Lecture on the treatment gap (underdiagnose & undertreatment) of alcohol use disorders. Presented at the 5th Conference of the Greek Psychiatric society in Thessalonika, march 21st, 2015.

1. Closing
the
treatment
gap
in
alcohol
dependence
:
the
role
of
nalmefene
Dr
Antoni
Gual
tgual@clinic.cat
Υπό την αιγίδα
19–21
Μαρτίου 2015
Θεσσαλονίκη
THE MET HOTEL
5
o
ΜΕ ∆ΙΕΘΝΗ ΣΥΜΜΕΤΟΧΗ
ΕΛΛΗΝΙΚΗ ΕΤΑΙΡΕΙΑ ΒΙΟΨΥΧΟΚΟΙΝΩΝΙΚΗΣ ΠΡΟΣΕΓΓΙΣΗΣ ΣΤΗΝ ΥΓΕΙΑ
ΣΥΝΕΔΡΙΟ ΒΙΟΨΥΧΟΚΟΙΝΩΝΙΚΗΣ ΠΡΟΣΕΓΓΙΣΗΣ
ΣΤΗΝ ΙΑΤΡΙΚΗ ΠΕΡΙΘΑΛΨΗ
Προκαταρκτικό
πρόγραμμα

2. Conflicts
of
interest
Interest
Name
of
organisa/on
Current
roles
and
affilia/ons
Addic;ons
Unit,
Psychiatry
Dept,
Neurosciences
Ins;tute,
Hospital
Clinic,
University
of
Barcelona;
IDIBAPS;
RTA;
Vice
President
of
INEBRIA,
President
of
EUFAS
Grants
Lundbeck,
D&A
Pharma,
FP7,
SANCO
Honoraria
Lundbeck,
D&A
Pharma,
Servier,
Lilly,
Abbvie
Advisory
board/
consultant
Lundbeck,
D&A
Pharma,
Socidrogalcohol
(Alcohol
Clinical
Guidelines)
2013

3. Index
• Burden
of
disease
• The
first
gap:
role
of
Brief
Interven;ons
• The
second
gap:
need
for
a
reduc;on
approach
• The
second
gap:
the
role
of
nalmefene
• Framing
Nalmefene
within
a
psychosocial
support
strategy
• Summary

4. Index
• Burden
of
disease
• The
first
gap:
role
of
Brief
Interven;ons
• The
second
gap:
need
for
a
reduc;on
approach
• The
second
gap:
the
role
of
nalmefene
• Framing
Nalmefene
within
a
psychosocial
support
strategy
• Summary

5. Prevalence
of
Alcohol
Dependence
(AD)
and
access
to
treatment.
Data
from
the
APC
study
AD
diagnosis
by
GP
Pa;ents
visited
by
the
GP
13,003
Pa;ents
iden;fied
as
alcohol
dependent
5.1%
(663)
Pa/ents
who
received
professional
help
21.8%
(n=145)
• Six
EU
countries
• GPs
interviewed
about
pa;ents
seen
in
a
given
day
• Pa;ents
interviewed
with
standardized
ques;onnaires
when
they
exit
consulta;on
Rehm
J,
et
al.
Ann
Fam
Med.
2015.

6. Treatmentgap*(%)
Kohn et al. Bull World Health Organ 2004;82:858–866
Treatment gap in alcohol dependence
6
*Treatment gap=difference between number of people needing
treatment for mental illness and number of people receiving treatment
Alcohol abuse and dependence have the widest treatment gap among all mental
disorders – less than 10% of patients with alcohol abuse and dependence are treated

7. The
double
gap
Pa;ents
with
AUD
in
PHC
sebngs
Risky
drinkers
offered
brief
advice
to
reduce
Alcohol
dependent
offered
treatment
1st GAP

8. Symptoms of depression and alcohol dependence frequently
overlap1,2
8
1. Boden JM, et al. Addiction 2011;106:906-914. 2. Watts M. B J Nursing. 2008;17(11):696-699 . 3. Shivani R, et al. Alcohol Research & Health. 2002;26:90-98

9. Symptom overlap between alcohol dependence and anxiety
disorders1
1. Brady, et al. Am J Psychiatry . 2007;164(2):217-221. 2.. DSM-IV. American Psychiatric Association. 1994. 3. Shivani, et al. Alcohol Research Health 2002;26(2),90-98.
4. The ICD-10 Classification of Mental and behavioral disorders - Clinical Description and diagnostic guidelines. WHO 1992

