ADDICTION

Substance addiction is conceived to involve a

loss of self-control
Despite their best efforts and expressed
preferences to remain abstinent, substance
addiction populations often appear incapable
of exerting sufficient control over their
substances urges, their substance-seeking
and substance taking behaviors
The origins of substance addictionappear to
be related to the long-term pharmacological
effects of substances on an already,
potentially genetically compromised set of
neural circuits in the brain (Nutt, Nestor, ,
2013)
WHAT IS ADDICTION?
KEY POINTS
Addiction is a brain disease
Addiction is a chronic relapsing disorder
Addiction involves the chronic pharmacological
actions of substances in the brain
There are different types of addiction (e.g. alcohol,
cocaine)
Individuals may be more vulnerable to addiction than
others
Endophenotypes of addiction may facilitate diagnosis
and treatment
WHAT IS ADDICTION?
KEY POINTS
Addiction may involve nemerous factors (e.g.
social, biological)
Addiction does not happen immediately
There are stages of addiction (e.g. preoccupation,
loss of control)
There are also non-substance behavioral
addictions (e.g. gambling)
Limited use of addictive drugs is clinically distinct
from addiction
From the latin word addictio (enslaved),
addiction is a concept that has been subject to
much debate for some considerable time
At its origin, addiction simply reffered to
giving over, being highly devoted, or
engaging in behaviour habitually, with positive
or negative implications
Subsequent and more modern views of
addiction to substances were framed around
observations that those afflicted experienced
strong, overpowering urges, which were
conceived to be more disease-like in their
origins
DEFINITION?
A CHRONIC RELAPSING DISORDER
CHARACTERIZED BY:
Compulsion to seek and take the substance
Loss of control in limiting substance intake, and
The emergence of a negative emotional state (e.g.
dysphoria, anxiety, irritability)
reflecting a motivational withdrawal syndrome when
access to the substance is prevented (defined as a
substance dependence by the Diagnostic and Statistical
Manual of Mental Disorders-DSM of the American
Psychiatric Association)
DSM-IV-TR CITERIA FOR SUBSTANCE
DEPENDENCE
1.Tolerance, as defined by the following:
a. a need for markedly increased amounts of the substance
to achieve intoxication or desire effect
b. markedly diminished effect with continued use of the same
amount of the substance
2. Withdrawal, as manifested by either of following:
a. the characteristic withdrawal syndrome for the substance
(refer to criteria A or B of the croteria sets for withdrawal
from specific substances)
b. the same (or a closely related) substance is taken to
relieve or avoid withdrawal symptoms
3.The substance is often taken in larger amounts or over a
longer period than was intended

DSM-IV-TR CITERIA FOR SUBSTANCE
DEPENDENCE
4.There is a persistent desire to use the substance or
unsuccesful efforts to cut down or control substance use.
5.A great deal of time is spent in activities necessary to
obtain the substance (such as visiting multiple doctors or
driving long distances), use the substance (such as chain
smoking), or recover from its effects
6. Important social, occupational, or recreational activities
are given up or reduced because of substance use
7. The substance use is continued despite knowledge of
having a persistent or recurrent physical or psychological
problem that is likely to have been caused or
exacerbated by the substance.
SUBSTANCE ADDICTIONS
Alcohol
Tobacco
Opioids (like heroin)
Prescription drugs (sedatives, hypnotics, or anxiolitycs-lyke
sleeping pills and tranquillizers)
Cocaine
Cannabis (marijuana)
Amphetamines (like metamphetamine, known as crystal
meth)
Hallucinogens
Inhalants
Phencyclidine (known as PCP or angel dust)
BEHAVIOURAL ADDICTIONS
Gambling
Shopping
Sex
Internet
STAGES OF ADDICTION-1
Addiction does not develop immediately
Addiction unfolds fore some individuals but others. This may be
a reflection of individual differences prior to engaging in
substance use
Many self-described addicts, for example, have reported feeling
different from others prior to developing an addiction
These differences have ben described to include feeling
relatively uncomfortable, lonely, restless, or incomplete
Once a behaviour is tried (e.g. drinking alcohol) that decreases
or eliminates the reference point of discomfort, a process of
addiction may unfold
This explain why pre-existing psychopathologies (e.g. anxiety,
depression) may be a trigger fro the emergence of substance
use in some individuals
STAGES OF ADDICTION-2
Many people, however, do not report feeling different prior o
developing an addiction. Instead, these individuals may engage
in substance use, as it is perceived as highly valued or
enjoyable
The preoccupation with substance use may begin to develop
following the initial appetitive effects (excessive thoughts about
the substance and exessive time spent planning to use the
substance)
Tolerance and withdrawal are physiological hallmarks of
addiction that contribute to preoccupation.
Tolerance is seen as a need to engage in substance use at a
relatively greater level in order to achieve the same desire
effects. As tolerance increases, the person needs more alcohol
or other drugs. This will lead to spending more time locating and
engaging in substanc use. This indicates an increasing
preoccupation.

