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Editor
Icro Maremmani
Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, "Santa Chiara" University
Hospital, Pisa, Italy, EU
Associate Editors
Thomas Clausen
Marta Torrens
Marc Auriacombe
James Bell
South London and Maudsley NHS FoundationTrust & Langston Centre, Sydney, Austrelia
Olof Blix
Barbara Broers
Miguel Casas
Liliana Dell'Osso
Michael Farrell
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
Loretta Finnegan
Gabriele Fischer
Carla Gambarana
Gilberto Gerra
Gian Luigi Gessa
Michael Gossop
Lars Gunne
Andrej Kastelic
Michael Krausz
Evgeny Krupitsky
Mercedes Lovrecic
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
Lubomir Okruhlica
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
Marc Reisinger
Lorenzo Somaini
Marlene Stenbacka
Leift Grnbladh
George Woody
Editorial Coordinators
Marilena Guareschi
Matteo Pacini
Angelo G.I. Maremmani
Luca Rovai
Silvia Bacciardi
Enrico Massimetti
Denise Gazzarrini
Fabio Rugani
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CONTENTS
Preventing opioid overdoses: Is the first still the best? Should we go back to the origins?
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
41
Isabelle Demaret, Graldine Litran, Ccile Magoga, Clmence Deblire, Anice Dupont,
Jrme De Roubaix, Andr Lematre, and Marc Ansseau
49
Shadan Tafreshian, Meisam Javadi, Fariba Fakhraei, and Seyedeh Seddigheh Fatemi
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
65
75
87
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
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
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.
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.
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 7-14
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
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;
Methods
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
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
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
-9-
250
227
200
150
100
58
50
38
23
13
19
Discussion
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
- 11 -
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.
References
1. International Strategic Report regarding narcotics
control. DEA Report for 2008., 2009, Feb 27,
Romanian National Antidrug Agency (Agentia
Nationala Antidrog).
2. National Report on Drug Situation 2010. ROMANIA.
New Developments, Trends and In-depth Information
on Selected Issues, 2011, National Anti-Drug Agency.
3. Abraham A. J., Obrien L. A., Bride B. E., Roman P.
M. (2011): HIV/AIDS services in private substance
abuse treatment programs. Drug Alcohol Depend.
115(1-2): 16-22.
4. Acker C. J. (2010): How crack found a niche in the
American ghetto: The historical epidemiology of
drug-related harm. Biosocieties. 5(1): 70-88.
5. Aguilar-Gaxiola S., Medina-Mora M. E., Magana C. G.,
Vega W. A., Alejo-Garcia C., Quintanar T. R., Vazquez
L., Ballesteros P. D., Ibarra J., Rosales H. (2006): Illicit
drug use research in Latin America: Epidemiology,
service use, and HIV. Drug Alcohol Depend. 84:
S85-S93.
6. Bal B., Mitra R., Mallick A. H., Chakraborti S., Sarkar
K. (2010): Nontobacco substance use, sexual abuse,
HIV, and sexually transmitted infection among street
children in Kolkata, India. Subst Use Misuse. 45(10):
1668-1682.
7. Bauer L. O. (2011): Interactive effects of HIV/AIDS,
body mass, and substance abuse on the frontal brain:
a P300 study. Psychiatry Res. 185(1-2): 232-237.
8. Brvar M., Mozina M. (2008): DRUG POISONING IN
SLOVENIA. Zdravniski Vestnik-Slovenian Medical
Journal. 77(1): 39-45.
9. Chan Y. F., Passetti L. L., Garner B. R., Lloyd J. J.,
Dennis M. L. (2011): HIV risk behaviors: risky
sexual activities and needle use among adolescents
in substance abuse treatment. AIDS Behav. 15(1):
114-124.
10. Curca G. C., Buda O., Capatana C., Marinescu M., Hostiuc
S., Dermengiu D., Cartina C., Cretoiu V. A., Stoica N.
- 12 -
A., Badescu I., Voinea M., Darie C., Apostu I., Banciu
D. P. G., Balica E. G., Brezeanu O., Constantinescu A.,
Gheorghiu V., Balan L. (2008): Study on domestic
violence: a legal medicine perspective. Romanian
Journal of Legal Medicine. 16(3): 226-242.
