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Periodico trimestrale - Sped. in Abb. Post. - D.L. 353/2003 conv. in L. 27/02/2004 n 46 art. 1, comma 1, DCB PISA Aut. tirb.

di Pisa n.5 del 9-3-2000

ISSN 1592-1638

Vol. 16 N. 3 September 2014

the official journal of

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Editorial Board
Editor
Icro Maremmani

Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, "Santa Chiara" University
Hospital, Pisa, Italy, EU

Associate Editors
Thomas Clausen

SERAF, Norwegian Centre for Addiction Research, University of Oslo, Norway

Pier Paolo Pani

Social Health Division, Health District 8 (ASL 8), Cagliari, Italy, EU

Marta Torrens

University of Barcelona, Spain, EU

International Advisory Board


Hannu Alho

National Public Health Institute (KTL), University of Helsinki, Finland, EU

Marc Auriacombe

Universit Victor Segalen, Bordeaux 2, France, EU

James Bell

South London and Maudsley NHS FoundationTrust & Langston Centre, Sydney, Austrelia

Olof Blix

County Hospital Ryhov, Jnkping, Sweden, EU

Barbara Broers

University Hospital of Geneva, Switzerland

Miguel Casas

University Hospital of "Vall dHebron" - University of Barcelona, Spain, EU

Liliana Dell'Osso

Department of Clinical and Experimental Medicine, University of Pisa, Italy, EU

Michael Farrell

National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia

Loretta Finnegan

National Institutes of Health, Bethesda, ML, USA, [Retired]

Gabriele Fischer

Addiction Clinic, University of Vienna, Austria, EU

Carla Gambarana

Department of Molecular and Developmental Medicine, University of Siena, Italy


Health and Human Development Section, Division for Operations, United Nations Office on Drugs
and Crime (UNODC), Vienna
University of Cagliari, Italy, EU, [Emeritus]

Gilberto Gerra
Gian Luigi Gessa
Michael Gossop

Lars Gunne

Kings College, University of London, UK, EU


Department of Neuroscience, Institute of Addictive Diseases, University Hospital of Uppsala,
Sweden, EU
University of Uppsala, Sweden, EU, [Emeritus]

Andrej Kastelic

Center for Treatment of Drug Addiction, University Hospital, Ljubljana, Slovenia, EU

Michael Krausz

St.Pauls Hospital, University of British Columbia, Canada

Mary Jane Kreek

The Rockfeller University, New York, USA

Evgeny Krupitsky

St. Petersburg Bekhterev Psychoneurological Research Institute, Saint Petersburg, Russia

Mercedes Lovrecic

Institute of Public Health of the Republic of Slovenia, Ljubljana, Slovenia, EU

Joyce Lowinson

Albert Einstein College of Medicine, The Rockfeller University, New York, USA, [Emeritus]

Robert Newman

Baron de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY, USA

Charles P. O'Brien

University of Pennsylvania, Phildelphia, USA

Lubomir Okruhlica

Centre for Treatment of Drug Dependencies, Bratislava, Slovak Republic, EU

Mark Parrino

American Association for the Treatment of Opioid Dependence, New York, USA

Einat Peles

Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel

Giulio Perugi

Department of Psychiatry, University of Pisa, Italy, EU

Marc Reisinger

European Opiate Addiction Treatment Association, Brussels, Belgium, EU

Lorenzo Somaini

Addiction Treatment Center, Cossato (Biella), Italy, EU

Marlene Stenbacka

Karolinska Institute, Stockholm, Sweden, EU

Leift Grnbladh

Alessandro Tagliamonte University of Siena, Italy, EU [Retired]


Ambros Uchtenhagen Research Foundation on Public Health and Addiction, Zurich University, Switzerland
Helge Waal

Center for Addiction Research (SERAF), University of Oslo, Norway, [Emeritus]

George Woody

University of Pennsylvania, Phildelphia, USA

Editorial Coordinators
Marilena Guareschi

Association for the Application of Neuroscientific Knowledge to Social Aims, AU-CNS,


Pietrasanta, Lucca, Italy, EU
"G. De Lisio" Institute of Behavioural Sciences, Pisa, Italy, EU

Matteo Pacini
Angelo G.I. Maremmani

Association for the Application of Neuroscientific Knowledge to Social Aims, AU-CNS,


Pietrasanta, Lucca, Italy, EU
School of Psychiatry, University of Pisa, Italy, EU
II level University Master Degree in Addictologia (60 ECTS).
School of Psychiatry, University of Pisa, Italy, EU
II level University Master Degree in Addictologia (60 ECTS)
School of Psychiatry, University of Pisa, Italy, EU
II level University Master Degree in Addictologia (60 ECTS)

Luca Rovai
Silvia Bacciardi
Enrico Massimetti

School of Psychiatry, University of Pisa, Italy, EU

Denise Gazzarrini

School of Psychiatry, University of Pisa, Italy, EU


II level University Master Degree in Addictologia (60 ECTS)

Fabio Rugani

II level University Master Degree in Addictologia (60 ECTS)

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Open Access at:


http://www.heroinaddictionrelatedclinicalproblems.org

CONTENTS
Preventing opioid overdoses: Is the first still the best? Should we go back to the origins?

Icro Maremmani and Angelo Giovanni Icro Maremmani

Substance abuse in Romania. A clinical medical-legal perspective

Dan Dermengiu, Hostiuc Sorin, Doina Radu, Florina Aciu, Vasile Astarastoae,
Beatrice Ioan, Gabriela Constantinescu, Alexandra Enache, Veronica Ciocan, Ioan Talos,
Gabriel Gorun, and George Cristian Curca

The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

15

Luca Rovai, Angelo Giovanni Icro Maremmani, Silvia Bacciardi, Fabio Rugani,
Enrico Massimetti, Denise Gazzarrini, Matteo Pacini, Liliana DellOsso,
and Icro Maremmani

Comparing emotional clarity, emotion experience, and emotion regulation in male heroin
addicts with and without withdrawal syndrome

35

Zhao Xin, Xie Lu, Fu Li, Zhou Renlai, Jin Ge,Yang Ling, and Cai Yueyue

Why do heroin users refuse to participate in a heroin-assisted treatment trial?

41

Isabelle Demaret, Graldine Litran, Ccile Magoga, Clmence Deblire, Anice Dupont,
Jrme De Roubaix, Andr Lematre, and Marc Ansseau

Sexual dysfunction in male patients receiving methadone and buprenorphine maintenance


treatment in Iran

49

Shadan Tafreshian, Meisam Javadi, Fariba Fakhraei, and Seyedeh Seddigheh Fatemi

Outcomes of clonazepam maintained benzodiazepine-heroin addicted patients during


methadone maintenance: A descriptive case series

55

Angelo Giovanni Icro Maremmani, Silvia Bacciardi, Fabio Rugani, Luca Rovai,
Enrico Massimetti, Denise Gazzarrini, Liliana DellOsso, Pier Paolo Pani,
Matteo Pacini, and Icro Maremmani

Gender differences in severity of addiction in opiate-dependent outpatients

65

Marcela Mezzatesta-Gava, Carlos Roncero, Laia Rodriguez-Cintas, Gideoni Fuste,


Carmen Barral, Nieves Martinez-Luna, Miquel Casas, and Laia Miquel

Limbic system irritability and drug dreams in heroin-addicted patients

75

Claudio Colace, Sergio Belsanti, and Antonia Antermite

Induction and switch to buprenorphine-naloxone in opioid dependence treatment:


Predictive value of the first four weeks

87

Sabine M. Apelt, Norbert Scherbaum, and Michael Soyka

Using oral or i/m morphine for rapid tolerance assessment in patients starting methadone
maintenance: A proposal for discussion based on over 25 years of experience

99

Colin Brewer

30 years of Naloxone
Massimo Barra and Vittorio Lelli

101

Editorial
Heroin Addict Relat Clin Probl 2014; 16(3): 5-6

Preventing opioid overdoses: Is the first still the best? Should we go back to
the origins?
Icro Maremmani1,2,3 and Angelo Giovanni Icro Maremmani1,2
1. Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Italy, EU
2. Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy, EU
3. G. De Lisio Institute of Behavioural Sciences, Pisa, Italy, EU

Philip Seymour Hoffman's death, in February,


shocked the population as well as all professionals involved in the addiction field. He was the latest
of a sequence of celebrities (including Anna Nicole
Smith, Chris Kelly, Michael Jackson and Whitney
Houston) who have died from drug-related problems.
These are the very moments at which the media shed
light on opioid addiction by looking at its more dramatic events deaths from an overdose. Suddenly,
the media can reflect on the democracy of opioid
addiction, which can disrupt the lives of anyone, from
the homeless to movie stars, making them all equal on
medical grounds.
This shocking news is in open contrast with the
capability of agonist opioid treatment to treat opioid
addiction, as first described by Vincent P. Dole almost
50 years ago [2], and to limit overdose mortality [1,
4]. Agonist opioid treatment is a life-saving treatment,
and the best made available by addiction medicine, to
deal with the severe chronic mental illness that opioid
addiction is. When applied using the correct methodology [7], agonist opioid treatment has proven to be
highly effective and over the last few decades it has
significantly reduced deaths related to substance use
[10].
Despite the evidence-based data, despite the
high percentages of those surviving in treatment, agonist opioid treatment has always been hampered,

whereas other models of treatment, such as detoxification, drug-free rehabilitation and psychotherapy,
have been encouraged. At the present time, in 2014,
agonist opioid treatment is still not provided in Russia
[9], whereas advances are occurring in South Asia.
Even where agonist opioid treatment is performed, an incorrect application of treatment methodology can often be observed [8]. There is the need to
strictly implement the 4 phases of treatment (induction phase, stabilization phase, maintenance phase,
medically supervised withdrawal phase), and to reach
blocking dosages instead of anti-withdrawal ones,
together with rehabilitation through behavioural and
social adjustment. The proper methodology is what
makes it possible to achieve the same results that
Dole had in treating his criminal addicts [3], while
also having a positive impact on psychopathology
and polyabuse levels [5, 6].
A comprehensive treatment includes various
different levels. Harm reduction is one of them, but
it is a model that is not directly linked with the preeminent criterion of a correct application of agonist
opioid treatment methodology, which means there is
absolutely no need to create a situation of conflict by
setting harm reduction against agonist opioid treatment. We think that it is now time to refer back to
the teachings of Dole and his basic concept of correctly applying the methodology of agonist opioid

Corresponding author: Angelo Giovanni Icro Maremmani, MD; Association for the Application of Neuroscientific Knowledge to
Social Aims (AU-CNS), Via 20 settembre 83, Pietrasanta, Lucca, Italy, EU.
Phone: +390584 790073; e-mail: angelogimaremmani@gmail.com

Heroin Addiction and Related Clinical Problems 16(3): 5-6

treatment, which is what makes it possible to successfully treat opioid addiction. Politicians and the media
can both play a crucial role in positively influencing
the general population to appreciate the advantages
of agonist opioid treatment, while politicians can facilitate access to the treatment (e.g. by eliminating
the problem of long waiting lists). In referring now
specifically to the medical field, there is an ongoing
need to educate doctors in Medical Schools and Universities about the effectiveness of a correct agonist
opioid treatment, and we can confidently saying that
the best harm reduction takes the form of a comprehensive agonist opioid treatment. After 50 years, we
are ready to re-launch Doles teachings by acting as
a neo-Dolian group, and defining the best treatment
solution as having been the first one.

6. Maremmani A. G. I., Rovai L., Rugani F., Bacciardi S.,


DellOsso L., Maremmani I. (2014): Substance abuse
and psychosis: the strange case of opioids. Eur Rev Med
Pharmacol Sci. 18: 287-302.
7. Maremmani I. (2009): The Principles and Practice of
Methadone Treatment. Pacini Editore Medicina & AUCNS, Pisa.
8. Maremmani I., Maremmani A. G. I., Lubrano S., Nardini
R., DellOsso L., Pacini M. (2013-Ahead of Print): Who
are resistant patients? Quality of treatment and disease
control. Addict Disord Their Treatment.
9. Maremmani I., Pacini M., Pani P. P., Parrino M. (2006):
Say Yes to Methadone and Buprenorphine in Russian
Federation. Heroin Addict Relat Clin Probl. 8(2): 5-22.
10. Mattick R. P., Breen C., Kimber J., Davoli M. (2003):
Methadone maintenance therapy versus no opioid
replacement therapy for opioid dependence. Cochrane
Database Syst Rev(2): CD002209.

References
1. Caplehorn J. R., Drummer O. H. (1999): Mortality
associated with New South Wales methadone programs
in 1994: lives lost and saved. Med J Aust. 170(3): 104109.
2. Dole V. P., Nyswander M. E. (1965): A medical treatment
for diacetylmorphine (heroin) addiction: A clinical trial
with methadone hydrocloride. JAMA. 193: 80-84.
3. Dole V. P., Nyswander M. E., Warner A. (1968):
Successful treatment of 750 criminal addicts. JAMA.
206: 2708-2711.
4. Gronbladh L., Ohlund L. S., Gunne L. M. (1990):
Mortality in heroin addiction: impact of methadone
treatment. Acta Psychiatr Scand. 82(3): 223-227.
5. Maremmani A. G. I., Rovai L., Pani P. P., Pacini M.,
Lamanna F., Rugani F., Schiavi E., DellOsso L.,
Maremmani I. (2011): Do methadone and buprenorphine
have the same impact on psychopathological symptoms
of heroin addicts? Ann Gen Psychiatry. 10:17.

Role of the funding source


No sponsor played a role in this editorial.
Contributors
Authors revised and approved the final form of the
editorial.
Conflict of interest
Authors declared no conflict of interest. IM served
as Board Member for Reckitt Benckiser Pharmaceuticals,
Mundipharma, D&A Pharma, and Lundbeck.

Received and Accepted August 22, 2014


-6-

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 7-14

Substance abuse in Romania. A clinical medical-legal perspective


Dan Dermengiu 1, Hostiuc Sorin 1, Doina Radu 2, Florina Aciu 2, Vasile Astarastoae 3,
Beatrice Ioan 3, Gabriela Constantinescu 4, Alexandra Enache 5, Veronica Ciocan 5, Ioan Talos 6,
Gabriel Gorun 7, and George Cristian Curca 1
1 Carol Davila University of Medicine and Pharmacy, Dept. of Legal Medicine and Bioethics, National Institute of Legal Medicine,
Dept. of Forensic Pathology, Bucharest, Romania, EU
2 National Institute of Legal Medicine, Dept. of Forensic Toxicology, Bucharest, Romania, EU
3 Iasi Institute of Legal Medicine, Dept. of Forensic Pathology, Iasi, Romania, EU
4 Iasi Institute of Legal Medicine, Dept. of Forensic Toxicology, Iasi, Romania, EU
5 Timisoara Institute of Legal Medicine, Dept. of Forensic Pathology, Timisoara, Romania, EU
6 Timisoara Institute of Legal Medicine, Dept. of Forensic Toxicology, Timisoara, Romania, EU
7 National Institute of Legal Medicine, Dept. of Forensic Pathology, Bucharest, Romania, EU

Summary
Objective. In Romania medical-legal studies on the pattern of drug consumption have not yet been conducted nationwide;
the purpose of this study was, therefore, to determine whether such a pattern could be identified. Methods. A total number
of 577 analyses were performed during a three-year period on people suspected of non-lethal substance abuse, in more
than two-thirds of the counties in Romania. Preliminary tests were conducted using immunoassay tests (blood or urine)
and confirmatory tests were carried out using either GC-MS or HPLC. Results. 240 cases (41.6%) were negative while
327 cases (58.4%) tested positive for illegal drugs, central nervous system medication or both. Men represented 89.5% of
all cases, while women accounted for only 10.5%. The pattern of substance abuse varied significantly, depending on the
geographical area. In most cases, the identified drugs of abuse were cannabinoids and opiates, with a significantly different distribution of cases, depending on the geographical area. The highest number of positive cases was identified in the
month of October, whereas the smallest numbers were identified in July and December. The annual trend of consumption
revealed a significant decrease in the analysed substances in 2011. Conclusions. Our study has determined the presence of
a specific pattern of consumption in different geographical areas a result that suggests the need for more targeted prevention programmes, addressing local particularities in consumption behaviours. A significant decrease in the identification
of drugs of abuse in the third year of our study, combined with data attesting the significant increase in the consumption
of legal highs suggests that the forensic toxicology laboratories need to be equipped with apparatus able to detect these
newer substances of abuse more efficiently.
Key Words: non-lethal substance abuse in Romania; drug abuse pattern in Romania; opiates; legal highs

1.

Introduction

Substance abuse and misuse is a severe problem


worldwide, affecting more than 185 million people
[17]. It leads annually to more than 200,000 deaths
due to illicit drugs only [34], causes a significant increase in violence-related traumas including suicides
[14, 16, 24, 31], domestic violence [10, 15, 21, 27,
29, 39], interpersonal violence by firearms and sharp
force injuries [34], an increased risk of contracting
various viral and bacterial infections [3, 6, 7, 9, 11,

22, 25], and so on. The pattern of consumption is


highly variable between countries [4, 5, 8, 12, 13, 19,
20, 28, 30, 33, 38], and in the same country between
different social or economic groups. These variations
are of the uttermost importance for physicians (who
may not have the time to perform a proper toxicological analysis in the emergency room, and must initially
act on incomplete data), forensic toxicologists and
pathologists (who can use more targeted procedures,
initially directed towards the most frequently used
drugs), or police officers (who have to screen driv-

Corresponding author: Sorin Hostiuc, Carol Davila University of Medicine and Pharmacy, Dept of Legal Medicine and Bioethics, National Institute of Legal Medicine, Dept of Forensic Pathology, Bucharest, Romania, Vitan Barzesti 9, 042122, Bucharest,
Romania, EU; E-mail: soraer@gmail.com;

Heroin Addiction and Related Clinical Problems 16(3): 7-14

ers using rapid tests, and need to know what kind of


screening tests to use in traffic). In Romania, nationwide studies on the pattern of consumption were only
conducted using sociological surveys [1, 2]; toxicological studies were only carried out in specific counties [13, 23, 28, 32, 35] and/or specific groups [26, 32,
35]. The purpose of this article was to determine the
pattern of substance abuse in Romania by using data
obtained from medical-legal services.
2.

Methods

The study was carried out in three medical-legal


institutions (in Bucharest, Iasi, and Timisoara) that
perform forensic toxicology tests for more than twothirds of the Romanian counties. Preliminary screen-

ing was performed using immunoassay tests (blood


or urine), and confirmatory tests were conducted using GC-MS for illegal substances, or HPLC for Central Nervous System (CNS) medication, including
barbiturates, benzodiazepines and anti-psychotics.
Each institute used its own detection methods.
A total number of 577 analyses were performed
between October 2008 and September 2011, of which
79.55% (459 cases) were done at the request of the
police, 12.82% (75 tests) were done in response to
a personal request and 7.63% (44 tests) were done
at the request of various other institutions. Age could
only be obtained in 193 cases, as the bulletins associated with the sampling biological products differed
between counties, and some did not include age as a
mandatory field. The results were then gathered using

Table 1. Distribution of positive cases between sex and age groups


Substance

Positives (rePositives
Positives
by other (requested by Pearson 2 for
(requested by quested
official institu- the person in
requests)
the police)
tions)
question)

Morphine

45

10

13.428
(p=0.001)

Methadone

19

Tramadol
Pethidine

3
0

1
2

0
0

Cocaine

Cannabinoids

221

Amphetamines

JWP_018

MDMA

Ketamine

MDPPP/MPP

5.675
(p=0.059)
n.a.
n.a.
1.011
(p=0.603)
49.609
(p=0.000)
n.a.
0.882
(p=0.644)
n.a
0.626
(p=0.731)
n.a

Benzodiazepines

27

14.384
(p=0.001)

Zopiclone
Antidepressants

2
2

0
2

0
1

Antiepileptic

Antipsychotic

n.a
n.a.
3.353
(p=0.187)
n.a.

Barbiturates

18.091
(p=0.000)

-8-

Comments
Tests for morphine were
significantly more frequently
positive when the analysis
was requested by other official
institutions

Tests for benzodiazepines were significantly less


frequently positive when the
police requested the analyses.

Tests for barbiturates were


significantly less frequently positive when the police
requested the analyses.

D. Dermengiu et al.: Substance abuse in Romania. A clinical medical-legal perspective

a common reporting methodology based on standardized forms and inserted into an SPSS database. Statistical analysis was done with SPSS v.20 for Mac OS
software. The following statistical tests were used:
descriptive statistics (frequencies, mean, standard deviation, range, minimum, maximum), and cross-tabulations (using the 2 Pearson test to test the presence
of a significant correlation between descriptive data).
A p value below 0.05 was considered significant.
3.

Results

Of the 577 analyses that were performed, 240


(41.6%) tested negative both for illegal substances
and CNS-medication, 308 (53.38%) tested positive
for drugs of abuse, six for CNS-medication (1.04%)
and 23 (3.98%) both for drugs of abuse and CNS-

medication. In 288 cases a single substance was


identified (85.46%), in 31 cases two substances were
identified (9.20%), and in 18 (5.34%) there were
more than two. Men accounted for 89.5% of all cases,
and had a mean age of 25.52 years (ranging between
16 and 50) while women only represented 10.5% of
all cases, had a higher mean age (29.84, and a range
between 15 and 73). Age distribution of people testing positive was as follows: below 20 years 54 positive cases (27.98%), 20-25 years 67 positive cases
(34.71%), 26-30 years 38 positive cases, (19.69%),
31-40 years 26 positive cases (13.47%) and over 40
years 8 cases (4.15%). Of the 459 tests requested
by the police, 159 (34.65%) were negative, and 300
(65.35%) were positive. Of the 44 tests requested by
other institutions, 22 were negative (50%) and 22
were positive (50%). Of the 74 tests done in response

Table 2. Distribution of cases on the basis of the person/agency who asked for the procedure
Substance

Positives (rePositives
Positives
quested
by
other
(requested
Pearson 2 for
(requested by official institu- the person by
in
requests)
the police)
tions)
question)

Morphine

45

10

13.428
(p=0.001)

Methadone

19

Tramadol
Pethidine

3
0

1
2

0
0

Cocaine

Cannabinoids

221

Amphetamines

JWP_018

MDMA

Ketamine

MDPPP/MPP

5.675
(p=0.059)
n.a.
n.a.
1.011
(p=0.603)
49.609
(p=0.000)
n.a.
0.882
(p=0.644)
n.a
0.626
(p=0.731)
n.a

Benzodiazepines

27

14.384
(p=0.001)

Zopiclone
Antidepressants

2
2

0
2

0
1

Antiepileptic

Antipsychotic

n.a
n.a.
3.353
(p=0.187)
n.a.

18.091
(p=0.000)

Barbiturates

Comments
Tests for morphine were
significantly more frequently
positive when the analysis
was requested by other official
institutions

Tests for benzodiazepines were significantly less


frequently positive when the
police requested the analyses.

Tests for barbiturates were


significantly less frequently positive when the police
requested the analyses.

-9-

Heroin Addiction and Related Clinical Problems 16(3): 7-14

250

227

200

150

100
58
50

38

23

13

19

Figure 1. Relative frequencies of the substances identified

to a personal request, 59 were negative (79.72%) and


15 (20.28%) were positive.
In 14 cases a positive drug test was associated
with a positive blood-alcohol test.
The substances most frequently identified in our
tests were: cannabinoids, with 227 positive results,
followed by morphine with 58 cases, benzodiazepines
with 38, methadone with 23, and barbiturates with 13
cases (see Tables 1 and 2 and Figure 1).
The distribution of positive cases between the
three centres of analysis was as follows: 122 positive
cases (36.2%) were identified in the Bucharest Institute (which is the centre assigned to counties in the
Southern part of Romania), 119 cases (35.3%) were
identified in the Iasi Institute (the centre assigned to
counties in the North-Eastern part of Romania), and
96 cases (28.48%) were identified in the Timisoara
Institute (the centre assigned to the counties in the
Western part of Romania).
The relative frequencies of the drugs of abuse
differed sharply between the three centres. In the
Bucharest Institute opiates were the most frequently
identified substances with 62 cases (50.81%, of which
37 tested positive for morphine, 20 for methadone,
three for Tramadol, and two for Pethidine), followed
by cannabinoids in 45 cases (36.88%), and benzodi- 10 -

azepines in 31 (25.4%). In 31 cases more than one


active substance was identified. At the Iasi institute
cannabinoids were identified in 102 cases (85.71%),
followed by JWP_18 in seven cases (5.88%), benzodiazepines in six (5.04%), and opiates in five
(4.20%). In the Timisoara Institute the most frequently identified substances were cannabinoids (80 cases,
83.33%), followed by opiates (20 cases, 20.83%) and
cocaine (six cases, 6.25%). The differences were statistically significant.
The most positive samplings occurred in October (61 cases, 18.5%), whereas the lowest numbers of
positive cases occurred in July (16 cases, 4.74%) and
December (11 cases, 3.27%) (see Figure 2). In year 1
(October 2008 - September 2009) 131 positive cases
(38.87%) were identified, in year 2 (October 2009 September 2010) 125 cases (37.09%) were identified,
and in year 3 (October 2010 - September 2011) 81
cases (24.04%) were identified.
4.

Discussion

Between 2008 and 2010 we identified a rise in


the number of positive cases, followed by a fall in
2011. Even if the data from 2011 were only based
on the first ten months, the value obtained is about

D. Dermengiu et al.: Substance abuse in Romania. A clinical medical-legal perspective

half the value calculated for 2010. The main reason


is a dramatic increase in the consumption of so-called
legal drugs [18, 19, 28, 36, 37], which often need
more specialized equipment like liquid chromatography mass spectrometry mass spectrometry (LCMS-MS) for a positive identification. This shift in
consumption is suggested by a study carried out in
2009 and the first six months of 2010 on the distribution of non-fatal emergencies associated with drug
consumption [2]. In 2009, 999 non-lethal drug-related emergencies were identified in Romania; of these
258 were opiate-related and 86 were cases of acute
intoxication induced at the legal highs (as declared
by the patients). In the first six months of 2010, 934
non-lethal drug related emergencies were identified,
of which legal highs accounted for 236 and opiates
for 126 cases. Cannabinoid-related emergencies almost doubled (48 cases in 2009, 49 cases in the first
six months of 2010).
The pattern of consumption is similar to the one
suggested by a study based on a survey involving
Romanian high school students[2], in which cannabinoids were the most frequently used type of drug
(34.1% of the students declaring substance abuse said
they had used marijuana, 8.6% cannabis, 6.5% hash-

ish, 3.6% weeds followed by drugs inducing legal


highs like Magic (3.6%), Spice (2.2%), and Ecstasy
(3.6%). Heroin was only used by 1.4% of high school
students [2].
We have found significant differences between
the profiles of drug consumption in different regions; in the capital and the counties surrounding it,
the most frequently used drugs were opiates, but in
other regions cannabinoids were far more frequently
identified. An accurate knowledge of the patterns of
consumption prevalent in different geographical areas
may help policymakers to develop specific, targeted
prevention programmes.
By analysing the number of cases per month
we have found that the lowest numbers of positive
cases have been found in July and December (months
in which a large number of people are on vacation),
while the highest numbers were recorded in October (the month in which all students go back to their
schools/universities). The most likely explanation is
that consumption is associated with (1) mobility its
prevalence is higher in people who travel (whereas it
falls in the months when they stay in their places of
residence) or (2) study (it rises when they go back
to school after holidays) in locations different from

70

18.15%

61

60
50

11.60%

40
30
20

9.82%

8.93%
7.14%

24

33

30

5.65%

19

39
8.63%

8.63%

29

29

6.25%

21

10

7.14%

24
4.76%

16

3.27%

11

Figure 2. Distribution of cases on a monthly basis

- 11 -

Heroin Addiction and Related Clinical Problems 16(3): 7-14

those where they live.


5.

Conclusions

Our study has determined the presence of a specific pattern of consumption in each of a number of
different geographical areas, a result which suggests
the need for more targeted prevention programmes,
so allowing particularities in consumption behaviours
to be investigated. The significant fall recorded in the
identification of drugs of abuse in the third year of
our study, combined with data documenting the significant rise in intoxication induced at the legal highs,
suggests that the forensic toxicology laboratories we
have studied need to be equipped with LC-MS-MSs.
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Acknowledgement
This article was supported by a UEFISCDI Grant,
Programme entitled Parteneriate in Domenii Prioritare,
No. 42153/2008.
Role of the funding source
Public finances (National Research Programme).
Contributors
All authors were involved in the study design, had
full access to the survey data and analyses, and interpreted
the data, critically reviewed the manuscript and had full
editorial control, including final responsibility for the decision to submit the paper for publication.
Conflict of interest
None

Received August 14, 2013 - Accepted January 26, 2014


- 13 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 15-34

The role of the opioid system in Eating Disorders. Perspectives for new
treatment strategies
Luca Rovai 1, Angelo Giovanni Icro Maremmani 1,2, Silvia Bacciardi 1, Fabio Rugani 1, Enrico
Massimetti 1, Denise Gazzarrini 1, Matteo Pacini 3, Liliana DellOsso 4, and Icro Maremmani 1,2,3
1 Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Italy,
EU
2 Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy, EU
3 G. De Lisio Institute of Behavioral Sciences, Pisa, Italy, EU
4 Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Italy, EU

Summary
Introduction: Growing evidence drawn both from observational and biological sources supports the hypothesis that eating disorders share the feature of inducing an alteration in the reward system, with a central role being played by opioid
neuropeptides. Aims: To estimate i) epidemiological and clinical correlations between opioid use disorder and eating
disorders; ii) the nature of the correlation between opioid medications, feeding behaviours and eating disorder symptoms;
iii) the feasibility of using opioid medications in the management of eating disorders, especially anorexia nervosa, bulimia
nervosa and binge eating disorder; iiii) the risk-benefit ratio of opioid medications compared with that of medications traditionally used to treat eating disorders. Methods: Overview after a thorough search on the Scopus data base. Results:
We found few available data on the correlations between opiate addiction and eating disorders, whether on the epidemiological or the clinical plane. Opioid full and partial agonists seem to present a promising profile of effects that could be
useful in treating anorexia nervosa. Opioid antagonists have been shown to be effective on both bulimia nervosa and binge
eating disorders. Nalmefene should be preferred to naltrexone in bulimic patients of normal weight who are able to benefit
from a double stabilization. Conclusions: Despite the scarcity of clinical and epidemiological data on the correlations
between eating disorders and opiate addiction, evidence from both human and animal studies prompts the suggestion that
opioid medications can play a far from negligible role in the treatment of eating disorders.
Key Words: reward system, opioid agents, eating disorders, feeding behaviours, treatment strategies

1.

Background

1.1. Neurobiology of reward system


The reward system is a relatively well-known
form of brain circuitry that plays a central role in
instinctual drives, such as those involved in sexual,
aggressive and feeding behaviours. It includes the
dopamine-containing neurons of the ventral tegmental area, nucleus accumbens, and prefrontal cortex,
and has the task of reinforcing behaviours that share
the property of being pleasurable and rewarding [21,
119, 124, 160, 161].
Closely related to one another, reward and reinforcement are terms that offer an objective way of de-

scribing the positive value that an individual ascribes


to an object, behavioural act or internal physical state.
Primary rewards include those that are required for
the survival of the species; secondary rewards derive
their value from primary rewards, and can be produced experimentally by pairing a neutral stimulus
with a known reward. Money is a good example [83,
159].
Diametrically opposed to reward is punishment,
which characterizes painful and unpleasant experiences. Individuals actively avoid punishing experiences. Just as reward and reinforcement describe
the effects of positive experiences, punishment and
avoidance offer an objective way of describing the
negative value that an individual ascribes to an object,

Corresponding author: Icro Maremmani, MD; Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara
University Hospital,University of Pisa, Via Roma, 67 56100 PISA, Italy, EU.
Phone +39 0584 790073 Fax +39 0584 72081; E-Mail: maremman@med.unipi.it

15

Heroin Addiction and Related Clinical Problems 16(3): 15-34

behavioural act or internal physical state.