STAGES OF ADDICTION-3
Withdrawal refers to physiological or acquired discomfort
exerienced upon the abrupt termination of the substance. If
withdrawal symptoms exist and worsen, a person is likely to
spend greater amounts of time recovering from after-effects
(e.g. hangovers)
Craving (i.e. urges) to engage in substance use has
become a defining feature of addiction. Craving is not the
same thing as physiological withdrawal. Instead, it involves an
intense urge to engage in a specific act and may be
experienced long after dissipation of withdrawal. Craving is
often a precipitator of relapse and is now a target for the
development of relapse prevention medication.
Temporary satiation, experienced during acute
engagement in the addictive behaviour, it is also experienced
during the process of addiction.
STAGES OF ADDICTION-4
Drug addiction is characterized by continued use and
recurrent relapse despite serious negative consequences.
Addicts often report feeling compelled towards substance
use while sensing incomplete control over their behaviour.
This appears to implicate decrements in higher order
cognitive functioning, akin to a loss of control
Negative consequences (e.g. physical discomfort, social
disapproval, fonancial loss, or decreased self-esteem) will
begin to take hol following chronic substance use. Indeed,
continuing to engage in the addictive behaviuor, despite
suffering nemerous negative consequences, is a criterion
for dependence. This may also be a fear of having to cope
with the perceived day-to-day stresses of life upon
substance use cessation.
STAGES OF ADDICTION-5
The failure to learn to cope without
substance use and suffering withdrawal-
related phenomena may additionally add to
this element of negativity. Negative
consequences may bring negative
reinforcement.
BURDEN OF ADDICTION
Tobacco use is still the leading cause of
preventable death in the world
Alcohol use is associated with massive and
growing global disability, particularly in young
males
Drug-related deaths are steadly increasing
The vast majority of global substance-related
problems are in men
Substance addiction confers
social/psychological/physical burden to the
individual
Substance addiction confers significant costs
to society
ALCOHOL ABUSE IN THE US
60% men, 30% women
> 1 alcohol-related adverse life
event

High morbidity and mortality,
violence, accidents, social and
legal problems

>100,000 deaths / yr
$167 billion annual cost

Dont ask, dont tell
Screening for alcohol consumption in health care
settings is < 50%
-- inaccurate diagnoses
-- inappropriate treatment
-- drug interactions
-- potential surgical complications
-- unexpected withdrawal
-- lost opportunities for prevention
Alcoholism
loss of control, compulsion, continuation despite
known consequences
long lasting or permanent neuroadaptations
12% of men, 6% of women in the US
40% develop first symptoms aged
15 19 yrs
greatest increase is in young women

The life of an alcoholic can be summarized as:
preoccupation/anticipation, binge/intoxication
and withdrawal/negative affect
Koob, 2003
ETIOPATHOGENY
Reward pathway -- mesolimbic dopamine system
Dopamine well-being, arousal,
reward
Opioid rewarding and
reinforcing
Serotonin behavioral inhibition
GABA
A
inhibitory
Glutamate excitatory
Important neurotransmitters in
the reward pathway
Dopamine D2 Receptors in Addiction
Cocaine
Food
Meth
Alcohol
DOE/BNL, NI DA, ONDCP
Ethanol interacts with neurotransmitter
receptors (post-synaptic effects)
Ligand-gated ion channels (fast)
glutamate GABA
A

glycine acetylcholine (nicotinic)

Metabotropic receptors (slow)
norepinephrine dopamine
GABA
B
acetylcholine (muscarinic)
serotonin purinergic (adenosine)