11. Delorenze G. N., Weisner C., Tsai A. L., Satre D. D.,
Quesenberry C. P., Jr. (2011): Excess mortality among
HIV-infected patients diagnosed with substance
use dependence or abuse receiving care in a fully
integrated medical care program. Alcohol Clin Exp
Res. 35(2): 203-210.
12. Delva J., Van Etten M. L., Gonzalez G. B., Cedeno M.
A., Penna M., Caris L. H., Anthony J. C. (1999): First
opportunities to try drugs and the transition to first
drug use: Evidence from a national school survey in
Panama. Subst Use Misuse. 34(10): 1451-1467.
13. Dermengiu D., Radu D., Aciu F., Broscauceanu A.,
Sereteanu L., Gorun G., Curca G. C., Hostiuc S. (2011):
Drugs of abuse identified in the National Institute
of Legal Medicine Mina Minovici Bucharest 2010.
Romanian Journal of Legal Medicine. 19(3): 229-232.
14. Dhossche D. M., Meloukheia A. M., Chakravorty
S. (2000): The association of suicide attempts
and comorbid depression and substance abuse
in psychiatric consultation patients. Gen Hosp
Psychiatry. 22(4): 281-288.
15. Easton C. J., Lee B., Wupperman P., Zonana H.
(2008): Substance abuse and domestic violence
interventions: the need for theoretical based
research. Am J Addict. 17(4): 341-342.
16. Epelbaum C., Taylor E. R., Dekleva K. (2010):
Immigration trauma, substance abuse, and suicide.
Harv Rev Psychiatry. 18(5): 304-313.
17. Factsheets, W. (2012). "Management of substance
abuse. The global burden." Retrieved 12/01, 2012,
from http://www.who.int/substance_abuse/facts/
global_burden/en/index.html.
18. Gorun G., Curca G. C., Hostiuc S., Buda O. (2011):
Legal highs in Romania: historical and present
facts. Romanian Journal of Legal Medicine. 19(1):
73-76.
19. Gorun G., Dermengiu D., Curca G. C., Hostiuc S., Ioan
B., Luta V. (2010): Toxicological drivers issues in
legal highs use. Romanian Journal of Legal Medicine.
18(4): 271-278.
20. Hill S. L., Thomas S. H. L. (2011): Clinical toxicology of
newer recreational drugs. Clinical Toxicology. 49(8):
705-719.
21. Hostiuc S., Curca C. G., Dermengiu D. (2011):
CONSENT AND CONFIDENTIALITY IN MEDICAL
ASSISTANCE FOR WOMEN VICTIMS OF DOMESTIC
VIOLENCE. Revista Romana De Bioetica. 9(1): 96-107.
22. Hostiuc S., Curca G. C., Ceausu M., Rusu M. C., Niculescu
E., Dermengiu D. (2011): Infectious risks in autopsy
practice. Romanian Journal of Legal Medicine. 19(3):
183-188.
23. Jung H., Matei D., Hecser L., Bohnert M., Pollak S.
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
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
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
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
[153].
1.3.2. Reward activity in bulimia nervosa
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
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
1.5.1. Naloxone
1.5.4. Buprenorphinenaloxone
1.5.2. Naltrexone
1.5.5. Buprenorphine
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
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.
Results
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
- 21 -
- 22 -
L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies
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
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.
Conclusions
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 -
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.
- 28 -
L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies
- 29 -
- 30 -
L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies
7(1): 29-37.
79. Jonas J. M., Gold M. S. (1988): The use of opiate
antagonists in treating bulimia: a study of low dose vs
high dose naltrexone. Psychiatry Res. 24/2: 195-199.
80. Kaye W. H., Pickar D., Naber D., Ebert M. H. (1982):
Cerebrospinal fluid opioid activity in anorexia nervosa.
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81. Keating C. (2010): Theoretical perspective on anorexia
nervosa: the conflict of reward. Neurosci Biobehav Rev.
34(1): 73-79.
82. Keating C., Tilbrook A. J., Rossell S. L., Enticott P. G.,
Fitzgerald P. B. (2012): Reward processing in anorexia
nervosa. Neuropsychologia. 50(5): 567-575.
83. Kelley A. E., Berridge K. C. (2002): The neuroscience of
natural rewards: relevance to addictive drugs. J Neurosci.
22: 3306-3311.
