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1May 2019 | Volume 10 | Article 339
REVIEW
doi: 10.3389/fpsyt.2019.00339
published: 16 May 2019
Frontiers in Psychiatry | www.frontiersin.org
Edited by:
Scott J. Moeller,
Stony Brook Medicine,
United States
Reviewed by:
Sara Blaine,
Auburn University,
United States
Keren Bachi,
Icahn School of Medicine at
MountSinai, United States
*Correspondence:
Christos Kouimtsidis
christos.kouimtsidis1@nhs.net
Specialty section:
This article was submitted to
Addictive Disorders,
a section of the journal
Frontiers in Psychiatry
Received: 31 January 2019
Accepted: 30 April 2019
Published: 16 May 2019
Citation:
KouimtsidisC, DukaT, PalmerE
and Lingford-HughesA (2019)
Prehabilitation in Alcohol
Dependence as a Treatment Model
for Sustainable Outcomes. A
Narrative Review of Literature on the
Risks Associated With Detoxification,
From Animal Models to Human
Translational Research.
Front. Psychiatry 10:339.
doi: 10.3389/fpsyt.2019.00339
Prehabilitation in Alcohol Dependence
as a Treatment Model for Sustainable
Outcomes. A Narrative Review of
Literature on the Risks Associated With
Detoxification, From Animal Models to
Human Translational Research
Christos Kouimtsidis 1*, Theodora Duka 2, Emily Palmer 1 and Anne Lingford-Hughes 1
1 Centre for Psychiatry, Imperial College London, London, United Kingdom, 2 Sussex Addiction Research and Intervention
Centre (SARIC), School of Psychology, University of Sussex, Brighton, United Kingdom
In this review paper, we discuss how the overarching concept of prehabilitation is applicable
to alcohol dependence. Central to prehabilitation are the concepts of expected harm, risks,
and proactive planning to eliminate the harm or cope with the risks. We review the evidence
from animal models, psychological experimental studies, as well as pharmacological
studies, on the potential risks and harms associated with medically assisted alcohol
detoxification and the current treatment paradigm for alcohol dependence. Animal
models provide an approximation mostly of the physical aspect of alcohol withdrawal and
detoxification process and make predictions about the development of the phenomena
in humans. Despite their limitations, these models provide good evidence that withdrawal
from chronic ethanol use induces cognitive impairment, which is worsened by repeated
bouts of withdrawal and that these impairments are dependent on the duration of
alcohol withdrawal. Initial clinical observations with alcohol-dependent patients confirmed
increased incidence of seizures. In recent years, accumulating evidence suggests that
patients who have had repeated episodes of withdrawal also show changes in their
affect, increased craving, as well as significant deterioration of cognitive abilities, when
compared to patients with fewer withdrawals. Alcohol dependence is associated with
tolerance and withdrawal, with neuroadaptations in γ-Aminobutyric Acid-A Receptor
(GABA-A) and glutamatergic N-methyl-D-aspartate (NMDA) receptors playing key roles.
It is suggested that dysregulation of the NMDA receptor system underpins alcohol-
related memory impairments. Finally, we discuss the Structured Preparation for Alcohol
Detoxification (SPADe) as an example of how prehabilitation has been applied in clinical
practice. We discuss the importance of partial control over drinking as an interim step
toward abstinence and early introduction of lifestyle changes for both the patient and the
immediate environment prior to detoxification and while the patient is still drinking.
Keywords: alcohol dependence, prehabilitation, withdrawal, detoxification, animal models, human research
Prehabilitation in Alcohol DependenceKouimtsidis et al.
2May 2019 | Volume 10 | Article 339Frontiers in Psychiatry | www.frontiersin.org
INTRODUCTION
e concept of pre-habilitation has been introduced in the eld of
orthopedics and describes a set of exercises and training routines
for certain groups of patients with the aim to maximize physical
strength and reduce the risk of expected harm or frequent injuries,
therefore taking a proactive rather than a reactive approach. e
concept is applied in surgery with the aim of preparing patients for
a surgical intervention. It is a strategy for proactive management of
risk factors associated with the surgical intervention. e approach
is therefore described as a shi away from an impairment-driven
reactive model and as an opportunity for introducing proactive
sustainable and appropriate lifestyle changes (1).
Central to the successful implementation of pre-habilitation
are the concepts of expected harm or risk and proactive planning.
Both concepts are considered to be crucial determinants of the
interaction between humans and the environment in general,
associated with human evolution and the progress from hunting
to agriculture, structured communities, and human civilization.
Planning is crucial in all aspects of everyday life. e ability
to predict or anticipate certain harm or assess certain risks is
associated with the human ability of learning from experience,
modify behavioral responses, and develop long-term and
sustainable response strategies. To that eect, planning in
advance of anticipation of risks can be considered as an essential
strategy associated with individual survival and progress.
Planning should not been viewed as a barrier for improvisation
and innovation; on the contrary, it provides a stable environment
for progress and positive change to take place.
e term “alcohol dependence” was rst introduced in
1976 (2) and was used in both International Classication of
Diseases (ICD-10) classication systems (3) and the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) (4). In DSM-5, dependence is now conceptualized on
a continuum with abuse, such that a single disorder is now called
alcohol use disorder (AUD) with mild, moderate, and severe sub-
classications (5). Alcohol withdrawal syndrome is a collection of
symptoms that occur aer an alcohol-dependent individual stops
consumption (6). Withdrawal from alcohol has been associated
with cognitive impairments in recovering alcohol-dependent
patients and furthermore the risk of relapse aer withdrawal is
associated with cognitive decit (7, 8).
In this paper, we introduce the concept of pre-habilitation
and its role in the clinical management of alcohol dependence.
e approach has many aspects that overlap with other clinical
management interventions, such as harm reduction and opioid
substitution treatment. e overall aim is to reduce medical and
other associated risks in a safe environment and to empower
the individual to achieve the psychosocial changes required for
recovery and social reintegration. Here, we focus on alcohol
detoxication and withdrawal, given that it poses substantial
risks to cognitive function. We review the evidence from animal
studies, human psychological experimental studies, and imaging
studies. We have conducted a narrative review of preclinical and
clinicalevidence regarding alcohol withdrawal or detoxication
using online resources, e.g., PubMed and Google Scholar, and
that were published in English prior to September 2018. For
the preclinical evidence,we have focused the review on studies
using cognitive behavioral paradigms rather than those on
physical withdrawal symptoms, e.g., seizures. For the clinical
review, we have focused on neuroimaging studies of relevant
neurobiological processes. We also discuss the limitations of
current pharmacological interventions. Finally, we discuss,
in some detail, an example of a clinical implementation of the
model. In this paper, we have chosen to use the older and longer
established term “patient” rather than client or service user. is
choice does not refer to a scientic or philosophical position.
CURRENTLY RECOMMENDED
TREATMENT PARADIGM TO MANAGE
ALCOHOL DETOXIFICATION
Current clinical guidelines suggest that medically assisted
withdrawal or detoxication is generally required for the treatment
of moderate to severe alcohol dependence. is should be planned
and the importance of providing structured aercare is emphasized
(9). Medically assisted detoxication is required to minimize the
risks of withdrawal-related symptoms and complications.
e guidelines suggest that the patient prepares for
detoxication by attending sessions at a specialist service to
enhance and maintain motivation to change and develop a
plan for structured aercare (9). As described, the latter is
considered important to ensure eective treatment. What
is delivered however may vary widely with sessions not
necessarily providing structured preparation to address issues
such as stabilizing the amount of drinking, enhancing partial
control over drinking, promoting early lifestyle changes, or
empowering changes within the immediate family or social
environment.
Detoxication may be medically assisted as an outpatient
in the community or as an inpatient in a general hospital or
a specialist unit. e choice between these two detoxication
settings depends on health risk factors and the availability
of social support to mitigate these risk factors during the
detoxication process, and it is usually made by the health
professionals (9). Medically assisted detoxication is discussed
in more detail in Section 6 below.
