A higher acceptance coping style in non-relapsed persons could have helped them accept or confront life problems due to alcohol than due to their environment or family. Such approach-oriented positive coping styles found in our non-relapsed persons could mean that they assumed greater responsibility for their actions including a relapse. In a review of protracted withdrawal by Satel and colleagues (1993), the authors concluded that symptoms extending beyond the period of acute withdrawal from alcohol—as well as opioids, for that matter—have been relatively consistently described but not conclusively demonstrated.

Treatment regimens used in alcohol withdrawal states

Neuroplasticity is defined as the brain’s ability to change and reorganize itself throughout life by forming new connections between nerve cells (i.e., neurons) and altering the activities of existing neurons. This ability allows the brain to compensate for injury or disease, to accommodate new experiences, and to adjust to new situations and changes in the environment (e.g., exposure to alcohol and other drugs AODs). With respect to AODs this means that even during the initial stages of AOD use, changes in brain chemistry occur that affect signaling molecules (i.e., neurotransmitters2), the proteins (i.e., receptors) that the neurotransmitters interact with, and various other molecules.

Role of Opioids and Opioid Receptor Antagonists During Alcohol Withdrawal

Further, the amount of work mice (Lopez et al. 2008) and rats (Brown et al. 1998) were willing to expend in order to receive alcohol reinforcement was significantly increased following repeated withdrawal experience. This suggests that the reinforcing value of alcohol may be enhanced as a result of experiencing repeated opportunities to respond for access to alcohol in the context of withdrawal. The release of cortisol, the endogenous stress hormone, is regulated by corticotrophin-release factor (CRF), whose levels increase during alcohol withdrawal (Heilig & Koob, 2007). Accordingly, individuals experiencing acute and protracted AWS have higher reported basal serum cortisol levels (Heilig & Koob, 2007). However, CRF-like peptides also appear to maintain a negative-affective state, suggesting that they have a specific role in mediating the underlying PAWS stress response (Bruijnzeel & Gold, 2005).

• Efficacy of fixed tapering dose regimens over symptom triggered regimens

The authors primarily attributed their conclusions to methodological limitations in the extant PAWS studies, such as the failure of studies to do multiple time point sampling, using standardized instruments and control groups, and re-administering the substance to suppress withdrawal symptoms (Satel et al., 1993). Further, the authors mentioned that the concept of protracted withdrawal was ambiguous, confounding interpretations of the literature, and precluded derivation of a unified vision of the term, which would be necessary for adding the diagnosis to the DSM (Satel et al., 1993). Ultimately, Satel and colleagues found insufficient empirical evidence for the existence of PAWS to justify its inclusion in the DSM (Satel et al., 1993). However, they proposed that PAWS could be a “global post-use syndrome with an attenuated physiologic rebound, toxic residuals, and the expression of pre-existing symptoms unmasked by the cessation of use,” indicating a need for future efforts to identify signs and symptoms of PAWS (Satel et al., 1993). Gabapentin, which has structural similarity to GABA, is shown to be effective in the treatment of alcohol withdrawal 63,64.

Glutamate Receptors

High concentrations of ethanol inhibited the normal responses to mGluR5 activation in cells into which the receptors had been artificially introduced (i.e., in a heterologous cell system) (Minami et al. 1998). In addition to subunit composition and association with other proteins, posttranslational modification also influences the exact function of specific GABAA receptor molecules. These modifications occur after the proteins comprising the receptor have been synthesized. At that point, other enzymes perform modifications, such as addition of phosphate groups (i.e., phosphorylation), that can influence receptor function (Brandon et al. 2002; Sigel 1995) and trafficking (Kittler and Moss 2003). For example, most GABAA receptor subunits have sites where phosphorylation can occur (Macdonald and Olsen 1994), and phosphorylation of GABAA receptor subunits by different kinases (e.g., PKA and PKC) has been observed. Phosphorylation also is important for the effects of modulators such as benzodiazepines on GABAA receptor function (see Kittler and Moss 2003).

