These stress-related adaptations produced by chronic alcohol exposure and withdrawal may underlie the long-lasting dampening of basal and stress-stimulated HPA axis activity that has been observed in abstinent alcoholics (Adinoff et al. 1990; Lovallo et al. 2000; Rasmussen et al. 2000). Alcohol dependence is thought to represent a persistent dysfunctional (i.e., allostatic) state in which the organism is ill-equipped to exert appropriate behavioral control over alcohol drinking. Functional changes in brain and neuroendocrine stress and reward systems as a result of chronic alcohol exposure and withdrawal play a key role not only in altering the rewarding effects of alcohol, but also in mediating the expression of various withdrawal symptoms that, in turn, impact motivation to resume drinking. Although currently few treatments are available for tackling this significant health problem and providing relief for those suffering from the disease, there is hope. Although the circumstances and manner in which stress influences drinking behavior are complex and not fully understood, it generally is acknowledged that stressful life events prominently influence alcohol drinking and, in particular, may trigger relapse (Brady and Sonne 1999; Sillaber and Henniger 2004; Sinha 2001; Weiss 2005).
Management of moderate to severe alcohol withdrawal syndrome
Importantly, this negative-affect state may contribute to increased risk for relapse as well as perpetuate continued use and abuse of alcohol (Becker 1999; Driessen et al. 2001; Koob 2003; Roelofs 1985). Indeed, both preclinical and clinical studies suggest a link between anxiety and propensity to self-administer alcohol (Henniger et al. 2002; Spanagel et al. 1995; Willinger et al. 2002). All the participants and their spouses/caregivers were explained in detail about the importance and potential benefits of taking part in this research.
- Benzodiazepines have the best evidence base in the treatment of alcohol withdrawal, followed by anticonvulsants.
- It also has multiple mechanisms of action, including inhibition of kainate iGluRs and activation of GABA receptors (Gibbs et al. 2000; White et al. 1997).
- For example, clear individual differences exist in sensitivity to, perception of, and responsiveness to stress and alcohol, and both clinical and preclinical evidence indicate that genetic factors help shape the nature of the relationship between stress and alcohol drinking (Clarke et al. 2008; Uhart and Wand 2009).
- Acute ethanol exposure also exhibits presynaptic effects on glutamatergic signal transmission.
Moreover, mice that alcohol dependence, withdrawal, and relapse pmc lack the gene for a protein which normally links Group I mGluRs and NMDARs in synaptic spines show reduced preference for alcohol (Szumlinski et al. 2005). More direct evidence supporting increased alcohol consumption as a consequence of repeated withdrawal experience comes from animal studies linking dependence models with self-administration procedures. For example, rats exposed to chronic alcohol treatment interspersed with repeated withdrawal episodes consumed significantly more alcohol than control animals under free-choice, unlimited access conditions (Rimondini et al. 2002, 2003; Sommer et al. 2008). Similar results have been reported in mice, with voluntary alcohol consumption assessed using a limited access schedule (Becker and Lopez 2004; Dhaher et al. 2008; Finn et al. 2007; Lopez and Becker 2005). Likewise, studies using operant procedures have demonstrated increased alcohol self-administration in mice (Chu et al. 2007; Lopez et al. 2008) and rats (O’Dell et al. 2004; Roberts et al. 1996, 2000) with a history of repeated chronic alcohol exposure and withdrawal experience.
Elevated glucocorticoid levels resulting from dependence-related HPA axis activation may contribute to amplified motivation to drink through an interaction with the brain’s reward system, the mesocorticolimbic reward circuitry (Piazza and Le Moal 1997). Central and systemic administration of corticosterone has been shown to increase alcohol consumption, whereas adrenalectomy or administration of a corticosteroid synthesis inhibitor (i.e., metyrapone) decreased alcohol intake in rodents (Fahlke et al. 1995, 1996). Likewise, a glucocorticoid receptor antagonist (i.e., mifepristone) reduced alcohol self-administration behavior (Koenig and Olive 2004).
- As mentioned earlier, this area contains cell bodies of neurons that release dopamine into the NAc.
- However, it needs to be based upon the severity of withdrawals and time since last drink.