Structured aercare (also referred to as rehabilitation)
is considered by clinical guidelines as the most important
component of the current treatment paradigm, with strong
evidence for its eectiveness (9). It is recommended that the
structured aercare that follows detoxication be delivered
within a Cognitive Behavioral erapy approach, either on an
individual basis or via membership of a Relapse Prevention
Group, alongside family interventions. It is highly recommended
that patients engage with peer-support or mutual aid groups, such
as Alcoholics Anonymous or SMART Recovery. Pharmacological
interventions such as acamprosate, naltrexone, or disulram
are also recommended. e existing evidence does not favor
outpatient over inpatient detoxication, or residential aercare
treatment over community treatment, or longer versus shorter
duration residential aercare treatment programs (9). However,
access to residential aercare programs is recommended for
Prehabilitation in Alcohol DependenceKouimtsidis et al.
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homeless individuals, and eorts should be made to address
accommodation issues prior to discharge (9).
Two of the long-term challenges for professionals (both
academics and clinicians) involved in the treatment of alcohol
dependence are the denition of successful outcome as well as
the high relapse rate. For example, statistics from Public Health
England for the period 2017–2018 suggest that 61% of clients
complete treatment successfully (i.e., are free from dependence,
which could mean abstinence but not necessarily), the same
proportion as the previous year (10). is number provides an
indication of how successful treatment is but is dependent on
the denition of successful treatment, the severity of presenting
problem, and the time when completion and exit are reported.
Other indicators such as maintenance of abstinence for 6months
and 12 months for alcohol-dependent patients could enhance
our understanding of the eectiveness of the current treatment
paradigm. Our local data suggest that only 60% of patients who
have completed planned detoxication have been engaged in
aercare interventions, which are considered to be essential
for long-term recovery (11). is ratio has improved to 82%
when a pre-habilitation approach has been implemented, such
as participation in the Abstinence Preparation Group (see
Section 7 below) (12). ere may be several explanations for this
improvement, including benets of participating in a group or
more specic theory-based factors such as regaining of partial
control over drinking and early lifestyle changes (12).
In summary, current treatment guidelines advocate
avoidance of unplanned and urgent detoxifications as
they do not lead to sustainable outcomes with regard to
drinking behaviors (9). They put emphasis on the provision
of psychological treatment following detoxification and
promotion of participation in peer-support interventions (9).
Given the challenges in improving treatment outcomes, we
consider that the main shortfalls of these guidelines are that
(1) the only therapeutic input prior to detoxication is restricted
to motivation enhancement and preparation of an aercare
plan without any theory-based structured intervention to
manage the risks expected once alcohol is withdrawn, and
(2) a large proportion of patients completing detoxication
do not engage with any evidence-based aercare to reduce
the risk for relapse. Given that the majority of psychological
interventions may not have an immediate eect, and the high
risk of relapse during the rst 3 months post-detoxication,
we need to consider an alternative approach such as pre-
habilitation to reduce the risk of relapse. Furthermore, the fact
that these interventions are taking place during a period of
mood dysregulation, which is the result of the detoxication
itself, might compromise their eect.
LEARNING AND HABIT DEVELOPMENT
INHUMANS
Humans have the ability to test out a new behavior as a solution
to a challenge and—depending on the results (e.g., reward)—
to either consolidate or abandon this behavior. Consolidated
rewarding behaviors then become repeated in similar (or
different) situations and, over time, become automatized. This
leads to the fast replication of such behaviors—a bypassing of
the conscious and careful consideration of pros and cons—
since the analysis of their efficacy has already been done, in
the past, and proven successful (13). The ability to automatize
successful behaviors allows humans to continue with further
learning and the accumulation of new skills and expertise.
This ability to bypass the conscious decision-making control
mechanism confers the advantage of fast and successful
responses to dangerous environmental stimuli, but it has
a major disadvantage: humans are not able to monitor the
appropriateness of the behavior or assess the possible need for
behavioral modification (13).
Whenever an automatized behavior requires modication,
the learning process must be slowed down, in order to allow
for the decision-making process to again become conscious.
is does not refer to a meta-cognitive process, but rather to
the creation of time and space between the high-risk situation
and the behavioral response. In other words, implicit cognitions
must again become explicit if the individual is to regain
conscious control in order to modify the extant behavior. It is
easier to undertake this reversal process (14) in a safe, practice-
friendly environment, where those factors necessitating the
fast reproduction of a behavioral response may be kept under
control. Factors such as stress, threat, or uncomfortable physical
symptoms typically provoke instinctive responses of a habitual
nature. Humans tend to think more clearly and laterally when
they can explore alternative solutions without facing immediate
threat or being subject to stress.
The Expected Risk in Alcohol Dependence
In the case of drinking (as well as other substance misuse),
this leads to the state whereby habitual drinking dominates
all other behaviors and becomes repeated despite the person’s
awareness of its loss of effectiveness and the accumulation of
evidence of the associated harm. This leads the person into
the paradox of wanting (implicit activation of need) although
not liking (conscious desire and choice) drinking (15). From
a psychological perspective, all explicit cognitions—such as
positive and negative expectancies of the effect of drinking—
which were conscious and under the control of the individual,
are rendered implicit, and bypass the conscious decision-
making pathway fuelling the continuation of drinking
(13). This phenomenon is described as “loss of control”,
an underlying theme common to 9 out of the 11 criteria of
Alcohol Use Disorder in DSM-5 (5), three out of six criteria
for alcohol dependence in ICD 10 (3), and one of three in
ICD11.
In the sections below, we discuss the risks associated with
alcohol withdrawal and medication-assisted detoxication
interventions. We review the evidence from animal models,
pharmacological studies, and psychological experimental studies
to explore risks such as cognitive impairment, stress sensitivity,
the limitations of medication-based protective roles, as well
as limitations of the existing treatment paradigm of planned
detoxication and rehabilitation.
Prehabilitation in Alcohol DependenceKouimtsidis et al.
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ANIMAL MODELS OF ALCOHOL
WITHDRAWAL AND DETOXIFICATION
ONCOGNITIVE IMPACT
Animal models have been used to try and understand the
phenomenon of alcohol withdrawal and specically to determine
if repeated withdrawals particularly have an impact on cognitive
function. Animal models have several advantages in alcohol
research. ey may be used to study determinants of alcohol-
related behavior where there are ethical issues with carrying
out such research in humans due to risks in giving volunteers or
patients addictive harmful substances (16).
Further, animal models are used because animals have similar
genetic, biochemical, and physiological compositions to humans.
erefore, research using animals can inform the understanding
of the human condition and help lead to the development of
new therapeutics. Some of the current medications approved
for the treatment of alcohol use disorders (e.g., naltrexone
and acamprosate) were developed using animal models (16).
However, animal models do not represent the entire complex
disorder; instead, they allow the study of component features of
the condition and help provide evidence for the determinants of
such behaviors (17).
ere are currently several dierent methods used to
model ethanol (alcohol) dependence in rodents such as forced
consumption in drinking water, ethanol containing liquid
diet, ethanol vapor inhalation, and repeated intraperitoneal
or intragastric administration (18). In addition to route of
administration, the length of ethanol exposure varies between
models of alcohol use, e.g., from a 4-day chronic intermittent
exposure (19) or a 6-month chronic model (20). e variation
in both administration and duration of chronic ethanol
administration complicates the interpretation of results. All of
these models aim to mimic the neuroadaptations in the brain,
which lead to tolerance and physical dependence of alcohol. A
key issue with these models is the forced exposure to ethanol,
which doesn’t accurately represent the compulsive element of
the human experience of alcohol dependency despite eorts
to assess operant re-enforcing and conditioned responses (16).
Induction of alcohol dependency in animals is considered to be
successful if withdrawal symptoms are present upon cessation of
exposure (18). However, this is representative only of a physical
dependency and lacks the complexity of all the environmental
and psychosocial inuences that contribute to the complex
human experience of alcohol addiction.
Animal models of alcohol consumption have also been
developed to reect voluntary alcohol consumption such as the
two-bottle choice test, using gradually increasing concentrations
of ethanol or adding sweeteners (17). Although preference
tests are oen inuenced mainly by taste, some animals show a
preference for the pharmacological eects of alcohol, and this
has allowed genetic manipulation to produce high or low alcohol
preference breeds. Rodents will voluntarily consume up to 40%
ethanol (16). For the study of alcohol withdrawal, these voluntary
consumption paradigms are oen not sucient because
consumption levels are not high enough to induce withdrawal
symptoms. Another limitation of these procedures is the
dicultly to determine an animal’s motivation to seek alcohol.