• There is no empirical basis for differentiating protracted withdrawal symptoms from PAWS from other conditions.
• Barbiturates are cross tolerance to alcohol and can ease withdrawal symptoms significantly.
• In a three-stage model of dependence, craving also has been conceptualized as the preoccupation/anticipation stage (Koob 2008).
• After chronic alcohol exposure and during withdrawal, glutamate release at the synapse is enhanced and the number of synaptic N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPARs) is increased.

In most cases, it is secondary to a general medical condition causing disturbance in the basic functions of the brain. PAWS symptoms include irritability, depression, insomnia, fatigue, restlessness, alcohol cravings, and distractibility. These are most severe in the first 4 to 6 months of abstinence and diminish gradually over several years of sustained abstinence. Among 27 patients with AUD investigated for impaired sleep, the authors concluded that impaired sleep emerging after the withdrawal period might be one of the hallmarks of PAWS, with 52% experiencing insomnia in the study and 33% experiencing prolonged insomnia up until the 169th day following abstinence (Watanabe et al., 2001).

As a result, an electrical signal (i.e., action potential) is generated that can be further transmitted throughout the cell to the axon. In addition, the increase in Ca2+ in the cell activates second messenger signaling pathways, including one involving a molecule called protein kinase A (PKA), and other kinases. Importantly, the location of AMPA receptors at the synapse is not fixed, and these receptors can be transported to and away from the postsynaptic membrane as needed. This trafficking of AMPARs plays an essential role in certain forms of experience-dependent plasticity and long-term changes in synaptic strength (Collingridge et al. 2004). 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 states18 and their use is not recommended in severe withdrawal states.

However, the mechanism(s) by which this effect occurs, and the adaptations in the systems after chronic alcohol exposure and withdrawal, still are being discovered (see Grobin et al. 1998; Wallner et al. 2006). After chronic alcohol exposure and during withdrawal, glutamate release at the synapse is enhanced and the number of synaptic N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPARs) is increased. Nevertheless, numerous pharmacotherapies have been employed to treat alcoholism, guided principally by advancing knowledge about alcohol’s interactions with various components of the brain’s reward and stress pathways (Heilig and Egli 2006; Litten et al. 2005; Spanagel and Kiefer 2008). Naltrexone operates as an antagonist of certain receptors (principally μ and δ receptors) for brain-signaling molecules (i.e., neurotransmitters) called endogenous opiates that are involved in reward systems, whereas acamprosate is thought to modulate signal transmission involving another neurotransmitter called glutamate.

Treatment with NMDAR antagonists to prevent excessive receptor activity when ethanol is withheld can reduce both the alcohol deprivation effect (Vengeliene et al. 2008) and cue-induced reinstatement of alcohol-seeking behavior in rats (Backstrom and Hyytia 2004). In alcohol-dependent humans, these antagonists can reduce cue-induced craving for alcohol, possibly because they can produce subjective effects that resemble those produced by alcohol (Krupitsky et al. 2007; Krystal et al. 1998). Similarly, treatment of animals with AMPAR antagonists reduced cue-induced reinstatement of alcohol-seeking behavior as well as the alcohol deprivation effect (Sanchis-Segura et al. 2006). Antagonists at mGluRs have demonstrated similar effects, resulting in reduced alcohol deprivation effect and attenuated anxiety and alcohol-seeking behavior in cue-induced reinstatement models of relapse (Backstrom and Hyytia 2005; Backstrom et al. 2004; Busse et al. 2004; Zhao et al. 2006). As a result of increases in iGluR expression and function induced by chronic ethanol exposure, the central nervous system enters a state of excessive activation (i.e., hyperexcitability) when ethanol is suddenly withdrawn.

