Within this system, stress induces the release of the hormone corticotrophin-releasing factor (CRF) from a brain area called the hypothalamus. CRF acts on the pituitary gland located directly below the hypothalamus, where it initiates the production of a alcohol dependence, withdrawal, and relapse pmc molecule called proopiomelanocortin (POMC). This compound is processed further into smaller molecules, such as β-endorphin and adrenocorticotropic hormone (ACTH).
As noted above, numerous studies have demonstrated a significant role for altered CRF activity in dependence-related alcohol drinking. The mouse model of dependence and relapse drinking described earlier has provided evidence for reduced HPA axis activation and compromised behavioral response to a stress challenge. At the same time, additional findings point to an accentuation of changes in the expression and release of CRF in extrahypothalamic brain regions that are implicated in motivational effects of alcohol (Doremus-Fitzwater and Becker 2010; Griffin et al. 2011; Lopez et al. 2010). The role of CRF further is emphasized by observations that a nonselective peptide CRF antagonist (i.e., D-Phe-CRF12–41) reduced excessive drinking in dependent animals when administered into the brain ventricles (Funk et al. 2007; Valdez et al. 2002) or into the central nucleus of the amygdala (Funk et al. 2006a, b). Further, systemic administration of selective antagonists for the CRF1 receptor reduced upregulated drinking in dependent mice (Chu et al. 2007) and rats (Funk et al. 2007; Gehlert et al. 2007; Gilpin et al. 2008a; Roberto et al. 2010; Sommer et al. 2008). The difficulty in demonstrating consistent changes in GABAA receptor function in dependent animals results, at least in part, from the complex changes in the production of different GABAA receptor subunits induced by chronic alcohol administration and withdrawal.
- The agent acamprosate, which has prolonged abstinence in alcohol-dependent patients in some studies (see Kranzler and Gage 2008) and is approved for the treatment of alcohol dependence in the United States, appears to act on both NMDA and mGluR5 receptors (Spanagel and Kiefer 2008).
- The mGluRs modulate glutamatergic neurotransmission by activating various signal transduction pathways.
- This perturbation in brain and neuroendocrine stress systems may have significant implications regarding motivation for alcohol self-administration.
- If depolarization exceeds a certain threshold, an electrical impulse (i.e., action potential) is generated that can travel along the neuron, toward the tip of the axon, where it is converted into a chemical signal.
Newer Drugs
- Furthermore, little information is available on potential changes in β-endorphin in other brain regions.
- In the absence of alcohol, glutamate leads to the activation of the postsynaptic neuron and the generation of a new nerve signal.
- 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.
- GABAB receptors, in contrast, like mGluRs, are linked to G-proteins (see Bettler and Tiao 2006; Kornau 2006).
Other important drugs used to manage AWS are anti-epileptics such as valproate, carbamazepine, gabapentin; adrenergic blockers such as Propanolol and clonidine; Baclofen; Barbiturates and recent drugs like levetiracetam, sodium oxybate and dexmedetomidine. For delirium tremens and withdrawal seizures, treatment with high-dose benzodiazepines (parenteral or oral) is recommended in ICU set up. Thiamine (B1) deficiency is commonly seen and serious complications in alcohol-dependent patients and hence, supplementation is widely recommended.
Brain Imaging and Genetic Factors
Ethanol may not only modulate the function of GABAA receptors directly or indirectly but also may act presynaptically to increase GABA release in numerous brain regions (Ariwodola and Weiner 2004; Nie et al. 2004). In the amygdala, the effect of ethanol on GABA release appears to be mediated by activation of CRF receptors (Nie et al. 2004), and other reports suggest a similar role for an opiate-like receptor (i.e., the noci-ceptin receptor) (The CRF system is discussed in the section “Stress, CRF, and Alcohol Dependence”). Additional in vitro studies demonstrated that low concentrations of ethanol potentiate GABAA receptor function in different experimental systems (Allan and Harris 1986; Suzdak et al. 1986; Ticku and Burch 1980). However, electrophysiological analyses of ethanol’s effects on GABAA receptor function did not yield consistent results (Grobin et al. 1998; Wallner et al. 2006). In some cases, very specific conditions (e.g., a specific test temperature) were needed to observe any effects, which raised questions regarding the physiological significance of these effects. At least in part, the variability of ethanol’s effects results from differences in the subunit composition of the GABAA receptors in different cells.
In this way, the apparent short-term effects of chronic ethanol treatment and withdrawal on glutamatergic transmission could lead to longer-term alterations. The synaptic population of AMPARs also changes in response to prolonged ethanol exposure. For example, chronic ethanol treatment increased AMPAR-mediated Ca2+ flow into the neurons as well as production of GluR1 and GluR2/3 subunits in neuronal cultures and in some brain regions (Chandler et al. 1999; Dettmer et al. 2003). However, in contrast to the NMDARs, no increased synaptic clustering of AMPARs occurred in cultured hip-pocampal neurons chronically exposed to ethanol (Carpenter-Hyland et al. 2004). Finally, in rats subjected to chronic intermittent ethanol exposure (i.e., periods of alcohol exposure followed by periods of abstinence), AMPAR-mediated spontaneous EPSCs in tissue slices obtained from a part of the amygdala exhibited a higher frequency (suggesting increased glutamate release) and amplitude (Lack et al. 2007).