Motivation to consume alcohol can be best demonstrated by an
operant task model (such as lever pressing to receive alcohol in
which the number of presses required increases) or a conditioned
place preference task [for a detailed description, see (21)].
The Impact of Withdrawal on Cognition
Physical withdrawal symptoms are similar in humans and
animals and include tremors, agitation, rigidity, spontaneous
seizures, audio sensitivity, handling-induced seizure sensitivity,
and weight loss (22). However, alcohol withdrawal induces much
more than just physical symptoms with low mood and anxiety
evident. is negative aective state is thought to contribute
to the risk of relapse in alcohol dependence and is therefore a
critical area of study (these eects in humans are discussed in
detail in Section 5 below). Withdrawal is thought to induce these
eects via neuroadaptations from chronic ethanol’s exposure
on brain areas that control fear and memory. For this review,
we focused on the studies assessing the impact on withdrawal
from chronic alcohol exposure on cognitive function in rodents,
which are summarized in Tab le 1. is table shows evidence that
cognitive decits are seen in animal models of withdrawal, that this
decit can worsen with repeated withdrawal, and nally that this
cognitive impact varies with the length of the withdrawal period.
The Presence of Cognitive Impact
e experiments in Tab le 1 used behavioral paradigms following
a variety of chronic alcohol models to assess cognitive function
including the elevated plus maze, the T maze, social interaction,
and conditioned fear response learning. ese have been used
to demonstrate withdrawal-induced impairments in learning
(19, 31), cognitive exibility (26), memory (20, 24, 25, 31,
36), sociability (38), as well as increasing anxiety (23, 27) and
sleep disruption (35). In addition to the previously described
limitations associated with animal models of chronic alcohol
consumption and withdrawal, these studies are also subject to
the limitations of the behavioral paradigms used. For example,
several studies that illustrate the eect of ethanol withdrawal on
inducing anxiety in rodents use paradigms such as the elevated
plus maze, the light–dark box, and the open eld (18). Measures
used in these paradigms such as line crossings or % of time spent
in the center, can be inuenced by impaired locomotion of the
animal, as well as anxiety, and therefore these results may lack
construct validity. However, taken together, given the multiple
cognitive defects assessed, it can be concluded that alcohol
withdrawal may induce some cognitive impairment.
The Effect of Multiple Withdrawals
Several of the studies described in Tabl e 1 indicate the worsening
of withdrawal symptoms given multiple withdrawal episodes,
which is consistent with the clinical picture. e best documented
example of this phenomenon in rodents is the frequency of
seizures following several detoxications: known as the kindling
Prehabilitation in Alcohol DependenceKouimtsidis et al.
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TABLE 1 | The effects of withdrawal on cognition; a summary of research using animal models.
Reference Animal Species Gender Age/weight Chronic alcohol model Daily alcohol
intake
Withdrawal
period
Cognitive testing/measure Cognitive
deficit present
(23) Rat Lister
hooded
Male 250–300 g Ethanol-containing diet for 24 days 2 ×
3-day withdrawal episodes
13–14 g/kg 2 weeks
2 weeks
2 weeks +
1month
Negative patterning task
Contextual fear conditioning via a foot
shock
Spatial learning in the Barnes maze
YES
NO
NO
(24) Rat Sprague–
Dawley
Male 160–180 g In drinking water as sole source of fluid
(20%) 8, 18, and 28 weeks
12.2 to 9.7g/
kg
4 weeks Eight arms radial maze (memory):
Spatial
Nonspatial
YES
YES
(25) Rat Sprague–
Dawley
Male 200–250 g 25% ethanol solution as the only
source of fluid for 9 months (increasing
concentrations from 10%)
53–26 mg% 2 weeks Memory performance shuttle box:
Active avoidance
Passive avoidance
NO
YES
(26) Mouse C57BL/6 Male At least 70
days old
Chronic intermittent ethanol exposure
ethanol vapor (16 h/day for 4 days with
8-h periods of withdrawal) 3 consecutive
cycles, with 3 days of withdrawal IP
primer 1.6 g/kg
175–225 mg/
dl)
Up to 1
week
Behavioral attentional set-shifting task
and reversal learning
YES
(27) Rat Wistar Male 250–280 g 2 g/kg ethanol via gavage twice a day for
28 days
BAC up to 120
mg/dl
5 days Open field (exploratory behavior) YES (lower
frequency of
rearing)
(28) Rat Hooded
Lister
Male 200–240 g Nutritionally complete liquid diet 7%
ethanol Single withdrawal, 24 consecutive
days
17.5 g/kg BAC
100 mg/dl
12 days Seizures (PTZ kindling)
Conditioned emotional response
YES
NO
Nutritionally complete liquid diet 7%
ethanol
Repeated withdrawal, 30 days, with two
periods of 3 days, 11, and 21, in which
they received control diet
12 days Seizures (PTZ kindling)
Conditioned emotional response
YES (faster than
either control or
SWD rats)
NO ↓
(19) Rat Sprague–
Dawley
Male 275–325 g Catheters in the stomach 5 g/kg 25%
in diluted nutritionally complete diet
Additional ethanol was administered every
8 h for 4 consecutive days
7.6 g/kg 4.5 days Morris water maze (learning) YES
(29) Rat Hooded
Lister
Male 200–240 g Nutritionally complete liquid diet 7%
ethanol
Single withdrawal, 24 consecutive days
12.5 ± 0.8
g/kg
2 weeks Conditioned emotional response (fear
conditioning low and high intensity):
Suppression
Extinction
Reversal
NO
NO
NO
Nutritionally complete liquid diet 7%
ethanol
Repeated withdrawal, 30 days, with two
periods of 3 days, 11, and 21, in which
they received control diet
12.9 ± 1.0
g/kg
2 weeks Conditioned emotional response (fear
low–high intensity):
Suppression
Extinction
Reversal
NO
YES
YES
(30) Rat Hooded
Lister
Male 200–240 g Nutritionally complete liquid diet 7%
ethanol
Single withdrawal, 24 consecutive days
15.0 ± 0.4
g/kg
2 weeks Pavlovian-to-instrumental transfer YES
(Continued)
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TABLE 1 | Continued
Reference Animal Species Gender Age/weight Chronic alcohol model Daily alcohol
intake
Withdrawal
period
Cognitive testing/measure Cognitive
deficit present
Nutritionally complete liquid diet 7%
ethanol
Repeated withdrawal, 30 days, with two
periods of 3 days, 11, and 21, in which
they received control diet
15.3 ± 0.6
g/kg
YES
(31) Mice CD-1 Male 8 weeks Only source of liquid increasing
concentrations up to 20% ethanol
4weeks
0.20 ± 0.01
g/dl
3 or 12
weeks after
T-Maze Foot shock Avoidance
GreekCross Brightness Discrimination
Step-Down Passive Avoidance
Shuttle box Active Avoidance
NO
NO
NO
NO
Only source of liquid increasing
concentrations up to 20% ethanol
8weeks
T-Maze Foot shock Avoidance
GreekCross Brightness Discrimination
Step-Down Passive Avoidance
Shuttle box Active Avoidance
YES
YES
YES
YES
(32) Mouse C57BL/6J Male Vapor exposure 16 h with 8-h break 2.5–3.0 g/kg 32 h Odor cue conditioning influence on
voluntary ethanol consumption 15%
presented in a free choice situation with
water 5 days
YES
(33) Rat Wistar Male 240–270 g Nutritionally complete liquid diet as the
sole source of nutrients.