Rewards are generally considered more effective than punishment in modifying human behaviour
[36, 38].
The reward system has been widely studied in
the field of substance use disorders, which gives us an
idea of the neurotransmitters involved. All addictive
drugs increase dopamine release in the mesolimbic
pathway [38], but it needs to be borne in mind that
dopamine is not the only neurotransmitter involved
in the acute reinforcing effects of abused drugs.
Other neurotransmitters include opioid peptides,
which mediate the reinforcing effects of opiates,
-aminobutyric acid (GABA), which mediates the
reinforcing effects of alcohol and benzodiazepines,
glutamate, neuropeptide Y, and the glucocorticoids
belonging to the hypothalamic-pituitary-adrenal axis
[6, 31, 85, 86, 143].
When the reward system is repeatedly stimulated by a pleasurable experience, it can develop neuroadaptive changes that, thanks to the participation of
memory functions, ultimately lead to learning phenomena [136]. While being adaptive in most of the
activities of daily life, learning can become maladaptive in many behavioural domains, which correspond
to substance abuse behavioural dependences and eating disorders [67, 120].
1.2. The role of opioids in reward activity
From a hierarchical point of view the opioid system has a dominant position within the reward system. It consists of three G protein-coupled receptors
(, , and ), which are stimulated by a family of endogenous peptides (enkephalins, dynorphins and endorphins), and are responsible for the control of pain,
reward, attachment and addictive behaviours. The
opioid receptors are mainly found in the central and
peripheral nervous system and in the gastrointestinal
tract; they share a variety of properties, but some distinctive traits can be highlighted [3, 51, 68, 93, 140].
Mu receptors, stimulated by endorphins, are the
principal opioid receptors, as they are responsible
for most of the therapeutic and addictive properties
of opioids. Their activation promotes the release of
dopamine in the reward pathway, inducing a state
of euphoria. Other effects mediated by receptors
include respiratory depression, suppression of the
cough reflection, nausea, vomiting and myosis, the
reduction of intestinal secretion and motility, and an
increase in the time transit of intestinal material [28,
45, 90, 93, 140, 150].
- 16 -

Delta receptors have enkephalins as their endogenous ligands. Their activation produces some analgesia and respiratory depression, even if less than that
of -opioid agonists, and also, to some extent, an antidepressant activity [7, 40, 84, 90, 140, 163].
Kappa receptors bind the opioid peptide dynorphin as their primary endogenous ligand. Their activation is thought to mediate the perception of pain,
consciousness, mood stability and motor control [90,
93, 140, 163].
1.3. The role of reward in eating disorders
Eating disorders are a heterogeneous group of
diseases distinguished by a persistent disturbance of
an eating-related behaviour that significantly impairs
physical health or psychosocial functioning [1]. Over
the past few decades the boundaries of this class of
disorders have been expanding, with the inclusion in
the common diagnostic system of new nosographic
entities, other than anorexia and bulimia nervosa.
Parallel individual disorders have been differentiated
both on the epidemiological and the clinical plane.
With regard to anorexia and bulimia nervosa,
they have their initial onset between 10 and 20 years
of age, and carry the burden of a high risk of mortality. The overall incidence of anorexia nervosa has remained stable over the last few decades, but there has
been an increase in the high-risk group of 15-19 year
old girls. More specifically, the incidence of bulimia
may have fallen since the early nineties of the last
century. It is well known that anorexia nervosa carries
the highest risk of mortality in the entire class of diseases. Although bulimia responds better to treatment,
it too brings with it a considerable risk of mortality,
and is closely related to suicide [8, 24, 34, 113, 125].
The pathophysiology of eating disorders is far
from having been adequately elucidated, and various classes of neurotransmitter systems have been
discussed in attempting to explain the behavioural
alterations of patients suffering from this class of diseases. Growing evidence both from observational and
biological sources support the hypothesis that eating
disorders share the feature of inducing an alteration
in the reward system, which plays a central role in
instinctual drives, including the drive to eat.
On the observational plane, the involvement of
the reward system in eating disorders is supported
by the fact that eating disorder-related symptoms resemble those typically endorsed by individuals with
substance use disorders. In the latest version of the
Diagnostic Statistic Manual it is stated that this re-

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

semblance may reflect the involvement of the same


neural systems in the two groups of disorders, but the
lack of any clinical evidence to support this theory
has precluded the inclusion of eating disorders in the
category of addictive disorders [1].
On the biological plane structural and functional
alterations in reward circuits have been hypothesized
as inducing a predisposition to develop an eating disorder in response to malnutrition or repeated binge
eating and purging [11, 42, 43, 141]. In developing
this hypothesis, a few authors have investigated the
predictive value of various biomarkers in anorexia
nervosa and bulimia. Both disorders have exhibited
an increase in the grey matter volume of the medial
orbitofrontal cortex. Antero-ventral insula grey matter
volumes have been shown to have risen on the right
side in anorexia nervosa patients, and on the left side
in patients suffering from bulimia nervosa, compared
with healthy controls. Anorexic and bulimic patients
present two patterns of biomarkers that seem to be
mutually exclusive [42].
This dichotomy has also been confirmed by
temperamental and personological measuring scales
(Temperament and Character Inventory and Tri-dimensional Personality Questionnaire). Anorexic and
bulimic patients have shown alterations in their sensitivity to reward that place them in opposition to each
other. In general, patients with a form of anorexia nervosa belonging to the restricting type have reported
having become less sensitive to reward than healthy
controls, whereas patients with bulimia nervosa and
anorexia nervosa of the binge/purging type reported having become more sensitive. Both groups of patients have shown a higher sensitivity to punishment
than healthy controls [60].
In summary, the sensitivity of dopamine reward
pathways has been implicated in the risks arising
from eating disorders, but the evidence is divided on
the issue of the direction of causal association. One
argument is that a Reward Deficiency Syndrome is
the risk factor, while others contend that hypersensitivity to reward enhances the motivation for pleasurable activities like eating, in such a way that those
activities become addictive.
In this review we will focus on Anorexia Nervosa, Bulimia, and Binge Eating Disorder, as these
three disorders are those in which the involvement of
the reward system has been most accurately defined.
1.3.1. Reward activity in anorexia nervosa

Anorexia nervosa is associated with a fear of


weight gain and the refusal to maintain a minimally

normal body weight [1]. Individuals with anorexia


nervosa are often described as possessing excessive
self-control and are unusual in their ability to reduce
or eliminate the consumption of palatable foods, a behaviour that suggests disturbances in reward processing [15].
Both animal and human studies assessing
mechanisms of self-starvation under conditions of
stress and diet have proposed a central role for the
mesolimbic reward system in the maintenance of the
core symptoms of anorexia nervosa [41]. Structural
imaging studies on clinical samples have demonstrated brain tissue abnormalities in anorexic patients, the
most important being a global reduction in grey and
white matter, and decreases in reward and somatosensory regions [148]. All these biological observations
are consistent with the hypothesis that, in anorexic
patients, reward has been linked to reduced food intake and excessive exercise, so that while patients'
pathological behaviours are initially rewarding, they
become reinforced in a pathological manner that
turns out to be punishing [81]. The impaired ability to
experience taste-related pleasure, shown by anorexic
patients, may thus reflect the altered motivational role
of weight loss rather than an impaired ability to experience reward [33, 82].
Some authors have focused on the increased
capacity to delay reward of anorexic individuals, as
a condition putatively involved in the maintenance
of food restriction. Patients suffering from anorexia
nervosa have shown a tendency to delay receipt of
a monetary, non-food related reward a parameter
suggestive of enhanced self-control that may go beyond food consumption. It is notable that this psychological profile is the opposite of that of substance
abusers, who are well known for their incapacity to
delay reward [142]. Other authors have focused on
the hyperactivity of patients with anorexia nervosa.
The link between restricted food intake and an increase in physical activity is very likely to bring an
evolutionary advantage which, initially, tends to be
both functional and rewarding. In anorexia nervosa
this paradoxical reward of hyperactivity has been hypothesized to be an expression of the neurobiological changes that may underlie the development of the
disorder [132].
Regardless of the problem of identifying the
primum movens of anorexia nervosa, neural overlap
between reward and punishment circuits has been put
forward as the most likely explanation of the difficulties shown by these individuals in differentiating between positive and negative eating-related feedbacks
- 17 -

Heroin Addiction and Related Clinical Problems 16(3): 15-34

[153].
1.3.2. Reward activity in bulimia nervosa

Bulimia nervosa is associated with recurrent


episodes of binge eating in which the subject eats a
large amount of food and experiences a sense of lack
of control. These episodes are followed by inappropriate compensatory behaviours that aim to prevent
weight gain, such as self-induced vomiting, misuse
of laxatives, diuretics, or other medications, fasting
or excessive exercise. These subjects self-evaluation
is unduly influenced by body shape and weight [1].
The impact of alterations to reward processing
have also been implicated in bulimia nervosa. The
specific eating patterns of bulimic patients show a
closer resemblance to the behavioural patterns of substance abusers than to those of anorexic patients, and
are thought to be particularly addictive. Binge eating and purging with intermittent dietary restriction
could, through their effects on the dopaminergic system, enhance the motivational role of food, especially
in individuals who are particular sensitive to reward
[149].
Both neurobiological and psychological evidence support the view that bulimia nervosa functions
in an addictive way. A neurobiological study has investigated the functional magnetic resonance patterns
of women with full and sub-threshold bulimia nervosa, the main result being the abnormal neural activation that is displayed in response to food intake and
anticipated food intake. It is probable that this altered
response pattern to food-related reward is the result of
a history of binge-eating highly palatable foods [19].
Responsiveness to reward has been studied in unmedicated bulimic subjects in remission, in some cases
by means of pharmacological catecholamine depletion. This experimental procedure has uncovered a
dopaminerelated disturbance of the central reward
processing systems which might reflect a trait-like
deficit that aggravates vulnerability to bulimia nervosa [54].
As in the case of anorexia nervosa, an altered
striatal response with neural overlapping between
reward and punishment processing has been put forward to explain difficulties in discerning the emotional significance of a food-related stimulus [152].
Moving on now to the psychological plane,
bulimic patients have mostly shown a cyclothymic
temperament, a construct that is closely related to
impulsivity and sensitivity to reward, and is thought
to predispose to substance abuse. This psychological
profile seems to some extent to be the opposite of that
- 18 -

of anorexic patients, who have a low sensitivity to reward and show a great ability to delay food-related
rewards [5].
1.3.3. Reward activity in binge eating disorder

Binge eating disorder is associated with recurrent episodes of binge eating in which the subject
quickly eats large amounts of food even if not physically hungry. The binge eating episodes, which are
dominated by feelings of disgust and embarrassment,
are to some extent similar to those of bulimic patients,
except for the lack of compensatory behaviours,
which are typically absent in binge eating disorder
[1].
On the neurobiological plane, a functional magnetic resonance imaging study, by exploring the neural correlates of visually induced food reward, has
made it clear that patients suffering from binge eating
disorder present different forms of brain activation in
response to visual food stimuli from those of patients
suffering from bulimia nervosa. Both groups experienced the food pictures as very pleasant; the first
group reported enhanced reward sensitivity, whereas
the second group of patients displayed greater arousal [133, 157]. Given the hypothesized link between
dopamine receptor subtypes and reward sensitivity,
some authors have assessed the role of those alleles
whose expression was a reduced dopamine receptor
density, but the results are controversial [35].
Moving to the field of experimental psychology, monetary reward processing has been studied in
obese individuals with and without binge eating disorder. Patients suffering from binge eating disorder
have performed a monetary reward/loss task that is
significantly different from that of other obese patients, as analysed by means of functional magnetic
resonance imaging [14].
1.4. The role of opioid system in eating disorders
If we intend to study the involvement of the reward system in the pathogenesis of eating disorders, it
is of primary interest to explore the role of the opioid
system, not only because of its neurobiological primacy, but also because of its close links with feeding
behaviours and metabolic regulation [74].
1.4.1. Opioid activity in anorexia nervosa

With reference to neurobiological factors, higher levels of cerebrospinal fluid opioid activity have
been found in patients with anorexia nervosa who
were severely underweight. This disposition might be

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

a compensatory response to weight loss or might be


aetiologically related to anorexia nervosa [80].
On genetic grounds, changes in the serotonergic
and opioidergic neurotransmitter system are among
the other developments observed in people suffering
from anorexia. In particular, the genes for serotonin
and opioid-delta receptors have been found in a region identified in a linkage analysis, and have been
discussed in attempts to explain the aetiology of anorexia nervosa [17, 18].
Moving from humans to animals, an atypical
endogenous opioid system in mice has been related
to an autoaddiction opioid model of anorexia nervosa, where the responsiveness of the opioid system is
thought to play a predisposing role in the development of the disease. Morphine-mediated activation of
the endogenous opioid system increases food intake
and causes sedation in most species, including normal humans and rats. By contrast, in mutant mice,
morphine causes anorexia and hyperactivity, in a way
similar to what can be observed in anorexia nervosa
patients [103].
From an evolutionary point of view, anorexia
nervosa may be a pathological consequence of the
triggering of a primitive mechanism for coping with
unforeseen food shortages. This mechanism would
lead to the short-term ability to mask a depressed
state related to food depletion, especially thanks to
the relationships that link the endogenous opioid system with other systems, such as the dopaminergic,
noradrenergic and hormonal ones [73].
1.4.2. Opioid activity in bulimia nervosa

On neurobiological grounds, regional -opioid


receptor binding in the insular cortex has been found
to be weaker in bulimic patients than in controls, and
to inversely correlate with fasting behaviour. In the
light of this observation it has been hypothesized that
the abnormal, recurrent activation of this system may
constitute a neural substrate for the maintenance of
the self-perpetuating behavioural cycle of bulimic
subjects, as the insula is the primary gustatory cortex,
and has often been implicated in the processing of the
reward value of food [16].
An animal model of bulimia nervosa, based on
opioid sensitivity to fasting episodes, has been considered too. A group of female rats have been deprived
and maintained at 75-80% of normal body weight at
three different stages of their development. Following
recovery to normal weight, food intake was measured
with and without butorphanol tartrate, a - agonist.
Animals with a history of deprivation showed an in-

crease in post-recovery feeding when they were tested at normal body weight and were not deprived of
food. More importantly, butorphanol had the effect of
prolonging food intake only in the rats that had a developmental history of food restriction. One possible
explanation for this is that a developmental history of
fasting in eating disorders may trigger changes in opiate systems that result in atypical feeding behaviour
in the adult [57].
1.4.3. Opioid activity in binge eating disorder

On neurobiological grounds, both the nucleus


accumbens and amygdala are thought to participate
in the control of opioid-mediated food intake, during binge episodes. As a matter of fact, the intra-accumbens administration of the -opioid encephalin
agonist is followed by a substantial increase in the
intake of fat, while this increase has shown to be
completely blocked by the concurrent inactivation
of either the basolateral or the central nucleus of the
amygdala, by means of a GABA agonist. A possible
explanation is that amygdala inactivation reduces the
hedonic properties of high-fat palatable food [158].
In animal models of binge eating, selective
-opioid receptor antagonists have been shown to
suppress food consumption. In humans, non-selective
opioid receptor antagonists have shown the property
of reducing hedonic taste preferences and food intake, particularly in the case of palatable foods, and
to cause short-term weight loss. These effects have
been linked to the negative modulation of dopamine
release within the reward circuitry. The suggestion is
that the reduction of the -opioid receptor-mediated
hedonic and motivational processes that drive the consumption of highly palatable foods may be a promising therapeutic approach for obesity and binge-eating
disorder [46, 117].
1.5. Opioid medications
Opioids are drugs that have similar effects to
opium, a substance that has been used by mankind
for thousands of years because of its therapeutic (analgesic, sleep-inducing, anti-diarrhoeal) and recreational (euphoric) properties. A number of drugs, such
as morphine, codeine, papaverine, and thebaine, are
derived from papaver somniferum, the plant that is
used to prepare opium [3, 68, 69].
Opioid agents are generally classified as agonists or antagonists according to their intrinsic activity on each kind of receptor. The overall effect of an
opioid agent depends on its activity on each single
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Heroin Addiction and Related Clinical Problems 16(3): 15-34

type of receptor; some opiates act as agonists on one


type and antagonists or partial agonists on another.
The potency of an opioid agonist depends on 1) the
affinity of the agonist for the receptor, that is, its tendency to bind to the receptor; and 2) the efficiency
of the agonist, also called intrinsic activity, that is,
its ability, once it is bound to the receptor, to induce
a series of changes that lead to the entire range of
pharmacological effects. Full agonists have maximal efficiency and produce similar effects to those
of endogenous opioids, whereas partial agonists have
intermediate efficiency and produce sub-maximal effects, compared with those of endogenous opioids
[64, 104, 105].

and opioid receptors, and medium affinity for


opioid receptors. As to functional activity, the drug
behaves as a moderately potent -opioid antagonist,
as a potent -opioid partial agonist, and as a -opioid
antagonist. Nalmefene is extensively metabolized,
and has a plasma half-life of almost 11 hours, compared with 60-90 min for naloxone. It has been shown
to reverse opioid intoxication for as long as 8 hours,
reducing the need for continuous monitoring of intoxicated patients and repeated dosing with naloxone.
Mainly used in the treatment of interstitial cystitis
and chronic alcohol dependence, its long duration of
action facilitates extended withdrawal reactions in
chronically opioid-dependent patients [47, 155].

1.5.1. Naloxone

1.5.4. Buprenorphinenaloxone

Naloxone is a -opioid receptor competitive


antagonist which, thanks to its extremely high affinity, displaces the opioid peptides that are related to
receptors (whether endogenous or exogenous) and
produces a rapid neutralization of their effects; in the
case of dependent patients, this leads to the onset of a
withdrawal syndrome. Naloxone has a 60-90 minute
half-life, and its most widespread use is the treatment
of respiratory depression in the context of an opiate
overdose. It also has an antagonist action, though
with a lower affinity, at the sites of - and -opioid
receptors [72, 104, 126, 164].

The combination buprenorphine-naloxone has


been developed to reduce the potential for abuse
and limit the grey market for oral buprenorphine; it
brings together a -opioid partial agonist and a and
-antagonist. If the combination is taken sublingually,
naloxone is absorbed to a negligible extent, and thus
has no significant effect, but if it is used intravenously
in subjects tolerant to opiates, the antagonist naloxone
can produce an acute but not life-threatening withdrawal syndrome [10, 56, 58, 137].

1.5.2. Naltrexone

Naltrexone is an opioid receptor antagonist used


primarily in the treatment of alcohol dependence
[121, 129] and pathological gambling [20], and secondarily in the management of opioid dependence,
especially where opioid agonists are not available.
Naltrexone is commonly used as an anti-reward medication, and should not be confused with naloxone.
Using naloxone in place of naltrexone can cause acute
opioid withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead
to insufficient opioid antagonism and fail to reverse
the overdose. Naltrexone and its active metabolite
6--naltrexol have half-lives of 4 hours and 13 hours,
respectively, and both are competitive antagonists at
sites of - and -opioid receptors, and, to a lesser extent, at sites of -opioid receptors [52, 104, 126, 139].
1.5.3. Nalmefene

Nalmefene is a selective opioid receptor ligand


without any significant affinity to targets apart from
opioid receptors. With respect to the opioid receptor
subtypes, nalmefene has an equally high affinity for
- 20 -

1.5.5. Buprenorphine

Buprenorphine is a synthetic, fat-soluble drug,


acting as a partial agonist at the -opioid receptor and
on opioid-like receptors, and exerting a not univocal
but mainly antagonist action on and -opioid receptors. It has greater affinity and less intrinsic activity than full agonists such as methadone, morphine
or heroin. This means that buprenorphine displaces
the other agonists from the receptor, but, in the short
term, does not produce an effect equivalent to that produced by higher dosages of other agonists that have
greater intrinsic activity. Because of this discrepancy,
buprenorphine may produce withdrawal symptoms
when there is an initial situation of opioid tolerance
induced by a full agonist, but it makes it possible to
achieve blockade effects in subjects with low tolerance to opioid agonists. Although buprenorphine is an
opioid, and thus can produce typical opioid agonist effects and side-effects such as euphoria and respiratory
depression, its maximal effects are less than those of
full agonists like heroin and methadone. The agonist
effects of buprenorphine rise linearly with increasing
doses of the drug, until at moderate doses they reach
a plateau, and no longer continue to increase as doses are raised. This is called a ceiling effect, whose

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

main benefit is the lower risk of side-effects and overdose, compared with full opioid agonists. Because of
its poor oral bioavailability, buprenorphine formulations for opioid addiction treatment are distributed
in the form of sublingual tablets. Buprenorphine is
highly bound to plasma proteins, and is metabolized
by the liver via the cytochrome P4503A4 enzyme
system into nor-buprenorphine and other metabolites.
Its half-life is 24-60 hours. The maximal effects of
buprenorphine appear to occur at a 16 mg dose. The
only probable effect of higher doses is higher levels
of opioid receptor blockade, without the higher doses
inducing any substantial increase in buprenorphines
intrinsic activity [75, 87, 144-147].
1.5.6. Methadone

Methadone was the first opioid agonist to be


made available for the treatment of patients with opiate addiction. It is a synthetic drug that acts on the
same receptors as heroin () and has a similar affinity
with them. Methadone is usually taken orally, and is
rapidly absorbed through the gastrointestinal mucosa,
with a bioavailability ranging from 40 to 100%. The
onset of its effects takes place within 30' after oral
intake, with a peak after an average of 2.5 hours. The
plasma concentrations increase in the first 3-4 hours
after oral intake and then gradually decline. Methadone has a slow metabolism and a very high fat solubility, making it longer lasting than morphine-based
drugs. It has a typical elimination half-life of 15 to
60 hours, with a mean of around 22, but metabolism
cycles vary greatly between individuals, up to a factor
of 100, ranging from as few as 4 hours to as many as
130 hours, or even 190 [2, 12, 13, 39, 59, 162].
Aims

A wide corpus of neurobiological evidence suggests that eating disorders share an addictive nature,
with the opioid system playing a central role in their
pathogenesis and maintenance. With this hypothesis
as starting point, we intend to:
Take into account the past and current literature
on the epidemiological and clinical correlation
between opioid use disorder and eating disorders.
Study the action displayed by opioid medications on feeding behaviours and eating disorder
symptoms.
Speculate whether opioid medications can be
used in the management of eating disorders, especially anorexia nervosa, bulimia nervosa and
binge eating disorder.


2.

Speculate whether opioid medications can be


used in the management of eating disorders.
Methods

In order to shed light on the epidemiological and


clinical correlation between opioid use disorder and
eating disorders, we carried out a thorough search
on the Scopus data base, to find papers whose title
contained the terms heroin, opioid and opiate,
matched with the terms eating, feeding, anorexia, anorexic, bulimia, bulimic, and binge
eating.
In order to recover the history of the actions displayed by opioid medications on feeding behaviours
and eating disorders symptoms, we searched for the
terms opioid, methadone, buprenorphine, buprenorphine-naloxone nalmefene and naltrexone, matched with the terms eating and feeding.
We followed up by comparing the risk-benefit
ratio of opioid medications with that of medications
traditionally used in this class of diseases.
3.

Results

3.1. Heroin addiction and eating disorder comorbidity


3.1.1. Epidemiological data

In the literature there is a low level of availability of data about comorbidity between addictive and
eating disorders. Most of the studies that have examined this comorbidity of heroin addicts have pointed
to bipolar spectrum disorders as the most frequent
form of comorbidity in such patients [98, 100], while
eating disorders have been shown to have only a marginal position.
In a population of young heroin users recruited
from outside the healthcare context, and resident in
Barcelona, Spain, psychiatric comorbidity has been
evaluated with the Psychiatric Research Interview
for Substance and Mental Disorders semi-structured
interview. Around two-thirds of the sample had
lifetime psychiatric comorbidity, with antisocial
personality and mood disorders being the most frequent conditions (33% and 26%, respectively). Eating disorders, which were, as expected, less frequent
than affective diseases, were more common among
women than men [127]. DSM-IV lifetime and current psychiatric comorbidity has also been assessed
in 404 consecutive patients with binge eating disorder
(BED), by means of semi-structured diagnostic and
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Heroin Addiction and Related Clinical Problems 16(3): 15-34

clinical interviews. Overall, 73.8% of patients with


BED had at least one additional lifetime psychiatric
disorder and 43.1% had at least one current psychiatric disorder. Lifetime-wise, mood (54.2%) and anxiety (37.1%) disorders were the most common form of
comorbidity, while substance use (24.8%) disorders
were ranked in third place, and were, as expected,
more frequent in men [53]. Interestingly, among anorexic nervosa patients, those who shared a lifetime
history of bulimia nervosa showed the highest rate of
substance use disorders [128].
3.1.2. Clinical data

In the literature there is a substantial lack of data


about the clinical features of patients suffering from
comorbid eating and substance use disorders.
3.2. Opioid antagonist in anorexia
Only a few studies have examined the therapeutic usefulness of opioid blockade in anorexia, and the
findings are disappointing. On the basis of the autoaddiction model proposed for anorexia nervosa, naltrexone has been administered to outpatient subjects suffering from various subtypes of anorexia nervosa and
bulimia nervosa, in a double-blind clinical trial with
randomized cross-over designs. Reduction in binge/
purge symptomatology was evident in the naltrexone
period over placebo for 18 out of 19 subjects with
either bulimia or anorexia nervosa of the bulimic subtype. No therapeutic response was shown by anorexic
subjects of the restricting subtype [91, 102]. Opioid
blockade has been shown to be ineffective even on
endocrinological manifestations of anorexia. A study
has tried to determine whether chronic treatment with
naltrexone can increase luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) secretion
in women with hypothalamic amenorrhea, anorexia
nervosa, and polycystic ovarian disease. A significant
increase in the LH pulse frequency was observed in
patients with hypothalamic amenorrhea and polycystic ovarian disease, but not in anorexic patients [9].
Some evidence from clinical settings even suggests
that opioid blockade could have a negative effect on
the feeding behaviours of psychiatric patients. It is
striking that, when a severe obsessive-compulsive
male patient was successfully treated with naltrexone,
symptoms resembling those of anorexic patients occurred [44].

- 22 -

3.3. Opioid antagonist in bulimia


Evidence gathered on the usefulness of opioid
blockade in bulimic patients is more comforting [76,
78]. As reported above, naltrexone has proved to be
effective in reducing the binge/purge symptomatology, not only in bulimic patients, but also in those suffering from anorexia nervosa of the bulimic subtype.
When a detailed longitudinal analysis conducted over
a 16-month period was performed on a bulimic subject from that study, it emerged that the therapeutic
response included multiple parameters such as binges, purges, urges to perform both behaviours, eating
patterns, emotional states, and Eating Disorder Inventory questionnaire scores [102]. The effectiveness of naltrexone in bulimia nervosa has also been
tested in combination with fluoxetine, which can be
considered a more conventional treatment for this
disease. Four patients matching DSM-IV criteria for
bulimia nervosa were treated in a crossover trial with
naltrexone alone, fluoxetine alone, and a fluoxetinenaltrexone combination. Three patients presented a
complete remission when treated with the fluoxetinenaltrexone combination [96]. In line with these observations, the use of naltrexone has been successfully
studied in ten individuals with antidepressant-resistant bulimia. Seven of the ten experienced at least a
75% reduction of their bulimic symptoms, and maintained their improvement throughout the three to five
month follow-up [77]. With regard to the use of naltrexone in bulimic patients, the evidence is not uniform. In a placebo-controlled, double-blind crossover
study, 16 normal-weight bulimic women were treated
in an outpatient setting with low-dose naltrexone and
placebo. The use of the active drug was not associated
with a clinically significant reduction in binge eating
or vomiting episodes [114]. It should, however, be
borne in mind that this result could be due to the low
dosages used, as may be concluded from a study of
low-dose versus high-dose naltrexone. Sixteen bulimic patients consented to a 6-week trial of naltrexone,
receiving either standard daily dosages of 50-100 mg
or high daily dosages of 200-300 mg. At the end of 6
weeks, there were no significant changes in the frequency of binge eating or purging in individuals in
the low-dose group, whereas those in the high-dose
group displayed significant reductions in both behaviours. Moreover, four individuals in the low-dose
group who crossed over to high-dose naltrexone at
the end of the study went on to experience significant
reductions in binge eating and purging. On one hand
these findings document the potential advantages of

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

opiate blockade in treating bulimia, and, on the other,


suggest that dosages of naltrexone greater than those
needed to block exogenous opiates may be required
for therapeutic efficacy in reducing binge eating and
purging [79].
3.4. Opioid antagonist in binge eating
Opioid antagonism has also proved to be of
some interest in cases of binge eating disorder, in
line with its partial clinical overlapping with bulimia
nervosa. A paper has measured the effects of a single
intracerebroventricular dose of nor-binaltorphimine,
a specific and long-lasting opioid antagonist, on
food intake, body weight, and satiety measures in an
animal model of binge eating disorder. The analysis
of individual human subjects revealed a differential
response to opioid antagonism, with some responding
and others responding poorly. These data suggest that
lessened sensitivity to opioid antagonists or increased
central dynorphin levels may contribute to the hyperphagic eating pattern observed in the obese Zucker
rat [71]. A randomized, placebo-controlled, flexible
dose, pilot study has preliminarily assessed the effectiveness of a novel opioid antagonist, ALKS-33, in 62
outpatients with binge eating disorder. No significant
differences emerged between treatment groups in
binge eating episode frequency or any other measure
of binge eating, body weight, or eating pathology, the
main conclusion being the ineffectiveness of ALKS33 on binge eating disorder, at least when administered
daily for 6 weeks [106]. Another paper has studied,
in a double-blind parallel group design, the effects of
the -opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviours in a sample of 63 binge-eating obese subjects. GSK1521498,
at two different dosages, was no different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, at the
higher dosage it caused a significant reduction in
hedonic responses to sweetened dairy products and
reduced calorific intake, particularly of high-fat foods
during ad libitum buffet meals. These findings further
support the clinical significance of -opioid receptor
blockade in binge-eating obese subjects [25, 165]. A
growing interest has recently been directed to the new
-opioid receptor antagonist nalmefene, which has
proved to decrease meal size, food and water intake
and weight gain in animal models of binge eating. In
obese male rats, nalmefene led to a fall in the size of
the first meal after a 10-hr fast and reduced general
food intake, with a long-lasting action. Administra-

tion of nalmefene daily for 7 days decreased average


meal size and daily food intake, while increasing meal
frequency. Feeding responses on day 7 were similar
to those on day 1, suggesting a lack of development
of tolerance. Food and water intake and weight gain
during a 3-week treatment period were reduced more
in lean rats by low doses of nalmefene and more in
obese rats by higher doses of nalmefene [109, 110].
The synergistic effects of nalmefene and cannabinoid
inverse agonist AM251 on food intake have been
demonstrated in mice. This pharmacological association has proved to determine a significant fall in food
intake in both lean and diet-induced obese mice; this
supports the idea of a synergistic interaction between
opioid and cannabinoid systems in regulating feeding
behaviour [27]. Nalmefene has been shown to suppress appetite in humans, but its effects on chronic
food intake and body weight are still unclear. A paper
has reported that chronic (21-day) oral administration
of nalmefene at 2 or 10 mg/kg/day in diet-induced
obese mice leads to significant increases (9-11%) in
cumulative food intake. Mice in the nalmefene-treated groups also gained body weight at a rate faster than
that of the control group. Body composition analysis
showed that the extra body weight gains in the treated
animals were mostly due to increased fat accumulation. Since acute nalmefene treatment showed a trend
towards a decrease rather than an increase in food intake, it is possible that the chronic administration of
nalmefene leads to increased food intake and body
weight gain. Pharmacologically active metabolites
rather than the drug itself might cause the orexigenic
effect of nalmefene. This result argues against the potential use of nalmefene for treating human obesity
[26].
3.5. Opioid partial agonists in eating disorders?
Opioid partial agonism has been studied in the
context of feeding behaviours, with special attention
directed to buprenorphine, which has been shown to
increase the intake of freely available and operant-contingent food in satiated rats. In particular, buprenorphine produced a significant increase in short-term
free feeding, an effect enhanced by repeated administration. In operant responding mice, buprenorphine
decreased latency, so initiating responding to food,
and increased the total number of pellets consumed
in a 1-h session. Increases in food intake relative to
controls were caused by continued responding to
food as the sessions progressed. Naloxone suppressed
both the free-feeding and operant-contingent intake
- 23 -

Heroin Addiction and Related Clinical Problems 16(3): 15-34

induced by buprenorphine [131]. In another animal


study, the effects of naloxone and three oripavine
derivatives diprenorphine, an antagonist, buprenorphine, a mixed agonist-antagonist, and etorphine,
an agonist were examined on food-reinforced responding in squirrel monkeys. A 12-min period of
unpunished responding was made to alternate with a
4-min period in which each response produced a brief
electric shock to the tail. Responding in the two components was not differentially affected by any of the
drugs. Naloxone decreased responding in both components, but only slightly at high doses. In contrast,
the three oripavines produced prominent dose-related
decreases in responding, with the following order of
potency for the non-punishment components: etorphine showed greater potency than buprenorphine,
which in its turn showed greater potency than diprenorphine. Although all three oripavines produced
comparable decreases in food-reinforced responding,
different mechanisms have been hypothesized for the
antagonists, compared with full and partial agonists
[37]. The effects of buprenorphine on feeding behaviours have also been studied in Macaque monkeys.
Low acute doses of buprenorphine (0.01 and 0.03
mg/kg) did not change the number of food pellets
earned, while the acute administration of high doses
(0.10 and 0.30 mg/kg) of buprenorphine significantly
suppressed food-maintained responding. Chronic buprenorphine self-administration (0.01-0.10 mg/kg/
injection) did not significantly suppress food intake,
even at total daily doses that were 3 to 9 times higher
than the highest dose (0.03 mg/kg) studied in the acute
pre-treatment paradigm. These data suggest that during the chronic self-administration of buprenorphine,
the acute suppressive effects on food-maintained responding are dose-dependent and subject to tolerance
phenomena [111].
In order to understand to what extent the effects
displayed by opioid agents on feeding behaviours
are affected by tolerance phenomena, some authors
have studied the changes appearing in rats in the progression of food-maintained responding over time,
following chronic buprenorphine or methadone administration. Seven lever-pressed rats were subjected
to a schedule of food presentation, with the number
of responses per reinforcer systematically increasing
during each session. Break point (the number of responses before session termination) was measured.
Both drugs initially eliminated the progression of
rats' food-maintained responding. Break points during chronic methadone administration did not return
to baseline levels after 80 drug sessions and a dose re- 24 -

duction. In contrast, break points during chronic buprenorphine administration were considerably above
baseline control levels for two rats and returned to
baseline levels for the third [92]. Rats seem to develop tolerance to the effects of buprenorphine, but
not to those of methadone, on feeding behaviours.
Other authors have investigated the effects of chronic
buprenorphine treatment on cocaine and food selfadministration by six rhesus monkeys. Cocaine selfadministration decreased significantly and remained
60 to 97% below baseline levels throughout 120 days
of buprenorphine treatment. After the substitution of
saline for buprenorphine, cocaine self-administration
resumed. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding
developed over 30 to 70 days of treatment. Food selfadministration returned to and significantly exceeded
treatment baseline levels, whereas cocaine self-administration remained significantly suppressed [112].
3.6. Opioid agonist in eating disorders?
A variety of opioid agents are known to increase
short-term food intake. Among opioid medications, a
series of studies has focused on methadone. In particular, the effect of methadone on free feeding has been
measured in satiated rats for 3 consecutive days. Two
hours after methadone administration, food intake
was inversely related to dose, but after 6 h a direct
relationship between dose and feeding was obtained.
Food intake increased with repeated methadone administration, with maximal scores occurring in the
third and fourth hours after methadone administration. These data indicate that methadone stimulates
short-term feeding in satiated rats. The apparent paradox of methadone is that the increase in food intake
is associated with a fall in food-reinforced operant
responses, both in free feeding studies and in operant
chambers [130]. Some authors have studied the effects on rhesus monkeys of chronic methadone treatment on cocaine- and food-maintained responding.
During saline treatment, cocaine maintained a dosedependent increase in the number of cocaine injections per day, and monkeys usually responded to the
maximum number of pellets. Methadone decreased
cocaine self-administration in a dose-dependent way,
with variable effects on food-maintained responding.
Methadone produced a dose-dependent, non-selective
decrease in the progression of both cocaine and food
intake. These observations provide evidence suggesting that methadone non-selectively lowers rates of

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

operant responding, both in the case of food and in


that of cocaine [118].
4. Discussion
4.1. Heroin addiction and eating disorder comorbidity
In this paper we raise the question of whether
opioid medications should be part of the pharmacotherapy of eating disorders. We have found a low
availability of epidemiological data regarding the
correlations between opiate addiction and eating disorders, and a substantial lack of data on the clinical
features of these correlations. Eating disorders seem
to occupy a marginal position among the comorbid
disorders shown by heroin addicts; on the other hand,
substance abuse disorders and eating disorders share
a high rate of comorbidity with bipolar spectrum
conditions [98, 100, 116, 123]. This convergence
strengthens the case for there being a bipolar connection between the two diseases, which would then play
the role of general diathesis to the pathologies of the
reward system.
4.2. Anorexia
The search for an effective psychopharmacological strategy in treating anorexia nervosa has been inconclusive for decades, and several medications have
been unsuccessfully evaluated, ranging from typical
and atypical antipsychotics to mood stabilizers, and
antidepressants, too. What emerges is the lack of a
standard protocol for pharmacotherapy trials in patients with bulimia nervosa and anorexia nervosa
[115].
With regard to antipsychotic medications, their
use in anorexia nervosa is only partially supported by
clinical evidence. A systematic review assessing the
effectiveness of antipsychotic medication for improving behavioural symptoms of anorexia nervosa has
included data from four randomized controlled trials,
concluding that there is insufficient evidence to either
support or refute the use of antipsychotic medication
in anorexia nervosa [32]. Another systematic review
and various meta-analyses have estimated the influence of atypical antipsychotics on body mass index,
eating disorder, and psychiatric symptoms in individuals with anorexia nervosa. Compared with placebo,
atypical antipsychotics turned out to be associated
with a less than significant increase in body mass index and a less than significant effect on the drive for

slimness and bodily dissatisfaction. The outcome of


these studies was that the medications tested led to an
increase in anxiety and overall eating disorder symptoms [88]. The use of risperidone has been tested in a
double-blind, placebo-controlled study for the treatment of adolescents and young adults with anorexia
nervosa [61], while olanzapine, in four randomized
clinical trials, has shown superiority to placebo, chlorpromazine, and aripiprazole in terms of weight gain
and reduction of obsessional symptoms [22].
With regard to antidepressant medications, a
retrospective study assessing the effects of SSRI
treatment in partially weight-restored children and
adolescents with anorexia nervosa, has revealed that,
despite evidence of an altered serotoninergic function
[23], SSRIs do not significantly influence body mass
index, core eating disorder symptoms, depression, or
obsessive-compulsive scores [62].
With regard to mood stabilizers, a double-blind
controlled trial has evaluated the effectiveness of
lithium carbonate in anorexia nervosa. In a 4-week
period, eight young women with primary anorexia
nervosa were evaluated for the effects of lithium
carbonate administration, while eight patients were
treated with placebo and served as a control group.
Group differences appeared in the areas of "denial or
minimization of illness" on the "selective appetite",
and on weight gain, especially at weeks 3 and 4 [55].
In summary, of all the medications studied for
the treatment of anorexia nervosa, only lithium carbonate has proved to be effective both on the physical and the psychic measurement scales. The use of
neuroleptics is controversial, while that of antidepressants has turned out to be fruitless.
If we look at opioid medications, on one hand
there are opioid antagonists that have been shown to
be useless in anorexic patients, as would be expected
from the low sensitivity to reward that is typical of
these patients. On the other hand there are full and
partial agonists, which seem to present interesting
properties such as that of increasing free food intake,
and decrease food-reinforced operant responding, at
least in animal models. More specifically, these effects are dose-dependent, and are liable to tolerance
phenomena only in the case of buprenorphine, while
methadone maintains its action unchanged, even in
chronic administration. Both full and partial agonists
offer the additional advantage of being known to possess all the pharmacological properties (mood-stabilizing as well as antipsychotic) that can be accredited
to the medications commonly used in treating anorexia.
- 25 -

Heroin Addiction and Related Clinical Problems 16(3): 15-34

The mood-balancing properties of opioid agents


that have emerged in clinical settings have been further documented by the long-term outcomes of heroin
dependent, treatment-resistant patients with bipolar
I comorbidity under enhanced methadone maintenance. When dual diagnosis heroin addicts have been
compared with non-dual diagnosis peers by means of
the Global Clinical Impression scale and DSM-IV
criteria, the best clinical outcomes were observed in
patients suffering from bipolar disorder [95]. The
mood-stabilizing property of opioid agents is supposed to be useful in anorexic patients, considering
the high rate of comorbidity with bipolar spectrum
disorders that has been recorded for them [116, 123].
Opioid full and partial agonists have also been
shown to possess antipsychotic properties, as suggested by the low frequency of psychotic spectrum
disorders in heroin-dependent patients, or those in
methadone treatment programmes [138]. As a matter of fact, a psychotic episode can occur, in previously psychotic patients, after rapid discontinuation
of methadone or buprenorphine [30, 89, 138, 156]. In
addition, when combined with methadone, low dosages of traditional antipsychotics are needed to control the psychotic symptoms of heroin addicts who
have been hospitalized for an acute psychotic episode
[94, 99, 122]. On the pharmacological plane, opiate
agonists are known to induce acute neuroleptic-like
effects on the endocrine system, such as hyperprolactinemia and the suppression of surrenal activity, so
suggesting an antidopaminergic activity. This property has been well documented in the case of methadone, whose administration is followed by an increase
in serum prolactin [29, 48, 151]. Similar properties
have been found for buprenorphine, in line with the
psychotomimetic properties shown by selective kagonists such as pentazocine [63, 70, 97]. As a matter
of fact, buprenorphine has been shown to be active
against hallucinations and delusions over a time-span
of four hours in a small group of heterogeneous psychotic patients [134].
In summary, opioid full and partial agonists
seem to present a promising profile of effects that
could prove to be useful in treating anorexia nervosa.
These compounds enhance food intake while displaying all the pharmacological properties presented
by the most commonly used medications, with the
advantage that they interact with the reward system
in a stabilizing rather than blocking manner. Methadone seems to be the most promising, as its actions
on feeding behaviours are not subject to tolerance
phenomena; at the same time it has more handling
- 26 -

problems and more side-effects than buprenorphine.