84. Kieffer B. L., Befort K., Gaveriaux-Ruff C., Hirth
C. G. (1992): The d-opioid receptor: Isolation of a
cDNA by expression cloning and pharmacological
characterization. Proc Natl Acad Sci U S A. 89: 1204812052.
85. Koob G. F. (1992): Drugs of abuse: anatomy,
pharmacology and function of reward pathways. Trends
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86. Koob G. F., Vaccarino F., Amalric M., Bloom F. E.
(1985): Positive Reinforcement Properties of Drugs:
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and Abuse Seventh International Berzelius Symposium
Goteborg, Sweden. Raven Press, New York. pp. 35-50.
87. Leander J. D. (1988): Buprenorphine is a potent k-opioid
receptor in pigeons and mice. Eur J Pharmacol. 151:
457-461.
88. Lebow J., Sim L. A., Erwin P. J., Murad M. H. (2013):
The effect of atypical antipsychotic medications in
individuals with anorexia nervosa: a systematic review
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89. Levinson I., Galynker, Ii, Rosenthal R. N. (1995):
Methadone withdrawal psychosis. J Clin Psychiatry.
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90. Loh H. H., Smith A. P. (1990): Molecular characterization
of opioid receptors. Annu Rev Pharmacol. 30: 123-147.
91. Luby E. D., Marrazzi M. A., Kinzie J. (1987): Treatment
of chronic anorexia nervosa with opiate blockade. J Clin
Pharmacol. 7(1): 52-53.
92. Macenski M. J., Schaal D. W., Cleary J., Thompson T.
(1994): Changes in food-maintained progressive-ratio
responding of rats following chronic buprenorphine or
methadone administration. Pharmacol Biochem Behav.
47(2): 379-383.
93. Mansour A., Khachaturian H., Lewis M. E., Al. E.
(1988): Anatomy of CNSopioid receptors. Trends in
Neurosciences. 11: 308-331.
94. Maremmani A. G. I., Dell'Osso L., Pacini M., Popovic
D., Rovai L., Torrens M., Perugi G., Maremmani I.
(2011): Dual diagnosis and chronology of illness in 1090
treatment seeking Italian heroin dependent patients. J
Addict Dis. 30(2): 123-135.
- 31 -
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L. Rovai et al.: The role of the opioid system in Eating Disorders. Perspectives for new treatment strategies
- 33 -
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 35-40
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
Corresponding author: Zhou Renlai, MD; Emotion Regulation Research Center, Beijing Normal University, Beijing 100875,China
E-mail: rlzhou@bun.edu.cn
35
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
treatment [6].
2.2.2 Emotional Clarity
Z. Xin et al.: Comparing emotional clarity, emotion experience, and emotion regulation in male heroin addicts with and without withdrawal
syndrome
3.
Results
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 -
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
Conclusions
References
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M. I., Sanchez-Barrera M., Perez-Garcia M. (2005):
Experience of emotions in substance abusers exposed
to images containing neutral, positive, and negative
affective stimuli. Drug Alcohol Depend. 78(2): 159-167.
2. Bagby R. M., Taylor G. J., Parker J. D. (1994): The
Twenty-item Toronto Alexithymia Scale--II. Convergent,
discriminant, and concurrent validity. J Psychosom Res.
38(1): 33-40.
3. Baker T. B., Piper M. E., Mccarthy D. E., Majeskie M. R.,
Fiore M. C. (2004): Addiction motivation reformulated:
an affective processing model of negative reinforcement.
Psychol Rev. 111(1): 33-51.
4. Boden M. T., Bonn-Miller M. O., Kashdan T. B., Alvarez
J., Gross J. J. (2012): The interactive effects of emotional
clarity and cognitive reappraisal in Posttraumatic Stress
Disorder. J Anxiety Disord. 26(1): 233-238.
5. Boden M. T., Gross J. J., Babson K. A., Bonn-Miller M.
O. (2013): The interactive effects of emotional clarity
and cognitive reappraisal on problematic cannabis use
among medical cannabis users. Addict Behav. 38(3):
1663-1668.
6. Bradley B. P., Gossop M., Phillips G. T., Legarda J. J.
(1987): The development of an opiate withdrawal scale
(OWS). Br J Addict. 82(10): 1139-1142.