All rats received the CON liquid diet for an
initial 3 days then (6% v/v) for 14 days
8.4–10.4 g/kg
BEC 80.3 ±
7.5–132 ± 5.9
mg/dl
8 h, 48 h
and 72 h
Elevated plus maze. (anxiogenic-like
effect)
Contextual fear conditioning (foot
shock freezing)
YES (8 h only)
YES
(34) Rats Lister
hooded
Male 130–160 g
350–400 g
Nutritionally complete liquid diet 7%
ethanol
Single withdrawal, 24 consecutive days
18 g/kg
Experiments
2 and 3 12.5
g/kg
8 h Elevated plus maze (anxiety)
Plasma corticosterone
YES
YES ↑
Nutritionally complete liquid diet 7%
ethanol
Repeated withdrawal, 30 days, with two
periods of 3 days, 11, and 21, in which
they received control diet
Elevated plus maze (anxiety)
Plasma corticosterone
YES but no
more than SWD
NO
(35) Mouse C57BL6/J Male 90–100 days
24–28 g
4 bouts of 16-h exposure to EtOH vapor
separated by 8-h periods of withdrawal
64.76 ± 31.97
mg/dl
4 days
continuous
Electrophysiological recording from
surgically implanted electrode:
Sleep time
Sleep architecture
YES ↓
YES
(36) Rat Wistar Male 250–300 g Self-administration continuous (24 h/day for
7 days/week) or intermittent (24 h/day for 3
days/week) access to alcohol (20%) using
a two-bottle choice procedure 5 months
<80 mg% 24 h to 68
days
Working memory performance in a
Y-maze and the delayed nonmatching-
to-sample task (DNMS)
Elevated plus maze
YES (24–72 h)
but not (16–68
days)
NO
(37) Mouse Swiss Male 8 weeks 1–8 weeks of intermittent access to 20%
3 days/week 24–48 h between EtOH
access days, two-bottle choice
11.10–284.3
mg/dl
6–8 h Aggressive and nonaggressive
behaviors with a conspecific
YES (aggression
and decreased
social contact)
(20) Mouse C57/BL6 Male 4 months at
start
Source of liquid, concentrated solutions
of ethanol 4% the 1st week, 8% the 2nd
week, and 12% for 6 months
15.34 ± 4.3
g/kg
Progressively
withdrawn 1
week (1 W)
Working memory task. Spontaneous
alternation was tested in a T-maze
Elevated plus maze
YES
YES
(Continued)
Prehabilitation in Alcohol DependenceKouimtsidis et al.
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eect (39, 40). e kindling eect is dened by Pinel et al. as “the
progressive intensication of elicited motor seizures that occurs
during a series of convulsive stimulations”; this leads to increased
susceptibility to convulsive seizures during alcohol withdrawal
due to previous seizure-inducing withdrawals (39). e impact
of multiple withdrawals also has a worsening eect on some of
the associated cognitive impairments. is was demonstrated
using rats fed an ethanol-containing diet (13–14 g/kg/day) for
24 days with two 3-day withdrawals compared with controls and
with rats undergoing continuous ethanol treatment (23). ese
rats performed worse at negative patterning tasks but not spatial
learning, which indicates that repeated withdrawals may aect
some areas of cognition such as plasticity but not others. is
dierential eect of repeated withdrawals on only some cognitive
defects is consistent with evidence that repeated withdrawals
in rats compromised the acquisition of a conditioned fear
response without impacting the recall of a previously learned
fear association (29). ese ndings led to a hypothesis that
multiple withdrawals induce aberrant neuronal plasticity, which
gives rise to interesting predictions. Based on the idea that
repeated withdrawal from alcohol results in repeated overactivity
within glutamatergic systems (see below), it is possible that
hyperactivation of glutamatergic systems would induce synaptic
plasticity, leading to synaptic strength. If repeated withdrawals
increase synaptic strengths, then stimulation of input pathways
will have an enhanced eects on outputs, leading to certain
excitability. However, if synapses are already strengthened, then
the capacity for further plasticity will be reduced, leading to
impaired learning of new associations (41, 42). However, further
research is required to determine the underlying mechanism(s)
behind multiple withdrawals reinforcing some but not all
cognitive defects.
The Duration of the Withdrawal Effect
onCognition
A key consideration is the duration of withdrawal from alcohol
treatment. Some studies have looked at immediate eects of
withdrawal aer 8–24 h (23, 36, 37), while others assess cognitive
defects present aer a much longer period (several weeks) (25,
31). One key question is whether any cognitive impairment is
long-lasting and/or persistent even following a signicant period
of abstinence. One study found that withdrawal caused signicant
working memory impairment during acute withdrawal (24–72h)
but not extended abstinence (16–68 days) (36). is contrasts
with another study in mice in which short-term memory was
not aected by withdrawal but learning and long-term memory
were still impaired when tested 12 weeks aer cessation of
ethanol consumption (31). is suggests that withdrawal, while
having a severe acute eect on cognition, may also cause long-
lasting impairments. erefore, the type of cognitive impairment
present may also dier depending on the duration of abstinence.
Proposed Mechanisms of Withdrawal-Induced
Cognitive Dysfunction
ere is much discussion about the mechanism by which
withdrawal from chronic ethanol induces cognitive impairments.
TABLE 1 | Continued
Reference Animal Species Gender Age/weight Chronic alcohol model Daily alcohol
intake
Withdrawal
period
Cognitive testing/measure Cognitive
deficit present
6 weeks
(6 W)
Working memory task. Spontaneous
alternation was tested in a T-maze
Elevated plus maze
YES
NO
(38) Mouse C57BL/6J Male At least 10
weeks old
Chronic intermittent vapor inhalation. 16 h
separated by 8-h periods of withdrawal
ip primer dose
211.2 ± 25.0
208.8 ± 14.3
211.2 ± 25.0
208.8 ± 14.3
3 to 10 days Social Approach
Novelty-Suppressed
Feeding
Digging
Bottle Brush Tests
NO
YES ↑.
YES ↑
YES ↑
DBA/2J Male At least 10
weeks old
Chronic intermittent vapor inhalation. 16 h
separated by 8-h periods of withdrawal
ip primer dose
253.3 ± 16.0
173.3 ± 14.7
169.5 ± 19.9
179.5 ± 22.3
3 to 10 days Social Approach
Novelty-Suppressed Feeding
Digging
Bottle Brush Tests
YES
NO
YES ↑
YES ↑
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Animal models have been used to link alcohol consumption
with neurodegeneration and changing brain structure by
neurotoxicity, reducing neurogenesis, and reducing the size of
existing neurons. is has been related to dysfunctional behavior,
which is suggestive of cognitive impairments (19). ere have
been several studies investigating the processes underlying
these neurotoxicities. One such experiment in both rats and
mice of both genders found increased levels of corticosterone
in the brain tissue and plasma of both acutely (plasma) and
prolonged (brain) withdrawn animals (43). Raised levels of
corticosterone are known to cause neuronal damage, and it
was therefore proposed as a potential mechanism underlying
withdrawal-induced cognitive dysfunction. ese raised
corticosterone levels are thought to increase neuronal damage
by potentiating excitatory transmission, inducing neuronal
atrophy. Additionally, increased expression of NMDA receptors
was found on the synaptic neurones of the medial prefrontal
cortex, using a mouse model of chronic intermittent ethanol
(26). is was also linked to a behavioral decit in cognitive
exibility a week aer the cessation of ethanol consumption.
ese ndings suggest that the neuro-adaptive changes as
a result of chronic alcohol consumption may contribute to
withdrawal-induced dysfunction.
Other studies have focused on which brain areas are
damaged during alcohol withdrawal, which may further inform
how cognitive defects occur. For example, rat performance on a
cognitive task was impaired by lesions of the basolateral amygdala
(conditioned reinforcement and reinforcer devaluation) and
central nucleus of the amygdala (Pavlovian-to-instrumental
transfer) to identify which area is aected during single or
repeated withdrawals. e result indicated that the central
but not basolateral nucleus was aected during withdrawal.
Similarity studies of mouse brains found that dendritic spine
density was reduced in the lateral orbitofrontal cortex of mice
following chronic intermittent exposure to ethanol (43). A
comprehensive review of all relevant research is beyond the
scope of this article; however, these examples provide evidence
that the induction cognitive dysfunction following withdrawal
is a complex process involving several brain regions. It is a vital
area of research if we are to protect the brain, or at least limit the
damage, in alcohol dependence.