10. 20%-30% of psychiatric patients are also alcohol dependent1
Lifetime prevalence of psychiatric disorders and co-occurrent alcohol dependence1,2
31%
Comorbid
alcohol
dependence
21%
21%
Comorbid
alcohol
dependence
26%
Anxiety disorder Mood disorder
Lifetime prevalence
of psychiatric disorder2
Lifetime prevalence
of co-occurrent alcohol dependence
and psychiatric disorder1
12%
24%
7%
28%
6%
30%
17%
26%
4%
28%
GAD Phobia PTSD
Major
depressive disorder
Bipolar
disorder
1. Kessler et al. American Journal of Orthopsychiatry 1996; 66(1): 17-31
2. National Comorbidity Survey Replication NCS-R. Lifetime prevalences estimates
www.hcp.med.harvard.edu/ncs/index.php

11. Screening
or
early
iden;fica;on?
• Screening:
Strategy
used
in
a
popula;on
to
iden;fy
an
unrecognised
disease
in
individuals
without
signs
or
symptoms.
• Targeted
screening:
Screening
limited
to
selected
popula;on
(because
of
high
risk
or
high
vulnerability)
• Early
iden/fica/on:
Evalua;on
of
pa;ents
in
whom
signs
of
alcohol
playing
a
nega;ve
role
in
a
case
history
are
present

12. The
AUDIT-­‐C
1.
How
ofen
do
you
have
a
drink
containing
alcohol?
2.
How
many
standard
drinks
containing
alcohol
do
you
have
on
a
typical
day
when
drinking?
3.
How
ofen
do
you
have
six
or
more
drinks
on
one
occasion
0)
Never
1)
Less
than
monthly
2)
Monthly
3)
Weekly
4)
Daily
or
almost
daily

13. The
AUDIT-­‐C
1.
How
ofen
do
you
have
a
drink
containing
alcohol?
2.
How
many
standard
drinks
containing
alcohol
do
you
have
on
a
typical
day
when
drinking?
3.
How
ofen
do
you
have
six
or
more
drinks
on
one
occasion
0)
Never
1)
Less
than
monthly
2)
Monthly
3)
Weekly
4)
Daily
or
almost
daily
Cut off point for Hazardous drinking:
• 4 or more in women
• 5 or more in men

14. • No
standard
defini/on
–
can
range
from
a
short
conversa/on
to
a
number
of
structured
sessions1-­‐5
• Brief
Interven;ons
are
carried
out
in
general
community
sebngs
(primarily
used
in
primary
care
clinics)
and
are
delivered
by
HCPs
(Health
Care
Professionals)
• Includes
the
giving
of
informa;on
and
advice
• Encouragement
to
the
pa;ents
to
consider
the
posi;ves
and
nega;ves
of
their
drinking
behaviour
• Offers
support
to
pa;ents
if
they
do
decide
that
they
want
to
cut
down
• Is
;mely
and
opportunis;c
Brief
interven;on:
Overview
1.
Raistrick
et
al.
Na;onal
Treatment
Agency
for
Substance
Misuse,
2006,
p79;
2.
Scobsh
Intercollegiate
Guidelines
Network,
2003;
3.
NICE
public
health
guidance
24:
Alcohol-­‐use
disorders:
preven;ng
harmful
drinking.
June
2010;
4.
NICE
guidance
CG115:
Alcohol
dependence
and
harmful
alcohol
use
(CG115).
February
2011;
5.
WHO.
Am
J
Public
Health
1996;86:948-­‐55

15. Brief
Interven;on:
Level
1
Raistrick
et
al.
Review
of
the
effec;veness
of
treatment
for
alcohol
problems,
2006
1. Some
assessment
of
alcohol
use
2. Feddback
on
the
screening
assessment
(clinical
findings
plus
compare
to
the
general
popula;on?
3. Some
clear
advise
on
how
to
cut
down
(or
stop
drinking)

16. Index
• Burden
of
disease
• The
first
gap:
role
of
Brief
Interven;ons
• The
second
gap:
need
for
a
reduc/on
approach
• The
second
gap:
the
role
of
nalmefene
• Framing
Nalmefene
within
a
psychosocial
support
strategy
• Summary