For these reasons we speculate that it could be used
in anorexic patients that have proved to be resistant to
buprenorphine. Conversely, buprenorphine might be
useful to patients who, while having a milder eating
disorder symptomatology, present a comorbid bipolar
disorder that would benefit from the anti-dysphoric
action of k-antagonism.
4.3. Bulimia
To date, bulimia nervosa appears to be a disease
that is easier to treat than anorexia nervosa. Several
drugs have been successfully tested, ranging from
antidepressant to mood-stabilizing medications.
With regard to antidepressant drugs, tricyclics,
monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors have been documented
to reduce bulimic symptoms [50]. A randomized,
double-blind, placebo-controlled, multicentre study
of short-term and long-term pharmacotherapy of
bulimia nervosa has identified fluvoxamine, among
serotoninergic agents, as a possible candidate for the
treatment of bulimic subjects [135]. Other authors
have focused on fluoxetine. A multicentre, doubleblind, randomized clinical trial of placebo, 20 mg of
fluoxetine, and 60 mg of fluoxetine for 8 weeks, has
assessed clinically significant attitudinal changes in
382 women suffering from bulimia nervosa. Behavioural changes were measured using self-monitored
measurement scales for binge eating and purging, and
psychological changes were measured with the selfrating Eating Disorder Inventory and the Hamilton
Rating Scale for Depression. In the short-term, the
treatment of bulimia nervosa with fluoxetine has been
shown to produce clinically significant attitudinal and
behavioural changes. These effects observed on attitudinal changes were unrelated to the presence of
depression at baseline [49, 50].
Among mood stabilizers, both lithium carbonate and anticonvulsant drugs have been tested.
With regard to anticonvulsants, lamotrigine and carbamazepine have been compared, in association with
fluoxetine, on 45 bulimic patients. Both combinations
allowed a marked, stable improvement in the patient's
state. Lamotrigine, compared with carbamazepine,
reduced the depression level and improved cognitive
functions. Moreover, lamotrigine provided a better
level of social rehabilitation, and was more effective than carbamazepine in preventing relapses [101].
With regard to lithium carbonate, an 8-week doubleblind controlled trial on 91 female bulimic outpatients

L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies

has shown that lithium is no more effective than placebo in reducing binge episodes and related psychopathology. As a limitation, lithium was administered
in a dosage that yielded relatively low plasma levels
[65, 66].
If we look at opioid medications, in the literature
there is a generic consensus on the ability of opioid
antagonists to reduce binge/purge symptomatology
and food intake, especially if used in association with
fluoxetine. The most widely studied drug is naltrexone, which has proved to significantly reduce the hedonic response to food, ultimately leading to weight
loss. With regard to the new opioid agent nalmefene,
it has been shown to decrease appetite, average meal
size and daily food intake and to increase meal frequency in animals, but its effects on body weight are
less clear in chronic administration, if compared with
naltrexone. We can speculate that the development of
tolerance to some of the effects of nalmefene could be
due to its partial agonism on k-opioid receptors. On
the other hand, the anti-dysphoric, mood-stabilizing
effects of k-partial agonism could be useful too in
treating normal weight bulimic patients, because they
have reported high rates of bipolar comorbidity, both
in the full-blown disorders and at the affective temperamental level.
In summary, opioid antagonists have been shown
to be effective in reducing bulimic symptomatology
and generic food intake, both in humans and animals.
Within this class of pharmacological agents, naltrexone and nalmefene seem to present some differences,
with the former being more effective on weight gain,
and the latter on mood instability. These opioid agents,
especially in the case of naltrexone, should be associated with serotoninergic and anticonvulsivant drugs,
the former used to counter the dysphoric effects of
naltrexone, the latter to achieve mood stabilization.
On the other hand, nalmefene should be preferred to
naltrexone in bipolar patients of normal weight, who
are likely to benefit from a double stabilization.

reuptake inhibitors have been reported to be modestly


effective in reducing binge eating over the short term
in both illnesses. Among mood stabilizers, topiramate
has consistently been shown to decrease binge eating
not only in bulimia nervosa but also in binge eating
disorder [107, 108]. Another review of double blind,
placebo-controlled pharmacological studies has suggested that antidepressant treatment might be associated with a reduction in binge frequency in obese
patients with binge eating disorder, without leading to
significant weight reduction [154]. The longer-term
effects of antidepressant medications, for the treatment of bulimia nervosa and binge eating disorder,
have also been reviewed. The use of a single antidepressant agent has resulted in the recovery of about
25% of patients entering treatment; continued treatment was accompanied by relapse in about one-third
of patients. The substitution of one or more antidepressants for the initial agent in patients who failed
to improve or could not tolerate side-effects led to the
improvement of long-term maintenance [4].
With regard to opioid medications, the compounds that have been tested for their use in bulimia
have been successfully evaluated in binge eating disorders too, with a few differences that are related to
the peculiarities of the two disorders. In binge eating
disorder one important issue is body weight, which
seems to undergo no substantial repercussions from
the antidepressant agents commonly used in these patients. For this reason we suggest that, among opioid
medications, the first choice should be naltrexone,
especially in obese patients who have no clear bipolar diathesis. Even more than in the case of bulimia,
opioid antagonists should be associated with serotoninergic compounds, which, while they have little
effect on body weight, have the advantage of counteracting the pro-dysphoric effects of naltrexone. The
most important considerations are summarized in table 1.
5.

Conclusions

4.4. Binge eating disorder


The presence of clinical and psychological overlapping between binge-eating disorder and bulimia
nervosa has prompted researchers to experiment, in
the first disorder, the agents that have to be of some
efficacy in the second one.
Randomized controlled trials on specific medications used to treat patients with bulimia nervosa
and binge eating disorder have been reviewed. With
regard to antidepressant agents, selective serotonin

Despite the low availability of clinical and epidemiological data on the correlations between eating
disorders and opiate addiction, evidence from both
human and animal studies prompt the suggestion that
opioid medications may play a significant role in the
treatment of eating disorders. The most impressive
findings so far have been those that refer to the usefulness of opioid antagonists and partial agonists in
binge eating disorder and bulimia nervosa, especially
when employed in association with standard treat- 27 -

Heroin Addiction and Related Clinical Problems 16(3): 15-34

Table 1. Most important considerations regarding the role of the opioid system in Eating Disorders
Eating disorders share an alteration in the reward system, a relatively well-defined form of brain circuitry that
plays a central role in instinctual drives, such as those involved in sexual, aggressive and feeding behaviours.
From a hierarchical point of view the opioid system is situated at the highest level of the reward system. It is
responsible for the control of pain, reward, attachment and addictive behaviours.
Opioid agents are generally classified as agonists or antagonists according to their intrinsic activity on opioid
receptors. Full agonists have maximal efficiency and produce similar effects to those of endogenous opioids.
Partial agonists have intermediate efficiency and produce sub-maximal effects, compared with those of endogenous opioids. Antagonists counteract the effects of full and partial agonists, inducing a withdrawal state in
people who are tolerant to opiates.
There is a low level of availability of data on the correlations between opiate addiction and eating disorders,
both on the epidemiological and the clinical plane. The high rate of comorbidity of both disorders with bipolar
spectrum conditions is supportive of there being a bipolar connection between the two diseases.
Opioid full and partial agonists seem to present a promising profile of effects that could be useful in the treatment of anorexia nervosa. Besides enhancing food intake, they display all the pharmacological properties
presented by the most commonly used medications.
Methadone is a synthetic full agonist of the mu-opioid receptors. It has a mean elimination half-life of 22 hours,
and its actions on feeding behaviours are not subject to tolerance phenomena. Because of poor handling and
more side-effects, we speculate that it might be used in anorexic patients that have proved to be resistant to
buprenorphine.
Buprenorphine works as a partial agonist at the mu-opioid receptors and as an antagonist on delta- and -opioid
receptors. It has a half-life of 2460 hours. We speculate that buprenorphine might be useful in anorexic patients who are resistant to standard treatments.
Opioid antagonists have been shown to reduce food intake by attenuating taste-related reward. Of these medications, naltrexone is the most effective on body weight, but is burdened by a pro-dysphoric effect, whereas nalmefene is less effective on body weight, but has the advantage of exerting a mood-balancing and anti-dysphoric
effect.
Naltrexone is an opioid receptor antagonist commonly used as an anti-reward medication. Its two most active
metabolites have half-lives of 4 hours and 13 hours, respectively. We propose using naltrexone in obese patients
suffering from binge eating disorder, especially in association with serotoninergic and anticonvulsivant drugs.
Nalmefene behaves as a moderately potent antagonist on delta-opioid receptors, as a partial agonist on -opioid
receptors, and as an antagonist on mu-opioid receptors. It has a plasma half-life of almost 11 h. We speculate
that nalmefene should be preferred to naltrexone in bulimic patients of normal weight who, because of their
bipolar comorbidity, would benefit from a double stabilization.
Opioid medications are good candidates for playing a significant role in the treatment of eating disorders. The
most impressive findings are those that refer to the usefulness of opioid antagonists and partial agonists in binge
eating disorder and bulimia nervosa, especially when employed in association with standard treatments. Further
studies are strongly encouraged to assess the possible effectiveness of opioid agonists on anorexia nervosa
symptoms.

ments. There is now an urgent need for further studies


to assess the possible effectiveness of opioid agonists
on anorexia nervosa symptoms.
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Role of the funding source
Authors states that this review was financed with internal funds. No sponsor played a role in the article elaboration and in the decision to submit the paper for publication.
Contributors
All authors revised and approved the final form of the
manuscript.
Conflict of interest
Authors declared no conflict of interest. IM served
as Board Member for Reckitt Benckiser Pharmaceuticals,
Mundipharma, D&A Pharma, and Lundbeck

Received December 15, 2013 - Accepted February 10, 2014


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Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 35-40

Comparing emotional clarity, emotion experience, and emotion regulation in


male heroin addicts with and without withdrawal syndrome
Zhao Xin1,2, Xie Lu1, Fu Li2, Zhou Renlai2, Jin Ge3,Yang Ling1, and Cai Yueyue1
1 School of Psychology, Northwest Normal University, Lanzhou 730070, China
2 Emotion Regulation Research Center, Beijing Normal University, Beijing 100875,China
3 College of Education, Lanzhou City University, Lanzhou 730070, China

Summary
Background: Emotional problems play a key role in inducing relapse among those who suffer from substance addiction. Methods: In the present study, we determine differences in emotional clarity and experience, and the regulation of
emotion in the two groups selected by us: 28 men with heroin addiction who were not experiencing physical withdrawal
symptoms (M = 39.64, SD = 4.12, range: 3250 years) and 28 men with heroin addiction who were experiencing such
symptoms (M = 40.96, SD = 4.47, range: 32-50 years). To measure these variables, we used the Positive and Negative
Affect Schedule, the identification subscale of the Toronto Alexithymia Scale, and the Emotion Regulation Questionnaire.
Results: Compared with the abstinent group, the non-abstinent group experienced increased negative emotion and made
less use of cognitive reappraisal strategies. In addition, the groups did not significantly differ in emotional clarity, positive
emotional experience, or frequency in their use of suppression strategies. Conclusions: Our study suggests that, among
heroin addicts, abstinence contributes to the release of negative emotions and the use of effective emotion regulation strategies, but that, at the same time, it failed to enhance positive emotional experiences.
Key Words: heroin addicts with physical withdrawal symptoms; heroin addicts without physical withdrawal symptoms;
abstinence; emotional clarity; emotional experience; emotion regulation

1.

Introduction

Emerging evidence suggests that emotional


processes may be involved in the development of addiction, and that emotional alterations may compromise the effectiveness of treatment approaches to substance abuse. Some studies have examined substance
abusers emotional experiences, especially with reference to natural affective stimuli that are motivationally relevant to the normal population. These results
suggest that the experience of emotions may be significantly altered in substance abusers, and that these
alterations may play an important role in the course
of drug abuse treatment and its results [1]. Even more
important is the fact that, according to the Affective
Processing Model of Negative Reinforcement, emo-

tional problems could induce drug-seeking behaviour


in drug addicts, ultimately leading to relapse [3].
In the context of emotional processes, the most
commonly studied domains include emotional clarity, that is, the ability to identify and understand ones
own emotions [4, 5], emotional experiences a domain which regards the polarity of the affective states
experienced by subjects [18] and the regulation of
emotions, which comprises the cognitive strategies
that are used to manage emotional experiences [10].
A large number of researchers are currently
investigating the emotional problems of drug-dependent individuals [1, 7, 12, 16, 17, 19], dedicating particular attention to heroin-dependent patients
[1, 17]. As partly shown by an earlier study, people
with heroin addiction share deficits in the way their

Corresponding author: Zhou Renlai, MD; Emotion Regulation Research Center, Beijing Normal University, Beijing 100875,China
E-mail: rlzhou@bun.edu.cn

35

Heroin Addiction and Related Clinical Problems 16(3): 35-40

emotions are processed, which explains why they are


weaker than non-addicted individuals in experiencing emotional stimuli [1]. Few studies, however, have
explored the influence of physical withdrawal on the
emotional experiences and the control over emotions
of heroin-dependent individuals. In order to fill this
gap, we compared the emotional states of heroinaddicted individuals with and without physical withdrawal symptoms, focusing on emotional clarity and
experience, and emotion regulation. We expected no
significant differences in emotional clarity between
the two groups. Heroin-addicted individuals with
physical withdrawal symptoms were hypothesized to
experience more negative emotions, and to possess a
lower level of cognitive resources, when compared
with heroin-addicted individuals who are free of such
symptoms.
2.

Methods

2.1. Sample
All 56 male participants were heroin addicts
coming from a drug rehabilitation centre in Gansu
Province, China. They were divided into two groups:
28 patients who reported they had experienced physical withdrawal symptoms and 28 patients who did not
report having experienced such symptoms. According
to the DSM-IV diagnostic criteria for opioid dependence, all participants had heroin dependence without
psychotic disorder or severe somatic disease. Participants in the abstinent group were in a labour camp
and had negative results on a urine test for morphine.
Those in the non-abstinent group were undergoing
heroin withdrawal. Age did not significantly differ
between the abstinent group (M = 40.96, SD = 4.47,
range = 32-50 years) and the non-abstinent group (M
= 39.64, SD = 4.12, range = 32-50 years), F(1,55) =
1.324, p=ns.
2.2. Instruments
2.2.1 Opiate Withdrawal

Opiate withdrawal symptoms in the two groups


were measured by means of the Opiate Withdrawal
Scale (OWS) [6]. This scale was developed by Bradley et al. in 1987 to assess the severity of opiate withdrawal symptomatology; it contains 32 items that
represent various different symptoms. Each symptom
is graded according to severity as follows: 0 = absent,
1= mild, with no need for treatment, 2 = moderate
and requiring treatment, and 3 = severe and requiring
- 36 -

treatment [6].
2.2.2 Emotional Clarity

Emotional clarity was measured by applying the


Identification Subscale from the Toronto Alexithymia
Scale (TAS) [2], which is frequently used to measure
individual differences in the ability to identify ones
emotional states. The Identification Subscale comprises seven items. Participants respond on a 5-point
Likert scale (1 = strongly disagree; 5 = strongly
agree). Scale scores are computed by calculating
the mean of all scale items and scored in such a way
that lower scores represent higher levels of emotional
clarity [4, 5]. Its reliability was good in the present
sample (Cronbachs alpha = .89)
2.2.3 Emotional Experience

Emotional experience was assessed with the


Positive and Negative Affect Schedule (PANAS), a
20-item self-report capable of measuring positive and
negative affect. Positive affect (PA) reflects the level
of positive affective states experienced by a given person. Negative affect (NA) reflects the degree to which
a person feels negative affective states. Responses are
assessed on a scale ranging from 1 (very slightly or
not at all) to 5 (very much) [18]. Cronbachs alpha
was satisfactorily high for the PA (.87) and NA (.80)
schedules.
2.2.4 Regulation of the Emotions

The Emotion Regulation Questionnaire (ERQ)


was employed to assess the use of emotion regulation
strategies. It measures the frequency of use of two
types of strategies: reappraisal (6 items) and suppression (4 items). Cognitive reappraisal is an effective
strategy for regulating emotions; it serves to reduce
an individuals negative emotion experiences. Cognitive suppression is the process of deliberately trying
to stop thinking certain thoughts. Participants respond
to items using a 7-point Likert scale (1 = strongly
disagree; 7 = strongly agree). Cronbachs alpha
was satisfactory for reappraisal (.75). It was only .53
for suppression frequency; the results related to suppression frequency should therefore be interpreted
with caution [10].
2.3. Data analysis
Data were examined using one-way analyses of
variance. The p values were Bonferroni-adjusted.

Z. Xin et al.: Comparing emotional clarity, emotion experience, and emotion regulation in male heroin addicts with and without withdrawal
syndrome

3.

Results

those of the abstinent group (M = 2.52, SD = 0.65),


F(1,55) = 4.41, p < .05, 2 =.08.

3.1 Socio-demographic Data


3.5 Regulation of the Emotions
Regarding educational level, in the abstinent
group 3 individuals graduated from primary school
(10.71%), 14 from middle school (50.00%), 10 from
high school (35.71%), and 1 from university (3.57%).
In the non-abstinent group, 10 graduated from primary school (37.04%), 13 from middle school (48.15%),
4 from high school (14.81%), and 1 individual failed
to provide any information on education (3.57%).
The two groups did not show significant differences
in educational level, 2(3) = 7.362, p=ns. In terms
of ethnicity, 27 participants (96%) in the abstinent
group were of Han ethnicity, and 1 (4%) was of Hui
ethnicity; in the non-abstinent group, 24 (86%) were
of Han ethnicity, and 4 (14%) of Hui ethnicity. As to
marital status, in the abstinent group 7 (25%) were
unmarried, 1 (3.6%) was cohabiting but unmarried,
13 (46.40%) were married, and 7 (25%) had divorced.
In the non-abstinent group, 2 (7.1%) were unmarried,
1 (3.6%) was cohabiting but unmarried, 12 (42.9%)
were married, 8 (28.6%) had divorced, and 5 (17.9%)
did not report their marital status.
3.2 Opiate Withdrawal
As expected, the scores of the non-abstinent
group (M = 48.96, SD = 17.95) on the Opiate Withdrawal Scale were significantly higher than those of
the abstinent group (M = 38.07, SD = 14.41), F(1,55)
= 6.271, p < .05, 2 = 0.104. The scale showed good
reliability in the present sample (Cronbachs alpha =
.96).
3.3 Emotional Clarity
There was no significant difference in emotional clarity between the abstinent group (M = 3.13,
SD = 0.54) and the non-abstinent group (M = 2.89,
SD=0.67), F(1,55) = .309, ns.
3.4 Emotional Experience
As shown in figure 1, there was no significant
difference in positive emotional experience between
the abstinent group (M = 2.26, SD = 0.64) and the
non-abstinent group (M = 2.20, SD = 0.72), F(1,55) =
.124, ns. However, in the assessment of negative emotional experience, scores of the non-abstinent group
(M = 2.89, SD = 0.67) were significantly higher than

As shown in figure 2, the use of suppression did


not differ significantly between the abstinent group
(M = 4.31, SD = 0.66) and non-abstinent group (M
= 4.33, SD = 0.88), F(1,55) = .007, p=ns. However,
cognitive reappraisal was used more frequently in
the abstinent group (M = 4.67, SD = 0.72) than the
non-abstinent group (M = 4.18, SD = 0.76), F(1,55) =
6.095, p < .05, 2 = .10.
4.

Discussion

We compared the emotional clarity and experience, and the emotion regulation of heroin-addicted
individuals with and without physical withdrawal
symptoms.
With regard to emotional clarity, our study demonstrated that there was no prominent difference between the two groups. Emotional clarity is the ability
to identify and understand ones emotional experiences, and is related to emotional intelligence and emotion regulation [4, 5]. It is plausible that emotional
intelligence acts as a stable individual quality that
is not affected by the presence of withdrawal symptoms. The absence of between-group differences in
emotional clarity indicates that it cannot account for
the differences in emotional experience and the regulation of emotion between the two groups.
With regard to emotional experience, our results offer substantial evidence that heroin-addicted
individuals with physical withdrawal symptoms experience stronger negative emotion than those without such symptoms, in line with our hypothesis. We
propose that the lower level of negative emotional
experience in the abstinent group was mainly caused
by the gradual reduction in physical symptoms. Further evidence in favor of this proposal comes from the
significant correlation between scores on the Opiate
Withdrawal Scale (OWS) and those on the negative
affect subscale of the PANAS, r = 0.41, p = 0.002.
Positive emotional experience did not noticeably differ between the two groups. Although no physical
symptoms were recorded in individuals who experienced physical withdrawal, they still appear to need
social attention and support to experience more positive emotions.
Moving on now to the regulation of the emotions, we found that heroin-addicted individuals
- 37 -

Heroin Addiction and Related Clinical Problems 16(3): 35-40

Figure 1. Scores on the Positive and Negative Affect Schedule of the group with physical withdrawal (PW) and the
group without physical withdrawal (NPW) (PW: physical withdrawal symptomatology, NPW: non-physical-withdrawal symptomatology)

Figure 2, Scores on the Emotion Regulation Questionnaire (frequency of using two types of emotion regulation: reappraisal and suppression) of the two groups (PW: physical-withdrawal symptomatology, NPW: non physical-withdrawal
symptomatology)

- 38 -

Z. Xin et al.: Comparing emotional clarity, emotion experience, and emotion regulation in male heroin addicts with and without withdrawal
syndrome

without physical withdrawal symptoms use cognitive


appraisal to a greater extent than those with physical
withdrawal, which is consistent with our hypothesis.
Cognitive appraisal is an antecedent-focused strategy employed in the early stages of emotion [11];
it changes an individuals understanding of emotional events in a way that reduces emotional reactivity [10, 11, 15]. We suggest that, compared with
the physical-withdrawal participants, who are affected by physical symptoms, participants in the abstinent group were more prone to experiencing severe
anxiety and depression. Under the influence of such
emotions, individuals would focus more on their obsessive thoughts, concerns, and negative cognitions,
which could occupy and consume limited cognitive
resources, ultimately leading to the use of appraisal
[8, 9, 14]. Although we also found a slight difference
in the use of suppression, the low reliability of the
suppression scale indicates that this result should be
interpreted with caution.
Limitations
There are several limitations that affect our study.
First, the small sample limits the extent to which our
findings can be generalized. To extend the validity of
our results, future studies should use a larger sample. Second, future studies could use a longitudinal
design with follow-ups instead of a between-group
design to identify long-term changes in emotional experience, regulation and clarity by assessing the same
group of participants before and after they experience
physical withdrawal. Lastly, all the participants in our
study were male, while it should be borne in mind
that previous researchers found gender differences in
emotional experience and regulation [13]. This raises
a number of questions about the differences in emotional experience and the regulation of emotions between heroin-addicted women who have experienced
physical withdrawal and those who have not.
5.

Conclusions

This study emphasizes the influence of heroin


withdrawal on the individuals emotional experience.
Heroin-addicted individuals without physical withdrawal symptoms tend to experience more negative
emotions, and to make less use of cognitive resources, than heroin-addicted individuals with such symptoms.

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13. Mcrae K., Ochsner K. N., Mauss I. B., Gabrieli J. J.
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Group Processes Intergroup Relations. 11(2): 143-162.


14. Miller H., Bichsel J. (2004): Anxiety, working memory,
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predicts substance dependence problems. Drug Alcohol
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17. Wang Z. X., Zhang J. X., Wu Q. L., Liu N., Hu X. P., Chan
R. C., Xiao Z. W. (2010): Alterations in the processing
of non-drug-related affective stimuli in abstinent heroin
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18. Watson D., Clark L. A., Tellegen A. (1988): Development
and validation of brief measures of positive and negative
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Role of the funding source


This work was supported by The National Natural
Science Foundation of China (31300838, 31360233), The
Young Teacher Research Capacity Advancement Program
of Northwest Normal University (SKQNYB12009) and
Open Research Fund of the Beijing Key Lab of Applied.
Contributors
Zhao Xin, Zhou Renlai and Jin Ge designed research;
Zhao Xin, Jin Ge, Cai Yueyue and Yang Ling analyzed
data; Zhao Xin and Fu Li wrote the paper. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.

Received November 3, 2013 - Accepted January 26, 2014


- 40 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 41-48

Why do heroin users refuse to participate in a heroin-assisted treatment trial?


Isabelle Demaret 2, Graldine Litran 2, Ccile Magoga 2, Clmence Deblire 2, Anice Dupont 2,
Jrme De Roubaix 1,2, Andr Lematre 1, and Marc Ansseau 2
1. Institute for Human and Social Sciences (Criminology), University of Lige, Belgium, EU
2. Department of Psychiatry, University of Lige, Belgium, EU

Summary
Background: Heroin-assisted treatment (HAT) can improve the condition of heroin addicts who are resistant to other
treatments. However, in a new HAT trial in Belgium, fewer subjects than expected were included. Aim: Our research team
explored the reasons given by heroin users in explaining why they did not want to participate. Methods: In 2011, during
the trial recruitment, we interviewed heroin users (n=52) who never took the opportunity to meet the research team during the recruitment process preceding the trial. Results: Of those 52 heroin users, 25 were afraid of the limited length of
the HAT and 11 feared becoming more dependent as a result of HAT. Conclusion: A trial that was planned to last for a
limited length of time may have demotivated heroin users who could otherwise have benefited from this new programme.
Key Words: Heroin; treatment; motivation; addiction

1.

Introduction

Methadone is the most strongly recommended


treatment for heroin addiction [1, 12]. However, a
considerable percentage of severely affected heroin
addicts still use street heroin frequently, in spite of
being in a methadone treatment. These heroin addicts
who are considered to be treatment-resistant display
numerous physical and mental health problems, social difficulties and criminal involvement [19].
Heroin-assisted treatment (HAT) is one of the
options available for improving the condition of these
treatment-resistant heroin addicts. In this second-line
programme, a physician prescribes diacetylmorphine
(DAM) to severely affected heroin addicts. Patients
administer DAM themselves under the supervision of

nurses, in a specific centre, as frequently as twice or


three times a day.
Since 1994, six randomized controlled trials
have been conducted using this supervised treatment
model: in Switzerland [17], in the Netherlands [19],
in Spain [10], in Germany [7], in Canada [15] and in
the United Kingdom [18]. In each trial, the research
team concluded that HAT showed greater efficacy in
the treatment of severely affected heroin addicts than
oral methadone maintenance. A Cochrane review [5]
confirmed that HAT could improve the condition of
this special target group: treatment-resistant, severely
addicted heroin users.
However, in each of these trials, fewer subjects
than expected were included, and each trial reported
between 14% and 45% of heroin users who went no

Corresponding author: Isabelle Demaret, Institute for Human and Social Sciences, Boulevard du Rectorat 3 (B31), 4000 Lige,
BELGIUM, EU
Telephone: 00.32.4.366.31.58; Fax: 00.32.4.366.98.08; E-mail:isabelle.demaret@ulg.ac.be

41

Heroin Addiction and Related Clinical Problems 16(3): 41-48

further in the inclusion process after at least one contact [2, 6, 9, 10, 14, 15, 17, 18]. The trial reports did
not include any information to explain why these users left the process.
The same phenomenon happened in Belgium,
during the recruitment process preceding a HAT trial.
Methadone centres, which had the responsibility of
referring participants to the trial, informed the research team that some heroin addicts did not seem
interested in the trial, despite their continuous use
of street heroin while in methadone treatment. With
the aim of exploring their attitude towards the trial,
we interviewed heroin addicts who had never taken
the opportunity to attend a meeting with the research
team. We encountered them in specialized addiction
centres and in the street. We hope that this study will
help health care workers and policy makers to understand why HAT programmes are not as attractive as
had originally been expected to severely ill heroin addicts.
2.

Methods

2.1. Trial
TADAM (Treatment Assisted by Diacetylmorphine) is an open label, randomized, controlled trial,
which began in Lige (Belgium) in January 2011 and
ended in January 2013. Results will not be published
before 2014. The expectation was for 200 subjects to
be recruited in 12 months, a hundred subjects for each
of the two groups. The experimental group received a
HAT for 12 months in a new setting, and the control
group received methadone maintenance treatment
in existing addiction centres (official partners of the
trial). Subjects had to come to the new HAT centre up
to three times a day. They could choose to inject or inhale diacetylmorphine, as in the Dutch trial [2, 4, 19].
After 12 months, HAT was definitively stopped, and
the best alternative treatment available was offered
to the participants. This limited time for the diacetylmorphine programme was decided by the Federal
government for legal and political reasons. The Ethics Committee of the Faculty of Medicine (University
of Lige) approved this trial in 2010. The TADAM
centre, located in the middle of the city of Lige, was
easily accessible by foot or public transport. In order
to forestall potential opposition from neighbours, the
City installed the centre next to a police station.