Conclusion From Animal Models
Ultimately, there are several dierent animal models of chronic
alcohol consumption that are used to study the impact of
withdrawal on cognition. While these models fail to replicate
all the complexities of psychosocial and compulsive factors that
occur in the human experience of withdrawal, these animal
models provide good evidence that withdrawal from chronic
ethanol induces cognitive impairment, that this impairment
is worsened by repeated bouts of withdrawal, and that these
impairments are dependent on the duration of alcohol
withdrawal and abstinence. ese animal models have led to
the identication of neuroadaptations and increased levels
of corticosterone as potential modiers of cognitive decits
caused by withdrawal and which brain regions are vulnerable
to or involved in these impairments. Understanding the risks
of withdrawal and the underlying neurobiology is vital if we are
to develop more eective therapies for reducing the damaging
consequences of alcohol withdrawal.
CONSEQUENCES OF REPEATED
DETOXIFICATION OF PATIENTS
DEPENDENT ON ALCOHOL
ere is strong evidence that repeated detoxications are
associated with several cognitive and emotional impairments.
Initial observations conrmed increased incidence of seizures
(44–46). During recent years, accumulating evidence suggests
that individuals who have experienced repeated episodes of
withdrawal show changes to their aect, increased craving, as
well as signicant deterioration of cognitive abilities, when they
are compared to patients with fewer withdrawals (47–49).
Several investigators had suggested that repeated episodes of
detoxication increase the risk of withdrawal seizures. Further
support to their suggestion came with the discovery of the
dierential response of alcohol-dependent patients to anxiety
evoked by the noradrenergic alpha2 agonist, yohimbine, between
those with two or more detoxications compared to those
with only one (50). ese initial observations were followed
by a plethora of experimental evidence showing that repeated
experience of repeated detoxications results not only in
increased incidence of seizures and anxiety but also in increased
craving and impaired inhibitory control of several behaviors in
tasks (50, and in more detail below, e.g., 51, 52). Such tasks are
challenging for high-order executive functions within problem
solving or emotional evaluation contexts like reward seeking
under conditions of incentive conict, cognitive exibility in an
intra-extra dimensional shi, and reversal task and recognition
of emotions in others.
Correspondingly, brain imaging shows that inaccurate
performance on the cognitive tasks in alcohol dependence
in humans who had experienced multiple detoxications is
associated with loss of gray matter in prefrontal regions; the
loss of gray matter is positively correlated with the number of
detoxications. Evidence also suggests that the ability to recognize
emotions in others (e.g., fearful faces) is associated with reduced
connectivity between insula and prefrontal areas, but increased
connectivity between insula and subcortical regions (colliculus)
and between amygdala and other subcortical regions [e.g., bed
nucleus of stria terminalis (BNST)].
Understanding the mechanisms that underlie the
associations between repeated detoxifications and cognitive
and emotional impairments as well as brain structure and
functions alterations is mainly based on animal models
[see previous section and (23)]. Additionally though, binge
drinking (a tendency to drink excessively in one session
leading to intoxication followed by abstinence) in young
human adults has also been used as a model to explore possible
predisposition to and early consequences of alcohol drinking
in the form of repeated cycles (53–58).
Here, we will summarize the empirical evidence of the
cognitive and behavioral decits and their brain substrates
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associated with repeated detoxications and how such decits
may increase vulnerability to relapse.
Cognitive Control Processes Involved
inRelapse
Increased urges to drink alcohol when induced by alcohol-
associated stimuli and reduced ability to control the amount are
recognized as the two basic processes of alcohol dependence.
Inhibitory control is necessary for self-regulation. is is linked
to executive function. Individuals who have low executive
capacity or have damage to brain substrates subserving executive
function display reduced ability for self-regulation and a greater
susceptibility to behavior driven by stimulus and relapse (59,
60). Stimuli irrelevant to the present task or in contrast to the
individual’s current goals can diminish self-regulatory behavior
in a stimulus-driven fashion and lead to relapse (61, 62). Other
evidence, however, suggests that a stimulus-driven eect may
be dependent on search goals driven by the individual’s desire
to consume alcohol (63). Several cognitive processes are
considered to support self-regulation such as working memory
and the ability to shi attention from previously relevant (but
now irrelevant) stimuli (e.g., alcohol cues) to currently relevant
factors (e.g., awareness of drinking consequences).
With the escalation of dependence, alcohol-associated
stimuli become more salient and attract attention faster, thus
diminishing the ability to inhibit the urge to drink. Such alcohol-
associated attentional bias predicts relapse rates and treatment
outcomes (64). Neuroimaging studies have provided strong
evidence for the increased involvement of stimulus-driven
networks (subcortical structures) and reduced involvement
of brain substrates associated with cognitive control (65–67).
us, as dependence progresses, relapse aer several eorts to
achieve and maintain abstinence becomes increasingly likely as
distinct places, people, and paraphernalia associated with the
reward oered by alcohol trigger an intense motivation within
the addicted person to consume alcohol. As mentioned above,
attentional processes (i.e., the ability to shi attention from
previously relevant (but now irrelevant) stimuli to currently
relevant factors may be crucial for self-regulation. Although
impairments of cognitive control are associated with increased
incidence of relapse in alcohol dependence, few studies have
directly examined the possible impact of repeated detoxications
on cognitive control.
Alcohol-dependent individuals show impaired cognitive
exibility as measured in an intra–extra dimensional shi and
reversal task (IED). is is associated with reduced volume of
gray matter in a cluster within the inferior frontal gyrus (BA47)
and the neighboring anterior insula. is is an area that shows
reduced gray matter volume in alcohol-dependent patients and
especially in those with a history of multiple detoxications
(52). e inferior frontal gyrus (IFG) is an area involved in
inhibitory control. Observed decreased gray matter volume in
this area suggests that decreased inhibitory control due to IFG
damage may be linked with repeated relapses (68). erefore,
inhibitory control seems to modulate the translation of desire
to drink into alcohol consumption and weakening of inhibitory
control may lead to addiction (68). To that eect, strengthening
inhibitory control may be an important cognitive strategy to
prevent relapse (69).
Social Competence as a Cause of Relapse:
Brain Mechanisms
e cognitive decits caused by reduced function of prefrontal
brain areas (41, 42) in alcohol dependence, arising from repeated
detoxications, may not only contribute to inexible behavior
and perseveration of drinking but also to the impairments in
social cognition, which is crucial for adaptive social interaction
(70, 71).
Earlier studies have demonstrated that alcohol-dependent
patients generally have reduced ability to recognize emotions
expressed by facial expression in others (72–74). Our research has
shown that such impairments may increase with greater numbers
of detoxifications (75). Emotional recognition deficits are
associated with less successful recovery (76, 77). A recent study
that examined prospectively objective treatment outcomes found
that alcohol-dependent patients who were poor in recognizing
emotions in others were also more prone to relapse (78).
Neuroimaging ndings have revealed brain changes associated
with emotion recognition decits most commonly in prefrontal
cortex, amygdala, and insula brain areas (51, 52). e amygdala is
the brain structure involved in processing of emotion (79) including
the recognition of fearful facial expressions (80); the insula is
associated not only with emotional processing but also with emotion
regulation. Imaging the brain of alcohol-dependent patients during
fear recognition in emotional facial expression of fear (74) revealed
reduced connectivity between insula and prefrontal emotional
regulatory regions (81–84). In particular, a reduced connectivity
of insula with the anterior cingulate cortex (ACC), orbitofrontal
cortex (OFC), and ventrolateral prefrontal cortex (VLPFC) was
seen in alcohol-dependent patients with two or more detoxications
compared with either controls or patients with a single or no prior
detoxication (51). Increased connectivity, also in patients with two
or more detoxications, was found between insula and a colliculus
neuronal cluster, a region representing an important subcortical area
for arousal mechanisms (85), as well as between amygdala and bed
nucleus of stria terminalis (BNST). BNST has been identied as the
key component area of stress-induced relapse in animal models of
addiction (86). From these ndings, it can be argued that increased
connectivity in amygdala-related networks could lead to an increased
emotional reactivity (84), whereas decreases in the network integrity
of insula-related networks could lead to inappropriate analysis of the
emotional input (87).
Importantly, the strength of connectivity between insula and
areas involved in control of behavior and regulation of emotion
(inferior frontal cortex, frontal pole) was negatively correlated
with the number of detoxications and with the ability to control
drinking as evaluated by a self-rating questionnaire (ICQ; 51),
suggesting a relationship between repeated detoxications and
the subjective perception of the ability to abstain. ese ndings
further support that focusing treatment in reducing the impact
of repeated experiences of detoxications represents a reasonable
approach.
