searched and further relevant articles were considered for inclusion.
- In animal studies, some GABAA receptor antagonists were found to reduce alcohol self-administration in nondependent animals, as described above.
- These changes depend on the treatment regimen, the time after withdrawal at which measurements are taken, and the brain area examined (Cagetti et al. 2003).
- This effect appears to involve CRF activity because CRF antagonists block stress-induced reinstatement of alcohol-seeking behavior (Gehlert et al. 2007; Le et al. 2000; Liu and Weiss 2002b).
Clinical management of alcohol withdrawal: A systematic review
These compounds produce anxiolytic, anticonvulsant, and sedative/hypnotic effects similar to other positive modulators of the GABAA receptor, including alcohol (Khisti et al. 2002; Morrow et al. 2001; Rupprecht and Holsboer 1999). Additionally, these neuroactive steroids can modulate a variety of alcohol effects, including anticonvulsant, anxiolytic, ataxic/sedative, and cognitive-impairing effects, as well as the discriminative stimulus and reinforcing effects of alcohol (Khisti et al. 2002; Morrow et al. 2001). The occurrence alcohol dependence, withdrawal, and relapse pmc of seizures during the AWS is indicative of severe alcohol withdrawal, although the CIWA-Ar score may not correlate. All patients with AWS, with seizures in the current withdrawal period or past history of withdrawal seizure should be given prophylactic intravenous/intramuscular injection of 2mg lorazepam 75. Lorazepam is considered more effective than diazepam in preventing seizure recurrence as lorazepam has consistent plasma level distribution unlike diazepam. These patients may require high doses of benzodiazepine (diazepam equivalents of about mg) to prevent further seizures and to prevent the development of DT 51.
One would expect that treatment of animals with a GABAB receptor antagonist might also reduce ethanol intake, but in this case, it would be because the animal would not feel the anxiolytic effect of ethanol. The hypothesis that the GABA system helps mediate alcohol’s acute effects was supported by early studies demonstrating that several behavioral effects of acute alcohol exposure were enhanced by GABAA receptor agonists and attenuated by antagonists. For example, benzodiazepines, which are positive modulators of GABAA receptor function, potentiated ethanol’s anxiolytic effects (Ho and Yu 1991). Conversely, different GABAA receptor antagonists decreased ethanol-induced intoxication (i.e., ataxia) (Martz et al. 1983; Suzdak et al. 1986) and sedation (Givens and Breese 1990). These and other findings suggested that alcohol exerts some of its acute effects by enhancing GABAergic neurotransmission (see Grobin et al. 1998; Wallner et al. 2006).
Location of some of the regions in the human brain that are affected by alcohol, including the mesolimbic dopamine system (which includes the ventral tegmental area VTA, nucleus accumbens, and prefrontal cortex), amygdala, striatum, and hippocampus. During PAWS, the brain is proposed to enter a relative state of hyperexcitability by activating central stress systems (Ahveninen et al., 1999). Several studies have attempted to describe the components of this process (summarized in Table 2). Although there was insufficient homogeneity to enable meta-analysis, we summarized findings across studies by describing their population, intervention, comparison, outcome, and design features as per previous descriptive reviews in addiction medicine (Bahji, 2019; Bahji & Bajaj, 2018, 2019; Bahji et al., 2021). We reviewed studies for eligibility using Covidence, a web-based systematic review manager, and Zotero citation manager (Roy Rosenzweig Center for History and New Media, 2018; Veritas Health Innovation, 2019). After removing duplicates, one investigator (A.B.) independently selected the studies, reviewed the main reports and supplementary materials, and extracted the relevant information from the included studies; a second author (N.E.) reviewed excluded studies for erroneous selection.
However, it is purely based on clinical experience as no clinical trials have been conducted in patients with DT. When light somnolence is achieved and the patient is relaxed, management may be shifted to oral/injectable symptom monitored schedule. BZD’s are the drugs of choice for AWS in most of the treatment settings; however, anti-convulsant drugs may represent suitable alternatives. Use of an anti-convulsant drug decreases the probability of a patient experiencing a withdrawal seizure, thereby reducing the complications of AWS. Anti-convulsant drugs have been effectively used to treat mood disorders, which share some symptoms with AWS, including depression, irritability, and anxiety.
Gabapentin was as effective as lorazepam in a randomized, double blind controlled study on 46 in-patients with alcohol withdrawal in the treatment of acute mild to moderate AWS 65. Vigabatrin, an anticonvulsant agent, which irreversibly blocks GABA transaminase, showed improvement in withdrawal symptoms after only three days of treatment and is a promising agent for detoxification 66. Reoux et al., and Malcolm et al., concluded that Valproic acid significantly affects the course of alcohol withdrawal and reduces the need for treatment with a benzodiazepine 61,62. These two double-blind, randomized studies showed that patients treated with Valproic acid for 4 to 7 days dropped out less frequently, had less severe withdrawal symptoms including fewer seizures, and required less oxazepam than patients receiving either carbamazepine or placebo. Although effective, Valproic acid use may be limited by side effects—somnolence, gastrointestinal disturbances, confusion, and tremor—which are similar to alcohol withdrawal symptoms, making assessment of improvement difficult.