Inheritance of Alcoholism
Alcoholism; genes and environment
Heritability is approximately 50-60% in men and
women based on large, population studies
Variability of presentation suggests genetic
heterogenity
Complex multifactorial disease in which
polygenic influences and environmental
influences interact
Genetic vulnerability to alcoholism
Alcohol seeking behaviors
-- mood disorders, anxious temperament, impulsivity
Response to the effects of alcohol
-- low response to sedation
-- flushing syndrome
Neurobiology

Low response (LR) to alcohol
Large, longitudinal studies (Schuckit) of response
to sedating effects of alcohol have found that LR:

heritability is 40%
increased in alcohol-nave children of alcoholics
predicts 4x increased risk of future alcoholism
genetic variants; 5HTTLPR LL genotype), GABA
a



Comorbidity -- shared genes?
drug (opioids, cocaine, cannabis) abuse
nicotine addiction
antisocial personality disorder
major depression
anxiety disorders
bulimia nervosa
Alcoholism linkages: Convergences
Chr 1 Etoh, LR, depression, anxiety [COGA]
Chr 4p Etoh, Beta EEG [COGA, LNG]
Chr 4q EtOH [COGA, LNG]
Chr 5 EtOH [LNG]
Chr 6 P300, Antisocial EtOH [COGA, LNG]
Chr 11 EtOH, Impulsivity [LNG]
COMT Met158/Met158, anxiety and
response to pain
The Met/Met genotype has been associated with:

Increased harm avoidance and low voltage alpha EEG in women, both
intermediate phenotypes for alcoholism (Enoch et al, Psychiatr Genet 2003)

Higher sensory and affective ratings for pain, a more negative internal
affective state plus diminished regional m opioid system responses to pain
Zubieta et al, Science 2003


Environmental Influences
Major role of alcohol availability
and price
Major differences between
populations
Major role for stress/trauma
Temporal variation and
effect of availability
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Temporal variation in cirrhosis deaths [U.S.]
Grant et al, 1986
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Early drinking onset is associated
with increased risk of alcoholism
NIAAA
Environmental influences:
Stress/trauma
Childhood sexual abuse and
psychiatric disorders in adulthood
Men Women

Substance abuse 4.8 4.2
Affective disorder 3.5 2.3
Alcoholism 2.8 2.1
PTSD 1.6 5.3
Anxiety disorder 1.9 1.8
Robin et al, Child Abuse & Neglect, 1997

Alcoholism: cause and effect of
trauma
Alcoholism is a key factor in accidents,
violence and sexual trauma

Alcoholism is a consequence of trauma

Genes mediate liability




Clinical subtyping of alcoholism
Cloninger classification:
Type 1: later onset, anxiety/dysphoria,
guilt, more common
Type 2: early onset, antisocial, impulsive,
mostly men, decreased CSF 5HT

Comorbidity with alcoholism
Drug abuse (opioids, cocaine, cannabis)
nicotine addiction
antisocial personality disorder
major depression
anxiety disorders
bulimia nervosa
Alcoholism and Nicotine
Addiction

Heavy smokers
> 20 cigarettes / day

70% of alcoholics
10% of the general
population

TERMS
Acute intoxication=transient following the administration of a
psycho-active drug resulting in disturbances in physiological,
psychological or behavioural functions or response;
Harmful use= pattern of psychoactive substance use which is
causing damage to health;
Tolerance= takes place when the desired CNS effects diminish so
that increasing doses need to be administered to achieve the same
effects;
Dependence=cluster of physiological, behavioural and cognitive
phenomena in which the use of pas takes on a much higher priority
for the individual than other behaviours that once had higher value.
The desire of consumption is very strong, overpowering; there is a
psychological and a physical dependence;
Withdrawal states=group of physical and psychological symptoms
occuring on a absolute or relative withdrawal from the pas; the acute
state is time-limited. The severe complications are delirium,
seizures.