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Incentive Conflict and Cognitive Control
as a Cause of Relapse: Brain Mechanisms
From the above, it becomes clear that controlling drug taking
depends on the ability of higher-level monitoring functions to
interrupt the incentive process that is induced by the rewarding
properties of the drug, but could also depend on the strengthening
of the incentive process as addiction progresses (88).
Drug taking is considered as an impulsive choice for an
immediate positive outcome based on previous hedonic experience
or relief from pain or stress but on the possible expense of long-
term health and social benets. Alcohol dependence may impair
processes that contribute to choice impulsivity (89), so that later
consequences of drinking are not taken into account. For the
alcohol-dependent patient trying for abstinence, the conict
between the desire to drink and the aim to abstain in order to
avoid adverse consequences may be particularly strong, leading to
erroneous choice at the time and a lapse.
We have studied aspects of the interaction between incentive
learning and behavioral control using the incentive conict task
(ICT) (90). is is a version of negative patterning tasks used in
cognitive psychology (91). When performing the ICT, subjects
rst learn that two independent discrete cues signal reward
(money gains), and in this way, they acquire incentive properties.
In a second phase, while the individual cues continue to signal
reward, when presented together in a compound, they signal
punishment (money losses). Participants have to learn to respond
appropriately so that they respond to gain money when the
stimuli are individually presented, but withhold responding to
avoid money losses when the stimuli are presented in compound.
e incentive conict task is thus a task that puts demands on
decision-making under conditions requiring conict resolution.
We have proposed that the task creates a conict between
abstaining and responding for reward, which is similar to that
experienced by the patient before lapse. erefore, the impaired
ability of patients who have experienced multiple detoxications
to perform the task might reect the consequences of the
detoxication process itself on behavioral control.
As the number of previously experienced detoxications
increases, patients become increasingly impaired in withholding
their responses in the condition of no reward, suggesting that
the process of detoxication may engender brain changes that
aect decision-making to avoid reward losses and lead to loss of
control (90). is is consistent with decits observed in a rodent
version of the same task, in rats chronically exposed to alcohol
(23). Importantly, in this well-controlled animal study, it was the
number of withdrawal events (“detoxications”) that determined
the extent of the decit.
Neuroimaging of the ICT task with human control participants
shows activation of several areas but most importantly those of
the supplementary motor area, striatum (including putamen),
gyrus rectus, ventromedial prefrontal cortex (vmPFC), and
superior frontal gyrus areas, which are implicated in cognitive
and emotional processing of reward (91–93) and regulatory
control over a behavioral response (94, 95). Smaller gray matter
volume in alcohol-dependent patients in the areas where
dysregulated brain responses are seen during ICT have been
reported, such as vmPFC and superior frontal gyrus, even more
so in patients who had experienced more detoxications. is is
consistent with suggestions that these smaller volumes are “brain
damage” associated with the detoxication experience. Further,
the smaller volumes likely are associated with impairments
in motivational decision-making, which involves the vmPFC
(96, 97), and behavioral control, which involves the superior
frontal gyrus (94, 95). Activation changes of vmPFC is shared
with the gambling task (97), which resembles incentive conict
in requiring decision-making. Alcohol-dependent patients
with several detoxications also show impairments in this task
(98). ese ndings are further supported by a study (99) that
found that resolution of emotional conict was associated with
activation of an area that included the vmPFC.
Blunted response of the vmPFC in alcohol-dependent humans
to the presentation of stress cues, a condition that the ICT also
possibly generates, has been found to predict the incidence of
relapse (100). Higher incidence of relapse with the possibility
of trying to detoxify again leads to experience of multiple
detoxications found in our studies to be associated with smaller
gray matter volume in vmPFC. Aberrant responsiveness to vmPFC
to stress (101) is proposed to be associated with autonomic neural
system dysfunction probably induced by the decreased ability
of vmPFC to regulate emotional responses to stress or conict
situations. Prefrontal gyrus activation on the other hand may
be more associated with the attentional and executive processes
involved in inhibitory control that govern responding to ICT (94,
95, 102). Recent work on brain network eciency of patients with
alcohol dependence has identied, among other areas, the superior
frontal gyrus area to show reduced nodal eciency, supporting
reduced ability of this area to carry out its functional activity (103).
e damage induced by alcohol—and detoxication—is
not restricted to the areas identied in the ICT experiments.
For example, the inferior frontal gyrus has been implicated in
previous research during cognitive set switching (104) and also
when resolving decision conict during an instrumental learning
task (105). Again, decreased inhibitory control due to IFG
damage may support the occurrence of repeated relapses.
BRAIN IMAGING OF ALCOHOL
DETOXIFICATION IN HUMANS
Alcohol dependence is associated with tolerance and withdrawal
with neuroadaptations in GABA-A and glutamatergic N-methyl-
D-aspartate (NMDA) receptors playing key roles (106).
Dysregulation of the NMDA receptor system is thought to
underpin alcohol-related memory impairments (107).
Imaging Glutamate in Humans
In humans, magnetic resonance spectroscopy (MRS) can be
used to measure glutamate levels in the brain, albeit oen with
other metabolites and neurotransmitter and metabolic pools
that cannot be robustly distinguished (108). A number of studies
have reported greater glutamate levels in alcohol-dependent
individuals during early withdrawal from alcohol.
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One study reported greater MRS glutamate + glutamine
(Glx) levels in the anterior cingulate cortex (ACC) at the
start (day 1) of alcohol detoxication in alcohol-dependent
individuals compared with controls, which normalized over the
next 14 days (109). Benzodiazepines were used for treatment.
Glx levels were not related to severity of alcohol withdrawal.
Complementary preclinical translational studies showed that
glutamate levels in the medial prefrontal cortex (mPFC) of
ethanol-dependent rats were increased at 12h of withdrawal
compared with controls and during intoxication; the glutamate
levels had declined by 60h. A further study from the same
group provided more evidence that a hyperglutamatergic state
is associated with brain neurotoxicity. In both humans and rats,
hippocampal glutamatergic function was found to be inversely
related to volume, although notably, no dierences were found
with controls in either species (110). is may have been due
to dierent methodology and lack of power to detect a group
dierence due to smaller hippocampal volume.
However, other studies have reported that human glutamate
levels were lower in the ACC, dorsolateral prefrontal cortex
(DLPFC), or parieto-occipital cortex (POC) 9 days after
stopping drinking compared with “light drinkers” and
normalized (i.e., increased) during the following month in
ACC only (109). The authors suggested that their first time
point may have missed the early elevation in glutamate
reported by others and that, altogether, studies suggest that
glutamate levels change during alcohol withdrawal and early
abstinence. Although glutamate levels at the earlier time point
were inversely associated with cognitive task performance,
improved cognitive function was not related to any
changes in glutamate or indeed other MRS markers [creatine,
N-acetylaspartate (NAA), choline, and GABA]. Similarly,
lower glutamine levels have been found in alcohol-dependent
individuals who are still drinking, though breathalyzed
negative at the time of the scan, compared with light drinkers
(111). An inverse relationship between glutamate, but not
glutamine, levels and number of heavy drinking days has been
reported in ACC of alcohol-dependent participants but not
light drinkers (18).
Higher levels of glutamate + glutamine in the nucleus
accumbens and anterior cingulate have also been shown to
be positively related to craving in recently detoxied alcohol-
dependent individuals (112, 113). However higher levels have
not always been reported in the anterior cingulate (112), which
may suggest a dierential rate of glutamatergic normalization
in brain regions. No moderating eect of medication, e.g.,
diazepam or clomethiazole, was seen on glutamate levels and
no relationship was seen with withdrawal symptoms (112). No
cognitive measures were described in this study.
Although studies did not necessarily nd any relationship
of glutamate levels with clinical variables, this is likely due to
the clinical heterogeneity of alcoholism in the small number
of participants in these imaging studies. Due to the lack of
appropriate longitudinal studies, it is not clear whether any
dierences in MRS-derived markers reect the neurotoxicity
or neuroadaptations from alcohol directly or predate alcohol
consumption and increase the risk of an alcohol use disorder.