2.2. Inclusion criteria


The inclusion criteria were intended to recruit
subjects with severe heroin addiction that had resisted
previous treatment. This was demonstrated by a heroin dependency of at least 5 years, a daily or almost
daily use of illicit heroin, and at least one previous
experience of methadone treatment (with a minimum
daily dose of 60 mg). We considered that these criteria showed a heroin addiction that resisted other treatments, even if we did not have data detailed enough
to allow us to assess whether the previous methadone
treatment was adequate or not. However, other HAT
trials [7, 15, 18] showed that, even with an optimized
and controlled methadone treatment, HAT was more
effective than methadone for participants who met our
inclusion criteria. Another requirement was for participants to have been legal residents of the judicial
district of Lige for at least 12 months. Each participant signed an informed consent form. The only official documents necessary for the first meeting with
researchers were a legal identification document and
a legal document with a history of domicile, directly
available from the municipal offices.
2.3. Partner centres
The TADAM trial worked with nine partner centres that were responsible for the first step of the recruitment process. Each heroin user interested in the
project had to be registered in one of these centres
before coming to the research team for evaluation.
Heroin users were free to choose a centre, and partner
centres were free to refer or not to refer a heroin user
to the research team.
2.4. Inclusion process
The partner centres referred 116 heroin users
who wanted to participate in the trial. Thirty-three users (28%) did not show up to meet the research team.
Nine potential participants (8%) were excluded from
the trial because they did not meet the inclusion criteria. As shown by their baseline characteristics, the
HUI (Table 1) were severe heroin users (they had
used street heroin for an average of 20 years) who
were resistant to existing treatments (they had experienced an average of nine previous treatments).
2.5. Opinions of heroin users who were not included
In order to understand the opinions of other

- 42 -

I. Demaret et al.: Why do heroin users refuse to participate in a heroin-assisted treatment trial?

Table 1: Baseline characteristics of the heroin users included (HUI)


Sociodemographic characteristicsa

n = 74
43 [7]
65 (88%)
2 (3%)
21 (28%)
69 (93%)
56 (76%)
37 (50%)

20 [7]
27 [5]
14 [7]
21 (28%)
34 (46%)
31 (42%)
60 (81%)
21 (28%)
9 [13]

Age years
Male sex
Employed (last month)
No stable housing last month
Ever convicted
Ever incarcerated
Illegal activities last month
Drug use
Regular heroin use years
Heroin last month days
Regular methadone use years
Alcohol last month (+ 5 glasses per day)
Cocaine last month
Benzodiazepines last month
Ever injected
Injection past month
Number of previous drug treatments
a

Data are number of heroin users (%) or mean [s.d.]

heroin users about the trial, we interviewed users


who had not met the research team during the recruitment process. To simplify the issue, they are called
"HUNI, an acronym standing for "heroin users not
included in the study". Our inclusion criteria for this
group were a current or recent history of street heroin
use, and the fact of having failed to meet the research
team during the recruitment process for the TADAM
trial. We encountered them on the street, in places
known for drug dealing (helped by a social worker
familiar with heroin users in the city), in two specialized addiction centres (partners in the project) and
in one harm reduction service for drug users (managed by another partner centre). The three services
were considered low threshold, as they accepted all
active heroin or cocaine users without requiring the
user to stop or reduce drug use. In order to collect the
spontaneous answers of heroin users, we arranged no
appointments; the subjects were interviewed directly
by us when first encountered. After posing questions
about sociodemographic and substance abuse characteristics, the researcher asked if the user was aware of
the TADAM trial, how he (or she) knew about it, if
he/she was interested in participating and why. With
the approval of the subject, we tape-recorded each
interview. The interviews were transcribed verbatim
with the protection of anonymity. We used NVivo 9
to analyse and sort the opinions expressed in the interviews.

2.6. Sample description: users not included


The research team interviewed 52 HUNI between July 11, 2011 and January 17, 2012. Two researchers interviewed the same heroin user, and their
separate interviews were then merged. The 52 HUNI
had never been assessed by the research team for the
TADAM trial and, therefore, had not been excluded
from the trial recruitment process. 22 interviewees
had taken part in a meeting in addiction centres, 18 in
a low threshold service and 12 on the street. 48 of the
HUNI (92%) were male. The mean age was 40 years;
and 30 (58%) had an unstable housing situation (Table 2). According to our interviews, 35% would not
have met the (almost) daily heroin use criterion set
for the trial.
3.

Results

3.1. Knowledge of the trial


One HUNI had not heard about the project. The
others (n=51) knew of it through the addiction field
(n=34), or through other heroin users (n=24), other
unspecified informants (n=17), the media (n=9) or the
police (n=2). The main source of information, the addiction field, included social workers, physicians and
street workers, but also folders and posters distributed
by the research team.

- 43 -

Heroin Addiction and Related Clinical Problems 16(3): 41-48

Table 2: Characteristics of the heroin users not includeda (HUNI)


n=52
Sociodemographic characteristics
- Male
- Mean age
- No stable housing

48 (92%)
40 [7]*
30 (58%)
Drug use

- Age at first heroin use - years


- Started heroin use at least 5 years ago
Current heroin use
- 2 times or more per week
- 1 time per week or less
- no heroin use
- no information
Usual route of administration
- by inhalation
- by injection
- no preference
- no information

19 [4]**
52 (100%)
25 (48%)
12 (23%)
6 (12%)
9 (17%)
33 (63%)
7 (13%)
3 (6%)
9 (17%)

Data given refer to the number of heroin users (%) or a mean value [s.d.]
* n=51 ** n=50
a

3.2. Desire to participate in the HAT trial


Of the 51 HUNI who were aware of the project,
40 were not interested in participating, 7 were interested, 3 did not answer clearly and 1 refused to answer. Of the 48 who explained their attitude towards
the project, 47 gave one or more reasons for their decision against participation, and 18 gave one or more
reasons for participating. 17 users gave reasons both
pro and con.
3.3. Why heroin users did not want to enter the TADAM
trial
A majority of HUNI (n=31) did not want to enrol in the project because of the trial conditions (Table
3), particularly the limit of the duration of HAT to one
year (n=25). 28 HUNI did not want to enter a HAT
because of the diacetylmorphine itself, mainly because they wanted to decrease their street heroin use
(n=14) or because they were afraid of exacerbating
their addiction by having a perpetually available supply of pure heroin (n=11). For 16 HUNI, HAT conditions (not linked to the trial) explained their refusal to
participate in the project. Their answers demonstrated that some of them had been accurately informed
about the specificity of HAT (Table 3). For 5 HUNI,
the proximity of the police station was a reason for
not participating. 3 HUNI were not against participation, but wanted more information about the project.

- 44 -

Another HUNI explained that he could not begin a


treatment because of his jail sentence.
Of the 40 HUNI who refused to participate, 18
were frequent heroin users (at least a few times a
week) and 17 of those frequent heroin users cited a
trial condition as a reason for not participating (data
not included in tables).
4.

Discussion

In the course of this study, we analysed the reasons given by heroin users for not participating in the
TADAM trial. 40 HUNI refused to enter the project.
Of these, 18 were frequent heroin users (belonging
to the target group of TADAM). The trial conditions
were the main reasons given for having refused to
enter the trial. More than half of the HUNI did not
want to participate because they were afraid for their
future: 25 were afraid to resume their street heroin
use after the 12-month treatment, 11 feared becoming
more addicted, and 30 gave one or both arguments.
These heroin users were conscious of their addiction
and afraid of aggravating it.
Refusal of the project by many potential participants because of the limited length of HAT can
be seen as a sign of their insight into their severe addiction: as they explained in many cases, they were
afraid of returning to their street heroin use if DAM
was scheduled to be stopped after 12 months. Moreover, 23 of the 25 HUNI who were afraid of the limited

I. Demaret et al.: Why do heroin users refuse to participate in a heroin-assisted treatment trial?

Table 3: Reasons for not participating


Users (%)
n=51
47 (92%)
31 (61%)
25 (49%)
7 (14%)
7 (14%)
2 (4%)
28 (55%)
14 (27%)
11 (22%)
8 (16%)
1 (2%)
16 (31%)
5 (10%)
5 (10%)
4 (8%)
3 (6%)
2 (4%)
2 (4%)
1 (2%)
1 (2%)

At least one reason against participating


Reasons linked to the trial conditions
- heroin-assisted treatment limited to 12 months
- randomizing
- problems with other trial conditions (formalities or inclusion criteria)
- being used as a guinea-pig
Reasons linked to diacetylmorphine
- want to decrease or stop heroin use
- afraid to become more addicted
- prefer methadone or buprenorphine
- do not like diacetylmorphine
Reason linked to diacetylmorphine treatment conditions
- diacetylmorphine centre is next to a police station
- being with drug addicts
- going every day
- being able to use diacetylmorphine only in the centre
- no smoking of cigarettes while inhaling
- not enough time to smoke heroin
- too much control
- using heroin in front of other people
Other reasons
- need more information
- will soon be in prison

length of HAT had been addicted for 10 years or more,


and 19 had experienced a methadone treatment. This
is consistent with the observation that insight into the
illness is high in heroin addicts who have a long history of severe heroin addiction [11].
It should be added that, even with an open-ended
duration of treatment, HAT would not attract every severely ill heroin addict. As shown by our interviews,
some heroin users seemed to have been repelled by
the process of undergoing HAT and probably by the
hetero-administrative aspects of this programme:
consuming in front of others, being controlled, no
take-away, going every day. Refusal of the trial for

3 (6%)
1 (2%)

these reasons could be seen as a refusal to enter a


HAT programme and as a serious outcome that was
due to heroin addiction.
The six other trials had been planned to include
a higher number of heroin users than the number
actually participating (Table 4), even though the recruitment period lasted more than 12 months in The
Netherlands [19], in Germany [7], in Canada [16]
and in the United Kingdom [18]. Between 14% and
45% of the heroin users who had at least one contact with a trial team refused to continue or did not
return. In publishing their results, the authors of the
studies did not explain why heroin users had stepped

Table 4: Trials recruited between 26% and 91% of the expected number of participants
CH
Subjects initially planned
Heroin users with at least one contact with the
recruitment team
Heroin users included
Ratio included/planned
Ratio included/with at least one contact

80

NL
625

73
51
64%
70%

SP
240

GE
1120

CA
470

UK
150

BE
200

1500

176

2083

581

301

116

549
88%
37%

62
26%
35%

1015
91%
49%

251
53%
43%

127
85%
42%

74
37%
64%

- 45 -

Heroin Addiction and Related Clinical Problems 16(3): 41-48

back from the recruitment process. One study showed


that willingness to participate in a HAT trial was associated with daily heroin use and current methadone
treatment, but failed to explain why 38% of the users
contacted refused to participate in a HAT programme
[13].
Limitations
52 heroin users is too low a number to adequately represent the hundreds of heroin users in the city
[3]; neither were they representative of the trial target
group, as 18 (35%) were not frequent street heroin
users. However, 52 interviews should make up a sufficently large sample to collect the main reasons given
by heroin users for or against entering our trial. We
recorded the interviews as a way to document each
reason that was given. So, even if our 52 users did not
represent the target group of the trial, the arguments
collected in our 52 interviews could still reflect the
main lines of argument circulating in this group. We
must remember that the reasons that were expressed
for and against acceptance were given by severely affected heroin addicts for whom (by definition) heroin
use was a central motivation.
5.

Conclusions

The HUNI were severely affected heroin addicts


and their reasons for refusing to participate were not
uniform. The explanation for the lack of interest of
heroin users was related to their attitude towards the
trial, HAT conditions or DAM itself. But the main
reason given was the limited length of HAT duration.
Heroin users were far more circumspect about a HAT
trial than expected. Their concern about the limited
duration of HAT and the related fear of resuming
heroin use after 12 months can attest a high degree of
insight into their illness.
Fixing an arbitrary time limit for HAT, even in
the framework of a pilot project, may have contributed to discouraging severe ill heroin addicts from
participating in a programme that has demonstrated
its efficacy [5] for this chronic relapsing disease [8].
A year of recruitment may also have been too short
a time for people to take the time they needed to observe the new programme and its outcome, to discuss
it with medical or social workers, think about it and
only then make up their minds. Even if there would
still have been a group of severely affected heroin
users who refused to enter in this programme, HAT
without a predetermined duration would have attract- 46 -

ed more heroin users especially those possessing a


high level of insight into their illness.
References
1. Amato L., Davoli M., Perucci C. A., Ferri M., Faggiano
F., Mattick R. P. (2005): An overview of systematic
reviews of the effectiveness of opiate maintenance
therapies: available evidence to inform clinical practice
and research. J Subst Abuse Treat. 28(4): 321-329.
2. Central Committee on the Treatment of Heroin Addicts
(2002). Medical co-prescription of heroin: Two
randomized controlled trials: Utrecht, the Netherlands.
p 180
3. Demaret I., Hern P., Lematre A., Ansseau M. (2011):
Feasibility assessment of heroin-assisted treatment in
Lige, Belgium. Acta Psychiatrica Belgica. 111(1): 3-8.
4. Demaret I., Lemaitre A., Ansseau M. (2012): Staff
concerns in heroin-assisted treatment centres. J Psychiatr
Ment Health Nurs. 19(6): 563-567.
5. Ferri M., Davoli M., Perucci C. A. (2011): Heroin
maintenance for chronic heroin-dependent individuals.
Cochrane Database Syst Rev(12): CD003410.
6. Gartry C. C., Oviedo-Joekes E., Laliberte N., Schechter
M. T. (2009): NAOMI: The trials and tribulations of
implementing a heroin assisted treatment study in North
America. Harm Reduct J. 6: 2.
7. Haasen C., Verthein U., Degkwitz P., Berger J., Krausz
M., Naber D. (2007): Heroin-assisted treatment for
opioid dependence: randomised controlled trial. Br J
Psychiatry. 191: 55-62.
8. Leshner A. I. (1997): Addiction is a brain disease, and
it matters. Science. 278(5335): 45-47.
9. Lintzeris N., Strang J., Metrebian N., Byford S., Hallam
C., Lee S., Zador D. (2006): Methodology for the
Randomised Injecting Opioid Treatment Trial (RIOTT):
evaluating injectable methadone and injectable heroin
treatment versus optimised oral methadone treatment
in the UK. Harm Reduct J. 3: 28.
10. March J. C., Oviedo-Joekes E., Perea-Milla E., Carrasco
F. (2006): Controlled trial of prescribed heroin in the
treatment of opioid addiction. J Subst Abuse Treat. 31(2):
203-211.
11. Maremmani A. G. I., Rovai L., Rugani F., Pacini M.,
Lamanna F., Bacciardi S., Perugi G., Deltito J., Dellosso
L., Maremmani I. (2012): Correlations between
awareness of illness (insight) and history of addiction
in heroin-addicted patients. Front Psychiatry. 3.
12. Mattick R. P., Kimber J., Breen C., Davoli M.
(2008): Buprenorphine maintenance versus placebo
or methadone maintenance for opioid dependence.
Cochrane Database Syst Rev (2): CD002207.
13. Miller C. L., Strathdee S. A., Kerr T., Small W., Li K.,
Wood E. (2005): Factors associated with willingness
to participate in a heroin prescription program among
injection drug users. J Opioid Manag. 1(4): 201-203.
14. Naber D., Haasen C. (2006). The German model project

I. Demaret et al.: Why do heroin users refuse to participate in a heroin-assisted treatment trial?

for heroin assisted treatment of opioid dependend


patients: A multi-centre, randomised, controlled
treatment study.: Hambourg, Germany. p 167
15. Oviedo-Joekes E., Brissette S., Marsh D. C.,
Lauzon P., Guh D., Anis A., Schechter M. T. (2009):
Diacetylmorphine versus methadone for the treatment
of opioid addiction. N Engl J Med. 361(8): 777-786.
16. Oviedo-Joekes E., Nosyk B., Brissette S., Chettiar J.,
Schneeberger P., Marsh D. C., Krausz M., Anis A.,
Schechter M. T. (2008): The North American Opiate
Medication Initiative (NAOMI): profile of participants in
North Americas first trial of heroin-assisted treatment.
J Urban Health. 85(6): 812-825.
17. Perneger T. V., Giner F., Del Rio M., Mino A. (1998):
Randomised trial of heroin maintenance programme for
addicts who fail in conventional drug treatments. BMJ.
317(7150): 13-18.
18. Strang J., Metrebian N., Lintzeris N., Potts L., Carnwath
T., Mayet S., Williams H., Zador D., Evers R., Groshkova
T., Charles V., Martin A., Forzisi L. (2010): Supervised
injectable heroin or injectable methadone versus
optimised oral methadone as treatment for chronic
heroin addicts in England after persistent failure in
orthodox treatment (RIOTT): a randomised trial. Lancet.
375(9729): 1885-1895.
19. Van Den Brink W., Hendriks V. M., Blanken P., Koeter
M. W., Van Zwieten B. J., Van Ree J. M. (2003):
Medical prescription of heroin to treatment resistant

heroin addicts: two randomised controlled trials. BMJ.


327(7410): 310.
Acknowledgement
We thank the heroin users and staffs who kindly received us in their addiction centres where we were able to
interview their patients. We also thank the Drug Cell of the
Federal Public Service of Health, Food Chain Safety and
Environment who was in charge of the administrative follow up of the TADAM assessment.
Role of the funding source
Besides authors' contribution, the funding sources
(Federal Minister of Social Affairs and Public Health, the
University of Lige and the City of Liege) were not involved in the collection, analysis and interpretation of data
and in the writing of the report.
Contributors
Isabelle Demaret, Graldine Litran, Ccile Magoga,
Clmence Deblire, Anice Dupont and Jrme De Roubaix
contributed to the collection and analysis of the data. Isabelle Demaret, Andr Lematre and Marc Ansseau contributed to the interpretation of the data and redaction of this
manuscript.
Conflict of interest
The authors report no conflicts of interest. This study
and the writing of this paper were funded by the Federal
Minister of Social Affairs and Public Health, by the University of Lige and the City of Liege.

Received October 19, 2013 - Accepted February 15, 2014


- 47 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 49-54

Sexual dysfunction in male patients receiving methadone and buprenorphine


maintenance treatment in Iran
Shadan Tafreshian, Meisam Javadi, Fariba Fakhraei, and Seyedeh Seddigheh Fatemi
Methadone Clinic, Mashhad University of Medical Sciences, Mashhad, Iran

Summary
Background: methadone and buprenorphine are the major modalities of substitution treatment for opioid dependence in
Iran. There are still only limited data on alterations in sexual function during methadone or buprenorphine maintenance
therapy (MMT, BMT) and the impact of sexual dysfunctions on patients' life and treatment. Aims: to evaluate whether the
incidence of sexual dysfunctions differs in samples of men in maintenance treatment with methadone or those with buprenorphine; evaluate correlations between sexual dysfunction and substitution treatment of opioid dependence. Methods:
158 opioid-dependent men were recruited from two methadone maintenance clinics in Mashad, Iran, between December
2011 and April 2013. Data were collected by organizing interviews and questionnaires. Sexual function has been investigated with IIEF, an extensively validated questionnaire covering five domains of male sexual function. Results: methadone has stronger effects on sexual dysfunction than buprenorphine. In both groups, erectile dysfunction seems to be the
main form of sexual dysfunction. Methadone dose and the duration of therapy showed a correlation with sexual dysfunction: (p=0.011) and (p=0.012), respectively. On the other hand, no valuable statistical correlations were found between
duration of opioid use and sexual complaints in our patients. Conclusions: the frequency of sexual dysfunction in people
treated with methadone is higher than in the BMT group. Sexual dysfunctions lowered the quality of patients sexual life
and damaged their most intimate relationships. This problem may increase the risk of treatment failure and illicit drug
abuse. Thus, physicians should screen sexual dysfunctions in men receiving opioid treatment and carefully assess the issue of the medication of choice. Erectile and orgasmic dysfunctions may respond to methadone dose reduction. Further
studies are needed to evaluate the benefits of methadone dose reduction in patients receiving treatment.
Key Words: Methadone; Buprenorphine; Methadone Maintenance Therapy (MMT); Buprenorphine Maintenance
Therapy (BMT); Sexual Dysfunction; Erectile Dysfunction

1.

Introduction

In Iran, as in many other countries, methadone


and buprenorphine are currently the most commonly
used, most effective medications for the treatment
of opioid dependence. A number of publications describe hypoactive sexual desire, erectile and orgasmic
dysfunction with opioid use [9]. Sexual dysfunctions,
including decline in libido, erectile and orgasm dysfunctions (delayed orgasm, or inability to achieve
orgasm), have been reported as an adverse effect of
methadone and buprenorphine maintenance therapy
[6, 7, 11]. The incidence of this type of sexual dys-

function is difficult to determine, and differs between


countries. The use of opioids, especially in a long
history of addiction, may cause a sexual dysfunction,
and patients may decide to report this disability during methadone maintenance treatment. At this stage,
when sexual symptoms are attributed to MMT by the
patient, and are not satisfactorily addressed by the
physician, adverse outcomes may occur. Use of Amphetamine and Cocaine, self-reduction of methadone
dose, and interruption of MMT are some examples
of self-treatment for sexual dysfunctions by these patients. Thus, consideration of sexual dysfunction as a
drug side-effect is important because, besides caus-

Corresponding author: Shadan Tafreshian, Medical Doctor and Technical Manager of Methadone Clinic, Mashhad University of
Medical Sciences, No 87, Moallem blv, 9188615119, Mashhad, Iran
E-mail: shadan.tafreshian@gmail.com

49

Heroin Addiction and Related Clinical Problems 16(3): 49-54

ing difficulty in intimate relationships, it is likely to


lead to an impairment of compliance with therapy, so
interfering with the known benefits of methadone and
buprenorphine.
Other factors may come into play to give rise
to sexual dysfunction in methadone-treated patients,
such as hormonal phenomena (pathologies of the testicles, hypogonadism, dysfunction of the pituitary
gland, hyperprolactinaemia), neurological, metabolic
and arteriopathic causes; psychological factors (anxiety, depression, stress, pressure to perform), environmental problems (the couple, the family, and financial
or professional issues), lack of information and ignorance about sexuality.
In addicted patients, toxic causes are the main
concern. It is well known that erectile dysfunctions
are increased by tobacco use, and are twice as frequent with heavy smoking. Nicotine can cause atherosclerosis in the arteries of the penis, lesions of the endothelium of small blood vessels, vasoconstriction of
the arteries of the penis, and contraction of smooth
intracavernous muscular fibres, all leading to erectile
dysfunctions. Furthermore, chronic alcoholism is a
well-known cause of erectile dysfunction through its
direct action on the testicles, or by leading to the hepatic degradation of testosterone. The chronic intake
of cocaine is another possible cause of sexual dysfunction, as happens too with opioids [6].
Because there are only a few available studies on
sexual dysfunction in opioid-addicted patients treated
with methadone or buprenorphine, we designed a
cross-sectional study with the aim of providing improved prevalence data for sexual dysfunctions in a
sample of men on MMT or BMT in our country.
2.

for a sexual dysfunction, such as androgen replacement treatment. The sample consisted of 158 opioid-dependent male patients in maintenance treatment.
Group A consisted of 102 MMT patients, and group
B of 56 BMT patients. The mean age of our patients
included in group A was 39 years (range: 23-64), and,
for those in group B, was 33 years (range: 24-45). Average duration of methadone maintenance treatment
was 122 months, and the mean methadone dose was
64 2 mg/d. For patients on BMT the corresponding
data were 92 months and 8 mg/d.
2.2. Instruments
We collected socio-demographic data and investigated sexual function by using IIEF, an extensively validated questionnaire covering five domains of
male sexual function: desire, erectile function, intercourse satisfaction, orgasm, and overall satisfaction
[14]. We evaluated lack of libido, erectile dysfunction
(difficulty in achieving or maintaining an erection)
and difficulties in achieving orgasm. Patients' reports
were collected and their responses were measured on
the basis of an evaluation of their symptoms. Our patients were followed at least once a month by visits
to physicians. By clinical assessment, further information was obtained on methadone or buprenorphine
maintenance dose and length of therapy, use of other
medications, evidence of other significant illnesses,
recent alcohol use and tobacco smoking or other drug
use such as benzodiazepines, cannabis, stimulants, or
heroin supported by urine toxicology, according to
our protocol.
This study was approved by the Ethics Committee of the Mashhad University of Medical Sciences.

Methods
2.3. Data analysis

2.1. Sample
The study included patients who had been registered in two Methadone Clinics in Mashhad, Iran
(Saman and Mashregh Zamin Clinics), during a period of 18 months. All subjects gave written consent to
their participation. These patients were self-referred
for a medical evaluation of sexual dysfunctions associated with MMT/BMT, and were evaluated and
treated by one of the authors. Patients were included
in the study if they had been on MMT or BMT for at
least one year, had a stable methadone/buprenorphine
dose, and if they were free from any medical condition associated with organic sexual disability, such
as diabetes. No patients had taken any medication
- 50 -

Final data were evaluated statistically by using


SPSS Software. Categorical variables were compared
using the chi-squared test, and continuous variables
were examined using regression analysis. For samples that were not normally distributed, the nonparametric T-test was used. All statistical tests were
two-tailed, and a P value 0.001 was considered as
statistically significant.
3.

Results

Demographic data, history of opioid use, abuse


of other drugs or substances, and treatment details
are shown in Table 1. With respect to loss of libido,

S. Tafreshian et al.: Sexual Dysfunction in Male Patients Receiving Methadone and Buprenorphine Maintenance Treatment in Iran

Table 1: Demographic and treatment details, history of opioid use, other drugs or substances

Number of men
Age (mean years, range)
Daily dose (mean mg/d SD)
Duration of current continuous opioid
treatment (mean value in months)
Mean duration of opioid dependency
(years SD)
Method of taking drugs

MMT
(Methadone maintenance therapy)
group
102
39 (23-64)
642

BMT
(Buprenorphine maintenance therapy)
group
56
33 (24-45)
81

122

92

122

92

Oral
40

History of chronic and metabolic


disorders
History of depression
Other regular substance use:
Tobacco
Alcohol
Benzodiazepine
Cannabis
Stimulants
Heroin

Smoking
24

Both of them
38

Oral
12

Smoking
12

Both of them
32

96 (94.1%)
7 (6.8%)
24 (23.5%)
2 (1.9%)
18 (17.6%)
12 (11.7%)

34 (60.7%)
6 (10.7%)
5 (8.9%)
9 (16%)
10 (17.8%)
20 (35.7%)

50.9% (52) of patients in MMT complained of a moderate to severe loss of libido, as against only 8.9%
(5) in the BMT group. Patients in MMT, compared
with patients in BMT, show a higher percentage of
erectile dysfunction: 72.5 and 12.5% (74 and 7 patients), respectively; they showed more difficulty in
achieving an orgasm, associated with a reduction in
sexual satisfaction: 45% (23 patients) versus 3.5% (2
patients), respectively. According to the International

Index of Erectile Function domains (IIEF), the methadone group has significantly lower scores than the
buprenorphine group in all domains (Table 2). 75% of
patients in the BMT group report a moderate to high
sexual drive, while the sexual life satisfaction scores
are significantly higher in the BMT than in the MMT
group (p<0.001). In both groups, erectile dysfunction
seems to be a major component of sexual dysfunction. Thus, a significant correlation between treat-

Table 2: IIEF domain scores for men in treatment for addiction


Methadone
N = 102

IIEF Domain Scores


Loss of libido
(Number, Percentage)

52 (50.9%)

Erectile dysfunction (Number,


Percentage)

74 (72.5%)

Intercourse: dissatisfaction
(Number, Percentage)

44 (43.1%)

Orgasmic difficulties (Number,


Percentage)

23 (45%)

Overall satisfaction (Number,


Percentage)

24 (23.5%)

Max Score: 10
Score in this
group: 5.1
Max Score: 30
Score in this
group: 18.2
Max Score: 15
Score in this
group: 6.8
Max Score: 10
Score in this
group: 6.7
Max Score: 10
Score in this
group: 5.9

Buprenorphine
N = 56
5 (8.9%)
7 (12.5%)
5 (8.9%)
2 (3.5%)
42 (75%)

Max Score: 10
Score in this group:
8.1
Max Score: 30
Score in this group:
24.3
Max Score: 15
Score in this group:
11.2
Max Score: 10
Score in this group:
8.7
Max Score: 10
Score in this group:
7.5

IIEF = International Index of Erectile Function.

- 51 -

Heroin Addiction and Related Clinical Problems 16(3): 49-54

ment mode on one hand and ejaculation and erectile


dysfunction on the other, can be observed. In addition,
people on MMT have a high prevalence of sexual excitation and proneness to orgasm disturbances: 50.9%
and 45%, respectively, compared with only 8.9% and
3.5% in the case of BMT. No valuable statistical correlation between duration of opioid use and sexual
complaints was found in our two groups. The dose
of methadone in MMT patients, in contrast with the
BMT group, shows a significant role in sexual dysfunctions (p=0.011), and the duration of therapy is
correlated with these complications (p=0.012). Most
of our patients report change or no improvement in
sexual function after treatment with methadone or
with buprenorphine, compared with opioid use.
4.

Discussion

Methadone has been available for more than 35


years, and has been used by millions of patients in
a variety of settings [8]. Buprenorphine is the other
commonly used substance for the maintenance therapy of addicted patients. In clinical practice, buprenorphine is often used in patients who have a low level of
opioid tolerance, and in patients whose doses are being reduced; methadone is indicated for patients with
heavy or persistent opioid use, or with chronic pain.
The frequency and the severity of side-effects seem to
be similar for methadone and for buprenorphine users, although the claim has been made that quality of
life is better in buprenorphine treatment [12]. Furthermore, in the list of the adverse effects of methadone,
unlike those of buprenorphine, a reduction in libido
and/or potency has been pointed out [5]. According
to our results, the methadone group had significantly
lower scores than the buprenorphine group in all domains of sexual function, but the recorded scores in
buprenorphine are not fully reliable.
In our study, in both groups (of methadone and
buprenorphine users), erectile dysfunction seems to
be a major cause of sexual dysfunction. According to
earlier studies, erectile dysfunction (ED) usually has
an organic or iatrogenic aetiology. A variety of systemic illnesses are associated with ED. These include
chronic liver disease, renal failure, arteriosclerotic
cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, and malignancy. Spinal
trauma and genitourinary surgery are potential aetiological causes of ED, too [10]. Though more rare, congenital and other anatomic genitourinary anomalies
(Peyronies disease, phimosis, post-traumatic aneurysm) should be considered [4]. None of our patients
- 52 -

suffered from these diseases. Medications commonly


associated with ED, which include antihypertensives,
psychotropic agents and medications with anticholinergic effects, were not used by our patients.
Mental and emotional health may be significant
contributors to healthy sexual function, and depressive symptoms have been most strongly associated
with ED, with 90% of men with severe depression
reporting ED in one study [1]. Anxiety disorders has
also been reported as causes of ED [15]. In our study,
patients with psychiatric disorders were excluded
from possible selection. So, except smoking, which
is a strong risk factor for ED [13], in our study, ED
seems to be a side-effect of opioid replacement treatment. Given the risk of sexual dysfunctions, physicians should screen patients who are receiving either
methadone or buprenorphine replacement treatment,
especially MMT patients.
Spring et al. provided some evidence demonstrating a relationship between sexual dysfunction
and methadone dose [16]. They found that men experiencing significant sexual dysfunctions were more
likely to be on higher doses of methadone. In their
study, however, men with a sexual dysfunction, in
contrast with our records, endorsed a greater number
of psychological symptoms that are important potential confounders for an effect due to a high methadone
dose. Teusch et al. found MMT patients reporting reduced libido and orgasm dysfunction more frequently
than controls, but the severity of dysfunction was
unrelated to the methadone dose [17]. In a more recent study, Brown et al. demonstrated a link between
methadone dose and orgasm dysfunction among 92
MMT patients on an average of 100 mg methadone
daily [3]. The mean dose of methadone in our patients
(64 mg/d) is significantly lower than the average
methadone dose for the clinic as a whole (120mg/d).
Most of the side-effects of drugs are dose-related.
Naturally, patients will have fewer side effects when
treated with homeopathic doses. This is not an indication to withhold effective doses. With methadone, as
with any other medication, the management of sideeffects is preferable to the discontinuation of therapy.
In summary, it is difficult to define the exact
prevalence of sexual dysfunction in men on MMT
compared with the general population. Despite this,
we have attempted to consider other factors (depression, the use of other substances, age, treatment duration) which might play a role in symptoms of sexual
dysfunction in MMT.

S. Tafreshian et al.: Sexual Dysfunction in Male Patients Receiving Methadone and Buprenorphine Maintenance Treatment in Iran

Limitations
The feature that may limit the value of these results is that, in the present study, some of the characteristics of methadone and buprenorphine treatment
differed, especially the duration of treatment. This
factor could limit the significance of the multivariate
analysis.
5.

Conclusions

In conclusion, buprenorphine may be less likely


than methadone to cause sexual dysfunction; transferring from methadone to buprenorphine is one therapeutic option in cases where sexual dysfunction has
been identified, as suggested by Bliesener et al [2].
It should, however, be borne in mind thattransferring from higher dose methadone may require
prior dose reductions, and it is possible that methadone dose reductions will lead to the normalization
of sexual function. So, further studies on sexual dysfunctions in opioid-treated patients should examine
the potential benefits of methadone dose reductions,
and the possible benefits of the reduction need to be
weighed against the risks of continuing opioid use.
References
1. Araujo A. B., Johannes C. B., Feldman H. A., Derby C.
A., Mckinlay J. B. (2000): Relation between psychosocial
risk factors and incident erectile dysfunction: prospective
results from the Massachusetts Male Aging Study. Am
J Epidemiol. 152(6): 533-541.
2. Bliesener N., Albrecht S., Schwager A., Weckbecker
K., Lichtermann D., Klingmuller D. (2005): Plasma
testosterone and sexual function in men receiving
buprenorphine maintenance for opioid dependence. J
Clin Endocrinol Metab. 90(1): 203-206.
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with Methadone and Buprenorphine: Sexual Dysfunction
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8. Espejo R., Hogben G., Stimmel B. (1973): Sexual


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9. Hallinan R., Byrne A., Agho K., Mcmahon C., Tynan P.,
Attia J. (2008): Erectile dysfunction in men receiving
methadone and buprenorphine maintenance treatment.
J Sex Med. 5(3): 684-692.
10. Kandeel F. R., Koussa V. K., Swerdloff R. S. (2001):
Male sexual function and its disorders: physiology,
pathophysiology, clinical investigation, and treatment.
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11. Paice J. A., Penn R. D., Ryan W. G. (1994): Altered
sexual function and decreased testosterone in patients
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12. Pende A., Musso N. R., Montaldi M. L., Pastorino G.,
Arzese M., Devilla L. (1986): Evaluation of the effects
induced by four opiate drugs, with different affinities
to opioid receptor subtypes, on anterior pituitary LH,
TSH, PRL and GH secretion and on cortisol secretion
in normal men. Biomed Pharmacother. 40(5): 178-182.
13. Rosen M. P., Greenfield A. J., Walker T. G., Grant P.,
Dubrow J., Bettmann M. A., Fried L. E., Goldstein I.
(1991): Cigarette smoking: an independent risk factor
for atherosclerosis in the hypogastric-cavernous arterial
bed of men with arteriogenic impotence. J Urol. 145(4):
759-763.
14. Rosen R. C., Riley A., Wagner G., Osterloh I. H.,
Kirkpatrick J., Mishra A. (1997): The international
index of erectile function (IIEF): a multidimensional
scale for assessment of erectile dysfunction. Urology.
49(6): 822-830.
15. Sbrocco T., Weisberg R. B., Barlow D. H., Carter M.
M. (1997): The conceptual relationship between panic
disorder and male erectile dysfunction. J Sex Marital
Ther. 23(3): 212-220.
16. Spring W. D., Jr., Willenbring M. L., Maddux T. L.
(1992): Sexual dysfunction and psychological distress
in methadone maintenance. Int J Addict. 27(11): 13251334.
17. Teusch L., Scherbaum N., Bohme H., Bender S.,
Eschmann-Mehl G., Gastpar M. (1995): Different patterns
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84-92.
Role of the funding source
Authors state that this study was financed with internal funds. No sponsor played a role in study design; in the
collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper
for publication.