- For delirium tremens and withdrawal seizures, treatment with high-dose benzodiazepines (parenteral or oral) is recommended in ICU set up.
- Sixty-six out of 103 (64.1%) study participants belonged to the age group of 31 and 50 years.
Alcohol Withdrawal
Alcohol dependence is one of the most common psychiatric disorders, second only to major depression 5. Data from the National Co-morbidity Survey and the NIMH Epidemiologic Catchment Program revealed that approximately 14% of the general population has a lifetime history of alcohol dependence. A recent National Household Survey of Drug Use in India 6 recorded alcohol use in only 21% of adult males. However, this figure cannot be expected to mirror accurately the wide variation that exists in a large and complex country such as India. The prevalence of current use of alcohol ranged from 7% in the state of Gujarat (officially under Prohibition) to 75% in Arunachal Pradesh.
Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond
For example, Group I receptors (i.e., mGluR1 and mGluR5) can enhance NMDAR function by activating a signaling molecule called protein kinase C (PKC); moreover, these receptors are physically linked to the NMDA receptors (Fagni et al. 2000; Tu et al. 1999). Group II and Group III mGluRs can regulate glutamate release from the presynaptic axon by inhibiting certain enzymes essential for glutamate release (e.g., PKA). Moreover, Group II and III mGluRs can be located on adjacent neurons releasing the neurotransmitter GABA and help regulate the actions of those neurons (Schoepp 2001). Thus, mGluRs may serve to maintain the normal balance (i.e., homeostasis) of glutamatergic transmission and modulate aberrant changes in neuronal excitability.
Duration of Abstinence
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 addition to physical signs of withdrawal, a constellation of symptoms contributing to a state of distress and psychological discomfort constitute a significant component of the withdrawal syndrome (Anton and Becker 1995; Roelofs 1985; Schuckit et al. 1998). These symptoms include emotional changes such as irritability, agitation, anxiety, and dysphoria, as well as sleep disturbances, a sense of inability to experience pleasure (i.e., anhedonia), and frequent complaints about “achiness,” which possibly may reflect a reduced threshold for pain sensitivity. Many of these signs and symptoms, including those that reflect a negative-affect state (e.g., anxiety, distress, and anhedonia) also have been demonstrated in animal studies involving various models of dependence (Becker 2000). For example, clear individual differences exist in sensitivity to, perception of, and responsiveness to stress and alcohol, and both clinical and preclinical evidence indicate that genetic factors help shape the nature of the relationship between stress and alcohol drinking (Clarke et al. 2008; Uhart and Wand 2009). The dynamic interaction of these biological and environmental variables along with experiential factors plays a critical role in defining subjective aspects of stress (i.e., the perception and appraisal of a stressful event) and alcohol intoxication.
Similarly, the efficacy of nal-trexone in reducing excessive drinking in alcohol-dependent people may result from the agent’s ability to reduce reinstatement of alcohol drinking, possibly by interfering with alcohol’s reinforcing effects (e.g., Pettinati et al. 2006). However, individuals differ in the development of sensitization to alcohol’s effect on dopamine release as well as in the nature of changes in other systems (e.g., GABA, glutamate, and serotonin) that modulate these effects. These differences may account for the relatively small overall effect that naltrexone has in reducing excessive drinking by alcohol-dependent people (Donovan et al. 2008).
ERPs are spikes in brain activity that occur in response to a specific signal, and the P3 wave is one component of such an ERP. The P3 amplitude is considered a marker for sensory processing and cognitive function, and a purported substitute indicator (i.e., endophenotype) for risk of alcoholism and other disinhibitory disorders. This cross-sectional research was performed in the outpatient de-addiction services of the Department of Psychiatry at Chengalpattu Medical College which is a tertiary care, teaching institution situated in Tamil Nadu, South India.
Finally, allopregnanolone can induce relapse-like behavior in mice (Finn et al. 2008) and rats (Nie and Janak 2003). Both alcohol and stress increase plasma and brain concentrations of neuroactive steroids in rodents (Barbaccia et al. 1999, 2001; Finn et al. 2010). This increase appears to be mediated by activation of the HPA axis because the increase in neuroactive steroid levels elicited by these stimuli can be blocked by disruption of the HPA axis via adrenalectomy (O’Dell et al. 2004a; Purdy et al. 1991). 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).