Modulating Glutamatergic Function
In human alcohol-dependent individuals undergoing alcohol
detoxication, those who received acamprosate compared
with placebo resulted in a reduction in a glutamate:creatinine
ratio between 4 and 25 days in the anterior cingulate (114).
Diazepam was allowed if required during detoxication. It
appears that any eect of acamprosate took a while to develop as
it did not have an eect on alcohol withdrawal symptoms or on
glutamate:creatinine ratio in the rst few days of detox. Another
study reported that glutamate levels were reduced aer 4 weeks
of acamprosate treatment compared with slight increases in those
patients who did not receive acamprosate (113). e evidence
from these studies is consistent with acamprosate having an
“anti-glutamatergic” eect and that this likely underpins its
clinical ecacy including reduction in craving. As no cognitive
measures were obtained in the participants in either study, it is
unclear if acamprosate did result in any cognitive benets.
Other MRS Markers
Other MRS markers of neuronal integrity and function have
also been studied in alcohol use disorder. For example, evidence
is not consistent with lower, higher, or no dierences seen in
the metabolite N-acetylaspartate (NAA), which is seen as a
marker of neuronal integrity and function. is likely reects
the heterogeneity of the disorder and methodologies used.
Nevertheless, there is evidence that NAA is lower as a result
of heavy alcohol consumption, that it increases on stopping
drinking, suggesting recovery, and that low thalamic NAA
levels have been shown to be associated with poorer treatment
outcomes at 3 months (115, 116).
Imaging Inflammatory Response
inAlcoholism
e inammatory burden of alcohol consumption and
dependence in regard to cognition is not well characterized in
humans though it is likely to be an important target for treatment
(115). Such inammation may also contribute to alcoholism,
increasing the risk of Alzheimer’s disease (117). Positron emission
tomography (PET) imaging studies assessing microglial activity
with translocator protein (TSPO) tracers have shown lower,
rather than higher, availability in abstinent alcoholics (106, 118,
119). Indeed one study showed that TSPO binding was positively
correlated with verbal memory performance (118). erefore,
these studies suggest that lower glial density or an altered
activation state with lower TSPO expression may contribute to
cognitive impairment in alcoholism.
Treatment of Alcohol Withdrawal/
Detoxification
As described, alcohol withdrawal and its complications develop
as alcohol levels decrease and recurrent withdrawals result in
increase in severity of symptoms due to kindling (120, 121). Such
complications are also more likely in those alcohol-dependent
patients who are hypoglycemic, hypokalemic, hypomagnesemic,
or with infection or trauma (e.g., subdural hematoma) (120).
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Treatment of alcohol withdrawal generally attenuates the risk
of such consequences, but too frequently, alcohol dependence
is missed due to lack of appropriate questioning or disclosure,
so appropriate treatment is not started. Clearly, since delirium
tremens and seizures reect brain toxicity, there may also be
an eect on cognition; thus, their prevention is paramount
to protect brain function and optimize recovery. e reader is
directed to clinical guidelines concerning more information
regarding treatment of alcohol detoxication and prevention of
complications (9, 122, 123).
Medically assisted alcohol withdrawal is generally treated with
a reducing regimen of a benzodiazepine (e.g., chlordiazepoxide,
diazepam, and lorazepam) (120, 122, 123). An alternative regimen
is “symptom-triggered”, where the benzodiazepine is given once
symptoms meet a threshold for treatment. is requires regular
monitoring of alcohol withdrawal symptoms with a validated
scale [e.g., Clinical Institute Withdrawal Assessment for Alcohol
(CIWA-Ar)] by appropriately trained sta and so is not suitable
in all circumstances, e.g., a busy admissions unit or nonverbal
patients. Other anticonvulsants may be used (e.g., carbamazepine
and sodium valproate); however, a Cochrane review did not nd
evidence in favor of their use to treat alcohol withdrawal (124).
It should be remembered that benzodiazepines are also eective
anticonvulsants and therefore risk of alcohol-related seizures can
be managed with sucient doses rather than adding in another
anticonvulsant (123).
Another important clinical intervention to reduce risk of brain
toxicity is consideration of thiamine deciency as this vitamin is
a key co-factor in metabolism. iamine deciency may present
with “paresthesia” (pins and needles) in hands and feet with
numbness and with Wernicke’s encephalopathy (WE), which
is a medical emergency. Clinicians are advised to be suspicious
as the classic triad of confusion, ataxia, and ophthalmoplegia,
suggesting the diagnosis of WE, are rarely seen together, whereas
the rst two symptoms are very commonly seen in alcoholism
(123, 125). Clinically, thiamine deciency and WE are generally
only considered with alcohol detoxication when greater
metabolic load increases the risk; however, it may occur at any
time and in other addictions with poor diet and absorption. For
those with WE or at risk of it, parenteral thiamine is required
since absorption from oral thiamine is insucient to replenish
stores (122, 123, 125). us, giving thiamine appropriately is
a critical intervention to protect brain function and prevent
irreversible alcohol brain-related brain disorder.
As described, current clinical treatment with benzodiazepines
may not be optimal in attenuating the hyperglutamatergic state of
alcohol withdrawal. As described, MRS studies have shown that
acamprosate reduces glutamate in the brain. Clinically, acamprosate
appears to be well tolerated during alcohol detoxication, when
added to benzodiazepines, though there is no impact on alcohol
withdrawal symptoms as measured with the CIWA-Ar (114, 126).
However, acamprosate during alcohol detoxication has been noted
to improve sleep and reduce arousal levels (alpha slow-wave index)
when assessed with magnetoencephalography (127). erefore, it is
unclear if acamprosate-related reduction in glutamatergic activity
does improve cognitive outcomes either in the short term or in the
longer term.
EXAMPLES OF IMPLEMENTATION
OF PRE-HABILITATION IN ALCOHOL
DEPENDENCE
As described, the concept of pre-habilitation can be applied to the
treatment of alcohol dependence, such as our model: “Structured
Preparation for Alcohol Detoxication” (SPADe). Although SPADe
has been applied on an individual basis, primarily it has been
applied as an open, rolling group program, and described initially
as Preparation for Alcohol Detox (PAD) and more recently as
Abstinence Preparation Group (APG). e intervention may be
regarded as a modied Cognitive Behavioral erapy approach
(128, 129), which is oered prior to detoxication and while the
person is still drinking. e basic components of this treatment
approach include (i) partial control over drinking, (ii) introduction
of lifestyle changes for the individual, (iii) and the immediate family
and social environment. Existing evaluations of SPADe treatment
pathways suggest that about 72% of individuals with alcohol
dependence presenting for treatment can engage and complete the
pre-habilitation intervention (APG) (12).
Partial Controlled Drinking
When presented as an alternative to lifelong abstinence as the
sole treatment outcome (130), the concept of controlled drinking
generates intense conict within the eld of addiction medicine.
However, within clinical guidelines (9) controlled drinking
within “healthy” limits may be considered as an appropriate
treatment objective for harmful drinkers. For dependent drinkers,
abstinence remains the preferred treatment objective (9).
e main aim of pre-habilitation is to pre-empt clinical
withdrawal symptoms and the associated urges to drink. Within
the SPADe treatment approach for alcohol dependence, controlled
drinking is referred to as “partial” for two reasons: (i) it is an
intermediate treatment stage rather than the nal treatment aim,
which is abstinence; and (ii) the amount and pattern of drinking
are not within healthy limits. erefore, within SPADe, the primary
aim of the “partial controlled drinking” stage is to stabilize both the
amount of alcohol consumed and the pattern of drinking. Alcohol
is considered as “if it were a medication” with frequent and regular
dosing to prevent the onset rather than to treat the appearance of
withdrawal symptoms. is proactive elimination of symptoms
is considered fundamental from a biological perspective, since it
protects against acute brain dysregulation, which, in turn, might
sensitize the brain, leading to an exaggeration of the negative
impact associated with the disturbance of the brain homeostatic
system. From a psychological perspective, it empowers the
individual by restoring some control over decision-making and
reducing the impulsivity associated with the experience and
avoidance of cravings and withdrawal symptoms. Furthermore,
partial controlled drinking provides a relatively stable environment
for the individual—and their social group–to begin implementing
lifestyle changes that lead to an increased sense of self-ecacy. is
is considered the nal mediating factor in social learning theory
and cognitive behavioral treatment models (131).
e aim is to avoid substantial and dramatic reductions to
the amount of alcohol consumed, which not only will prove
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unsustainable but might also lead to the precipitation of
withdrawal symptoms, which could be life threatening. us,
small sustainable changes are implemented, and once stability
is achieved, a further gradual reduction of alcohol intake
can be safely undertaken. In our experience, about half of the
patients following this approach will be able to come o alcohol
without the use of detoxication medication (12). is model
of detoxication is called “guided self-detox”, and alcohol is
regarded as if it was a medication that is gradually discontinued.