- 53 -

Heroin Addiction and Related Clinical Problems 16(3): 49-54

Contributors
Authors contributed equally to this article. All authors
revised and approved the final form of the manuscript.
Conflict of interest
Authors declared no conflict of interest.

Received June 27, 2013 - Accepted January 22, 2014


- 54 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 55-64

Outcomes of clonazepam maintained benzodiazepine-heroin addicted patients


during methadone maintenance: A descriptive case series
Angelo Giovanni Icro Maremmani 1,2, Silvia Bacciardi 1, Fabio Rugani 1, Luca Rovai 1,
Enrico Massimetti 1, Denise Gazzarrini 1, Liliana DellOsso 5, Pier Paolo Pani 4, Matteo Pacini 1,3,
and Icro Maremmani 1,2,3
1 Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Italy, EU
2 AU-CNS, Association for the Application of Neuroscientific Knowledge to Social Aims, Pietrasanta, Lucca, Italy, EU
3 G. De Lisio Institute of Behavioural Sciences Pisa, Italy, EU
4 Social and Health Services, Health District 8 (ASL 8) Cagliari, Italy, EU
5 Department of Experimental and Clinical Medicine, University of Pisa, Italy, EU

Summary
Background. The use of benzodiazepine (BDZ) by patients on methadone maintenance treatment (MMT) has the effect
of complicating the clinical picture. The relative safety of BDZ use by methadone- or buprenorphine-treated patients has
still not been systematically examined. It is not yet clear whether a maintenance strategy with clonazepam is a useful BZD
treatment modality for BZD-dependent MMT patients with a long-term history of abuse and previous attempts at detoxification. Methods. In this study our aim has been to collect and present detailed information regarding the outcomes of a
small group of our patients who were treated with clonazepam maintenance during methadone maintenance. Results. In
our sample of BZD-dependent MMT patients, who were treated with a methadone-clonazepam combination, the retention
rate, at 8 years, was 57.1%. Baseline-endpoint improvements were significant for clinical global impression and the level
of social adjustment. Conclusions. Patients with a severe comorbid dependence, when treated with over-standard dosages
of methadone and co-treated with CMT, may have outcomes that are satisfactory as long as they are maintained on their
medication in the long term.
Key Words: Methadone Maintenance; Long-term Outcome; Benzodiazepines; Polyabuse; Clonazepam Maintenance

1.

Introduction

The use of benzodiazepine (BDZ) by patients


on methadone maintenance treatment (MMT) has
the effect of complicating the clinical picture and
may negatively influence treatment outcomes (poorer
psychosocial adjustment, higher levels of polydrug
use, more risk-taking behaviours and a shorter retention in treatment) [8, 11, 14, 18, 48, 51]. A history
of benzodiazepine prescription is significantly associated with drug-dependent death [40], and intermittent
benzodiazepine abuse was found to be significantly
associated with lower rates of opiate abstinence during methadone maintenance treatment [23].
Benzodiazepine MMT users are more likely to
have injected recently, to have used cocaine and am-

phetamines, to have borrowed or lent used needles


and syringes, and to have reported polydrug use in
the preceding month. Benzodiazepine MMT users
also exhibit higher levels of psychopathology and social dysfunction than other methadone maintenance
patients. Benzodiazepine-using methadone maintenance patients are a dysfunctional subgroup of the
methadone population, and they are likely to require
more clinical intervention than other patients [13].
Some authors stress the high priority that should
be given to stopping benzodiazepine use during [42]
or before entering MMT. For example, the Stockholm
Centre for Dependency Disorders has suggested that
benzodiazepines should hardly ever be prescribed to
patients on methadone/buprenorphine. Before entering MMT/buprenorphine treatment, the patient must

Corresponding author: Angelo Giovanni Icro Maremmani, MD; Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Via Roma, 67 56100 PISA, Italy, EU.
E-mail: angelogimaremmani@gmail.com

55

Heroin Addiction and Related Clinical Problems 16(3): 55-64

be negative for un-prescribed benzodiazepines, and,


if a patient on MMT/buprenorphine becomes positive for benzodiazepines, the MMT/buprenorphine
therapy should discontinued (Johan Franck, 2013
-personal communication).
Others claim that cautiously prescribing benzodiazepines may be a beneficial strategy, due to the reduction of overall illicit use [14].
The relative safety of BDZ use by methadoneor buprenorphine-treated patients has still not been
systematically examined. BDZs may significantly alter the response to opioid substitution treatment with
methadone or buprenorphine. In any case, BDZ had
greater peak effects on performance measures (simple reaction time, digit symbol substitution task, and
cancellation time) in methadone-treated than in buprenorphine-treated patients [28].
Opiate/benzodiazepine co-dependent patients
reported less severe withdrawal symptoms during
treatment with buprenorphine than with methadone
[44].
While methadone maintenance treatment
(MMT) has been demonstrated to be an effective
treatment for opiate dependence, its impact on the
treatment outcome of other types of illicit drug abuse
is not as clear. Therapeutic approaches for benzodiazepine (BZD) dependence in patients in methadone maintenance treatment (MMT) have met with
limited success. Clonazepam detoxification (CDTX)
and clonazepam maintenance treatment (CMT) have
been experimented. Maintenance strategy with clonazepam is a useful BZD treatment modality for BZDdependent MMT patients with a long-term history of
abuse and previous attempts at detoxification [55]
Aims: In this study our objective was to collect
and present detailed information about the outcomes
of a small group of our patients who had been kept on
clonazepam maintenance concomitantly with methadone maintenance, with special reference to our specific therapeutic context.
2.

Methods

2.1. Design of the study


We designed an exploratory (or pilot) Case
Studies project before implementing a large-scale
investigation. The question we wished to study was
the feasibility of CMT during MMT. We considered
as relevant data the outcomes of our CMT-MMT patients. We collected data regarding their addiction
history, and we continued to follow up the patients
- 56 -

clinical situation and social adjustment over a period


lasting between 1 and 7 years. Then we studied correlations between demographic and clinical aspects,
on one hand, and patients survival in treatment time,
on the other.
2.2. Setting
In Italy, low-threshold facilities for drug addicts
are available in each territorial district. When opioid
agonists are employed in those settings, dosage and
duration of treatment are usually limited, regardless
of clinical indications [46, 47] that suggest the value
of raising the dosage or extending the treatment [7,
10, 15, 43]. Patients are allowed to negotiate the lowering of dosages regardless of urinalyses, and to have
their medication tapered earlier than would be advisable on the basis of the scientific literature.
All the patients participating in the study were
recruited from the Pisa Methadone Maintenance
Treatment Programme (Pisa-MMTP), which belongs
to the Pisa University Department of Psychiatry.
Since 1993, the Pisa-MMTP has been using a clinical
protocol that has the characteristics of a high-threshold treatment facility for opioid addiction focusing on
pharmacological maintenance. After patients at the
Pisa-MMTP have been safely inducted into treatment
with methadone, their doses are gradually increased
until the point is reached where there is no more than
one urine drug screen which is positive for illicit opiates, cocaine, or benzodiazepines in the previous sixty-day period.
Once this requirement is fulfilled, the patient is
defined as having being stabilized, and the dose at
which this goal has been accomplished is referred to
as the stabilization dose. No upper limit for dosage exists. Despite this, one single time limitation is
imposed in this setting: patients who cannot achieve
stabilization within one year have to leave the programme, to be transferred to local treatment units. The
dosage is increased to reflect the results of urinalyses,
and evidence of improvement on social grounds is
not enough by itself to justify dose stability as long
as the urinalyses stay positive for opiates. Patients
are not allowed to raise or lower the dose by themselves. Take-home doses, without limitations, and at
most for a 7-day period, are allowed, once patients
have shown complete compliance with the rules of
the programme. Urine samples for toxicology analyses are collected randomly almost once a month, to
allow evaluation of the metabolites of illicit drugs and
benzodiazepines.

A.G.I. Maremmani et al.: Outcomes of Clonazepam Maintained Benzodiazepine-Heroin Addicted Patients During Methadone Maintenance: A
Descriptive Case Series

In our programme, patients are required to become actively involved in treatment by attending the
clinic whenever that is scheduled, participating in the
development of their treatment plan, working towards
treatment goals, meeting with medical and case management staff, and attending groups when needed.
Patients with psychiatric comorbidity receive
additional treatment with psychoactive drugs (mood
stabilizers, antipsychotics or antidepressants) and
supportive psychotherapy, as needed.
In our clinical practice, BZD dependence is
treated systematically, according to the following
procedure, which is very similar to an agonist substitution approach. We started by switching the patient
from the abused BZD to a slow-onset, long-acting,
high potency BZD agonist clonazepam. As the dosage of the abused benzodiazepine was progressively
lowered, the clonazepam dosage was progressively
raised until the substitution was complete. In this
way the patient stopped his primary abuse of BZD
without any switch from intoxication to withdrawal
states. Afterwards, patients passed through four successive phases: induction, stabilization, maintenance,
and, whenever possible, medication withdrawal. This
methodology was recently described by Liebrenz et
al. in BDZ-dependent patients [27]. For more information on this procedure, see Maremmani et al. [33]
All the physicians working in the Pisa-Methadone Programmes are psychiatrists who have been
trained for at least two years in the treatment of addictive disorders.
2.3. Sample
We considered all the patients admitted to our
programme over an 8-year time period (from January
1995 to May 2003) and enrolled in previous studies
[31, 37].
We selected 14 patients diagnosed as heroindependent patients according to the DSM-IV-R diagnostic criteria (304.00); they also fulfilled DSM-IV
criteria for severe dependence on sedatives, hypnotics
or anxiolytics (F13.24). All these patients entered our
CMT-MMT-programme and were followed up.
2.4. Instruments and procedure
2.4.1. DAH-Q, Drug Addiction History Questionnaire
(administered at the beginning of treatment)

The DAH-Q [35] is a multidimensional questionnaire that comprises the following 8 areas: 1-demographic data, 2-physical health, 3-mental status,

4-social adjustment and environmental factors, 5-substances abused, 6-substance abuse modalities (heroin
intake, modality of use, stages of illness, nosography), 7-treatment history and 8-addiction history (age
at first contact, age at onset of continuous use, dependence length and age at first treatment). The Scale
rates 10 presence-absence items: 1-somatic comorbidities, 2-abnormal mental status, 3-work problems,
4-household problems, 5-sexual problems, 6-socialization and leisure time problems, 7-drug-related legal
problems, 8-polysubstance abuse, 9-previous treatment, 10-combined treatments.
We encoded the modality of use as follows:
1-stables, 2-junkies, 3-two worlders, 4-loners, according to Lahmeyers classification [26]. Stables
are opioid addicts who have adopted conventional
values, hold legitimate jobs, are generally law-abiding
and do not associate with other addicts. Hustlers,
otherwise called junkies or criminal addicts, are
closely identified with an addict subculture, are not
legitimately employed, and subsist on the proceeds
of criminal activities. Two-worlder addicts engage
in criminal activities and associate with other addicts,
but are also legitimately employed. Loner addicts
are not involved either in the addict subculture or the
conventional culture. They are usually unemployed,
and live on welfare benefits rather than on the proceeds of criminal activities. These uninvolved addicts
may have severe psychological disorders.
The development of addiction may be considered to consist of three stages: 1-acute (immediate)
drug effects (Honeymoon Stage); 2-transition from
recreational use to patterns of use consistent with addiction (Increasing Dose Stage); and 3-end-stage addiction, which is characterized by an overwhelming
desire to obtain the drug, a diminished ability to control drug-seeking and reduced pleasure from biological rewards (Revolving Door Stage) [22].
Considering the clinical typology, drug addicts
can be divided into 1-reactive (presence of psychosocial
stressors before using heroin), 2-self-therapeutic (presence of psychiatric stressors before using heroin), and
3-metabolic (no psychosocial or psychiatric antecedents) [38]. Regarding the pattern of use, data were
recorded by us on whether the user of illicit opioids
typically undergoes periods of voluntary or forced abstinence lasting weeks to months, followed by periods
of relapse. For more details, see [29, 30, 32, 34, 36].
2.4.2. Global Assessment of Functioning, DSM-IV-GAF
(administered monthly).

The GAF considers psychological, social and


occupational functioning within the sphere of a hypo- 57 -

Heroin Addiction and Related Clinical Problems 16(3): 55-64

thetical mental health-illness continuum, without including any impairment of functioning due to physical or environmental limitations. The point allocation
follows a specific code, with a maximum of 100 and a
minimum of 0, with the possibility of using intermediate codes if necessary [1].
2.4.3. Clinical Global Impression (CGI) (administered
monthly)

The CGI considers the severity of the disorder,


the degree of the improvement or worsening following the intervention and any adverse reactions [21].
2.4.4. Toxicological urine analyses (carried out randomly
every week during the induction phase and almost
every month during the stabilization phase)

The enzyme-multiplied immune technique for


opiates was used. The toxicological urinalyses were
expressed using two indices: PC-CU (per cent clean
urines) and TS-CU (per total specimens clean urines).
PC-CU represents the percentage ratio between urinalyses proving negative for the presence of morphine and the total number of urinalyses carried out
for each patient during the treatment period. TS-CU
is the percentage ratio between the number of urinalyses testing negative for the presence of morphine
and the number of urine analyses that the protocol
has envisaged throughout the process. In this case the
reference number was 386 (the theoretical maximum
number of urine samples per patient, considering an
8-year period). PC-CU tends to give a preference to
patients who remain opiate-free, but who terminate
the study in advance, for reasons not correlated with
the study (for example, imprisonment). TS-CU also
considers how long the patient remains in the protocol, but give priority to patients who show clean urine
during a long-lasting treatment. These two indices
represent the two extremes, and the results tend to
balance out.
2.5. Data analysis
Retention in treatment was analysed by means of
the survival analysis. For the purpose of this analysis,
the term terminal event refers to patients who left
the treatment as a not stabilized patient (see the section appearing above entitled Setting for details),
while withdrawing during interval refers to patients
who are still in treatment at the end-point, or leaving
treatment for reasons unrelated to the treatment itself
(e.g. patients moving to other towns, and periods of
imprisonment for past crimes) or patients detoxified
- 58 -

after the maintenance period. In other words, we consider 2 kinds of positive outcome: the first when a patient left the programme after successful detoxification (after the maintenance period) or was referred, as
a stabilized patient, to other programmes, the second when a patient was still in treatment, at the endpoint, as a stabilized patient. We consider it to be a
negative outcome when a patient has failed to achieve
stabilization within a year or has relapsed into addictive behaviour after a period of stabilization.
The association between demographic and clinical variables and retention in treatment, adjusting for
potential confounding factors, was summarized using
Cox regression.
Differences in demographic and outcomes
measures were analysed by applying the general linear model, repeated measure methodology, and adjusting for outcome.
3.

Results

3.1. Demographic characteristics


addiction history

and

heroin-

Mean age was 30.143.8 (range: 26-38). 14


(71.4%) were males and 4 (28.6%) females. 5 (35.7%)
were highly educated people (with over 8 years of education) and 9 (64.3%) had a low level of education.
12 (85.7%) were single and only 2 (14.3%) had a partner. 2 (14.3%) had a white collar job and 3 (21.4%)
had a blue collar one, 9 (64.3%) were unemployed.
Low income was found in 1 (7.1%) subject, and adequate income (sufficient to satisfy a requirement or
meet a need) in 13 (92.9%) subjects. 13 (92.9%) had
an urban birth location and 11 (78.6%) were living in
an urban zone. Only 2 (14.3%) subjects were living
alone. All patients were recruited in Central Italy.
At treatment entry, at least one of the somatic
complications that were investigated (hepatic, vascular, lymphatic, gastrointestinal, sexual, dental, HIV+,
AIDS) was observed in 13 (92.9%) subjects. Mean
was 2.281.5 (0-6 ranged). At least one of the mental status areas that were investigated (insight, consciousness, memory, anxiety, depression, sleep, eating, excitement, violence, suicidality, delusions and
hallucinations) was found to be altered in all subjects.
Mean was 6.281.6 (4-10 ranged). Only 3 (21.4%)
subjects were enjoyed their job; 5 (35.7%) were unsatisfied with their household relationship; 6 (42.9%)
with their erotic situation; 12 (85.7) with their socialleisure activities. 8 (57.1%) reported current or past
legal problems. Polyabuse (more than 3 substances of

A.G.I. Maremmani et al.: Outcomes of Clonazepam Maintained Benzodiazepine-Heroin Addicted Patients During Methadone Maintenance: A
Descriptive Case Series

abuse) was occasionally present in 10 (71.4%) subjects. Mean number of occasionally abused substances was 3.571.6 (range: 1-6). Only 2 (14.3%) patients
had never been treated. Mean number of past different kinds of treatment was 2.711.8 (range: 0-6). We
investigated 12 different kinds of treatment: therapeutic community, psychopharmacology, psychotherapy,
short-term detoxification with opioid agonists, partial
agonists and antagonists, maintenance treatment with
opioid agonists, partial agonists and antagonists.
As to comorbid substance use, 9 (64.3%) patients occasionally used alcohol, 10 (71.4%) CNSstimulants, 11 (78.6%) cannabinoids, 10 (71.4%) hallucinogens and 1 (7.1%) inhalants. Heroin intake took
place at least once a day in 11 (78.6%) patients. Modality of heroin use was unstable in 12 (85.7%), periodic self-detoxification occurred in 10 (71.4%), Stage
3 of heroin addiction was reached by 11 (78.6%),
psychosocial stressors, before starting heroin, were
present in 4 (28.6%). Mean age at first heroin use was
20.574.8 (range: 14-31), mean age at start of continuous heroin use was 22.294.4 (15-31), mean age,
at 1st treatment, was 25.644.4 (17-33) years. Mean
dependence length (months) was 79.7970.1 (range:

12-240).
At treatment entry, mean dose of abused BZD
(expressed as diazepam-equivalents) was 166.7857.6
mg/daily (range: 100-250). 11 (78.6%) patients were
using between 100 and 200 diazepam-equivalent mg/
daily, 3 (21.4%) over 200 mg/daily.
Severity of illness was considered moderate
in 3 (21.4%), marked in 7 (50.0%) and severe in 4
(28.6%) patients. Global assessment of functioning
classified 4 (28.6%) subjects in cluster 3 (inability to
function in almost all areas (e.g., staying in bed all
day; no job, home, or friends); 3 (21.4%) in cluster
4 (major impairment in several areas, such as work
or school, family relations, judgment, thinking, or
mood); 5 (35.7%) in cluster 5 (any serious impairment in social, occupational, or school functioning
(e.g., no friends, unable to keep a job); only 2 (14.2%)
showed a better than described social adjustment.
3.2. Survival in treatment
At start of the first year we had 14 subjects in
treatment. During the first year there was one terminal event (0.07%) with a survival index of 0.93. At

1$
0.90$

Cumula&ve)survival)rate))

0,9$
0,8$
0,7$

0.64$
0.64$

0,6$

0.58$
0,5$
0,4$

0+1$yrs$
N=)

14)

1+2$yrs$
13)

0.56$

0.56$

0.56$

0.56$

2+3$yrs$

3+4$yrs$

4+5$yrs$

5+6$yrs$

6+7$yrs$

7+8$yrs$

9)

8)

7)

6)

6)

6)

Figure 1. Survival in treatment of 14 clonazepam maintained benzodiazepine-heroin addicted patients during Methadone Maintenance

- 59 -

Heroin Addiction and Related Clinical Problems 16(3): 55-64

Table 1. Outcomes (baseline-endpoint) in clonazepam-maintained patients during methadone maintenance according


to the outcome
Measures
N
Outcome
Msd
CGI (baseline)
6
Negative
5.170.7
8
Positive
5.000.7
CGI (end-point)
6
Negative
2.580.9
8
Positive
1.500.7
DSM-IV-R GAF (baseline)
6
Negative
43.33 8.1
8
Positive
45.0015.1
DSM-IV-R GAF (end-point)
6
Negative
71.66 4.0
8
Positive
82.50 7.0
Multivariate tests: time effect: F137.49, p<0.001; time-outcome effect: F=3.04, p=0.089

Statistics
Source
Time
Time-outcome

Measure
CGI
DSM-IV-R GAF
CGI
DSM-IV-R GAF

Time
Level 2 vs level 1
Level 2 vs level 1
Level 2 vs level 1
Level 2 vs level 1

the start of second year we had 13 in-treatment patients. During this year there were 4 (31%) terminal
events, with a fall in the cumulative survival index to
0.64. At the start of third year we had 9 in-treatment
patients. During the 3rd year one patient successfully
terminated the treatment by leaving the programme
in an opioid-detoxified condition and without BZD.
No terminal events were observed. At the start of the
4th year 8 patients were in treatment. During the 4th
year one (13%) terminal event was observed, and the
cumulative survival index fell to 0.56. At the start of
the 5th year 7 patients were in treatment. During the
5th year one patient successfully terminated the programme, in an opioid-detoxified condition and taking
only a small amount of clonazepam (2mg/daily in two
doses). No terminal events were observed during the
6th or 7th years of treatment, the cumulative survival
index remaining at 0.56. At the end of the 7th year,
6 patients were still in treatment. Figure 1 summarizes the situation for the survival in treatment of our
patients. In summary, the outcome was negative in
6 (42.9%) subjects and positive in 8 (57.1%). No
patient with a negative outcome voluntarily abandoned the programme, whether for side-effects, altered bio exams, imprisonment, hospitalization or
death. All negative-outcome patients lost their status
as a stabilized patient and were transferred to lowthreshold programmes.
Using Cox regression, only the opiate PC-CU
index significantly predicted survival in treatment
(Chi-square =12.43, df=1, p<0.001; Exp(B)=0.001,
CI95%: 0.001-0.079).

- 60 -

F
266.72
73.28
6.05
1.42

df
1
1
1
1

P
<0.001
<0.001
0.030
0.256

3.3. Baseline-end point changes


Multivariate tests showed that CGI severity
of illness and DSM-IV GAF (global assessment of
functioning) demonstrated significant improvements
in our patients independently of their outcome. For
details see table 1.
3.3. Medication dosages
On average, patients with severe comorbid BDZ
dependence needed an over-standard methadone dosage in the stabilization phase (190.73103.4 mg/day).
Patients who had a positive outcome did not receive
different stabilization dosages (Students T-test=0.55,
p=0.586). The clonazepam stabilization dosage was
21.367.2 mg/daily (min 12.50, max 32.50.
3.5. Urinalyses
After eliminating from the analysis the toxicological examination performed at the time of enrolment in the programme (which was required to be
positive), 2,947 urine samples were analysed in all.
Of these, 2,554 (86.6%) were opiate-clean.
In positive-outcome patients the opiate PC-CU
index was 0.900.05; in negative-outcome patients, it
was 0.640.1 (Students T-test =5.81, p=<0.01). The
opiate TS-CU index revealed differences (T=5.97;
p<0.001) between positive (0.730.2) and negative
(0.120.6) outcome.

A.G.I. Maremmani et al.: Outcomes of Clonazepam Maintained Benzodiazepine-Heroin Addicted Patients During Methadone Maintenance: A
Descriptive Case Series

4.

Discussion

We examined treatment retention and outcomes


for clonazepam-maintained patients during methadone maintenance. We observed that:
Patients were assessed at baseline, in terms of
somatic and psychopathological complications, frequency of unsatisfactory social and leisure time, and
the presence of polyabuse.
These data are in agreement with the observations of Drake et al. [13] on whether MMT patients
with BDZ dependence can be considered to belong
to a dysfunctional group. However, the characteristics found by us did not appear to be related to the
patients retention or their outcome.
Patients with concomitant severe BDZ dependence were recorded as having been successfully retained in long-term treatment; they showed good
results for opiate-negative urine specimens; they
required over-standard doses of methadone. In particular, the outcome and the percentage figures for
retention in therapy of our patients did not differ
from those of long-term standard MMT programmes
[5, 12, 16, 25, 50, 52]. The main difference between
our programme and standard Italian MMT lies in the
amount of methadone administered during the stabilization phase; this ranges from 80 to 400 mg/day in
our protocols and from 40 to 100 mg/day in standard protocols. A possible explanation for the need
for these relatively higher doses in BDZ dependentpatients may be related to a pharmacokinetic and/or
pharmacodynamic mechanism. Methadone is metabolized in the liver by the P450 cytochrome system and, more specifically, by the CYP3A4 isoform,
which is involved in the metabolism of over 50% of
the medical agents [9, 17]. The wide inter-individual
variability [3, 24, 49, 53, 54, 56] recorded, and the
fact that CYP3A4 can be induced by several active
principles [20, 41], may explain why a number of
patients are under-medicated if a standard dose of
methadone is used.
Unfortunately we did not measure plasma methadone levels in our patients during the stabilization
phase, so we cannot determine whether the doses
used were necessary to maintain a proper therapeutic
window or to control an underlying underestimated
psychopathology.
In our patients the existence of a minor form of
psychopathology in the other patients concealed under the main addictive symptoms cannot be excluded.
There is significant overlapping between behaviours
in some types of psychiatric disorders and drug-relat-

ed behaviours: maladaptive behaviours, such as those


commonly displayed by drug-addicts, may sometimes be due to, or accentuated by, concurrent psychiatric disorders. Thus, a low degree of compliance
with therapies is a common symptom of drug addiction and of several forms of psychiatric disorders [4,
6, 19, 45]. In addition, we found that the outcome of
MMT patients with or without dual diagnosis is the
same in the short [39] and long term [37].
The low CGI score and the high GAF score values recorded for our patients and the absence of hospitalizations throughout the treatment period showed
that these subjects were simultaneously compliant
both with MMT requirements and with the specific
benzodiazepine therapy adopted. Cox regression suggests that the effectiveness of methadone treatment
supports the results obtained with methadone-clonazepam combined treatment. Additional clonazepam
for the treatment of benzodiazepine abuse medication not completely changed by the need to treat addiction may partly explain the positive outcomes
obtained in our comorbid patients, which cannot be
attributed exclusively to the effects of methadone.
A lack, whether of appropriately flexible methadone
doses and/or of specific medications given in association with methadone treatment for these patients,
could have been responsible for the conflicting results
obtained by other researchers, who reported that benzodiazepine and alcohol abuse were linked to worse
treatment outcomes (retention in treatment) [8, 11,
14, 18, 48, 51]. In addition, the psychotherapeutic
support provided by our team and the high therapeutic pressure of our programme could have been responsible for good results [2].
Limitations
In any case, the incisiveness of our study was
limited by several factors, such as the observational
nature of the protocol, the impossibility of evaluating
a follow-up in the case of the patients who dropped
out, the multiple interference caused by inter-individual variability (personality traits and their neurobiological correlates), the clinical setting and the temporary use of adjunctive medications. We therefore
chose this kind of research because of the fact that
we had little control over events, and there was a contemporary focus within a real life context. The goal
of our case study is to offer new points of view and
questions for further research, considering that 35%
of patients who enter methadone treatment can be described as regular/problem users [8].
- 61 -

Heroin Addiction and Related Clinical Problems 16(3): 55-64

5.

Conclusions

We can stress that patients with severe comorbid


BDZ dependence, if they are treated with over-standard dosages of methadone and co-treated with CMT,
may have outcomes that are satisfactory as long as
they are maintained on their medication in the long
term.
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Role of the funding source


Authors states that this study was financed with internal funds. No sponsor played a role in study design; in the
collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper
for publication.
Contributors
AGIM, SB, FR, LR, and IM revised literature and
conceived the methodology of the study (sample selection,
statistical analyses) discussed results and wrote the preliminary report. EM, LDO, PPP, MP discussed results. All
authors revised and approved the final form of the manuscript.
Conflict of interest
Authors declared no conflict of interest. IM served
as Board Member for Reckitt Benckiser Pharmaceuticals,
Mundipharma, D&A Pharma, and Lundbeck.

Received February 2, 2013 - Accepted April 18, 2014


- 64 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 65-74

Gender differences in severity of addiction in opiate-dependent outpatients


Marcela Mezzatesta-Gava 2, Carlos Roncero 1,2, Laia Rodriguez-Cintas 1,2, Gideoni Fuste 1,2,3,
Carmen Barral 1,2, Nieves Martinez-Luna 1,2, Miquel Casas 1,2, and Laia Miquel 1,2,4
1 Outpatients drug clinic (CAS) Vall dHebron, Hospital Universitari Vall dHebron, Agencia de Salut Pblica de Barcelona (ASPB), Spain, EU
2 Department of Psychiatry. Hospital Universitari Vall dHebron. CIBERSAM. Universitat Autnoma de Barcelona, Spain, EU
3 Private Practice, A Corua, Spain, EU
4 Network Group for Research in Woman Mental Health (GTRD).

Summary
Background. Opioid dependence is a prevalent health problem. The literature now available on how to achieve a better
knowledge of how this problem affects women, and on the importance of gender differences, is still limited. Aim. The
aim of this study was to characterize gender differences in socio-demographic features, clinical manifestations, comorbid
disorders and severity of opiate addiction, so as to define the role of gender differences in the severity of the addiction.
Methods. A cross-sectional, observational, descriptive study evaluated a total of 124 opiate-dependent patients seeking treatment from an urban outpatient programme. Both Axis I and Axis II diagnoses were assessed by applying the
Structured Clinical Interview for DSM Disorders I and II (SCID-I and SCID-II). The severity of addiction was evaluated
through the application of the European Addiction Severity Index (EuropASI) instrument. Results. Women experienced
a stronger impact from opioid addiction on their employment status, considering that the risk of presenting a severe ASI
composite score was 4.4 times higher than the risk for men (IC95% 1.3-15.1). Females had a higher likelihood of being
diagnosed with an affective disorder. Men showed a greater duration of regular heroin use, and were more likely to meet
the current criteria for alcohol dependence; these data correlated with a higher severity of the related ASI composite score
(OR=3.8 (IC95% 1.1-13.5)). Conclusions. Significant differences in the severity of addiction, substance use profile, psychiatric comorbidity and areas of impaired functioning were found to be due to gender differences.
Key Words: Drug Use; Gender Differences; Mental Health; Heroin; Psychiatric Comorbidities

1.

Introduction

Opioid abuse and dependence is a health problem that necessarily raises deep concerns. During the
last few decades, efforts have been made to achieve
a better knowledge and understanding of how this
problem affects women and gender differences. Initially, substance use disorders were classified as a
male problem, and most studies were focused on
male populations [34]. As a result, the available literature on the severity of opiate addiction in women
is still limited.
Severity of addiction has been related to the
presence of other psychiatric conditions age at onset of drug use, polydrug use, and so on. Previous
studies have shown that 34.2-83% of patients with

opiate dependence have one or even more comorbid


psychiatric disorders [16, 23, 28, 31]. Furthermore,
numerous studies have concluded that female opioid
users are more likely to exhibit higher levels of psychological distress [7, 16, 26, 31, 32]. In 2007, for example, Shu-Chuan found that 37.5% of female opiate
dependents had another axis I diagnostic, compared
with 11% for the male participants. Consistent findings about higher rates of depression in women have
been described [1, 27]. However, data related to anxiety disorders such as specific phobia [31], posttraumatic stress disorder (PTSD) [27] or eating disorders
[27] are contradictory [6, 16, 31].
Personality disorders (PD) are very frequent in
opiate-dependent patients (from 19 to 80%) [8, 11,
22] and their prevalence does not differ between

Corresponding author: Marcela Mezzatesta-Gava, Department of Psychiatry. Hospital Universitari Vall dHebron. CIBERSAM.
Universitat Autnoma de Barcelona, Passeig de la Vall D'Hebrn 35, 08035, Barcelona, Barcelona, Spain;
Phone: + 34 934893880; Fax: + 34 934893880; Mobile: +34692609890; E-mail: marcelamezz@hotmail.com

65

Heroin Addiction and Related Clinical Problems 16(3): 65-74

the sexes [16]. However, gender differences in the


type of PD were detected. While men had significantly more Antisocial Personality disorders [16, 27],
female subjects were more commonly diagnosed with
Borderline Personality disorder [27] and were twice
as likely as men to suffer from Paranoid Personality
disorder [16].
In most studies, the ASI instrument has shown
that opiate-dependent women experienced more severe effects in their employment status [2, 15, 20],
and in the medical [2, 10, 15, 19, 20] and psychiatric
areas [2, 10, 15, 19, 20], whereas men were more susceptible to legal problems [2, 27]. In any case, contradictory data still exist in the family & social [2, 33],
alcohol [2] and drug areas [2, 10]. These differences
might be due to different treatment settings and/or
cultural differences. Even though consistent findings
exist, there is still a lack of knowledge on differences
in severity that are due to gender in some areas of
importance. In planning treatment, it is important to
know whether gender differences exist, and which areas of functioning should be acted upon to achieve
better outcomes.
The present study aims to develop previous research by specifying gender differences in terms of the
severity of the addiction, and describing which functional areas are most affected in an opiate-dependent
sample recruited from an outpatient programme in a
drug treatment setting.
2.

Methods

2.1. Design of the study


We performed a cross-sectional, observational
study. The participants were patients that were attending the outpatient drug clinic at the Vall d'Hebron
University Hospital (Barcelona, Spain). The research
was approved by the Ethics Committee at the Vall
d'Hebron Hospital. This study is part of a more extensive research project on comorbidity in drug-dependent outpatients.
2.2. Sample
Inclusion criteria were: age over 18, opiate dependence according to DSM-IV criteria, and signing
an informed consent document prior to participation.
Exclusion criteria were: intoxication at baseline examination, severe somatic disease at baseline examination and low language proficiency. Patients did not
receive any financial compensation for participating
- 66 -

in this study.
Participants attending an outpatient programme
for opiate dependence were recruited consecutively
from 2006 until 2011. These patients had been referred
from primary care settings, the psychiatry emergency
department or from inpatient units. 269 patients seeking treatment for opiate dependence were accepted.
Of those, only 124 patients provided written informed
consent prior to any study procedures. The evaluation
process consisted initially in a mental examination by
a psychiatrist, followed by three interview sessions
conducted by trained psychologists.
2.3. Instruments
Sociodemographics and clinical data were recalled with a questionnaire designed ad hoc with
this proposal fulfilled by patients at the moment of
admission. The Spanish version of the European Addiction Severity Index was used [3,4] to assess the
severity of opiate addiction. This is a relatively brief,
semistructured interview designed to provide important information about aspects of a clients life that
may contribute to his/her substance abuse syndrome.
It measures several domains: medical status, alcohol
and drug use, employment and support status, family
and social relationships, legal status and psychiatric
status. The EuropASI is an adaptation of the fifth version of the Addiction Severity Index [12,13]. It is one
of the most widely used assessment and diagnostic
tools in Europe. As the European Addiction Severity
Index was the first psychological evaluation administered, no dropouts were registered. Diagnoses in Axis
I were assessed by the Structured Clinical Interview
for DSM Disorders, SCID-I; this instrument ensures a
good level of agreement between interviewers, with a
Kappa value of 0.70 to 1 [13]. Axis I diagnoses other
than Substance Use Disorders were studied, including Major Depression, Adjustment Disorders, Bipolar Disorders, Anxiety, and Psychotic Disorders. Dual
diagnosis was considered when patients had an Axis I
or II diagnosis other than SUD. Personality disorders
were evaluated through SCID-II; in assessing the degree of agreement between interviewers, we found a
Kappa value of 0.74 to 0.87 [12]. Personality disorders were classified in 3 groups: Cluster A (paranoid,
schizoid or schizotypal), Cluster B (histrionic, narcissist, borderline or antisocial), and Cluster C (avoidant, obsessive-compulsive and dependent). Drug use
assessment included mainly opiates and alcohol, and
then other drugs such as cannabis, amphetamines and
cocaine.