Acute alcohol intoxication
Legal limit for impaired driving is 50 mg/dl reached by 2-3 drinks/h for
men and 1-2 drinks/h in women
Coma can occur with 60+ mmol/l (non-tolerant drinkers) and 90-120
mmol/l (tolerant drinkers);
Simple;
The degree of drunkenness depends to the cerebral level of alcohol;
Belligerence, mood lability, cognitive impairment, hilarity, somnolence,
coma;
Pathological;
The deep state of drunkenness occurs after small amounts of alcohol;
Heteroagression, violence, black-out;
Is dismissed of penal responsivity;
Is reproducible.
Chronic alcohol dependence
- 5-7 years years of constant consume;
-The person makes great efforts to reduce the daily alcohol
consume;
-The interest narrow;
-The drinking habits become more restrictive (towards
distilled drinks);
-Neglect of family, job, various accidents;
-Typical face, mouth smell, trembling, bradipsychia,
paranoid ideation, general hypoprosexia, sectorial
hyperprosexia for drinks, personality change, hallucinations
Some medical sequelae of heavy, long
term drinking
Liver cirrhosis and pancreatitis
Alcoholic gastritis, haematemesis
Malignancies: liver, mouth, esophagus, colon, breast
-- 95% esophageal Ca due to alcohol + tobacco
Peripheral and autonomic neuropathy, Wernicke-Korsakoff
syndrome, dementia
Proximal myopathy
Subfertility, spontaneous abortion, impotence
Cardiac dysrhythmias, cardiomyopathy, hypertension
Asthma

WITHDRAWAL SYNDROME

After alcohol cessation: morning worsening, trembling,
perspiration, slight confusion, , dysphoria;
Complicated: With seizures/with delirium tremens: impressive
tremor, sweeting, high fever, marked confusion, vivid
hallucinations, critical general state
Other forms:
Delusional
Postoniric sequelae
Alcoholic hallucinosis
Amnestic syndrome
Gayet-Wernicke
Alcoholic dementia
Dipsomania
Fetal embriopathy
WERNICKE-KORSAKOFF SYNDROME
Alcohol-induced amnestic disorders due to the
thiamine deficiency
Necrotic lesions-mammillary bodies, thalamus,
brainstern
Wernickes encephalopathy (acute and reversible):
triad of nystagmus (CN VI palsy), ataxia and confusion
Korsakoffs syndrome (chronic and only 20%
reversible with treatment): anterograde amnesia and
confabulations; cannot occur during an acute delirium
or dementia and must persist beyond usual duration of
intoxication/withdrawal
MANAGEMENT
WERNICKEs: Thiamine, 2-3 weeks
KORSAKOFFs: Thiamine, 3-12 months
THERAPY
Acute intoxication: let the alcohol eliminate; eventually, hydric and vitaminic
supplement
Dependence-the patient has to be strongly motivated; he has to be abstinent for
few months;
Aversive medication: Carbamazepine,, AA, psychotherapy, treatment of
depression;
Aversive drugs: Disulfiram;
Vitamins complex: Milgamma, Thiogamma;
Withdrawal states: attentive checking of somatic condition;
2-3 l of sweet liquids; Vitamins B1, B6, C (i.m., i.v.);
Diazepam 100-150 mg/day;
Perfusion-serum, glucose;
Electrolytes; hepatoprotection, cardiotonics, antithermics, AB;
Further: substitution-CBZ, Meprobamat, Buspiron


THERAPY

Psychosocial/behavioral approach is still the
mainstay of therapy; 40% 70% relapse after 1
yr
Development of medications to target
neurotransmitter systems in reward pathway
Aims:
-- to augment psychosocial/behavioral Rx
-- to produce individually targeted drugs

Naltrexone -- m opioid antagonist
Decreases craving
and relapse rates
small to moderate
effect
Best response in
less severe, socially
stable, motivated
alcoholics
Reduces alcohol
consumption if
taken 2 hrs before
expected drinking
0 1 2 3 4 5 6 7 8 9 10 11 12
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Placebo
Naltrexone
No. of Weeks Receiving Medication
C
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OMalley et al, 1992
Acamprosate: Glutamate antagonist
Reduces intensity of
craving on exposure
to high-risk drinking
situations
Small to medium
effect in maintaining
abstinence
Sass et al, 1996
Selective serotonin reuptake
inhibitors (SSRIs)
Chronically, SSRIs
reduce 5HT synthesis
and turnover, thereby
enhancing DA function
and substituting for
alcohols rewarding
effect
Treat comorbid
depression
Best for late onset, not
early onset, alcoholics
Fetal Alcohol Syndrome
>10% of children exposed in utero to alcohol
toxicity



7-14 drinks/wk (particularly > 5/occasion) can cause
moderate fetal damage

FAS: growth deficiency, abnormal facies, mental retardation, attentional
and behavioral problems
FAE: learning disabilities, intellectual impairment, behavioral problems