There remains a need for further research regarding the post-acute withdrawal abstinent period (Williams & McBride, 1998). Although several studies have described PAWS symptoms, there is a need to develop a consensus definition, distinguishing PAWS from acute withdrawal or subjective patient experiences. There is no empirical basis for differentiating protracted withdrawal symptoms from PAWS from other conditions. It remains unclear if PAWS symptoms represent an underlying untreated mood, anxiety, or cognitive disorder. Alcohol also acts on N-methyl-D-aspartate (NMDA) receptor as an antagonist, thereby decreasing the CNS excitatory tone.

Consequently, the goal of this article was to summarize the extant literature examining the neurobiology and symptomatology of PAWS, paralleling findings from a complimentary review focusing on PAWS treatment. All subclasses of benzodiazepines appear to be equally effective in treating AWS 24. Therefore, choosing a benzodiazepine depends on selection of preferred pharmacokinetic properties in relation to the patient being treated. The most commonly used benzodiazepines for alcohol detoxification are chlordiazepoxide, diazepam (long acting) and lorazepam, oxazepam (short/intermediate acting). To measure discriminative stimulus properties of alcohol, an animal is trained to give a certain response when it receives alcohol.

• Activation of extrasy-naptic GABAA receptors plays a role in producing a stable electrical current that is present in neurons at their resting potential and is not dependent on synaptic GABA release (known as tonic inhibition).
• All patients with seizures or DT should have immediate intravenous access for administration of drugs and fluids.
• In most cases, it is secondary to a general medical condition causing disturbance in the basic functions of the brain.

For example, whereas synaptic GABAA receptors contain α1, α3, or α5 subunits as well as γ1 or γ2 subunits, extrasynaptic GABAA receptors contain α4, α6, and δ subunits. The synaptic GABAA receptors have relatively low affinity for GABA compared with extrasynaptic receptors; conversely, extrasynaptic receptors are relatively insensitive to benzodiazepines. Moreover, activation of synaptic and extrasynaptic GABAA receptors leads to inhibitory effects through different mechanisms (Michels and Moss 2007).

Comorbid Substance Use Disorder

Endogenous opiates, however, can act on μ receptors on the GABAergic neurons, thereby inhibiting GABA transmission and ultimately leading to increased dopamine release (Di Chiara and North 1992; Margolis et al. 2003). Therefore, it is possible that ethanol can induce β-endorphin release, resulting in activation of μ receptors in the VTA. 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). Thus, acamprosate inhibits NMDAR-mediated calcium influx in cultured rat neurons from some, but not all, brain regions (Allgaier et al. 2000; Popp and Lovinger 2000). Moreover, acamprosate recently was shown to inhibit mGluR5 signaling (Harris et al. 2003) and is ineffective in mice lacking mGluR5 (Blednov and Harris 2008).

Different stressors likewise robustly reinstated extinguished alcohol-reinforced responding in different operant reinstatement models of relapse (Funk et al. 2005; Gehlert et al. 2007; Le et al. 2000, 2005; Liu and Weiss 2002b). 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). HPA axis activity also can influence brain activity through the actions of molecules known as neuroactive steroids. Neuroactive steroids are endogenous neuromodulators that interact with several neurotransmitter systems via rapid membrane action (as opposed to other steroid molecules that act via slower intracellular genomic mechanisms) (Genazzani et al. 1998; Patchev et al. 1994, 1996). Among the neuroactive steroids, compounds 3α,5α-THDOC and 3α,5α-THP, or allopregnanolone, which are the 3α,5α-reduced metabolites of deoxycorticosterone and progesterone, respectively, are the most potent positive modulators of GABAA receptors.

Furthermore, mifepristone administered systemically or into the central nucleus (but not the basolateral nucleus) of the amygdala attenuated stress-induced reinstatement of alcohol alcohol dependence, withdrawal, and relapse pmc seeking behavior (Simms et al. 2012). Higher emotional support in our non-relapsed subjects could indicate positive family behaviors and better social support. In contrast, relapsed persons shared with us during their follow-up sessions a higher degree of poor social support in the form of interpersonal conflicts and also negative family behaviors like avoiding alcohol-dependent persons.