M. Mezzatesta et al.: Gender Differences in Severity of Addiction in Opiate-Dependent Outpatients

2.4. Data analysis


Statistical descriptive analyses were carried out
for sociodemographic and clinical data in terms of
frequencies, means and standard deviation. Normality assumptions were verified using the KolmogorovSmirnov test. The ASI composite score was transformed into a binary variable due to its irregular
distribution. The median of each ASI composite score
for the whole study sample was used as the cut-off
to distinguish between severe and non-severe problem areas included within the composite score (ASI:
Medical >0.255; Employment >0.69; Alcohol > 0.05;
Drugs >0.263; Legal >0; Family and Social >0.31;
Psychiatric >0.36). The relationship between categorical variables was investigated by using the 2
Pearson test. When the expected frequency was lower
than 5, Fishers exact test was applied, as happened
with the following variables: Antisocial Personality
disorder and cluster C PD. T-tests were used to examine quantitative measures by gender. All statistical
tests were two-sided. The statistical difference for all
tests was set at p values less than or equal to 0.05.
A multiple logistic regression was carried out with
gender as the dependent variable. The objective was
to determine the relationship between gender and the
Addiction Severity Index, after adjusting for alcohol
dependence and the mean length of years of regular
use of opiates. Variables in which gender differences
reached statistical significance in the univariate analysis, and could, theoretically, act as confounding factors, were included in the logistical regression as covariates. The Statistical Package for Social Sciences
(SSPS 18.0) was used for data analysis.
3.

Results

higher for women than for men (Men: median 0 children, range (0-2) vs Women: Median 1, range (0-3);
t= 2.7, p=0.009).
3.2. Gender differences in substance use profile
At the time of the evaluation, 30% of patients reported active opiate consumption. Out of the 70% that
were abstinent, 30% had sustained abstinence for a
brief period, while the remaining 40% had been able
to sustain abstinence for over a month. In addition,
48.4% of the sample had a daily use of opiates, 34.4%
were abstinent and 17.2% consumed once a week or
less, but no gender differences were observed. The
most frequently used route of administration was intravenous (56.6%). The mean length of regular use
was higher in men than in women: 12.8 (SD 9.1)
years vs. 8.4 (SD 6.8) years (t= 2.6, p=0.047).
Men were more likely to meet the criteria for
alcohol dependence than female participants (40.4%
vs 14.3%; 2 = 5.9, p= 0.015). Abuse of sedatives and
dependence on them were higher in women. At least
14.8 % of the female sample abused benzodiazepines,
against 10.5% of their male counterparts. Similarly,
women showed a stronger tendency to depend on sedatives than their male counterparts (39.3% vs. 21.1%),
although this difference was not at a significant level.
3.3. Medical comorbidity
69.1% of the total sample presented at least one
medical comorbidity. 47.2% of the sample were affected by an infectious disease and 49% presented
a history of hepatic disease (including Hepatitis C).
Even though no significant differences were detected,
78.8% of women reported a previous medical record
vs. 65.6% of the male sample.

3.1. Description of the sample:

3.4. Other Psychiatric Diagnoses

A total of 124 patients (27.4% women) were


evaluated. The mean age of the whole sample was
37.7 years (S.D. 8.0).
Table 1 shows sociodemographic and clinical gender differences. No significant differences
between genders were observed in the sociodemographic features except for marital status. Half of
the women in the sample were married, 41.2% were
single, and only 8.8% divorced. On the other hand,
most men were single (47.2%), 21.8% were married
or lived with a partner, and 24.7% had divorced (2=
6.7; p=0.0035). The mean number of children was

Regarding Axis I, the female group showed a


greater likelihood of being diagnosed with a Major
Depressive Disorder (2= 5.04, p=0.024) or an Anxiety Disorder (2= 6.04, p=0.014) (Table 1).
In addition, with reference to Personality Disorders, 41.9% were diagnosed with a cluster B Personality Disorder. Moreover, 40% of the males in the
sample presented Antisocial Personality Disorder,
compared with 20% of women (F=3.7, p=0.055).
Furthermore, 4.3 % of the sample met the criteria for
cluster A Personality Disorder and 5.4% were suffering from a cluster C Personality Disorder, with a
- 67 -

Heroin Addiction and Related Clinical Problems 16(3): 65-74

Table 1. Sociodemographic and clinical characteristics by sex

Men

Women

n=90

n=34
%

Academic Level
Uncompleted Primary School

18

20.2

26.5

Completed Primary School

27

30.3

26.5

Secondary School

38

42.7

15

44.1

6.7

2.9

University
Marital Status
Single

42

47.2

14

41.2

Married/Stable Couple

25

28.1

17

50

Separated/Divorced

22

24.7

8.8

Employment Status
Employed

13

14.8

14.7

Unemployed

40

45.5

13

38.2

Pensioner/Sick leave

18

20.5

14.7

Other

17

19.3

11

32.4

Mean

SD

Mean

SD

1.19

0.75

6.7

0.03

2.54

0.46

Opioids Use profile


Age at onset

20.8

6.8

20.9

7.2

0.25

0.8

Age at regular use

22.9

6.9

22.9

8.7

0.46

0.6

Years of regular use

12.8

9.1

8.4

6.8

2.63

0.01

Route of administration
Intravenous
Intranasal

52

57.3

18

54.5

23

25.8

12.1

0.08

0.02

Smoked
Other
Current pattern of drug use
Daily
Several times per week
Once a week
Others
Abstinence during evaluation

15
0

16.9
0

8
3

24.2
9.1

34
10
5
14
35

37.1
11.2
5.6
15.7
71.4

13
3
0
2
16

39.4
9.1
0
6.1
69.6

0.08

0.25

0.02

0.87

Previous treatment

77

85.4

26

73.5

0.12

0.29

Overdose episodes

36

41.9%

12

35.3%

0.51

0.54

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M. Mezzatesta et al.: Gender Differences in Severity of Addiction in Opiate-Dependent Outpatients

Table 1. Sociodemographic and clinical characteristics by sex


Men

Women

n=90

n=34

Co-morbid substance use


Alcohol Dependence

23

40.4

14.3

5.8

0.01

Sedatives Dependence

12

21.1

11

39.3

3.16

0.07

Cannabis Dependence

16

28.1

21.4

0.43

0.51

Cocaine Dependence

40

70.2

18

64.3

0.30

0.58

Psychiatric History

52

58.4

17

51.5

0.46

0.49

Dual Diagnosis

55

61

15

44.1

2.89

0.08

Bipolar Disorders

3.5

1.06

0.31

Depressive Disorders

5.4

21.4

5.04

0.02

Anxiety Disorders

10.5

3.21

6.03

0.01

Psychotic Disorders

1.8

0.49

0.48

Cluster A PD

4.7

3.4

0.07

0.78

Cluster B PD

29

45.3

10

34.5

0.96

0.32

Cluster C PD

1.6

13.8

5.86

0.01

Medical Comorbidity

31

34.4

21.2

1.98

0.15

Infectious Diseases

43

47.8

15

45.5

0.05

0.82

Hepatic Diseases

32

45.1

18

58.1

1.45

0.22

higher percentage recorded for women (1.6% men vs.


13.8% women) (F=5.6, p= 0.032).
3.5. Gender differences in severity of addiction
Data on gender differences in the severity of
these problem areas (medical status, employment/
support status, alcohol and drug use, legal status,
family/social relationships and psychiatric status) are
shown in Table 2. Regarding the composite employment total, women experienced greater severity in
this problem area than men (67.6% vs 41.1%). Even
though the differences in employment status were
not significant, after adjusting for alcohol dependence and years of regular opiate use, women had an
OR=4.4 (IC95% 1.3-15.1) of having a severe setback
in the ASI employment status problem area, a figure
higher than that for men (Table 3).
On the other hand, men showed greater severity in the alcohol use problem area, as almost 51.1%

of men, vs 29.4% of women, had a severe repercussion 2= 4.7, p=0.03). After adjusting for confounding factors, opiate-dependent men had 3.8 times more
risk of having a higher score in the ASI alcohol composite score (IC95% 1.1-13.5) (Table 3). Moreover,
despite the fact that no significant differences were
found, men showed more problems in the legal status
problem area (38.9% of men vs 23.5% of women).
No statistically significant differences were observed
in drug status, medical status, psychiatric status or in
the family and social relationships composite scores
recorded for the ASI, although these areas were found
to be severely affected in around half of the sample
(Table 2).
4.

Discussion

The present study examined gender differences


in the severity of opiate dependence among 124 opioid-dependent outpatients seeking treatment. We only

- 69 -

Heroin Addiction and Related Clinical Problems 16(3): 65-74

Table 2. ASI composite scores in terms of severity by sex.


Severe Composite
Medical
Employment
Alcohol
Drugs
Legal
Family and social
Psychiatric

Men
n
39
37
46
44
35
44
43

Women
%
43.3
41.1
51.1
48.9
38.9
48.9
47.8

found gender differences in the severity of employment and alcohol areas. Women experienced greater
repercussions in the employment area, whereas men
had a more severe impact in the alcohol area.
Consistently with previous studies of treatmentseeking inpatient and outpatient samples, less than
one-third (27.4%) of the current sample were women
[3, 4, 16, 17, 29, 33]. No differences in sociodemographic features were found, in contrast with other
studies, where fewer women, percentagewise, were
found to be divorced or separated, widowed, living
with their children and unemployed [4, 7, 16, 17, 30,
31, 33].
Despite there being no evidence of gender differences in the sociodemographic data related to employment aspects, women showed greater severity in
the repercussions on this problem area, as revealed
by a higher ASI composite score. This inconsistency might be due to the role that having a driving
licence plays in the ASIs employment status composite score, since, in our environment, using public
transport is a common way of travelling to work, and
not having a driving licence is not a major obstacle
to working. This kind of item was not included in the
sociodemographic questionnaire, which was mainly
focused on working status.
As to the substance use profile, the only statistically significant gender differences found were those

n
19
23
10
18
8
18
16

%
55.9
67.6
29.4
52.9
23.5
52.9
47.1

c2
1.7
7.0
4.7
0.2
2.6
0.2
0.01

p-value
0.2
0.008
0.03
0.7
0.1
0.7
0.9

on the length of regular use, with men having a longer


duration of regular use (12.8 vs. 8.4 years) by the time
they enrolled in treatment. This finding matches results described by previous studies [18,25,35]. Even
though age at onset was similar for the two genders,
the male sample presented a greater length of opiate
use than the female sample a finding that could be
attributed to sustained abstinence during pregnancy
and a better level of compliance with treatment by
female drug-dependent patients. Supporting this hypothesis, the women included in our sample had more
children than the men. No gender differences were
found to arise from the family/social relationships
shown in the ASI composite score.
The literature currently available has reported
that males are more likely to meet the criteria set for
another substance use disorder [16, 29, 31, 32, 33],
while women were said to become more rapidly addicted to drugs such as cocaine and heroin [10]. Those
results, however, were not confirmed by the present
study.
The assessment of comorbidity with the abuse of
other drugs made it clear that men were more likely
than women to meet the criteria for alcohol dependence (40.4% vs. 14.3%); this finding was correlated
with the greater severity recorded in the ASI alcohol
composite score [33]. On the other hand, women
were found to be more likely to abuse or depend on

Table 3. Logistic regression: Relationship between sex and ASI composite score after adjusting for confounding variables
95% C.I. for EXP(B)
B
S.E:
Wald
df
Sig.
Exp (B)
Lower
Upper
Years of regular use
-0.074
0.036
4.1
1
0.042
0.9
0.9
1.0
Alcohol dependence
-1.688
0.755
5.0
1
0.025
0.2
0.0
0.8
ASI Employment
1.47
0.633
5.4
1
0.020
4.4
1.3
15.1
ASI Alcohol
-1.347
0.638
4.4
1
0.035
0.3
0.1
0.9
Constant
0.409
0.647
0.4
1
0.528
1.5
Dependent variable (gender): 0 males 1 females.

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M. Mezzatesta et al.: Gender Differences in Severity of Addiction in Opiate-Dependent Outpatients

sedatives, although that had not proved to be a significant factor in the reports published in the previous
literature [9, 10, 16, 33].
69.1% of the sample had a comorbid medical condition. Nevertheless, no differences appeared
between female and male subjects in their previous
medical conditions a finding that is partly discordant with previous reports [3, 33, 25]. These discordant
outcomes might be explained by the fact that studies
display important differences in the recruiting setting.
In the study conducted by Back et al, for example, the
only patients included were those with a prescription
opiate dependence comprising a previously diagnosed
medical condition [2]. Moreover, Haugh et al evaluated the severity of addiction in a sample consisting
mainly of HIV patients who were attending a methadone maintenance programme [19]. This study failed
to detect any significant differences between genders
as attested by the Medical ASI composite. It is worth
noting that our centre is an integral part of a general
hospital that offers patients a suitable follow-up of
their organic diseases and easy coordination with the
outpatient infectious disease programme.
Significant gender differences in psychiatric
comorbidity were revealed, with women being more
likely than men to report a current and past history
of psychiatric problems, as shown too in previous
reports [9, 16, 20, 31]. Almost half (48.5%) of our
female participants reported experiencing psychiatric problems in the past. This study also shows
higher frequencies for Major Depression Disorders
and Anxiety Disorders in treatment-seeking opioid-dependent women than in men (20.6% vs. 4.6%
depression; 31.3% vs. 9.3 anxiety, respectively). Despite having found a significantly higher prevalence
of psychiatric comorbidity in women, no statistically
significant differences were found in the measurement of severity shown in the composite scores of
the psychiatric status problem area, in contrast with
the findings described by other authors [3, 10, 16, 20,
33]. A possible explanation for this result might be
the tendency among female patients from our sample
to seek treatment when they are in a more stable clinical phase, consistently with previous findings which
report that women tend to enter treatment at an earlier
stage of the course of their addiction, which is also
generally viewed as a positive outcome factor [10].
Another possibility is that a bias in prioritizing the
assessment of the drug abuse at the expense of comorbidity might have taken place. A further feasible explanation may be found in the intrinsic characteristics
of the set of items used to assess the psychiatric status

problem area. The item having depressive symptoms


unrelated to substance abuse is found to be difficult
to assess without a maintained period of abstinence
a condition achieved in our sample. Another item is
receiving a pension for psychiatric disability, and,
as shown previously, no significant differences were
found in the prevalence of psychotic disorders, which
normally accounts for the impairment of disabled
people, so increasing the likelihood that they will obtain a pension. In our study, the main differences were
found in the prevalence of affective disorders that are
rarely severe enough to make someone eligible for a
disability pension. In the end, the item being hospitalized in the past 30 days is a finding that is limited
in time and delimited in intensity; in other words, it
does not necessarily reflect the presence of mental illness. In any case, this study did not detect more severe repercussions for women in the ASI psychological/psychiatric composite.
In general, among treatment-seeking samples of
individuals with substance use disorders drawn from
a specific community, women consistently demonstrate higher rates of psychiatric comorbidities than
men. It is thought that, in women, psychiatric illness
may precede the development of substance use disorders, as postulated by the self-medication hypothesis,
suggesting that women often use substances to cope
with negative affect [11, 31, 33].
On the topic of axis II, the men in our sample
showed a stronger tendency to have Antisocial Personality disorder (40% vs. 20%), in agreement with
previous research [14, 16, 23, 24, 29, 31]. Despite this
finding, the present study failed to detect any differences in the ASI legal status composite, as might have
been expected, considering the close relationship between this disorder and legal problems. Another significant discovery was that no differences could be
recognized in Borderline Personality disorder, in contrast to the study carried out by Grella in 2009 [16].
Even though the present study has observed a higher
prevalence of cluster C Personality Disorder in the female sample, this finding should be interpreted with
caution, considering the small size of the sample.
Limitations
The sample of patients examined may not be
representative of the population of women and men
seeking treatment for opiate dependence, as a large
number of eligible subjects declined to participate.
Moreover, we had no opportunity to compare our
sample with those who did not participate. Further- 71 -

Heroin Addiction and Related Clinical Problems 16(3): 65-74

more, the small number of women showing some


characteristics (for example, cluster C Personality
Disorders) included in the study might not allow us to
detect significant gender differences [4, 3, 21, 33]. In
addition, even though the instrument used to evaluate
severity was the European version of the ASI, some
items might be not strictly comparable. For instance,
there are descriptive variables, such as employment
status, which are different for men and women, regardless of whether they have a substance use disorder (e.g., the high percentage of women who are
housewives).
5.

Conclusions

Opiate dependence has been shown to determine a serious impairment in several areas of functioning. In our study, in line with previous research,
women experienced more severe repercussions in the
employment problem area than men. Men reported
a greater severity in the ASI alcohol use composite
score, which, in our sample, was correlated with a
greater comorbidity with alcohol dependence. Women presented higher comorbidity with depression,
even though these differences compared with men
were not reflected by the psychiatric status composite
score. Contrary to other outcomes, no differences in
family/social relationships, legal status, medical status or drug use ASI composite scores were observed.
These findings may prove to be useful for other
outpatient drug programmes run by public health care
systems in similar settings. Integrated treatments for
opioid dependence and co-occurring psychiatric conditions are needed, as well as specific interventions
(such as prevention of alcohol dependence in male
patients) and systems of care that address collateral
functional areas in the lives of women for instance,
working rehabilitation and other social services.
By studying gender differences in terms of
substance-related epidemiology, social factors and
characteristics, biological responses, progressions
to dependence, medical consequences, co-occurring
psychiatric disorders, and barriers to treatment entry, retention, and completion can all be recognized
as having a wide range of clinical, treatment, and research implications.
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Acknowledgments
We are grateful to our research team for their support, particularly our Psychologist Research team: Susana
Gmez-Baeza, Sonia Fuentes and Yasmina Pallars. Special thanks are due to Sergi Valero for his methodological
assistance.
Role of the funding source
Grant of the Departament de Salut, Government of
Catalonia, Spain, for publication.
Contributors
All authors revised and approved the final form of the
manuscript.
Conflict of interest
The authors have no potential conflicts of interests
to declare.

Received January 6, 2014 - Accepted April 4, 2014


- 73 -

Regular article
Heroin Addict Relat Clin Probl 20xx; xx(x): xx-xx

Limbic system irritability and drug dreams in heroin-addicted patients


Claudio Colace 1, Sergio Belsanti 2, and Antonia Antermite 3
1 U.O.C. Psychology, AUSL Viterbo, Civita Castellana, Italy, EU
2 Centre for Drug Addiction, AUSL Viterbo, Tarquinia, Italy, EU
3 U.O.C. Psychology, AUSL Viterbo, Viterbo, Italy, EU

Summary
Background. Drug dreams, that is, the dreams of drug-addicted patients with contents related to their craving for the
drugs they are addicted to, have been investigated to determine their clinical and prognostic significance, as well as for
their implications from the standpoint of general dream research and theory. Recent progress in the neurobiology of drug
addiction and drug craving, affective neuroscience, and the neuropsychology of dreaming, provide a background for
investigating the possible neurobiological correlates of these dreams, which may deepen our understanding of the close
link between drug dreams and the craving for drugs. Aim. This paper investigates the relationship between drug dreams
and limbic system activity in drug-addicted patients as measured by means of the Limbic System Check List-33 (LSCL).
Methods. 53 heroin-addicted subjects were interviewed about their drug dreams; the interviews made use of the Drug
Dreams Questionnaire. Results. The results show that drug-addicted patients reported an LSCL mean score that indicates
limbic system irritability. Furthermore, patients whose experience included drug dreams reported a higher, statistically
significant LSCL mean score than patients who had not had any drug dreams. Our results are also consistent with previous
studies regarding the phenomenological picture of drug dreams and their clinical applications. Discussion and conclusion. We assume that, in the patients who reported drug dreams, the higher LSCL scores may be due to the presence of
a stronger drug craving, of which the higher mesolimbic-mesocortical dopamine tone is the neurobiological correlate.
The association between the greater limbic DA tone and the occurrence of drug dreams appears to be consistent with
the results of clinical-anatomical studies on dreaming with reference to the crucial role of the mesolimbic-mesocortical
dopamine system in the instigation of dreams.
Key Words: drug dreams; addiction; limbic system; seeking system.

1.

Introduction

Drug dreams is the term commonly used in the


literature to define the dreams of drug-addicted patients that have contents related to their craving for
the drugs they are addicted to [10, 12, 15, 21, 36, 56,
59]. These dreams are a well-documented clinical
phenomenon in all forms of addiction [10, 18, 19, 36,
49, 59] and have been investigated in terms of clinical
usefulness and prognostic significance in the treatment of addicted patients [4, 10, 12, 29, 36, 46, 57,
59, 65, 72], as well as in their implications from the
standpoint of general dream research and theory [15,
18, 28, 14, 16, 42, 45].
More recent studies have also made an attempt
to investigate the possible neurobiological substrate

of drug dreams [17, 19, 42] by integrating current


knowledge of the neurobiological substrate of drug
addiction [54], the findings of what is now known as
affective neuroscience [55, 71], and the results of
clinical-anatomical studies of dreaming [61, 62, 73].
Studies on the neurobiology of addiction converge in indicating the mesolimbic-mesocortical
dopaminergic (ML-MC DA) system as the principal
area engaged in addiction diseases [9, 55, 64]. This
system arises in the mid-brain ventral tegmental area
(VTA) and is projected towards the limbic structures
in particular, the nucleus accumbens (NAc), the
amygdala (and the so-called extended amygdala),
the hippocampus, the prefrontal cortex, including the
orbitofrontal portion (OFC) and the cingulate gyrus
[20, 24, 25, 33, 47, 48]. According to the incentive-

Corresponding author: Claudio Colace, Ph.D., via Luigi Volpicelli, 8, 0133 Roma, Italy, EU
Phone: 3336148977; e-mail: claudio.colace@yahoo.it

75

Heroin Addiction and Related Clinical Problems xx(x): xx-xx

sensitization model of drug addiction [60], repeated


exposure to addictive drugs produces a long-lasting
sensitization in the ML-MC DA system that normally
regulates the attribution of incentive salience to stimuli, so that an abnormal level of incentive salience
comes to be attributed to drugs and drug-associated
stimuli, which, as a result, become pathologically
amplified (so leading to abnormal wanting, and a
craving for drugs).
The ML-MC DA system has also been described
in affective neuroscience studies as the core component of the SEEKING system [38, 55] or wanting
systems [5,6], that is, the neuronal circuits involved in
the instigation of goal-seeking behaviours and appetitive interactions with the world, including hunger and
sexual desire (i.e., the basic drives), which comprise
the craving for drugs experienced by people who have
become drug-addicted.
According to Solmss clinical-anatomical studies, the part of the brain involved as the primary
generator of dreaming is the white matter surrounding the frontal horn of the lateral ventricles (i.e., the
ventromesial quadrant of the frontal lobes), exactly
the part of brain that includes the ML-MC DA system
[61, 62]. Actually, Solms found an overall cessation
of dreaming in a group of patients affected by bilateral frontal lobe lesion [61]. This finding was later
confirmed by Yu [73].
Johnson [42 43, 44], in the first attempt made
to integrate the above evidence, suggests that drug
dreams arise from an alteration of normal dreaming
processes (drug dreams do not occur in healthy people) caused by persistent changes in the neurological
functions of drug-addicted patients (i.e., the upregulation of the ML MC DA system). Subsequently, Colace [17] and Colace et al. [19], in agreement with
Johnsons hypothesis, found that a sample of drugaddicted patients showed limbic system irritability,
as measured by means of the Limbic System Check
List-33 (LSCL-33) [68], and a high frequency of
drug dreams, while occasional drug users (i.e., those
with no diagnosis of drug dependence, and without
any presence of drug craving) did not report either
limbic irritability or drug dreams. These authors hypothesized that the limbic system irritability of drugaddicted subjects, as the expression of the upregulation of ML-MC DA circuits, could be the signal of
a greater availability of dopaminergic tone that, in
its turn, could be the specific neurobiological background in which drug dreams might preferentially
occur [19]. Actually, there is evidence that: a) drugaddicted patients show a limbic system irritability [7,
- 76 -

39, 67] which is positively correlated with alcohol


craving [7, 39], and that: b) drug dreams are more
frequent when there is an increase in drug craving [3,
12, 28] that is neurobiologically mediated by greater
ML-MC DA release levels [23, 24, 26, 69].
Investigation of the neurobiological substrate
that underpins drug dreams could have a useful impact on our understanding of the close link between
drug craving and these dreams; this, in its turn, could
lead to a better clinical and prognostic use of these
dreams, and to their use in evaluating the effectiveness of the pharmacological treatment of drug addiction. The study of Colace et al. [19] was the only one
in which drug-addicted patients were scrutinized both
in terms of their recollections of drug dreams and of
the measurement, even if indirect, of limbic system
activity, and was not followed by any attempt at replication. Furthermore, the hypothesis about the role
that high dopamine levels might have in the onset of
drug dreams still calls for some more direct testing.
The twin aims of this study were to evaluate
limbic system activity in heroin-addicted patients,
and compare the degree of limbic system activity
between drug addicts who reported drug dreams and
those who did not.
We formulate two main hypotheses: (a) drugaddicted patients all show high LSCL-33 scores, so
suggesting limbic irritability; (b) the drug-addicted
patients who report having had drug dreams actually
record LSCL scores that are higher than than those
of drug-addicted patients who do not report that kind
of event. The questionnaire on drug dreams used in
the present study also allowed us to investigate the
following topics: 1) frequency of drug dreams, 2)
when drug dreams appear (i.e., abstinence vs. regular
use), 3) contents and emotions in drug dreams and on
awakening, 4) the role of drug dreams in making abstinence more likely on the next day, 5) the influence
of pharmacological treatment for drug addiction on
the occurrence of drug dreams.
2.

Methods

2.1 Subjects
There were 53 drug-addicted subjects (45 male,
8 female), mean age 34, who arrived consecutively
at the Centre for Drug Addiction over a six-month
period. Their drug dependence diagnosis was based
on DSM IV criteria (2). All subjects used heroin as
their primary drug of dependence. Of these subjects,
8 were also dependent on cocaine, 2 on alcohol, and

C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients

2 on cannabis.
Of these subjects, 50 were pharmacologically
treated. Forty-four (88%) of them were treated with
methadone, six (12%) with buprenorphine. The remaining three subjects were treated with psychological support only.

2.4 Ethical standards

2.2 Assessments

Analyses were performed using the Statistical


Package for Social Science (SPSS) for Windows, Version 11.0. Frequencies, percentages, means, median,
binomial test and t-test were the statistical indicators
used.

The data on drug dreams were collected through


a Drug Dreams Questionnaire (DDQ) that included
questions about drug dreams since the start of heroin
dependence and the latest drug dream recalled (Appendix 1).
Limbic system activity was assessed by means of
the Limbic System Checklist, LSCL-33 [68]. LSCL
is a 33-item self-report questionnaire designed to
measure temporo-limbic activity. This questionnaire
was originally devised to ascertain the frequency
symptoms suggestive of temporal lobe epilepsy. Subjects with well-documented temporal lobe epilepsy
that was responsive to anticonvulsants reported high
scores. The questionnaire included four item areas:
somatic, sensory, behavioural and memory symptoms
suggestive of limbic system dysfunction. The LSCL33 showed good psychometric properties and internal
consistency (Cronbachs alpha 0.90). Subjects rated
the frequency of symptoms using a 4-point Likert
scale (never=0, rarely=1, sometimes=2, often=4).
The subjects who had temporal lobe epilepsy reported high scores (range 23-60), while normal adults reported scores <10. The LSCL-33 is correlated with
other measures of limbic dysfunction (e.g., the Hopkins Symptom Checklist) [45]; and the CPSI (Complex Partial Seizure-like) [67].
The following information was noted for each
subject: type of pharmacological therapy (buprenorphine, methadone, psychological support only), dosage (mg/day) related to the time when the patient had
the latest drug dream, and other possible forms of
secondary drug dependence (Appendix 1).
2.3 Procedures
The data were collected in two Centres for Drug
Addiction. The interviewers, who were not aware of
the research aims, after obtaining the patients informed consent, asked each one of them to answer
the DDQ questionnaire and the LSCL-33.

The study was carried out according to the principles laid down in the Helsinki Declaration.
2.5 Statistical analyses

3.

Results

Two subjects did not complete the LSCL-33.


LSCL-33 mean score in drug addicted subjects was
23.29. Drug-addicted patients who reported drug
dreams had significantly higher LSCL-33 scores
(mean = 26.59) than the other patients (mean = 16.71)
(T-test = -2.214, df = 47.525, p = .03)
The patients recalled two (general) dreams a
week (median score). There were 35 patients (66%
of the group) who reported having had drug dreams
since they started using heroin; the remaining 18
(34%) did not report having had any drug dreams.
Almost half of the patients had drug dreams
while not using heroin (45.7%) (Table 1). Very few
patients had drug dreams during a period of regular
drug use (8%).
Table 1. When drug dreams occur
Occurrence of drug dreams
When I decided to stop using heroin
When I could no longer use heroin
When I was using heroin
Either (both during use and non-use)
Uncertain

N
9
7
3
15
1

%
25.7
20.0
8.5
42.8
2.8

Among the patients who recalled their most


recent drug dreams, 53% had not used heroin for at
least a week previously, while 47% had used it.
Drug dreams were reported even after a long
period of abstinence (six months or more), but they
mostly occurred (56%) after abstinence from drug
use lasting for a period of 15 days to 3 months (Table
2).
Of the patients interviewed, ten had been in a
community (without any opportunity to use drugs) in
previous periods. Of these ten, five (50%) reported
having had drug dreams while they were staying in a
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Heroin Addiction and Related Clinical Problems xx(x): xx-xx

Table 2. Duration of abstinence before onset of drug


dreaming
Abstinence
N
%
15 days
3
16.7
At least 1 month
4
22.2
About 3 months
3
16.7
About 6 months
2
11.1
More than 6 months
6
33.3
N=18 (17 patients were unable to answer this question)

Table 3. Type of dream about drugs


Type of dream about drugs
Seeking (buying, seeing, having) my
drug
Using the drug
Unsuccessful attempt to use heroin
Seeing others use heroin
Fear of being caught
Refusing heroin

15

23.0

7
13
4
3
0

20.0
37.1
11.4
8.6
0

therapeutic community.
The dream contents are shown in table 3. The
most frequent type of drug dream comprised those
that were about seeking or using heroin (43%). This
category was created by putting together the answers
of patients who used heroin in their dreams with other
responses in which patients sought, bought, saw, or
took heroin in the dream (i.e., activities related to drug
Table 4. Emotions in the most recent drug dream and
on waking up
Emotions felt in dream
N
%
Anguish
15 42.9
Pleasure
6 17.1
Guilt
3
8.6
Fear
3
8.6
Anger
1
2.9
Other emotions
3
8.6
Do not recall
4 11.4
Emotion felt on waking up
Anger at realizing that I had not really
7 22.6
used heroin
Relief, on realizing that I had not real4 12.9
ly used heroin
I felt no emotion
6 19.4
I felt other emotions
4 12.9
I felt anguished
3
9.7
I felt satisfied
3
9.7
I felt irritated by the idea of having
4 12.9
dreamt about heroin
No answer
4 11.4

- 78 -

use). The second category of drug dreams was about


unsuccessfully attempting to use heroin. In these
dreams, the attempt to use heroin failed for some reason. No dreams of drug refusal were observed. The
drug that appeared in the dreams was the one that
subject was dependent on. The majority of dreamers
reported feelings of anguish in their drug dreams, and
then a feeling of anger and disappointment on waking
up because they had not really taken heroin. Other
emotions during the dreams and on waking up are
shown in table 4.
Most patients who had drug dreams did not use
heroin on the next day (71.8%, 23/32), while the remaining patients (28.2%) used heroin (binomial test,
p = .022 based on Z approximation). The patients
who stayed clean felt a lower perceived drug craving
(26%, 6/17) on waking up, while the others experienced no change (73.9%). Of the patients who used
heroin on the next day, 33% (3/9) felt a greater drug
craving, while 66% did not.
At the time of reported drug dreams, 25 out of
34 patients were receiving methadone treatment, 4
were being treated with buprenorphine (mean: 15 mg/
day, range 2-25 mg/day), and 5 were not receiving
any pharmacological treatment.
Of the patients being treated with methadone, 14
were on a low, anti-withdrawal dosage (50 mg/day)
and 10 were on a high, anti-craving dosage (70 mg/
day or more): drug dreams occurred in a similar way
in patients in these two situations.
4.