17. The
double
gap
Pa;ents
with
AUD
in
PHC
sebngs
Risky
drinkers
offered
brief
advice
to
reduce
Alcohol
dependent
offered
abs;nence
oriented
treatment
1st GAP 2nd GAP

18. Nalmefene blocks
the µ-opioid receptor3
Nalmefene modulates
the κ-opioid receptor3
2.9%
3.0%
3.1%
4.2%
5.7%
5.9%
5.9%
6.5%
8.1%
8.4%
8.6%
8.9%
10.6%
30.3%
49.5%
0 10 20 30 40 50 60
Treatment would not help
Other barriers
No openings in a programme
Did not want others to find out
Did not have time
No programme having type of treatment
Did not feel need for treatment
No transportation/inconvenient
Thought could handle without treatment
Health coverage did not cover cost
Social stigma
Did not know where to go for treatment
Might have negative effect on job
No health coverage & could not afford cost
Not ready to stop using
Percentage of patients
Reasons
given
for
not
receiving
alcohol
treatment
in
the
past
year
by
persons
who
needed
treatment
and
who
perceived
a
need
for
it:
2009
to
2012
Survey
of
approx.
67500
interviewed
persons
in
the
US
SAMHSA.
Results
from
the
2012
Na;onal
Survey
on
Drug
Use
and
Health,
2013
Why
does
the
gap
exist?

19. Pa;ents’
treatment
goal
preference
UKATT: 742 patients seeking help for
alcohol problems1
Canada: 106 patients with chronic
alcoholism2
1. Heather et al. Alcohol Alcohol 2010;45(2):128–135;
2. Hodgins et al. Addict Behav 1997;22(2):247–255
54%
46%
0
20
40
60
80
100
Abstinence Alcohol reduction
Percentageofpatients(%)
Treatment preference
46% 44%
9%
0
20
40
60
80
100
Abstinence Moderate
drinking
Unsure
Percentageofpatients(%)
Treatment preference

20. Benefits
of
reduc;on:
reducing
consump;on
by
a
constant
amount
translates
to
a
higher
reduc;on
in
mortality
if
the
reduc;on
is
at
higher
levels
• Reduc;on
of
36
g/day
(3
drinks)
from
a
baseline
of
60
g/day
corresponds
to
reduced
mortality
risk
of
38
per
10,000
• Reduc;on
of
36
g/day
from
a
baseline
of
96
g/day
corresponds
to
reduced
mortality
risk
of
119
per
10,000
It’s
the
heavy
drinking
day
that
leads
to
harm!!
Men
Women
Riskofdeath(%)
0
20
40
60
80
100
Alcohol
consump;on
(g/day)
18
12
4
0
16
8
10
2
14
6
Rehm et al. Addiction 2011;106(Suppl 1):11–19;
Rehm & Roerke. Alcohol Alcohol 2013;48:509–513
Lifetime risk of death due to
alcohol-related injury

21.
‘…For
all
people
who
misuse
alcohol,
offer
interven7ons
to
promote
abs7nence
or
moderate
drinking
as
appropriate’
‘...For
harmful
drinking
or
mild
dependence,
without
significant
comorbidity,
and
if
there
is
adequate
social
support,
consider
a
moderate
level
of
drinking
as
the
goal
of
treatment’
NICE.
Clinical
guideline
115,
2011
‘…it’s best to determine
individual goals with
each patient. Some
patients may not be
willing to endorse
abstinence as a goal,
especially at first. If a
patient with alcohol
dependence agrees to
reduce drinking
substantially, it’s best to
engage him or her in
that goal while
continuing to note that
abstinence remains the
optimal outcome.’
NIAAA.
Helping
Pa;ents
Who
Drink
Too
Much,
2007
“In case an alcohol-dependent patient is not able
or willing to become abstinent immediately, a
clinically significantly reduced alcohol intake with
subsequent harm reduction is also a valid,
although only intermediate, treatment goal, since
it is recognised that there is a clear medical need
in these patients as well.”
EMA.
Guideline
on
the
development
of
medicinal
products,
2010
Reduc;on
is
included
in
several
interna;onal
guidelines,
either
as
an
intermediate
goal,
or
for
those
pa;ent
that
cannot
accept
or
achieve
abs;nence,
as
an
acceptable
treatment
goal
in
itself
16
countries
in
EU
have
guidelines
for
treatment
of
alcohol
dependence,
and
10
out
of
these
countries
have
guidelines
that
recommend
both
abs;nence
and
reduc;on.
14
countries
in
EU,
do
not
have
any
guidelines
for
treatment
of
alcohol
dependence,
but
a
clinical
prac;ce,
and
12
out
of
these
countries
recommend
both
abs;nence
and
reduc;on
in
their
clinical
prac;ce.
Reduc;on
accepted
as
a
treatment
op;on
by
26/30
European
countries
Reduc;on
of
alcohol
consump;on
is
endorsed
by
interna;onal
guidelines