Early Introduction of Lifestyle Changes
e stabilization of drinking provides for a short period a relatively
stable and safe environment for the patient, the immediate family,
and the patient’s social network to develop and test out lifestyle
changes. Such early and gradual changes implemented within the
individual’s lifestyle are necessary to provide (i) a routine in everyday
life that will protect against early relapse, (ii) a response to the void
that alcohol detoxication would otherwise leave in its wake, (iii) a
distraction strategy against the onset of craving, (iv)anenhancement
of personal responsibility, (v) a de-mystication of alcohol and a
challenge to the omnipotence of cravings or withdrawal symptoms,
and, nally, (vi) protection against the acute sense of stress
experienced in the early days of abstinence.
e involvement of family members and the immediate
social support system in treatment helps in reframing the
environment, modifying unrealistic expectations, and supports
the gradual adaptation to the new family dynamics (following
the removal of alcohol). It will help in managing the anxiety
and dicult feelings/emotions associated with broken trust
and promotes a partnership approach. Fundamentally, recovery
is easier to achieve and more sustainable within a respectful,
stress-free, and supportive environment. It is far easier for the
patient to maintain abstinence (in particular during the rst
few weeks) within a family environment that is also abstinent,
thus removing proximal cues/triggers (smell or sight of alcohol)
as well more distant cues, such as elevated levels of stress or
negative emotional states.
CONCLUSION
In this review, we have described how alcohol detoxication is a
neurobiologically challenging time for the brain and is associated
with cognitive impairments that contribute to the high risk of
relapse. Despite their limitations, animal models have demonstrated
that alcohol withdrawals induce impairments in learning, cognitive
exibility, memory, sociability, increased levels of anxiety, and
disrupting sleep. e evidence is mixed on the duration of these
eects, suggesting that, potentially, in addition to the acute eects,
there might be long-lasting impairments. Furthermore, repeated
withdrawals may aect some areas of cognition such as plasticity but
not all. Evidence supports roles for elevated levels of corticosterone
or increased expression of NMDA receptors in neuro-adaptations
underpinning alcohol withdrawal.
How does this evidence translate into human patients? ere
is evidence that with repeated detoxications, withdrawal seizures,
levels of anxiety, and experience of cravings increase, whereas
inhibitory control of certain behaviors such as reward seeking,
cognitive exibility, and recognition of emotions in others is reduced.
Furthermore, attentional bias towards alcohol-associated stimuli is
increased and predicts relapse rates and poorer treatment outcomes.
e evidence from neuroimaging studies is unable to clarify
whether any dierences observed reect the neurotoxicity or
neuro-adaptations from alcohol directly or predate alcohol
consumption and increase the risk of an alcohol use disorder.
Nevertheless, it seems that current clinical treatment with
benzodiazepines may not be optimal in attenuating the
hyperglutamatergic state of alcohol withdrawal.
How could the above evidence guide our clinical practice?
e evidence reviewed in this paper suggests that the process of
detoxication from alcohol in humans seems to have a negative
impact on cognitive functioning and create or worsen mood
dysregulation. ese eects are temporal, although the exact
duration is not specic as multiple factors might have an eect
beyond and above the severity of the baseline alcohol intake
(chronicity, amount, and pattern). Nevertheless, given that this
impact is anticipated, it is prudent to be prepared and proactive
into managing the associated risks. To that eect, stabilization of the
amount and pattern of drinking, empowerment of the individual
patient and the immediate environment to prepare and implement
lifestyle changes in advance of stopping alcohol, and furthermore
the avoidance, if possible, of detoxication by a gradual withdrawal
might prevent or provide protection against or increase the ability
of the patient and the immediate environment to cope with them.
ere is some evidence that people who had more than two
detoxications do worse than those who had less than two
detoxications. Although some of the cognitive impairment
observed might be pre-existing (i.e., as part of increasing
vulnerability to addiction), this evidence indicates that there
might be an accumulating eect with worsening of outcomes and
reduction of the possibility of achieving sustainable outcomes.
If this evidence is correct and the hypotheses that repeated
detoxications have a long-term negative impact, then it is
crucial to avoid repetition of detoxications and approach each
detox as if it would be the last one. A proactive approach within
the spirit of pre-habilitation to maximize the chances of lifelong
abstinence following detoxication is even more relevant.
Further, evidence presented suggests that the medication used
at the moment does not protect from or necessarily reverse the
negative cognitive impact and therefore is not optimal to reduce
the risk of relapse and possible long-term accumulative negative
eects of detoxications. Until such medication is developed, active
participation with aercare interventions to maintain abstinence
or at least keep drinking at low risk level is crucial and every eort
should be made for patients to continue their treatment beyond the
end of detoxication. A pre-habilitation approach that exposes and
familiarizes patients to psychosocial interventions will enhance their
ability to participate in aercare interventions.
ere are several clinical questions for which we require
evidence. How many detoxications should we oer within a
specic period of time? How soon aer a relapse should we oer
another detoxication? Is there a washout period following a
detoxication or are these eects permanent? Does this mean that,
Prehabilitation in Alcohol DependenceKouimtsidis et al.
14 May 2019 | Volume 10 | Article 339Frontiers in Psychiatry | www.frontiersin.org
following two failed detoxications, there is no further negative
impact and therefore detoxication should be oered at any given
opportunity? Given the above clinical uncertainties and the potential
risks indicated by the reviewed evidence and until further evidence
provides answers, a new treatment paradigm based on the principles
of pre-habilitation in addition to rehabilitation seems to have major
advantages in providing aspects of the rehabilitation treatment
before detoxication. SPADe provides such a model, in which a
structured Cognitive Behavior erapy-based intervention, which
aims to stabilize drinking, introduce early lifestyle changes, and
involve immediate social system into proactive changes to support
the early stages of abstinence, is consistent with pre-habilitation
and is supported by preliminary evidence that might be eective
(11, 12). It is important though to remind ourselves that one of
the primary objectives of a pre-habilitation treatment paradigm is the
empowerment of the person with the drinking problem and for the
immediate social environment to take responsibility for the problem
and be active agents of the solution. Structured interventions prior to
detoxication should be oered within the spirit of pre-habilitation
and not as a screening process to manage the ever-reducing budgets
for inpatient detoxication as suggested in the most recent report of
PHE (10). If implemented to screen patients, then such a use of pre-
detoxication groups could create barriers into accessing treatment
and compromise rather than enhance long-term treatment
outcomes (10).
AUTHOR CONTRIBUTIONS
CK: overall coordination of the manuscript with nal editing and
writing up of sections Introduction, Currently Recommended
Treatment Paradigm to Manage Alcohol Detoxication, Learning
and Habit Development in Humans, Examples of Implementation
of Prehabilitation in Alcohol Dependence, and Conclusion. TD:
written section Consequences of Repeated Detoxication of Patients
Dependent on Alcohol; EP: written section Animal Models of Alcohol
Withdrawal and Detoxication on Cognitive Impact; and AL-H:
written section Brain Imaging of Alcohol Detoxication in Humans.
FUNDING
e publication cost of this paper has been supported by the
UK National Institute for Health Research (NIHR) under its
Research for Patient Benet (RfPB) Programme (grant reference
number PB-PG-0815-20014).
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Conict of Interest Statement: CK and TD declare that any personal research
and the review paper was conducted in the absence of any commercial or nancial
relationships that could be construed as a potential conict of interest. EP and
AL-H declare that an unrestricted grant from Alcarelle funds a PhD studentship
for EP (student) and AL-H (supervisor).
Copyright © 2019 Kouimtsidis, Duka, Palmer and Lingford-Hughes. is is an open-
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