By modifying the required response (e.g., increasing the number of lever presses required before the alcohol is delivered) researchers can determine the motivational value of the stimulus for the animal. In operant procedures, animals must first perform a certain response (e.g., press a lever) before they receive a stimulus (e.g., a small amount of alcohol). Epinephrine and norepinephrine (also known as adrenaline and noradrenaline) are two hormones and neurotransmitters that are produced in some nerve cells (i.e., neurons) as well as in the adrenal glands and which have many functions in the body. Sixty-six out of 103 (64.1%) study participants belonged to the age group of 31 and 50 years.
Severity of Alcohol Dependence Questionnaire (SADQ)
The propensity of anti-convulsant drugs to cause sedation is much less as compared to BZD’s 30. The advantage of the STR lies in the fact that detoxification is monitored through a standardized scale that results in administration of less benzodiazepines for a significantly shorter duration thereby reducing the cost to the patient as well as to the hospital. Day et al., concluded that STR is acceptable to both patients and staff and is potentially a useful technique for busy acute psychiatric wards 53. Cassidy et al., reported that symptom-triggered approach reduced cumulative benzodiazepine dose and length of stay in an emergency department set up 54.
Factors Associated with Treatment
Chronic alcohol exposure can alter CRF neurotransmission as evidenced by withdrawal-related HPA axis activation and long-lasting dysregulation (Adinoff et al. 1990; Rivier 2000). In addition, time-dependent changes in extracellular levels of extra-hypothalamic CRF occur during withdrawal (Merlo Pich et al. 1995; Olive et al. 2002; Zorrilla et al. 2001). Numerous studies have shown that such changes in brain CRF activity have important ramifications regarding alcohol self-administration. For example, CRF infusion into the brain ventricles3 reduces voluntary alcohol intake in rats (Bell et al. 1998; Thorsell et al. 2005). Likewise, mice genetically engineered to produce higher-than-normal CRF levels (i.e., CRF transgenic mice) exhibited reduced voluntary alcohol intake compared with nontransgenic control animals (Palmer et al. 2004), whereas CRF-deficient mice showed the opposite effect (i.e., increased alcohol drinking) (Olive et al. 2003).
Together, these findings implicate GABA systems in aspects of relapse drinking in dependent animals but again suggest that the complexity of adaptations in the GABA receptors is not yet fully understood. Nevertheless, it is important to note that several human studies have now shown evidence of association between alcohol dependence or related characteristics and specific variants in genes coding for GABAA receptor subunits (Dick et al. 2006; Enoch 2008; Matthews et al. 2007). Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. Patients with moderate or severe alcohol withdrawal, medical complications and multiple failed attempts at abstinence may need close monitoring, in indoor setting. Oral benzodiazepines are the best studied and most effective drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures and delirium. The management should be individualized with the help of rating scales and use of Symptom Triggered regime, which is proved to be more effective as compared to Fixed Tapering dose regime.
Adequate nutrition must be ensured with care to prevent aspiration in over-sedated patients. 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. During alcohol use and withdrawal the increase in CNS dopamine levels contribute to the clinical manifestations of autonomic hyper arousal and hallucinations. As previously noted, alcohol activates the HPA axis, with the magnitude and response profile influenced by a host of variables, including the individual’s genetic makeup (i.e., genotype) and sex as well as dosing parameters (Rivier 2000; Wand 2000).
• Alcohol withdrawal syndrome with alcohol withdrawal seizures and/or delirium
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. Taken together, a substantial body of evidence suggests that changes in CRF function within the brain and neuroendocrine systems may influence motivation to resume alcohol self-administration either directly and/or by mediating withdrawal-related anxiety and stress/dysphoria responses. This experimental design can be further modified by the use of discriminative contextual cues. This means that certain contextual cues (e.g., a unique odor or testing environment) will indicate to the animal that responding will pay off with delivery of alcohol reinforcement, whereas a different contextual cue is used to signal that responding will not result in access to alcohol. If the responding is extinguished in these animals (i.e., they cease to respond because they receive neither the alcohol-related cues nor alcohol), presentation of a discriminative cue that previously signaled alcohol availability will reinstate alcohol-seeking behavior.
There is credible evidence to support the concept of PAWS based on this review’s findings. High-quality treatment studies involving agents addressing its neurobiological underpinnings are also recommended. Alcohol use is a pervasive problem that is taking an increasing toll on the world’s population. The World Development Report 1 found that the alcohol related disorders affects 5-10% of the world’s population each year and accounted for 2% of the global burden of disease. Globally alcohol consumption has increased in recent decades, with most of the increase in developing countries.
Carbamazepine has been shown to be superior in ameliorating global psychological distress and reducing aggression and anxiety compared to oxazepam 57. Carbamazepine was also reported to be an effective alternative to benzodiazepines in the treatment of alcohol withdrawal syndrome in patients with mild to moderate symptoms 58. Carbamazepine was found superior to benzodiazepines in prevention of rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple repeated withdrawals 59. Carbamazepine use, however, has been limited due to its interaction with multiple medications that undergo hepatic oxidative metabolism, making it less useful in older patients and patients with medical co-morbidities 60. When these GABA neurons are activated, their signals decrease the firing of dopamin-ergic neurons.