7. Cheetham A., Allen N. B.,Yucel M., Lubman D. I. (2010):
The role of affective dysregulation in drug addiction.
Clin Psychol Rev. 30(6): 621-634.
8. Derakshan N., Eysenck M. (2009): Anxiety,
Processing Efficiency, and Cognitive Performance.
New Developments from Attentional Control Theory.
European Psychologist. 14(2): 168-176.
9. Elliman N., Green M., Rogers P., Finch G. (1997):
Processing-efficiency theory and the working-memory
system: Impairments associated with sub-clinical
anxiety. Personality and Individual Differences. 23(1):
31-35.
10. Gross J. J., John O. P. (2003): Individual differences
in two emotion regulation processes: implications for
affect, relationships, and well-being. J Pers Soc Psychol.
85(2): 348-362.
11. John O. P., Gross J. J. (2007): Individual differences
in emotion regulation strategies: Links to global trait,
dynamic, and social cognitive constructs. In: Press G.
(Ed.) Handbook of emotion regulation. New York. pp.
351-372.
12. Magyar M. S., Edens J. F., Lilienfeld S. O., Douglas K.
S., Poythress N. G. (2011): Examining the relationship
among substance abuse, negative emotionality
and impulsivity across subtypes of antisocial and
psychopathic substance abusers Journal of Criminal
Justice. 39: 232-237.
13. Mcrae K., Ochsner K. N., Mauss I. B., Gabrieli J. J.
D., Gross J. J. (2008): Gender differences in Emotion
Regulation: An fMRI Study of Cognitive Reappraisal.
- 39 -
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 41-48
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
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
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.
- 42 -
I. Demaret et al.: Why do heroin users refuse to participate in a heroin-assisted treatment trial?
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
Results
- 43 -
48 (92%)
40 [7]*
30 (58%)
Drug use
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
- 44 -
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?
3 (6%)
1 (2%)
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 -
Conclusions
I. Demaret et al.: Why do heroin users refuse to participate in a heroin-assisted treatment trial?
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 49-54
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
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
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 -
Results
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
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-
52 (50.9%)
74 (72.5%)
Intercourse: dissatisfaction
(Number, Percentage)
44 (43.1%)
23 (45%)
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
- 51 -
Discussion
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
- 53 -
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.
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 55-64
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
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
Methods
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).
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)
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
and
heroin-
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 -
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
A.G.I. Maremmani et al.: Outcomes of Clonazepam Maintained Benzodiazepine-Heroin Addicted Patients During Methadone Maintenance: A
Descriptive Case Series
4.
Discussion
5.
Conclusions
- 62 -
A.G.I. Maremmani et al.: Outcomes of Clonazepam Maintained Benzodiazepine-Heroin Addicted Patients During Methadone Maintenance: A
Descriptive Case Series
- 63 -
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 65-74
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
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
Methods
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.
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.
Men
Women
n=90
n=34
%
Academic Level
Uncompleted Primary School
18
20.2
26.5
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
20.8
6.8
20.9
7.2
0.25
0.8
22.9
6.9
22.9
8.7
0.46
0.6
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
- 68 -
Women
n=90
n=34
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
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
- 69 -
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
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.
- 70 -
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
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.
References
1. Arfken C.L., Klein C., Di Menza S., Schuster C.R. (2001):
Gender differences in problem severity at assessment
and treatment retention. J Subst Abuse Treat 20: 53-57.
- 72 -
Regular article
Heroin Addict Relat Clin Probl 20xx; xx(x): xx-xx
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
Corresponding author: Claudio Colace, Ph.D., via Luigi Volpicelli, 8, 0133 Roma, Italy, EU
Phone: 3336148977; e-mail: claudio.colace@yahoo.it
75
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.
2.2 Assessments
The study was carried out according to the principles laid down in the Helsinki Declaration.
2.5 Statistical analyses
3.
Results
N
9
7
3
15
1
%
25.7
20.0
8.5
42.8
2.8
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 -
Discussion
C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients
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 -
C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients
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
- 82 -
References
1. Anderson C.M., Teicher M.H., Polcari A., Renshaw P.F.
(2002): Abnormal T2 relaxation time in the cerebellar
vermis of adults sexually abused in childhood: potential
role of the vermis in stress-enhanced risk for drug abuse.
Psychoneuroendocrinol. 27: 232-244.