22. The
double
gap
Pa;ents
with
AUD
in
PHC
sebngs
Risky
drinkers
offered
brief
advice
to
reduce
Alcohol
dependent
offered
abs;nence
oriented
treatment
2nd GAP

23. Pa;ents
with
AUD
in
PHC
sebngs
Risky
drinkers
offered
brief
advice
to
reduce
Alcohol
dependent
offered
abs;nence
oriented
treatment
Which
are
the
clinical
characteris;cs
of
those
pa;ents?

24. Which
are
the
clinical
characteris;cs
of
those
pa;ents?
a. Demographic
characteris;cs
b. Clinical
status
c. Level
of
mo;va;on
d. Pa;ent
goals

25. Alcohol dependence is typically a progressive disease1,2
References >
EARLY-STAGE
Ability to function:
Most likely functional
(e.g. employed, in a relationship)
Ability to function:
Likely non-functional
DEPENDENCE
MID-STAGE
DEPENDENCE
LATE-STAGE
Health consequences:
Minimal/not life-threatening
Anxiety, depressive symptoms
Elevated liver enzymes
Hypertension
Health consequences:
Severe/possibly life-threatening
Liver cirrhosis
Stroke
Social consequences:
Family conflict, neglect
Inability to concentrate on job, absenteeism
Social consequences:
Divorce, spouse/child abuse
Job loss, chronic unemployment, deviant
behaviour
DEPENDENCE
1. Burge et al. Am Fam Physician. 1999 59(2): 361-370
2. Edwards & Gross. BMJ 1976; 1: 1058-1061
Ability to function:
Marginally functional
(e.g. employed in non-demanding job,
problems in marriage or relationship)
Health consequences:
More severe health consequences, already
carrying alcohol-related medical history
eg. depression, obesity, visits to hospital,
withdrawal symptoms (tremor,anxiety), sleep
disorders, clinical signs of liver deficiency
(oedema, portal hypertension, coagulation
disorder), injuries (driving, other accidents)
ischemic encephalopathy, heart hypertophy
Social consequences:
Significant loss of social interaction, irritability,
difficulty to follow team rules, occasionally
violent (eg. when provoked, have gone to
football match or lost patience by kid’s
behaviour). Financial problems, legal problems
(eg. due to debts, car accident, caught drunk
when driving, violence)

26. Some
prac;cal
examples.
• Jesús M. 49 años, broker
• Maria R. 35 años, housewife
• Juana F. 26 años, student

27. Some
prac;cal
examples.
Jesús M. 49 years.
• Married, 2 sons, works as a broker at an insurance
company
• Moderate hypertension. Smoker 1 pack/day
• Drinks with clients (6 beers) and also after dinner at
home (3 whiskies).
• Comes under his wifes’ pressure. He is worried with
hypertension since his father died from a CVD.
• Has tried unsuccessfully to reduce his drinking. He
does not want to stop drinking with clients but thinks
he should stop drinking at nights.

28. Some
prac;cal
examples.
Maria R. 35 years
• Married, a daughter 7 years old. Housewife.
• No somathic diseases. Depression treated with
sertraline since 2 years.
• Drinks alone, above 1 liter of wine daily. Refers
moderate depression and anxiety symptoms.
• Ready to stop drinking initially, but wants to drink
moderately at family events (because of social
pressure) at a later stage.

29. Some
prac;cal
examples.
Juana F. 26 years.
• Last year in a Business school. Lives with her
parents.
• Gets drunk on weekends. Abstainer the rest of the
week.
• Decreased academic performance, low mood and
difficulties with parents.
• Worried because of her sexual behaviour when
drunk.
• Wants to avoid drunkeness on weekends, but thinks
a bit of drinking is essential when meeting with
friends in order to overcome her social phobia.