Discussion

4.1. When drug dreams are likely to appear


Almost one out of two patients reported having
had drug dreams during periods of drug unavailability, while only three patients stated explicitly that they
had had drug dreams while using drugs regularly. A
substantial number of patients, probably due to the
difficulty they experienced in remembering in which
condition abstinence or regular use they had had
drug dreams, responded ambiguously: "in both conditions. The first result is consistent with patients who
had spent time in a therapeutic community, without
any opportunity to use drugs; the proportion of these
patients who reported having had drug dreams was
one out of two.
Focusing now on the last drug dream remembered, as a qualitative observation (without statistical
significance) it should be noted that more than half
of the patients reported that they had not used drugs

C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients

at least during the preceding week, and that they had


remained abstinent during the three months preceding the most recent drug dream. Among the patients
who reported having used drugs during the week preceding the drug dream, the answers collected did not
allow us to understand whether such use referred to
daily, continuous use, or to a single relapse after a period of abstinence. In the latter case, the relapse itself
may have been preceded by a sudden recrudescence
of drug craving, as indicated, in fact, by the onset of
drug dreaming.
The above data are in line with previous studies that had found that the onset of drug dreaming is
triggered by a condition of abstinence (10, 13, 15).
For example, previous observations have shown that
during imprisonment or after admission to hospital,
in fact, whenever these patients find difficulty in obtaining drugs for example, due to lack of money or
due to being detained by the police they report drug
dreams [13, 15, 17, 49, 72]. Similarly, previous studies show the presence of drug dreams in the initial
stage of abstinence from drug use, that is, from one or
two weeks to two or three months counting from the
start of treatment of drug-addicted patients [10, 18,
36, 57]. It is very likely that the increased frequency
of drug dreams in a condition of abstinence is due to
the frustration arising from drug craving (i.e., an increase in drug craving pressure) that patients experience in this circumstance. Indeed, some authors have
suggested that abstinence produces a motivational
state resembling a biological deprivation (e.g., hunger), and increases the motivational impact of drugassociated cues, multiplying craving intensity through
a greater presence of acute drug craving episodes [24,
27, 47, 51, 66]. In any case, when drug craving is, in
itself, already at a high level (without being exacerbated by abstinence), or when it suddenly becomes
recrudescent, this may result in a return and/or increase in the occurrence of drug dreams [18].
4.2. Phenomenological aspects of drug dreams
Our data confirm that drug dreams are a widespread phenomenon among drug-addicted patients.
Indeed, even if our patients were generally not good
dream recallers, they reported drug dreams in a high
percentage of cases, as found in previous studies with
heroin-addicted patients and with patients with other
forms of dependence [4, 12, 18, 37, 59]. Most studies agree on the fact that the most frequent content
of drug dreams is the use of the drug the patient is
addicted to (i.e., the patient finds him- or herself us-

ing that particular drug) and other activities related to


drug use, that is, seeing/seeking drugs, handling or
buying drugs/alcohol. Another frequent content is an
unsuccessful attempt to use drugs [10, 12, 13, 15,
19, 37, 49, 59, 72]. Drug dreams presenting an explicit rejection of the drug have been observed more
rarely [4, 59]. Our results confirm this phenomenological picture. The common theme of drug dreams
in our patients is their craving for drugs that they attempt to satisfy, sometimes successfully, sometimes
not. As noted in other studies, in these dreams there
may also be no more than the pleasant possession of
a drug, a feature that may forerun or partly predict its
use (18).
The main emotions in drug dreams were anguish and pleasure. The reasons for these emotions are quite clear. In drug dreams there may be the
pleasure of using, or attempting to use drugs, without
the presence of anguish when the desire for the drug
seems to be consciously accepted by the dreamer.
These types of drug dreams have been interpreted, in
psychoanalytic terms (31), as an infantile form of
wish-fulfilment dreams in adults [10, 13, 15, 18, 50].
For drug dreams as assessed from a psychoanalytic
viewpoint, see also: [22, 28, 58]. On the other hand,
when the desire for a drug is rejected by the dreamers conscience (i.e., when the drug is the aim of a
repressed wish), and then its satisfaction or attempted
satisfaction in the dream clashes with the patients
new intention to change (i.e., stay clean, refrain from
using heroin), feelings of anguish and sometimes guilt
may occur. As found in previous studies, drug dreams
were followed, on awakening, by two main feelings
in particular, anger on realizing that drug use was
not real, or, by contrast, relief on realizing that the
relapse was not real [8, 15, 30]. Colace [15] observed
that the feeling of relief is usually associated with
dreams about drug use, while anger, on waking up,
may be associated with drug dreams about an unsuccessful attempt to use a drug. The data collected here
are not numerically sufficient to determine whether
these different feelings match the different types of
dreams (e.g. evoking the use of a drug, or else a failed
attempt to use it).
4.3. Limbic system irritability and drug dreams
The present study confirms previous indications
of high LSCL-33 scores among drug-addict patients
(research hypothesis a). The LSCL mean score shown
by our patients was similar to the scores obtained in
previous studies by heroin-addicted patients [17, 19]
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Heroin Addiction and Related Clinical Problems xx(x): xx-xx

and by alcoholic patients [7, 39], and it suggests limbic irritability. The LSCL mean score obtained by
drug-addicted patients is considerably higher than
the score obtained by normal subjects and sporadic
drug abusers (i.e., those not meeting the criteria for
a diagnosis of drug dependence) (< 10) [1, 19]. It is
therefore plausible to interpret the limbic irritability
of drug-addicted patients as the expression of MLMC DA pathway upregulation caused by prolonged
drug exposure [60]. The present study shows that
patients who reported drug dreams had higher LSCL
scores than those who did not (research hypothesis
b). We now hypothesize that, in the patients who reported drug dreams, the higher LSCL scores may be
due to the presence of a stronger and more persistent
drug craving, of which the higher ML MC dopamine
tone is the neurobiological correlate. A positive relationship between drug craving, and drug dream onset
and frequency has, in fact, been found repeatedly [3,
10, 11, 15, 18, 28, 57], together with an increase in
ML MC dopamine release when drug-addicted patients experienced a strong desire for drugs (i.e. drug
craving), as shown in functional neuroimaging studies (34, 35, 69, 70). In any case, LSCL-33 scores have
been found to be correlated with alcohol craving and
with substance abuse among college students [1, 7,
39].
From the point of view of general dream research and theory, the association between a more
intense limbic DA tone and the occurrence of drug
dreams appears to be consistent with the results of
clinical-anatomical studies on dreaming, as regards
the crucial role of ML MC DA triggering the dream
[61, 62, 73]. In fact, according to Solms, the part of
the brain that is involved as the primary generator
of dreaming is the white matter surrounding the frontal horn of the lateral ventricles (i.e., the ventromesial
quadrant of the frontal lobes), that is, the part of the
brain which includes the mesolimbicmesocortical
dopamine pathways (MLMC DA) that arise from
the cell group of the ventral tegmental area, and extend towards the limbic and frontal structures. The
MLMC DA pathways are also described in affective
neuroscience as the core of the seeking system the
instigator of goal-seeking behaviour and of appetitive
interactions with the world, the system that houses
the basic drives (hunger, sexual desire, etc.) [55].
Now the seeking system also houses the new drive in
drug-addicted subjects, that is, the craving for drugs,
with the possibility, which is exclusive to these subjects, of triggering dreams linked to this drive (i.e.,
drug dreams).
- 80 -

Colace [16] and Colace et al. [19] in their


dopaminergic model of drug dreams, assumed
that the onset of drug dreaming might be favoured,
in abstinent conditions (i.e., drug craving intensification), by the fact that the non-use of drugs hinders
the discharge at a higher level of drug craving/
DA release. In other words, in a condition of an already upregulated MLMC DA system, at a moment
of high vulnerability to drug-conditioned cues, due
to abstinence from drugs, the onset of drug dreaming should be instigated by a temporary increase in
DA release that has not yet been discharged. Conversely, during regular (daily) use of drug, when the
increased level of drug craving / dopamine release are
continually discharged, zeroed and the baseline DA
levels are re-established (i.e., drug craving satisfaction), drug dreams should not appear, or should appear less frequently. In the light of the data reported
here, we may suppose that the dopaminergic onset
of drug dreaming has a higher probability of being
implemented in those subjects who are already experiencing limbic system irritability and a greater availability of dopamine.
4.4. Drug dreams and maintenance of abstinence
upon awakening
Most of our patients who had had drug dreams
did not use heroin on the next day. This is consistent
with other studies that have shown that drug dreams
increase a patients probability of staying abstinent
from drugs [10, 36, 46, 50, 57)]. Many authors have
suggested that one function of drug dreams is to offer
the dreamer a safe way [3, 10, 13, 15, 22, 46, 53,
58] and have pointed out that drug dreams (or drinking dreams) may help the dreamer to develop strategies for coping with drug craving and staying sober/
clean, [32, 53, 57, 63]. Indeed, drug dreams seem to
enable a safety-valve type of compensation, at a hallucinatory level, of the continuous urge to use drugs
(drug craving). In this sense, their function is to
discharge the pressure of drug craving. In parallel
with this, Choi [10] observed that alcoholics who reported "drinking dreams" had been tolerating better,
and for longer periods, their craving for alcohol than
alcoholic patients who did not have such dreams.
Providing an alternative view, some authors suggest that drug dreams serve as reminders of the adverse consequences of drug use or of drinking, or as
reminders of the advantages of staying clean. These
dreams help patients to prevent relapses [10, 36, 40].
In particular, Hajek and Belcher [36], in their "aver-

C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients

sive conditioning theory", assumed that drug dreams,


because of their emotionally negative impact on the
dreamer (i.e., by inducing panic and/or guilt), probably reduce the chances of repeated drug use. From
this point of view, Hajek and Belcher [36] proposed
attaching more importance to these dreams in therapy
(e.g., by promoting their recollection by these patients
and focusing patients attention on their contents).
In a smaller number of cases, we found that patients had relapses after their drug dreams. This effect
has also been observed in the existing literature. In
this case, drug dreams may even have a function that
stands in opposition to discharge, that is, a function
of providing an incentive for drug craving [27, 52].
For example, Christo and Franey [12] observed that
some polydrug users who had experienced relapses
claimed that the presence of drug dreams had contributed to those relapses. According to these authors,
there is the possibility that drug dreams constitute
vivid memory recall cues that may induce drug craving. This same effect was also found in some tobacco
smokers [57]. It has been hypothesized that this incentive effect on drug craving should be particularly
pertinent to those drug dreams that were not entirely
gratifying, or in which the use of drugs failed or was
interrupted by the dreamer waking up [15]. These
drug dreams can trigger drug craving upon awakening and during the following days. By failing to fulfil drug craving, these dreams eventually turn it on.
They act as a sort of appetizer before a meal that is
not eaten, leaving the dreamer even hungrier than before. Here we can distinguish at least two cases: a)
drug craving is heightened in the post-dream state of
being awake because the dream has failed (fully or
partially) in its discharge action, or b) the dream
in itself acts as a drug-related appetitive cue for craving [15, 18]. The quality of the data collected (i.e.,
the non-availability of the written text of the dream)
has prevented a further classification of dreams with
respect to remaining abstinent on waking up, so, at
present, the hypothesis that prolonged abstinence may
be associated with dreams that represent particularly
gratifying results, and, conversely, that the increased
risk of relapse may be associated with dreams that, by
failing to satisfy the craving, end up by stimulating
it, cannot be confirmed. At a purely descriptive level,
however, we can report our finding that, in those who
had relapses on the following day, the dreams centred
on drug issues dealing mainly with the non-use of
heroin, and, conversely, in those who were experiencing a prolonged abstinence, the themes of their drug
dreams were mostly about buying, having, seeing,

looking at and using heroin (i.e. themes that were all


emotionally rewarding).
It should be noted that in both cases, i.e. situations of prolonged abstinence or of relapse, this rarely
corresponds to a decrease or to an increase, respectively, in the craving perceived by the subject. The
conscious desire to use the substance is not always indicative of an unconscious craving that may increase
or decrease the risk of a relapse.
4.5. Drug dreams and pharmacological treatment
for addiction
We know that the goal of pharmacological treatment in drug addiction is to mitigate the adverse withdrawal symptoms and reduce the craving for drugs.
The agonist pharmacological treatments, such as
methadone for opiates, act mainly on the phobic aspect of craving, that is, the need to avoid withdrawal
symptoms, whereas antagonist treatments, such as
naltrexone for opiates, and, to some extent, buprenorphine too, take effect by barring any opportunity to
experience the pleasant effect of drugs (i.e., they exert
an anti-craving action), in the attempt to fight the
very desire for drugs (i.e. the appetitive aspect of
craving).
In our patients the presence of drug dreams does
not seem to have been influenced by the type of pharmacological therapy or by its consequences on various aspects of drug craving. According to the previous
literature [13, 15, 18, 19], it has been shown that drug
dreams occur in heroin-addicted patients who take a
low, antiwithdrawal methadone dosage, but also in
those who take a high, anticraving methadone dosage,
and again by those who take buprenorphine, which
has a mixed action as a -opioid partial agonist/k-opioid partial antagonist. Thus, pharmacological action,
whether directed against phobic craving or against
appetitive craving, can attenuate a strong drug craving, so much so that it continues to occur regularly in
dreams. The fact that drug dreams are present in people undergoing therapies that act on different aspects
of craving suggests that these pharmacological treatments do not always succeed in reducing drug craving. Its extraordinary strength, far from being tamed,
is ready to trigger drug dreams. The study of drug
dream frequencies in patients receiving various types
of pharmacological treatment that act on different aspects of drug craving is likely to contribute to a better
understanding of drug craving itself.
These results are also consistent with studies on
the drug dreams of alcoholics and tobacco addicts.
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Heroin Addiction and Related Clinical Problems xx(x): xx-xx

Hajek and Belcher [36] observed that smoking-related dreams appear in abstinent tobacco-addicted
subjects who receive pharmacological treatment with
nicotine chewing-gum to mitigate most withdrawal
symptoms, and they concluded that these dreams appeared to be generated primarily by cognitive processes of craving, rather than directly by falling blood
nicotine levels. Choi [10] noted too the presence of
drinking dreams among patients who were taking disulfiram, an aversive treatment for alcohol that causes
an unpleasant reaction when alcohol is consumed.
In his study, although the alcoholics who were being treated with disulfiram could remain abstinent
for a greater number of days than those who did not
take disulfiram (so allowing a better control over drug
craving), they continued to report drug dreams.
5.

Conclusions

Drug dreams are a widespread phenomenon


among drug-addicted patients.
In this study we have confirmed the phenomenological picture of these dreams and their potential
clinical applications, especially as a window function on the degree of drug craving and the evolution
of drug-addicted patients.
The onset of drug dreaming is related to the presence of drug craving, which is the result of an upregulation of the ML MC dopaminergic system; this, in its
turn, as suggested by this study, is revealed by limbic
system irritability in all these patients, but is more
marked in those who have drug dreams. We interpret
limbic system irritability (which is directly mirrored
in an increased availability of ML MC dopamine), as
the neurobiological background condition in which,
especially during abstinence from drugs a condition known to show a greater propensity to acute drug
craving episodes and higher DA release levels drug
dreams are more likely to appear. Further studies
are now needed to investigate this neurobiological
background of drug dreams, which might deepen our
understanding of the close connection between drug
dreams and the craving for drugs.
In terms of general dream research and theory,
drug dreams are found to be particularly revealing in
showing the dopaminergic activation of dreaming and
the key role of the brain areas involved in the basic
motivations that induce the dreaming process.

- 82 -

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Role of the funding source
The authors no have funding sources.
Contributors
All authors revised and approved the final form of the
manuscript.
Conflict of interest
Authors declared no conflict of interest.

C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients

APPENDIX 1.
DRUG DREAMS QUESTIONNAIRE

We are collecting information on the dreams of our patients. Please answer the following questions by placing a cross in
the squares. Every answer that you give is strictly confidential. Thanks for your cooperation.
Date _________ Age_________ Sex___________
How many dreams do you usually recall in a week?
0 1 2 3 4 5 6 7 8 9 10
Did you have dreams about heroin right from the start of your use of this drug?]
! Yes

! No

Usually, when you have these dreams about heroin?


! When I use heroin
! When I cannot use heroin (e.g., when I do not have the money to buy it)
! During periods when I decide to stop using heroin
! Both when I use heroin and when I do not use heroin
ABOUT YOUR MOST RECENT DREAM ABOUT HEROIN, ANSWER THE FOLLOWING QUESTIONS:

When did you have this dream?: ______________________


In my dream:
! I used heroin
! I was trying to use heroin, but I could not
! I saw others who were using heroin
! I refused to use heroin
! Other: __________________ (If possible, mark the date or period) ____
In your dream, what did you feel?:
! Fear

! Pleasure

! Anguish

! Anger

! Guilt

! Other _____! Dont know


On waking up from your dream, did you feel?:
! Disappointed, because I understood that I had not really had any heroin
! Reassured, because I understood that I had not really made use of heroin
! Normal, without any particular emotion
! Other ________________________________
On waking up, was your desire to use heroin: ! Unchanged ! Increased ! Decreased

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Heroin Addiction and Related Clinical Problems xx(x): xx-xx

The day after that dream, did you use heroin?

! Yes

In the week prior to this dream, did you use heroin? ! Yes

! No
! No

If you have answered No, indicate how much time had passed since you last used heroin before having this dream:
! 15 days

! At least 1 month

! About 3 months

! About 6 months

! ______ months

(Only for users who have been in a Therapeutic Community)


Do you remember having had dreams about heroin when entered your therapeutic community? !Yes ! No
To be completed by the Drug Addiction Unit operator
Drug therapy taken by the patient (NB: when the patient's dream about heroin indicated therapy in the period in which
he recalled the dream):
Buprenorphine mg.__________Methadone mg._______
Presence of secondary dependences: ! Cocaine ! Alcohol ! Cannabis
! Other

Received February 22, 2014 - Accepted July 5, 2014


- 86 -

Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 87-98

Induction and switch to buprenorphine-naloxone in opioid dependence


treatment: Predictive value of the first four weeks
Sabine M. Apelt 1,2, Norbert Scherbaum 3, and Michael Soyka 2,4
1 Certum Consulting Scientific Research, Ruhpolding, Germany, EU
2 Ludwig Maximilian University, Munich, Germany, EU
3 LVR-Hospital Essen, University Duisburg-Essen, Germany, EU
4 Private Hospital Meiringen, Meiringen, Switzerland

Summary
Background: Clinical studies report the highest risk of dropout in the first few weeks of opioid dependence treatment.
This secondary analysis of data from a non-interventional study with buprenorphine-naloxone (BNX) aims to evaluate
the predictive value of the treatment outcomes after the first four weeks in routine care. Methods: Data collected from 69
sites in Germany, came from a multicentre 12-month study involving 337 opioid-dependent patients.
Results: Patients with negative urine screenings for opiates, cocaine or benzodiazepines at screening, a maximum daily
dose of 8mg BNX during the first four weeks, significantly lower Global Severity Index (GSI) on the SCL-90-R at day
0 and again at week 4, had a significantly higher chance of being retained in treatment. The patients who switched from
d/l-methadone, levo-methadone, buprenorphine or active heroin use showed differences in almost all the parameters that
were evaluated. Conclusion: The first four weeks of treatment with BNX have a high predictive value for the treatment
outcome, especially in terms of urine screening, dosing of BNX and psychiatric distress. But the physician in charge needs
to determine if the patient has been pre-treated with d/l-methadone, levo-methadone or buprenorphine, or whether the
patient is inducted to BNX directly from heroin, because most of the predictive values seem to be unique for a subgroup
of patients only.
Key Words: buprenorphine-naloxone, opioid dependence treatment, predictors of treatment outcome, first weeks of
treatment

1.

Introduction

Drug dependence therapy with maintenance


drugs is an established method for the reduction of
criminal behaviour and somatic disorders, including
infectious diseases and drug-related deaths, while
improving the somatic, mental and social well-being
of drug-dependent users [10, 21, 26, 27,28, 32,]. The
first goal of maintenance treatment is to stabilize the
patient with an adequate dose of the maintenance
drug, to prevent withdrawal symptoms, and risky and
health-damaging behaviour. An improved status of
this kind will give a drug-dependent patient an opportunity to regain control over his/her life [8, 10].
The first four weeks of treatment seem to be

extremely important for the general course of opioid


dependence treatment. Some clinical studies report
the highest risk of dropout and relapse in the first
week of opioid dependence treatment [20, 30]. But
the longer a patient stays in maintenance treatment,
the higher the chances are of accomplishing positive
treatment outcomes, including complete abstinence
from illicit drug use [11, 23, 24, 30]. To keep the patient in treatment is one of the major challenges of
maintenance therapy [6], and is influenced by many
factors. Adequate dosing seems to play a major role.
Buprenorphine doses of 8 mg/day or less resulted
in lower retention rates [12] and higher numbers
of positive opioid urine screenings [3]; by contrast,
higher doses (12-16mg) resulted in higher chances of

Corresponding author: Sabine M. Apelt, Dipl.-Psych, Certum Consulting Scientific Research, Ort 1, D-83324 Ruhpolding, Germany, EU & Ph.D. student at Ludwig Maximilian University, Nussbaumstr. 7, D-80336 Munich, Germany, EU
E-mail: sma@certum-consulting.com

87

Heroin Addiction and Related Clinical Problems 16(3): 87-98

achieving complete abstinence from opioid drug use


[7, 18, 19, 22,]. Thus, an adequate dose of buprenorphine-naloxone is a crucial factor in keeping drugdependent patients in treatment.
Other predictive variables for high retention and
positive treatment outcomes are being older, having
a job, having a history of treatment, being cocainefree at baseline [1, 4, 15, 23, 24, 30], and having cocaine- and heroin-free urine screenings in the first few
weeks of treatment [9]. Predictors of negative treatment outcomes include cocaine use and polydrug use
at baseline and during treatment [6, 9, 20, 25, 30].
Opioid-dependent drug users show extreme
heterogeneity in many of their characteristics [32].
In any case, it can be assumed that, especially in the
early phases of treatment, certain characteristics and
variables are unique to each patient, and can be used
as reliable signals of a positive or negative course
and outcome of opioid dependence treatment. These
signals, if recognized at an early stage of treatment,
could be used to sdjust the treatment plan, and help
the patient to be retained and/or reach the ultimate
objective of complete abstinence.
Despite several clinical trials with tight assessment schedules for the early weeks of treatment [14,
16, 31], there have been no published multisite, longterm, observational, non-interventional studies in routine care that provide a detailed description of the first
four weeks of treatment with buprenorphine-naloxone
(BNX), and allow an assessment of the reliability of
predictors for positive treatment outcome. Only one
single-site, observational cohort study by Stein et al.
[30] described the results of 41 opioid-dependent patients treated with buprenorphine-naloxone, with a
follow-up of 6 months; their results on retention and
its predictive factors reflected those found in clinical
trials [30].
This secondary analysis of data from a nationwide, non-interventional, observational study with
buprenorphine-naloxone in routine care [2] aims to
evaluate the predictive value of the first four weeks
for the treatment outcomes.
2.

Methods

A detailed description of the study design, goals,


population, assessment and measures has been given
in Apelt et al. [2].
2.1. Design of the study
The study, conducted from 2008 to 2010, was
- 88 -

a nationwide multicentre 12-month prospective, noninterventional, post-marketing safety study with 12


assessment points involving 384 opioid-dependent
patients from 69 general practitioners, clinics and
outpatient clinics in Germany. Opioid-dependent
patients over 15 years of age with written informed
consent and for whom the switch to buprenorphinenaloxone (BNX) was indicated and planned were
eligible for selection. Therapeutic indications and
contraindications of the Summary of Product Characterization (SmPC) for BNX had to be considered. The
physician had full responsibility for deciding which
patients should be enrolled, how the treatment with
BNX was to be implemented and which BNX dosage should be applied. Altogether, 337 data sets were
eligible for analysis. A detailed description of the
methods used in the study and which datasets were
excluded from the final analysis is given in Apelt et
al [2].
2.2. Assessment within the first four weeks
The assessment was performed at day 0 before
induction into, or a switch to BNX, at days 1, 2, 3, 5
and 7, and at the end of weeks 2 and 4 of treatment
with BNX. An extensive clinical research form, completed by the treating physician, and four standardized
questionnaires completed by the patients, were used
to obtain comprehensive data on sociodemographics,
substance use and addiction history, treatment history,
comorbidities, co-medication, concomitant drug use,
urine drug screening, reason for switching to BNX,
details of BNX treatment, premature discontinuation
before end of observation, effectiveness, withdrawal,
craving, quality of life and safety.
The physicians questionnaire specially developed for the non-interventional study comprised evaluation tools to cover the sections mentioned above,
including standardized instruments such as a modified version of the Clinical Global Impression scale
(CGI) and the Objective Opiate Withdrawal Scale
(OOWS) [17]. The patients questionnaires were the
Short Form 36 Health Survey (SF-36) [5], the Subjective Opiate Withdrawal Scale (SOWS) [17], the
revised psychiatric Symptom Checklist (SCL-90R)
[13] and, specially invented for the studyvisual analogue scales for craving [2].
2.3. Aims
The general aim of this evaluation was to find

S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks

predictors for treatment outcomes. The predictors


specially selected for treatment outcomes were:
Screening phase (day 0): Gender, age, dose of
prior maintenance drug for pre-treated patients,
drug screening results, withdrawal and craving,
psychiatric status, health-related quality of life.
Induction phase (days 1 to 7): Withdrawal and
craving, dose of BNX.
Stabilization phase (weeks 2 to 4): Withdrawal
and craving, psychiatric status, health-related
quality of life, dose of BNX.
2.4. Statistics and Analyses
The following groups were selected and will
now be compared:
2.4.1.Retention Status
Positive Outcome (PO): Patients still in treatment with BNX at the end of observation
(month 12) including patients with regular end
of treatment before end of observation (patient
abstinent) (n = 195)
Negative Outcome (NO): Patients with documented premature discontinuation of the treatment with BNX for any reason other than regular end of treatment (patient abstinent) before
end of observation (month 12) (n = 142). Reasons for premature discontinuations were, for
example: lost to follow up (16.7%), concomitant drug use/relapse (12.2 %), side effects (12.2%) and non-compliance/disciplinary reasons (10.9%) [2].
2.4.2. Previous Drug:
MTD: Pre-treated patients switched from d/lmethadone (n = 51).
L-MTD: Pre-treated patients switched from
levo-methadone (n = 24).
BUP: Pre-treated patients switched from the
mono buprenorphine product (n = 162).
HER: Patients with no current maintenance
treatment inducted BNX directly from heroin
use (n = 93).
Logistic regressions, analysis of variances or
chi-square tests were used to analyse correlations between the defined patient groups and selected predictive parameters. Missing values and no test were
both defined as positive results. The Kaplan-Meier
method was used to estimate retention rates and
times. For the determination of group differences in

retention rates, the log rank test was used. All statistical analyses were performed using STATA/SE 9.0
[29].
3.

Results

3.1. Patients Characteristics


Table 1 summarizes patients characteristics at
day 0. Predictors of the screening phase for positive
treatment outcome (PO) were: older age, stable relationship and own flat, or living with family members.
Patients with PO had a longer drug dependence history and pre-treated patients had been significantly
longer in their previous maintenance treatment before switching to BNX, especially those who had
previously been BUP patients. Fewer withdrawal
symptoms and less craving for opiates were further
predictors forPO. By contrast, patients with negative
treatment outcome (NO) were more likely to be single, homeless, hepatitis C-positive and more severely
burdened with psychiatric comorbidity. They reported higher rates for craving and withdrawal at day 0.
3.2 Prior maintenance treatment
The prior treatment status (i.e., whether the patient had been switched from a previous treatment,
or had been inducted directly from active heroin use)
had no impact on treatment outcome. Conversely, a
patient switched from L-MTD had a higher chance
of being retained in treatment with BNX for the complete 12 months of observation. A higher last dose of
the prior maintenance drug before switching to BNX
was a factor predictive for PO in patients switched
from MTD and L-MTD.
3.3 Urine drug screening
An overall lower total number of positive drug
screenings at day 0 was predictive for PO (2.61.7
vs. 3.21.7 NO, p=.004, OR 0.83, 95%CI 0.72-0.94),
particularly for opiates (33.3% vs. 45.8%, p=.021),
cocaine (6.2% vs. 16.2%, p=.003) and benzodiazepines (21.0% vs. 35.9%, p=.002). A significant
difference in the total number of positive drug screenings was only found in L-MTD patients (1.41.0 PO
vs. 4.31.9 NO, p<.001, OR 0.23, 95%CI 0.06-0.79).
3.4 Dose of BNX
Patients with NO started with slightly higher
- 89 -

Heroin Addiction and Related Clinical Problems 16(3): 87-98

Table 1: Patients characteristics at baseline.

Age in years [mean (SD)] N=336


Male [n (%)] N=337
Marital status [n (%)] N=334
- Single
- Married/living with a partner
- Divorced
Occupation [n (%)] N=337
- Employed
- Unemployed
Residential status [n (%)] N=337
- Own flat/house or living with family
- Homeless
Years of dependence [mean (SD)] N=311
Currently in substitution treatment [mean (SD] N=337
Years of current substitution treatment [mean (SD]
N=213
- Buprenorphine
- D/L-Methadone
- Levo-Methadone
Type of current substitution treatment [n (%)]
- Buprenorphine
- D/L-Methadone
- Levo-Methadone
Dose of prior substitution treatment [mean (SD)]
- Buprenorphine (N=161)
- D/L-Methadone (N=50)
- Levo-Methadone (N=23)
Hepatitis C infection [n (%)] N=335
HIV infection [n (%)] N=272
Psychiatric comorbidity physicians assessment [n
(%) N=337
Number of psychiatric comorbidities [mean (SD)]
N=193
Psychiatric Status SCL90R [mean (SD)]
- GSI (N=316)
- PST (N=321)
- PSDI (N=318)
Withdrawal [mean (SD)]
- Objective Opiate Withdrawal Scale (N=337)
- Subjective Opiate Withdrawal Scale (N=325)
Craving [mean (SD)]
- Total Score (N=325)
- Opiate Craving (N=323)
Quality of Life SF36 [mean (SD)]

Total Sample
337*
35.18.8
258 (76.6)

PO
195
36.09.0
154 (79.0)

NO
142
33.98.4
104 (73.2)

p
.029
.220

201 (60.2)
102 (30.6)
30 (9.0)

108 (56.3)
69 (35.9)
14 (7.3)

93 (65.5)
33 (23.2)
16 (11.3)

.088
.013
.209

125 (37.1)
179 (53.1)

75 (38.5)
100 (51.3)

50 (35.2)
79 (55.6)

.542
.429

296 (87.8)
5 (1.5)
13.8 (8.7)
244 (72.4)

177 (90.8)
0 (0.0)
14.6 (8.5)
140 (71.8)

119 (83.8)
5 (3.5)
12.8 (8.8)
104 (73.2)

.053
.008
.077
.958

3.83.6

4.34.0

3.13.0

.022

4.2 3.8
3.1 3.1
3.3 3.6

5.0 4.3
3.1 2.8
2.7 3.0

3.0 2.5
3.2 3.6)
5.0 4.7

.003
.931
.177

162 (66.4)
51 (20.9)
24 (9.8)

93 (66.4)
29 (20.7)
18 (12.9)

69 (66.4)
22 (21.2)
6 (5.8)

.989
.933
.066

7.7 4.3
41.8 37.2
26.5 17.1
121 (36.1)
4 (1.2)

7.2 4.1
53.6 42.4
31.0 16.2
62 (31.8)
2 (1.0)

8.4 4.4
25.6 20.1
10.2 8.6
59 (42.1)
2 (1.4)

.088
.007
.013
.009
.637

193 (57.3)

106 (54.4)

87 (61.3)

.206

2.0 1.5

1.9 1.6

2.1 1.5

.538

0.7 0.6
37.0 24.0
1.5 0.5

0.7 0.6
34.3 24.5
1.5 0.5

0.8 0.6
40.523.1
1.6 0.5

.051
.023
.161

8.8 8.1
17.2 13.5

8.4 8.0
15.9 13.4

9.4 8.2
19.0 13.6

.259
.043

12.4 11.1
32.3 33.2

10.2 9.6
27.6 30.9

15.4 12.3
38.9 35.4

<.001
.003

* Eligible datasets
PO = Positive Treatment Outcome; NO = Negative Treatment Outcome

doses of BNX on day 1 of treatment. On day 2 the


average dose increased in both groups. While the
average dose in patients with PO already started to
decrease on day 3, in patients with NO the average

- 90 -

dose was stable until day 7. In week four both groups


reached almost the same average dose of their day of
induction.
Clean patients were excluded from this analy-

S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks

Table 1: Patients characteristics at baseline.

- Physical Health (N=324)


- Mental Health (N=320)
Positive Urine Drug Screening [n (%)]
- Opiates (N=331)
- Cocaine (N=330)
- Cannabis (N=252)
- Benzodiazepines (N=330)
General Health physicians assessment mean (SD)]
N=335

Total Sample
337*
52.9 18.6
50.8 24.2

PO
195
54.3 18.3
52.0 25.1

NO
142
51.0 18.9
49.0 22.9

p
.118
.277

124 (37.5)
28 (8.5)
83 (32.9)
85 (25.8)

60 (31.6)
6 (3.2)
45 (31.5)
37 (19.4)

64 (45,4)
22 (15.6)
38 (34.9)
48 (34.5)

.010
<.001
.570
.002

1.7 1.0

1.7 1.0

1.8 1.0

.384

* Eligible datasets
PO = Positive Treatment Outcome; NO = Negative Treatment Outcome

sis, because their dosing was significantly lower, and


it also decreased more rapidly during the first four
weeks; it therefore fails to reflect the expected normal course of dosing after induction, or switch to
buprenorphine-naloxone.
Figure 1 shows the average dose of BNX during
the first four weeks of treatment (N = 323)
If controlled for prior treatment/drug (see Table
2), there is no difference in dosing between PO and
NO in patients switched from MTD or HER. Patients
with PO switched from L-MTD received slightly
lower doses of BNX on day 1 and considerably higher doses at week 4. The switch from BUP to BNX led
to an average dose increase of 0.5 mg in both groups.
However, BUP patients with PO received significantly lower doses of BNX.
Table 2 shows dosing of BNX by previous drug

during the first four weeks of treatment


No significant differences in dosing of BNX
within the first four weeks were found concerning
regions of Germany. Since only 3 outpatient clinics
participated in the study, the type of setting was not
analysed as a possible influencing factor.
3.5 Withdrawal
To measure the signs and symptoms of opiate
withdrawal, the subjective and objective opiate withdrawal scales (OWS) were used [17]. Lower opiate
withdrawal predicted positive treatment outcome
(PO). In the objective scale (OOWS) patients with
PO received lower scores from day 3 to week 4, and
in the subjective scale (SOWS) they achieved lower
scores from day 2 to week 4. There were no differenc-

Figure 1. Average dose of BNX during the first four weeks of treatment (N = 323).