2. A.P.A. (1994): Diagnostic and Statistical Manual of
Mental Disorders, DSM-IV. American Psychiatric
Association, Washington (D.C.).
3. Araujo R.B., Oliveira M., Piccoloto L.B., Szupszynski
K.P.D.R. (2004): Dreams and Craving in Alcohol
Addicted Patients in the Detoxication Stage. Rev Psychiat
Clin. 31: 63-69.
4. Beaman H.A. (2002): Self reported dream experiences
of alcohol and amphetamine dependent men and
women during their initial 30 days of abstinence.
Dissertation Abstract. Accessed 21 October 2002,
at: www.phddissertations.com/display_abstract.
asp?dissertation_id=63.
5. Berridge K.C. (2001): Reward learning: reinforcement,
incentives and expectations. In: Medin D.L. (Ed.),
Academic Press, New York (NY): (vol. 40) pp. 223-278.
6. Berridge K.C., Robinson T.E. (1998): What is the role of
dopamine in reward: hedonic impact, reward learning,
or incentive salience? Brain Res Rev. 28: 309-369.
7. Bob P., Jasova D., Bizik G., Raboch J. (2011):
Epileptiform activity in alcohol dependent patients and
possibilities of its indirect measurement. PlOS One. 26
apr: 10.1371/journal.pone.0018678.
8. Brown S. (1985): Treating the Alcoholic: A Developmental
Model of Recovery. Wiley Press: New York (NY).
9. Childress A.R., Mozley P.D., McElgin W., Fitzgerald
J., Reivich M., OBrien C.P. (1999). Limbic activation
during cue-induced cocaine craving. Am J Psychiatry.
156: 11-18.
10. Choi S.Y. (1973): Dreams as a prognostic factor in
alcoholism. Am J Psychiatry. 130: 699-702.
11. Christensen RL. (2009): A multi-level analysis of
attentional biases in abstinent and non-abstinent problem
drinkers. Dissertation. Florida State University College
of Arts and Sciences.
12. Christo G., Franey C. (1996): Addicts drug-related
dreams: their frequency and relationship to six-month
outcomes. Subst Use Misuse. 31: 1-15.
13. Colace C. (2000): Dreams in abstinent heroin addicts:
four case reports. Sleep and Hypnosis. 2: 160-163.
14. Colace C. (2001): Needs and dreaming processes:
observations on dreams of abstinent heroin addicts.
Sleep. 24: A185.
15. Colace C. (2004). Dreaming in addiction. A study on
the motivational bases of dreaming processes. Neuropsychoanalysis. 6 (2): 167-181.
16. Colace C. (2007): I correlati neuroanatomici e
neurobiologici dei drug dreams. Prevenzione e Salute.
La Rassegna Italiana sulle Tossicodipendenze. 48: 5-16.
17. Colace C. (2009): Drug dreams, drug craving e misura
C. Colace et al.: Limbic system irritability and drug dreams in heroin-addicted patients
- 83 -
- 84 -
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
! Pleasure
! Anguish
! Anger
! Guilt
- 85 -
! 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
Regular article
Heroin Addict Relat Clin Probl 2014; 16(3): 87-98
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
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
Methods
S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks
retention rates, the log rank test was used. All statistical analyses were performed using STATA/SE 9.0
[29].
3.
Results
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
- 90 -
S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks
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
Figure 1. Average dose of BNX during the first four weeks of treatment (N = 323).
- 91 -
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
- 92 -
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
- 93 -
- 94 -
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
Conclusions
- 96 -
S. M. Apelt et al.: Induction and switch to buprenorphine-naloxone in opioid dependence treatment: Predictive value of the first four weeks
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
99
2.
3.
4.
5.
6.
7.
8.
9.
30 years of Naloxone
Massimo Barra and Vittorio Lelli
Villa Maraini, Italian Red Cross (CRI), Rome, Italy, EU
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
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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
Forum
Sunday, March 29, 2015
EUROPEAN OPIATE ADDICTION TREATMENT ASSOCIATION (EUROPAD)
WFTOD meeting during AATOD Conference:
EUROPAD Forum
TIME: 13:00 - 17:00
Question time
Scientific Secretariat
EUROPAD Committee
http://www.europad.org/board-of-directors.php
Icro Maremmani