30. • Mild to moderate AUD
• Socially stable
• Psychological distress (anxiety/
depression that may or may not be linked
to alcohol intake)
• Desire to reduce their drinking to avoid
problems
• Desire not to stop drinking completely
What
do
those
cases
have
in
common?

31. Index
• Burden
of
disease
• The
first
gap:
role
of
Brief
Interven;ons
• The
second
gap:
need
for
a
reduc;on
approach
• The
second
gap:
the
role
of
nalmefene
• Framing
Nalmefene
within
a
psychosocial
support
strategy
• Summary

32. Alcohol
use
Abs;nence
-­‐
low
risk
-­‐
hazardous
use
-­‐
harmful
use
-­‐-­‐
dependence
Alcohol
related
problems
Recommended
psychosocial
interven;ons
Primary
preven;on
-­‐-­‐
Brief
interven;ons
-­‐-­‐
Specialized
treatment
Pharmacological
interven/ons

33. Alcohol
use
Abs;nence
-­‐
low
risk
-­‐
hazardous
use
-­‐
harmful
use
-­‐-­‐
dependence
Alcohol
related
problems
Recommended
psychosocial
interven;ons
Primary
preven;on
-­‐-­‐
Brief
interven;ons
-­‐-­‐
Specialized
treatment
Pharmacological
interven/ons

34. Widening
the
scope
of
pharmacological
treatments
• Classical
approach:
Abs;nence
oriented
(disulfiram*,
acamprosate*,
naltrexone*,
topiramate)
• Subs;tu;on
therapy:
BZD,
sodium
oxibate,
baclofen
• Reduc;on
approach:
nalmefene*,
naltrexone,
topiramate,
gabapen;ne.
*
Registered
indica;on

35. Nalmefene – What it does!
• Nalmefene diminishes
the reinforcing effects
of alcohol, helping the
patient to reduce
drinking possibly by
modulating cortico-
mesolimbic functions.
Nalmefene Summary of Product Characteristics;
Nalmefene European Public Assessment Report, 2012; Clapp et al. Alcohol Res Health 2008;31(4):310–339
Prefrontal cortex
Nucleus accumbens
Amygdala
Ventral tegmental area
Hippocampus
Nalmefene
Areas in the brain affected by alcohol,
including the mesolimbic dopamine system

36. Nalmefene indication
Nalmefene Summary of Product Characteristics, 2012
• Nalmefene is indicated for the reduction of alcohol consumption in adult
patients with alcohol dependence who have a high drinking risk level
(DRL), without physical withdrawal symptoms and who do not require
immediate detoxification
• Nalmefene should only be prescribed in conjunction with continuous
psychosocial support focused on treatment adherence and reducing
alcohol consumption
• Nalmefene should be initiated only in patients who continue to have a
high DRL two weeks after initial assessment

37. Mann et al. Biol Psychiatry 2013;73(8):706–713;
Gual et al. Eur Neuropsychopharmacol 2013;
van den Brink et al. Poster at Research
Society on Alcoholism 2012; Data on file
Living with
someone:
65–86%
(65–85%)
Higher
education:
24–40%
(23–32%)
Employed:
54–63%
(61–64%)
Gender:
62–78%
(67–77%) men
Age:
44–53 yrs
(44–52 yrs)
Family history:
36–62%
(49–61%)
Years since
onset:
11–15 yrs
(11–14 yrs)
Not previously
treated:
59–78%
(60–70%)
Number of patients:
854 (1,997)
High and very high drinking-risk levels at
baseline and randomisation – demographics*
Numbers in ()=total sample
*No significant differences
between placebo and nalmefene arms;
Data show range of the means from individual studies

38. HDD: change from baseline in the 6-month studies
– patients with at least high DRL at baseline and randomisation
23
HDDs
11
HDDs
23
HDDs
10
HDDs
Difference:
-­‐3.7
HDDs,
p=0.0010
Difference:
-­‐2.7
HDDs,
p=0.0253
ESENSE
2
ESENSE
1
van
den
Brink
et
al.
Alcohol
Alcohol
2013;48(5):570–578;
Data
on
file
MMRM
(OC)
FAS
es;mates
and
SE;
*p<0.05, **p<0.01, ***p≤0.001;
MMRM=mixed-­‐effect
model
repeated
measure;
OC=observed
cases;
FAS=full
analysis
set;
SE=standard
error