- 91 -

Heroin Addiction and Related Clinical Problems 16(3): 87-98

Table 2: Dosing of BNX by previous maintenance treatment and previous drug, during the first four weeks of
the study
MTD (n=51)
L-MTD (n=24)
BUP (n=162)
HER (n=93)
PO
NO
p
PO
NO
p
PO
NO
p
PO
NO
p
Day 1
12.8
12.5
.793
8.2
11.0
.124
7.7
8.9
.066
9.2
8.7
.641
Day 2
13.3
12.8
.793
11.5
12.0
.857
7.8
9.3
.021
9.7
9.5
.855
Day 3
11.9
12.4
.724
12.4
12.0
.900
7.9
9.6
.021
9.6
9.6
.995
Day5
11.4
11.4
.960
12.1
12.0
.964
8.0
9.6
.028
9.4
9.7
.797
Day 7
10.8
10.6
.894
12.1
12.0
.964
7.9
9.9
.008
8.9
9.7
.440
Week 2
11.0
10.3
.450
11.9
10.7
.607
8.0
9.4
.070
8.5
9.7
.199
Week 4
10.6
10.3
.805
12.0
7.5
.083
7.9
9.3
.057
8.3
9.6
.226
MTD: Patients switched from d/l-methadone
L-MTD: Patients switched from levo-methadone
BUP: Patients switched from the mono-compound buprenorphine
HER: Patients inducted directly from heroin use
PO = Positive Treatment Outcome
NO = Negative Treatment Outcome

es in withdrawal symptoms between the two groups


in prior MTD patients. Prior L-MTD patients with
PO showed significantly fewer objective withdrawal
symptoms from day 3 to week 4. A similar pattern
is found in the SOWS, with significantly lower withdrawal symptoms for patients with PO as early as day
2 of BNX treatment. According to the ratings given
by the treating physicians, prior BUP patients with
PO showed significantly fewer opiate withdrawal
symptoms in the first two weeks of BNX treatment.
Figure 2. Craving for opiates by previous substance

- 92 -

By week 4, however, the difference was no longer


significant compared with BUP patients with NO.
The same pattern can be found in the scores from the
self-assessment questionnaire SOWS for this group.
Prior HER users with PO achieved significantly lower
scores for opiate withdrawal between day 7 and week
4 of BNX treatment, but only on the subjective scale.
According to physicians, neither group of HER users differed in terms of opiate withdrawal at screening and during the first four weeks of treatment with

S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks

BNX.
3.6 Craving for Opiates
Craving was measured with the self-assessment
100 mm visual analogue scales for 12 substances [2].
Lower craving for opiates predicted PO in all three
phases of the first four weeks of treatment with BNX.
As shown in Figure 2, the significant difference between PO and NO is only found in patients previously
treated with L-MTD or BUP. At screening and in the
first two days of treatment with BNX, patients with
PO previously treated with MTD experienced higher
craving for opiates, but at the end of week 4 these
patients experienced marginally lower craving. No
differences in terms of craving were found in prior
HER users.
3.7 Psychiatric Distress (SCL-90-R)
The psychiatric distress status was measured
with the standardized self-assessment tool SCL90-R. The Global Severity Index (GSI) is the best
indicator for the current extent of overall psychiatric distress [13]. A lower value for this global scale
at screening (0.70.7 vs. 0.80.6 NO, p=.051) and

week 4 (0.30.4 vs. 0.40.5, p=.030) predicted PO.


The most severe forms of psychiatric distress were
measured in L-MTD patients at screening for both
groups (1.10.5 PO vs. 0.90.3 NO, p=.609) and at
week 4 for patients with NO (0.30.3 vs. 0.60.4,
p=.098). The mildest psychiatric distress was measured in BUP patients at screening for both groups
(0.50.5 vs. 0.70.5, p=.004). MTD patients did not
differ at screening or at week 4. At screening, prior
HER users received scores that were similar to those
of patients previously on MTD, with no differences
between PO and NO, but at week 4 prior HER users
with PO reported significantly milder psychiatric distress (0.30.3 vs. 0.50.5, p=.025).
3.8 Health-related Quality of Life (SF-36)
The health-related quality of life (QoL) was
evaluated with the self-assessment tool SF-36, which
measures the subjective core indicators of physical
and mental health [5]. No predictive value was found
in the two global scales, physical and mental health.
In any case, patients with positive treatment outcome
(PO) achieved slightly higher scores in both global
scales at screening (physical health: 54.318.3 PO vs.
51.018.9 NO, p=.118; mental health: 52.025.1 vs.

Figure 3. Kaplan-Meier Survival Curves by previous Drug

- 93 -

Heroin Addiction and Related Clinical Problems 16(3): 87-98

49.022.9, p=.277) and at week 4 (physical health:


62.913.3 vs. 60.114.7, p=.112; mental health:
65.620.0 vs. 61.820.9, p=.142). No differences
at screening or in week 4 were found in patients
switched from MTD, L-MTD or HER at screening, or
at the end of week 4. But previous BUP patients with
PO achieved significantly higher scores at screening
(physical health: 62.814.4 vs. 54.817.6, p=.002;
mental health: 64.621.7 vs. 53.823.7, p=.003). By
week 4 the scores were no longer significant (physical health: 66.413.4 vs. 62.215.1, p=.093; mental
health: 71.320.0 vs. 65.221.8, p=.098).
As itemized within the nine single scales, higher
scores in the scales for physical role functioning
at week 4 (7.21.3 PO vs. 6.81.5 NO, p=.046), and
for pain at screening (9.12.9 vs. 8.13.3, p=003)
and week 4 (10.61.8 vs. 9.95.5, p=.010) predicted
a positive treatment outcome (PO).
The extent of improvement between baseline
and week 4 was only predictive for L-MTD patients,
but, conversely, neither for the total population nor
for MTD, BUP or HER. L-MTD patients with PO
achieved higher improvement scores in both global
scales (physical health: improvement 23.111.8 PO
vs. 4.36.5 NO, p=.008; mental health: improvement 40.220.8 vs. 10.89.7, p=.015) and again in
the single scales for physical functioning (4.23.0
vs. 0.32.1, p=.024), pain (3.21.7 vs. -0.51.9,
p=.001), social functioning (2.31.5 vs. -0.51.3,
p=.004) and emotional well-being (7.44.6 vs.
7.82.6, p=.033). For BUP patients the only predictive value for PO was found in the scale for drug
dependence (2.26.9 vs. 4.98.7, p=.049).
3.9 Retention and dropout
The 4-weeks survival probability for the total
population was 89.3%. One quarter (25.4%) of all
patients with negative treatment outcome (NO) (n =
142) prematurely terminated treatment with BNX in
the first four weeks, including 9 of the group during
the first week.
Figure 3 shows the survival probability by previous drug. The highest retention and lowest dropout
rate in the first four weeks was found in prior MTD
patients (13.6%). 24.6% of patients with NO in prior
BUP patients and 23.7% of HER users dropped out
of treatment during the first four weeks. Of prior LMTD patients, 2 out of 6 patients with NO terminated
their treatment prematurely during the first 4 weeks.
Log-rank test and logistic regression revealed no dif-

- 94 -

ferences in survival and treatment duration between


the four previous drug groups.
Patients with a maximum dose of 8 mg per
day BNX during the first four weeks stayed significantly longer in treatment compared with patients
with at least one dose of >8 mg per day during the
first 4 weeks (Log-rank: 2 = 3.78, p=.052; twosample t-test: mean retention 282.0136.6 days vs.
241.1149.2 days, t = 2.57, p=.011).
Patients showing no cocaine use at screening
stayed significantly longer in treatment than those
with positive urine screening for any illicit drug
(log-rank 2 = 7.06, p=.008). Patients with negative
urine screenings for opiates, cocaine and/or benzodiazepines had a significantly longer treatment duration
than those with positive test results for all three substances (Log-rank 2 = 5.08, p=.024).
4.

Discussion

The results of this study proved that opioid-dependent drug users are, indeed, an extremely heterogeneous group [32]. Most of the characteristics
evaluated at baseline and during the first four weeks
of treatment with buprenorphine-naloxone (BNX) are
specific for certain patient groups, especially concerning prior substance and treatment experience.
Despite all the individual differences, this evaluation
found parameters that can be reliably used as signals
to adjust the treatment plan, and influence course and
outcome of opioid dependence treatment with BNX.
The major challenge in drug-substitution treatment is to retain patients in treatment [6] and thus
enable them to regain control over their lives [8, 10].
The overall 4-week retention rate was 89.3%, irrespective of whether the patient was switched from an
ongoing maintenance treatment, or inducted directly
from heroin use (HER). As found in previous studies,
being older, treatment experienced, and showing no
cocaine use at screening predicted higher chances of
retention [1, 4, 15, 23, 24, 30]. In this study, employment status at screening had no significant impact on
retention, but patients who had their own flat, or were
still living at home with their family, seemed to benefit from a more stable living condition. By contrast,
homeless patients had practically no chance of a positive treatment outcome.
In previous studies, polydrug use predicted low
retention and a high chance of dropout [6, 9, 20, 25,
30]. In this study this criterion only applied to patients switched from levo-methadone (L-MTD). Single negative test results for benzodiazepines, cocaine

S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks

or opiates at the screening phase were predictive for


positive treatment outcomes in patients switched
from BUP and L-MTD. Previous drug use clearly
had no impact on retention or on dropout for patients
switched from d/l-methadone (MTD) or inducted to
BNX from active heroin use.
Contrary to international findings on a positive
correlation between higher doses of BNX (12-16mg)
and high retention [7, 18, 19, 22], in this study a lower
dose of BNX in the first four weeks (8 mg) predicted a higher level of retention. The reason might be
that patients with a positive treatment outcome (PO)
had, in general, a more favourable sociodemographic,
medical and addiction history profile than those with
a negative outcome (NO). Physicians seem to allocate
their patients to a certain induction dose in line with
specific patient characteristics such as social circumstances, physical and mental health, withdrawal and
craving. The high probability of treatment retention
in patients with a maximum dose of 8 mg per day
during the first four weeks of treatment with BNX
might be explained by the fact that these patients start
their therapy from a more favourable level than those
who received over 8 mg per day of BNX at least once
during the first four weeks. At present this largely unexpected outcome cannot be adequately explained. It
follows that this surprising finding calls for further
detailed analysis after taking into account the impact
of craving, withdrawal, and prior maintenance dose,
as well as psychiatric distress, quality of life and other important parameters pertinent to the correlation
between BNX dose and retention. In addition, in future studies the concerns of patients over the effects
of naloxone in the combination product and the importance of the physician-patient relationship should
become a focus of attention.
Parameters assessed in the screening phase (day
0) have a high predictive value and should be studied
for treatment planning by physicians. Still more importantly, week 4 of the stabilization phase in BNX
treatment seems to play a major role in measuring
predictive values for positive treatment outcomes and
high chances of retention. Differences between patients with PO and NO were most frequently found
in this phase. In particular, scores for psychiatric distress, withdrawal, craving and dosing of BNX differ
strongly at week 4, and could therefore be used as
signals for operative improvements to the treatment
plan. As a result, the physician in charge should test
these variables by applying standardized patient
questionnaires at the end of the stabilization phase, so
as to provide patients, who have rather unfavourable

characteristics, their best possible treatment setting.


The predictive value of some of the variables
only applied to patients switched from L-MTD,
whereas for MTD patients almost none of the variables could be used as predictors at this early stage
of BNX treatment. In addition, prior MTD patients
and HER users did not differ in their characteristics at
baseline, but HER users seemed to draw considerably
more benefit from the BNX treatment than MTD patients. These findings support the suitability of BNX
as a first-line medication for active heroin users.
One of the limitations of the study might be the
absence of a control group. Since the study did not
examine the efficacy of BNX, but aimed to evaluate
the safety and effectiveness of the switch from an ongoing maintenance treatment to BNX in routine care,
this limitation is acceptable. Another limitation is the
disproportionate distribution of patients to the prior
treatment/drug group. The high predictive value for
L-MTD patients might be due to their low number of
only 24 patients. Future studies should be conducted
with a higher, more evenly distributed number of patients to evaluate the switch from L-MTD, MTD and
HER to BNX, and to generate more robust data. Another limitation might be the recruiting process: Only
patients who agreed to participate in the study and
signed the informed consent form were eligible for
inclusion in the 12-month observation period. That
leaves open the possibility of a positive selection bias.
Patients who refused to participate, as well as those
who were excluded from consideration as study candidates by the participating physician were not evaluated, and no comparison with the group of study participants in assessing certain parameters is possible.
The major strength of the study is its authentic
reflection of the real life situation in opioid dependence treatment in Germany. It was the sole responsibility of the physician who was in charge to decide
which patients should be enrolled, how the treatment
with BNX was to be implemented, and what dose of
BNX the patients would receive.
5.

Conclusions

The first four weeks of BNX treatment after a


switch from d/l-methadone, levo-methadone, buprenorphine or active heroin use have a high value
in predicting a positive treatment outcome, especially
with reference to the parameters: withdrawal, craving
and psychiatric distress, to be measured at the screening phase (day 0), and at the end of the stabilization
phase (week 4). These values need to be considered
- 95 -

Heroin Addiction and Related Clinical Problems 16(3): 87-98

in close conjunction with age, current drug use, social


status and treatment experience. For optimal treatment redefinition to raise the patients chances of
being retained and of achieving a positive treatment
outcome, the physician in charge needs to take into
account whether the patient has been pre-treated with
d/l-methadone, levo-methadone or buprenorphine, or
whether the patient was inducted into BNX directly from heroin. Many predictive values seem to be
unique to a subgroup of patients only.
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16. Greenwald, M. K., Johanson, C.-E., Moody, D. E.,
Woods, J. H., Kilbourn, M. R., Koeppe, R. A., et
al. (2003). Effects of Buprenoprhine Maintenance
Dose on mu-Opioid Receptor Availability, Plasma
Concentrations, and Antagonist Blockade in HeroinDependent Volunteers. Neurpsychopharmacology (28):
2000-2009.
17. Handelsman, L., Cochrane, K., Aronson, M., Ness, R.,
Rubinstein, K., Kanof, P. (1987). Two New Rating Scales
for Opiate Withdrawal. The American Journal of Drug
and Alcohol Abuse, 13 (3): 293-308.
18. Kamien, J. B., Branstetter, S. A., Amass, L.
(2008). Buprenorphine-Naloxone Versus Methadone
Maintenance Therapy: A Randomised Double-Blind
Trial with Opioid-Dependent Patients. Heroin Addict
Relat Clin Probl, 10 (4): 5-18.
19. Kraus, S. W., Logan, M. E. (2009). Examining
Buprenorphine Retention in a Rural Solo Addition
Medicine Practice: A Retrospective File Review .
Research and Practice in Social Sciences, 4 (2): 14-26.
20. Krook, A. L., Brrs, O., Dahlberg, J., Grouff, K., Magnus,
P., Rysamb, E., et al. (2002). A placebo-controlled
study of high dose buprenorphine in opiate dependents
waiting for medication-assisted rehabilitation in Oslo,
Norway. Addiction (97): 533-542.
21. Kfner, H., Hackmann, K., Schnabel, A., Soyka, M.
(2004). Optimierung der substitutionsgesttzen Therapie
Drogenabhngiger (OSTD): Entzugssymptome und
Suchtverlangen in der ersten Einstellungswoche.
Suchtmed, 6 (1): 95-97.
22. Ling, W., Charuvastra, C., Collins, J., Batki, S., Brown,
L., Kintaudi, P., et al. (1998). Buprenoprhine maintenance
treatment of opiate dependence: a multicenter,
randomized clinical trial. Addiction (93): 475-586.
23. Maremmani, I., Pacini, M., Lamanna, F., Pani, P. P.,
Trogu, M., Perugi, G., et al. (2008). Predictors for
Non-Relapsing Status in Methadone-Maintained Heroin
Addicts. A Long-Term Perspective Study . Heroin Addict

S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks

Relat Clin Probl, 10 (4): 19-28.


24. Mintzer, I. L., Eisenberg, M., Terra, M., MacVane, C.,
Himmelstein, D. U., Woolhandler, S. (2007). Treating
Opioid Addiction With Buprenorphine-Naloxone in
Community- Based Primary Care Settings. ANNALS
OF FAMILY MEDICINE, 5 (2): 156-150.
25. Oehlin, L., Hesse, M., Fridell, M., Taetting, P.
(2011). Poly-substance use and antisocial personality
traits at admission predict cumulative retention in a
buprenorphine programme with mandatory work and
high compliance profile. From BioMed Central Ltd.:
http://www.biomedcentral.com/1471-244X/11/81
26. Somaini, L., Giaroni, C., Gerra, G. (2008). Opioid
Therapy and Restoration of the Immune Function in
Heroin-Addicted Patients. Heroin Addict Relat Clin
Probl, 10 (4): 39-44.
27. Soyka, M., Kranzler, H., van den Bring, W., Krystal, J.,
Mller, H.-J., Kasper, S. (2011). The World Federation of
Societies of Biological Psychiatry (WFSBP) Guidelines
for Biological Treatment of Substance Use and Related
Disorders. Part 2: Opioid Dependence. World Journal
of Biological Psychiatry, 12 (3): 160-187.
28. Soyka, M., Trder, A., Klotsche, J., Haberthr, A.,
Bhringer, G., Rehm, J., et al. (2012). Criminal Behavior
in Opioid-Dependent Patients Before and During
Maintenance Therapy: 6-year Follow-Up of a Nationally
Representative Cohort Sample. Journal of Forensic
Sciences, doi: 10.1111/j.1556-4029.2012.02234.x.
29. Stata Corp. (2005). Stata Statistical Software: Release
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Buprenorphine retention in primary care. J Gen Intern
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31. Stoller, K. B., Bigelow, G. E., Walsh, S. L., Strain,
E. C. (2001). Effexts of buprenorphine/naloxone in
opioid-dependent humans. Psychopharmacology (154):
230-242.
32. Wittchen, H.-U., Apelt, S., Bhringer, G., Gastpar, M.,
Backmund, M., Glz, J., et al. (2005). Buprenorphine
and methadone in the treatment of opioid dependence:
methods and design of the COBRA study. International
Journal of Methods in Psychiatric Research, 14 (1): 1428.

Role of the funding source


The original study was part of the Risk Management
Plan (RMP) for the newly marketed product buprenorphine-naloxone (Suboxone) and a requirement of the
European Medicine Agency (EMA). The study is registered with the National Institute of Health (NIH) at clinicaltrials.gov (NCT00723749).
Essex Pharma GmbH & Reckitt Benckiser Pharmaceuticals conducted this strictly observational, non-interventional study. All physicians received honoraria for the
additional effort to document the start and course of the
treatment with buprenorphine-naloxone in the comprehensive paper-based clinical research form. The honoraria were in line with the German medical fee schedule
(Gebhrenordnung fr rzte, GO), which controls the
invoicing of medical attendance outside of the statutory
health insurance.
Contributors
All authors contributed to and have approved the final manuscript.
Conflict of interest
Sabine M. Apelt has a financial interest/arrangement
or affiliation with one or more organizations that could be
perceived as a real or apparent conflict of interest in the
context of the subject of this presentation. She receives or
has in the past 3 years received honoraria from: Schering
Plough, Essex Pharma GmbH, MSD SHARP DOHME
GmbH and Reckitt Benckiser Pharmaceuticals.
In the past three years Norbert Scherbaum received
honoraria from Essex Pharma GmbH, Reckitt Benckiser
Pharmaceuticals, Molteni and Sanofi-Aventis.
For the past five years Michael Soyka has received
travel grants, unrestricted research funding or has worked
as a consultant for Presspharm, Reckitt Benckiser, Lilly,
Astra Zeneca, Roche, Essex Pharma GmbH, Lundbeck and
Sanofi Aventis.

Received February 22, 2014 - Accepted July 3, 2014


- 97 -

Letter to the Editor


Heroin Addict Relat Clin Probl 2014; 16(3): 99-102

Using oral or i/m morphine for rapid tolerance assessment in patients starting
methadone maintenance: A proposal for discussion based on over 25 years of
experience
Colin Brewer
The Stapleford Centre. London, UK, EU

TO THE EDITOR: For many years, the standard advice and practice for starting patients on Methadone Maintenance Treatment (MMT) has been
to start low and go slow. This is supposed to protect patients against overdose and death from either
over-estimating tolerance to the initial dose or from
cumulation after successive doses of a drug with a
long half-life. However, deaths still occur and postmortem usually reveals significant levels of both heroin and methadone, probably because the start low
methadone dose is not enough to prevent significant
withdrawal distress. In a patient with relatively modest or even borderline levels of tolerance, using even
modest amounts of heroin on top of the methadone
may prove fatal. This is unlikely to happen to patients
with higher levels of tolerance.
I want to argue here that this approach, while
understandable historically and politically, is unnecessary and condemns many patients to seriously inadequate treatment in the early stages. This, in turn,
forces many of them to continue using illicit opiates
at precisely the time when motivation to stop using
them is often high. In some cases, continued illicit use
will lead to arrest and even incarceration, just when
the patient has accepted that treatment is indicated
and requests it.
An alternative, at least in Britain, is to use a
shorter-acting opiate to establish approximate levels

of tolerance to agonists and then convert the dosage


needed to methadone. At one time, this had to be done
on a rather empirical basis but in the past decade, there
have been several trials of oral morphine (OM) as an
alternative to methadone in patients for whom MMT
caused unpleasant side effects. All of them show that
many MMT patients who dislike methadone do, in
fact, feel better on OM. However, what all of them
also show (and the most important finding in this context) is that the ratio of OM to methadone, expressed
as 24-hour equivalents, is remarkably consistent at an
average of around 6:1, with most studies falling between 6:1 and 8:1. [1-9].
The proposed alternative safely used by me
and several colleagues in several hundred patients since
about 1988 means that a new MMT patient arriving at
a clinic in slight withdrawal, as is usually advised, can be
given repeated doses of oral morphine, under observation,
over a period of a few hours until pupil size and other objective manifestations of opiate withdrawal have normalised.
The process can be shortened by using repeated i/m injections, especially in patients who normally use the i/v route.
Take, for example, a patient who claims a typical street
heroin habit of 0.5g/day. In Britain, with heroin typically
around 40% pure, this usually means around 200mg of
diamorphine/24hrs. This corresponds roughly to 4-500mg
of morphine/24hrs, or 100-125mg four times daily. (Some
widely-used opiate equivalence tables calculate only single-

Corresponding author: Colin Brewer, The Stapleford Centre, London, UK, EU


E-mail: brewerismo@gmail.com

99

Heroin Addiction and Related Clinical Problems 16(3): 99-102

dose equivalents of methadone and do not give the 24-hour


equivalents of opiates with a short half-life.) For comparison, a typical post-operative analgesic dose of morphine in
a 70kg non-tolerant person will be 20-30mg i/m.
If the patient is in obvious withdrawal, he/she will
almost certainly have some tolerance but a test dose of 2030mg will quickly demonstrate it since in such cases, it will
have little or no agonist effect. Further doses of 30-60mg
of morphine at 30-40 minute intervals (orally) or 10-15
minute intervals (i/m) will confirm approximate levels of
tolerance within a single morning or afternoon clinic session. This approximate tolerance can then be confidently
converted to an equivalent dose of methadone, between 1/6
and 1/8 of the 24-hour morphine equivalent. It can safely be
administered a few hours later in the same day as the effects
of the morphine test dose wear off. Observing the patient
for an hour or two after the methadone dose will further
confirm tolerance. Even if a very cautious attitude means
that only 60-70% of that dose is given on the first day, it will
be much nearer the desirable maintenance dose than the 2030mg that is conventionally recommended.
This approach is particularly helpful for the quite numerous patients with high tolerance who take large doses of
heroin. Instead of having their methadone dose gradually
increased over several weeks, it can be correctly titrated
against objective clinical signs within a week. While the
law in some countries prevents the use of morphine in this
way, I believe the same technique can be used with dihydrocodeine, which is not a restricted opiate in most countries and, like morphine, is generally available in both oral
and parenteral preparations.
I shall be presenting a paper on this topic at the May
2014 EUROPAD meeting in Glasgow and this letter is intended to give both critics and supporters of my proposal
plenty of time to study the relevant literature; and perhaps
even to try the technique for themselves.
References
1. Bond A. J., Reed K. D., Beavan P., Strang J. (2012): After
the randomised injectable opiate treatment trial: post-trial
investigation of slow-release oral morphine as an alternative

2.

3.

4.

5.

6.

7.

8.

9.

opiate maintenance medication. Drug Alcohol Rev. 31(4):


492-498.
Fischer G., Jagsch R., Eder H., Gombas W., Etzersdorfer P.,
Schmidl-Mohl K., Schatten C., Weninger M., Aschauer H. N.
(1999): Comparison of methadone and slow-release morphine
maintenance in pregnant addicts. Addiction. 94(2): 231-239.
Giacomuzzi S., Kemmler G., Ertl M., Riemer Y. (2006):
Opioid addicts at admission vs. slow-release oral morphine,
methadone, and sublingual buprenorphine maintenance
treatment participants. Subst Use Misuse. 41(2): 223-244.
Kastelic A., Dubajic G., Strbad E. (2008): Slow-release oral
morphine for maintenance treatment of opioid addicts intolerant
to methadone or with inadequate withdrawal suppression.
Addiction. 103(11): 1837-1846.
Madlung-Kratzer E., Spitzer B., Brosch R., Dunkel D., Haring
C. (2009): A double-blind, randomized, parallel group study
to compare the efficacy, safety and tolerability of slow-release
oral morphine versus methadone in opioid-dependent inpatients willing to undergo detoxification. Addiction. 104(9):
1549-1557.
Mitchell T. B., White J. M., Somogyi A. A., Bochner F.
(2004): Slow-release oral morphine versus methadone: a
crossover comparison of patient outcomes and acceptability
as maintenance pharmacotherapies for opioid dependence.
Addiction. 99(8): 940-945.
Vasilev G. N., Alexieva D. Z., Pavlova R. Z. (2006): Safety
and efficacy of oral slow release morphine for maintenance
treatment in heroin addicts: a 6-month open noncomparative
study. Eur Addict Res. 12(2): 53-60.
Verthein U., Haasen C., Reimer J. (2012): Maintenance
treatment for opioid dependence with slow-release oral
morphine versus methadone: a randomized cross-over study.
Presented at International Society of Addiction Medicine
Annual Meeting, Geneva.
Winklbaur B., Jagsch R., Ebner N., Thau K., Fischer G.
(2008): Quality of life in patients receiving opioid maintenance
therapy. A comparative study of slow-release morphine versus
methadone treatment. Eur Addict Res. 14(2): 99-105.

Role of the funding source


None.
Conflict of interest
None.

Received and Accepted December 13, 2013


- 100 -

Letter to the Editor


Heroin Addict Relat Clin Probl 2014; 16(3): 103-106

30 years of Naloxone
Massimo Barra and Vittorio Lelli
Villa Maraini, Italian Red Cross (CRI), Rome, Italy, EU

TO THE EDITOR: Since August 1976, when


we started our therapeutic activities at the Villa Maraini Foundation in Rome, our team has considered
the safeguarding of drug users lives as being the top
priority of any antidrug intervention.
The ancient Romans used to say:primum vivere, deinde philosophari, meaning:first survive,
then theorize. So, if you want to treat a drug user, he/
she has to be alive!
At that time, naloxone was not available in Italy,
whereas nalorphine was; this substance, which is an
opioid antagonist, can only be taken under medical
supervision, because of possible breathing depression
which can arise if an overdose has been caused by the
use of a mixture of opioids and other substances that
depress the central nervous system.
The arrival of naloxone, which does not present
any such negative effect, made us think about its possible use by specifically trained non-medical staff.
We learnt that naloxone is probably the only
medication in the pharmacopoeia which is free from
contraindications. Being a pure antagonist of opium
derivates, it can save life in a case of heroin overdose,
while it has no negative consequences in any other
case: of course, it can provoke a temporary withdrawal syndrome, if the patient in question has a physical
dependence on heroin.
As early as 1980, during the first meeting that
took place in Strasbourg from 19th till 21st May, the
Red Cross/Red Crescent international group of drug

experts run by us considered [...] the possibility of


including this specific opioid antagonist in the Red
Cross/Red Crescent first aid kits, while training first
aiders, including volunteers, in the use of that substance. This is possible because that life-saving medicine for drug users [i.e. naloxone] is free from contraindications [...] (Figure 1).
Since then, thanks to our intense and evidencebased advocacy action, we have succeeded in reaching the point where naloxone is considered a lifesaving medicine, which has to be available in any
pharmacy without a prescription. At the beginning,
this was a unique case together with saline liquid,
distilled water and immunizing serum for viper poison of an injectable substance in a phial being sold
over the counter. Lately, thr immunizing serum was
made subject to the medical prescription regime because of contraindications that had been noted in the
meantime.
In the 80s and 90s, many people were against
the proposal that non-medical staff could be allowed
to administer naloxone, considering this to be exclusively a medical act. Even the nurses of the Italian
RC emergency units considered the use of naloxone
as falling outside their sphere of competence. But we
supported, and still support, the idea that a state of
necessity may actually justify the violation of laws,
if this is the only way to prevent a death that is otherwise inevitable.
We assume that a credible antidrug strategy

Corresponding author: Massimo Barra, MD, Fondazione "Villa Maraini", via Bernardino Ramazzini, 31, 00151 Roma, Italy, EU
Phone: +39 06 6575 3058; E-mail: mbarra@villamaraini.it

101

Heroin Addiction and Related Clinical Problems 16(3): 103-106

Figure 1. 1980 International Red Cross Statement

should be able to reach as many drug users as possible.


Antidrug centres should adopt any possible initiative in order to guarantee full access to patients;
currently that is not happening in far too many parts
of the world.
Anyone who goes to an antidrug centre is more
motivated than someone who does not.
Antidrug centres services should reach out to
drug users in the streets, where they live out their
daily tragedy.
That is why, since March 25th, 1992 we have set
up an emergency service, which is operational twenty-four hours every day, and has two mobile units that
can quickly reach areas highly exposed to drug trafficking and drug use.
In a case of overdose, first aid intervention at
a hospital might not be enough, because the patient
could be dead on arrival there. This is the reason why
we need to use naloxone in a timely way in the
streets, at home and wherever an overdose occurs.

- 102 -

By now there are many situations similar to


shooting rooms, even if they are illegal in Italy.
Many drug users, even those not motivated for treatment and rehabilitation, ask the staff of these mobile
units for sterilized injection kits, often informing
them about where they will take drugs. In this way
we can intervene in cases of overdose. Many of these
drug users are trained to use naloxone, in the sense
that they receive elements of advice on overdose prevention; besides, those considered most exposed to
overdose are periodically provided with two naloxone
phials.
This health education, together with the distribution of naloxone phials, is also addressed to drug
users parents, relatives, friends and anybody else
who is interested.
During such training sessions, we point out that
overdose risk normally increases after periods of
prolonged abstinence related to detention or detoxication. In fact, we explain that, in such cases, doses
have to be adapted, by considering the fall in tolera-

M. Barra &V. Lelli: 30 years of Naloxone

tion levels.
It has to be considered that physical detoxification does not cover all the therapeutic requirements of
a drug addict; it may not even be suitable, or actually
dangerous.
For example, wealthy drug addicts, in an attempt
to safeguard their own reputation, often resort to temporary remedies, such as detoxification, instead of undergoing the ordinary treatment based on methadone
or buprenorphine therapies, because their privileged
social position make them think that an expensive detoxification treatment will be more effective than a
low-cost therapy.
However, these interventions, which can clean
a drug user in a few weeks, or even in a few days,
do not allow any control over the development of the
addiction, because there is the factor of exposing the
patient to a high risk of overdose.
The overdose risk also increases in connection
with:
1. A combined intake of heroin together with
other depressants such as alcohol;
2. Any use of the drug when alone, whether at
home or in hard-to-reach places;
3. New dealers;
4. The use of heroin that is too pure or of bad
quality.
Our experience in the field has shown us that,
contrary to common beliefs, long-lasting drug users
are more exposed to the risk of overdose than younger
ones; furthermore, we have noted that, in certain areas, overdose cases normally occur in three or four
episodes, with only short time-lapses in between, followed by a sequence of other days in which no further
episodes are recorded.
Only a few grams of heroin are needed to provide many people with their own dose and, if it is
badly prepared or too pure, that will easily result in
an overdose situation.
In August 1995, the death of 6 people in Palermo, occurring within a few hours, due to heroin that
had arrived in that city in an excessively pure state,
represents a striking case in that sense. The local government representative as well as the mayor asked us
for immediate intervention and, already on the first
day, we saved 6 drug users in a state of overdose and
more than a hundred in the following 3 months.
In cases of overdose, our protocol prescribes an

immediate intramuscular injection of two naloxone


phials; if the skin is hard to reach, the injection has,
whenever necessary, to be performed through the
clothes.
After this first intervention the next step must be
diversified to take into account the age and medical
condition of the patient.
For young drug users, for whom it is normally
easy to find an accessible vein, we perform an intravenous injection of naloxone, which can be repeated
a number of times.
For long-lasting drug users, instead, we inject a
further phial of naloxone under the tongue, because
in their case suitable veins are normally hard to find,
and unsuitable ones often give rise to occlusions in
needles.
From the beginning of our outreach work until
31st December 2013, we carried out 2,139 overdose
interventions, all of them duly recorded, saving as
many drug users lives.
In addition, there are many interventions that
cannot be quantified exactly because they are merely
reported by drug users who have been previously instructed, and provided with naloxone phials by Villa
Maraini.
As pointed out above, so far we have never noted contraindications in the use of naloxone.
We therefore see it as being the most effective
measure for preventing the lethal consequences of
opiate overdoses.
We claim to have been the first practitioners in
the world to theorize the use of injected naloxone
by non-medical staff for overdose prevention, and
to have performed the highest number of successful
overdose interventions in non-medical settings.
Role of the funding source
No sponsor for this letter
Contributors
Authors revised and approved the final form of the
letter.
Conflict of interest
Authors declared no conflict of interest.

Received and Accepted April 3, 2014


- 103 -

Forum
Sunday, March 29, 2015
EUROPEAN OPIATE ADDICTION TREATMENT ASSOCIATION (EUROPAD)
WFTOD meeting during AATOD Conference:
EUROPAD Forum
TIME: 13:00 - 17:00

Chairman: Icro Maremmani, MD (Pisa, Italy, EU)


13:00-13:20 The misuse: a part of opioid maintenance treatment
A. Deschenau, D. Touzeau (Villejuif, France, EU)
13:20-13:40 Measuring outcomes in opioid dependence care: expert consensus on need for improved outcome measurement tools
I. Maremmani (Pisa, Italy, EU), H. Alho (Helsinki, Finland, EU), R. Littlewood (London,
UK)
13:40-14:00 Agonist Opioid Treatment and sexual dysfunctions
L. Somaini (Biella, Italy, EU)
14:00-14:20 Replacement therapy method resettlement in prisons - yes or no?
S. Kasper, J. Softic, H. R. Awad (Zenica, Bosnia & Erzegovina)
14:20-14:40 Emerging trends in alternative routes reported for prescription drug misuse: An international
perspective
J. Green (Denver, CO, USA)
14:40-15:00 Motivational interviewing to facilitate 12 Steps for Opiate Addiction
S. R. Andrew (Portland, ME, USA)
15:00-15:20 Treatment of chronic hepatitis C in drug users : ethic, successful and useful
A.J. Remy, H. Wenger, H. Bouchkira (Perpignan, France, EU)
15:20-15:40 Factors associated with outcome of inpatient opioid addiction treatment
M. Delic, L. Lusa, P. Pregelj (Ljubljana, Slovenia, EU)
15:40-16:00 Risk factors for weight gain during Methadone Maintenance Treatment
E. Peles, S. Schreiber, A. Sason, M. Adelson (Tel Aviv, Israel)
16:00-16:20 Introducing a Naloxone nasal-spray project as part of a national overdose prevention campaign in Norway; first experiences and results
T. Clausen (Oslo, Norway)
16:20-17:00

Question time

Scientific Secretariat
EUROPAD Committee
http://www.europad.org/board-of-directors.php

Walking on Red Square, Moscow, Russia, January 2006

Icro Maremmani

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