Stress, CRF, and Alcohol Dependence
While 49 persons (46.6%) were involved in semi-skilled jobs, 17 (16.5%) of them were unemployed. We screened 3,024 studies, from which 2,008 were unique citations and 1,016 were duplicate citations. From these, we excluded 1,416 records during the title and abstract screening phase, leaving 592 full-text articles for review. We did not find any additional articles by reviewing reference lists from the articles we identified. One reviewer (A.B.) extracted the following data from included studies while the other two (D.C. and N.E.) confirmed the extracted data for accuracy. We used a standardized tool to extract information about authors, study objectives, sample characteristics, inclusion/exclusion criteria, study design, and outcome variables in Covidence, which we transferred to a Microsoft Excel spreadsheet (Veritas Health Innovation, 2019).
However, clinical studies testing a CB1 receptor antagonist, rimonabant, for weight loss have noted side effects of severe depression, anxiety, and increased risk of suicide, which could limit the use of such antagonists. Some studies using animal models involving repeated withdrawals have demonstrated altered sensitivity to treatment with medications designed to quell sensitized withdrawal symptoms (Becker and Veatch 2002; Knapp et al. 2007; Overstreet et al. 2007; Sommer et al. 2008; Veatch and Becker 2005). Moreover, after receiving some of these medications, animals exhibited lower relapse vulnerability and/or a reduced amount consumed once drinking was (re)-initiated (Ciccocioppo et al. 2003; Finn et al. 2007; Funk et al. 2007; Walker and Koob 2008). Indeed, clinical investigations similarly have reported that a history of multiple detoxifications can impact responsiveness to and efficacy of various pharmacotherapeutics used to manage alcohol dependence (Malcolm et al. 2000, 2002, 2007).
For example, receptors that contain the δ subunit may be most sensitive to ethanol-induced increases in activity (Sundstrom-Poromaa et al. 2002). Because receptors with this subunit typically are extrasynaptic, this would suggest that ethanol has greater effects on tonic inhibition than on phasic inhibition by synaptic GABAA receptors. Other investigators, however, have questioned whether the presence of the δ subunits does, in fact, lead to more potent effects of ethanol (Borghese et al. 2006; Korpi et al. 2007; Krystal et al. 2006; Mody 2008; Sundstrom-Poromaa et al. 2002). Many different classes of receptor subunits—known as α, β, γ, δ, ɛ, θ, and π subunits—have been identified, and for some classes there is more than one type of subunit (e.g., α1 to α6, and β1 to β3). The specific composition of a given receptor molecule determines its distinct physiological and pharmacological properties.
Chronic alcohol exposure alters both the synthesis of endogenous cannabinoids and the characteristics of CB1 receptors (Vinod and Hungund 2005). In addition, alcohol consumption and alcohol-induced mesolimbic dopamine release were reduced in mice lacking the CB1 receptor (Hungund et al. 2003). Finally, a CB1 receptor antagonist reduced cue-induced alcohol reinstatement and the alcohol deprivation effect in rats (Colombo et al. 2007).
Neurobiology and Symptomatology of Post-Acute Alcohol Withdrawal: A Mixed-Studies Systematic Review
These include the stress hormones released by the adrenal glands in response to HPA axis activation (i.e., corticosteroids), neuromodulators known as neuroactive steroids, CRF, the neurotransmitter norepinephrine, and other stress-related molecules. Studies found that in some instances, mesolimbic dopamine release in animals is altered for longer periods after alcohol withdrawal (Diana et al. 2003; Thielen et al. 2004). Furthermore, researchers found large decreases in dopamine release in the ventral striatum of detoxified alcohol-dependent humans (Volkow et al. 2007). Such long-term decreases in baseline dopamine release, combined with increased sensitivity to the dopamine-releasing effects of alcohol, could represent a basis for relapse drinking after a period of abstinence. However, as described above, these changes would be sensitive to blocking by opiate receptor antagonists. Indeed, μ receptor antagonists can block cue- and alcohol-induced reinstatement of alcohol consumption in rats (Bienkowski et al. 1999; Lê et al. 1999).