39. TAC: change from baseline in the 6-month studies
– patients with at least high DRL at baseline and randomisation
113
g/day
43
g/day
102
g/day
44
g/day
Difference:
-­‐18.3
g/day,
p<0.0001
Difference:
-­‐10.3
g/day,
p=0.0404
ESENSE
2
ESENSE
1
MMRM
(OC)
FAS
es;mates
and
SE;
*p<0.05, **p<0.01, ***p<0.001;
MMRM=mixed-­‐effect
model
repeated
measure;
OC=observed
cases;
FAS=full
analysis
set;
SE=standard
error
van
den
Brink
et
al.
Alcohol
Alcohol
2013;48(5):570–578;
Data
on
file

40. Onset of action
37th
RSA
&
17th
ISBRA
JUNE
21-­‐25,
2014;
BELLEVUE,
WASHINGTON

41. Index
• Burden
of
disease
• The
first
gap:
role
of
Brief
Interven;ons
• The
second
gap:
need
for
a
reduc;on
approach
• The
second
gap:
the
role
of
nalmefene
• Framing
Nalmefene
within
a
psychosocial
support
strategy
• Summary

42. Basic
psychosocial
strategies
• Monitor
alcohol
consump;on
– TLFB
– Apps
• Mo;va;onal
approach

43. Timeline
followback
• Retrospec;ve
assessment
of
drinking
behaviour.
• Reliable
and
valid
for
a
variety
of
popula;ons
for
;me
frames
of
up
to
one
year.
(Sobell
&
Sobell,
1992,
1996)

44. Avoid a confrontational approach
• Review of four decades of treatment outcome research.
• A large body of trials found no therapeutic effect of
confrontational strategies relative to control or comparison
treatment conditions.
• Several have reported harmful effects including increased
drop-out, elevated and more rapid relapse.
• This pattern is consistent across a variety of confrontational
techniques tested.
• In sum, there is not and never has been a scientific evidence
base for the use of confrontational therapies.
WR. Miller, W. White; 2007

45. Mo;va;onal
Interviewing
• New
golden
standard
for
the
psychological
approach
to
addic;ve
behaviours
• Radical
change:
– external
confronta;on
as
a
technique
vs
internal
confronta;on
as
a
goal
– Pa;ent
centered
– Spirit:
partnership,
compassion,
evoca;on
and
acceptance
WR. Miller, S. Rollnick; 2012

46. B
R
E
N
D
A
BRENDA
Biopsychosocial
evaluation
Report to the
patient on
assessment
Empathetic
understanding
of the patient’s problem
Needs expressed by the
patient that should be
addressed
Direct advice
on how to meet
those needs
Assessing response/
behaviour of the
patient to advice and
adjusting treatment
recommendations
Clinical
management
–
BRENDA

47. Brief
Interven/on:
Level
2
Raistrick
et
al.
Review
of
the
effec;veness
of
treatment
for
alcohol
problems,
2006
Structured, motivation enhancing intervention, as opposed to just screening and
brief advice:
1. Careful History
2. Clinical Examination
3. Laboratory testing
4. Detailed and repeated review of drink diaries
5. Motivational approach

48. • AUD are a brain disease and a public health problem
• AUD are underdiagnosed (First Gap)
• Patients who do not respond to BI should be offered more
intensive treatments, including a reduction approach (Second
Gap)
• Reduction of alcohol consumption is a feasible goal with
nalmefene – efficacy is evident immediately and maintained up
to 1 year
The ‘as-needed’ dosing, and the reduction goal are well
accepted and empower the patient
• Nalmefene must be prescribed within a psychosocial support
strategy that is based on motivational principles and monitors
alcohol consumption carefully
Summary and conclusions

49. Closing
the
treatment
gap
in
alcohol
dependence
:
the
role
of
nalmefene
Dr
Antoni
Gual
tgual@clinic.cat
Υπό την αιγίδα
Γ΄ Ψυχιατρικής Κλινικής ΑΠΘ
Τµήµατος Ιατρικής ΑΠΘ
19–21
Μαρτίου 2015
Θεσσαλονίκη
THE MET HOTEL
5
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