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Vol. 19 • N. 4 • August 2017
Periodico bimestrale - Sped. in Abb. Post. - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1, DCB PISA -
Aut. tirb. di Pisa n.5 del 9-3-2000
ISSN 1592-1638 - ISSN 2531-4122 (on line)
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Icro Maremmani VP Dole Dual Diagnosis Unit, Santa Chiara University Hospital, University of Pisa, Italy, EU
Associate Editors
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Pier Paolo Pani Socio Health Local Area, Sardinia Region Health Protection Trust, Olbia, Italy, EU
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International Advisory Board
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Marc Auriacombe Université Victor Segalen, Bordeaux 2, France, EU
Alexander Baldacchino University of St Andrews Medical School. North Haugh, St Andrews, Scotland, United Kingdom, EU
James Bell South London and Maudsley NHS FoundationTrust & Langston Centre, Sydney, Austrelia
Olof Blix County Hospital Ryhov, Jönköping, Sweden, EU
Barbara Broers University Hospital of Geneva, Switzerland
Miguel Casas University Hospital of "Vall d’Hebron" - University of Barcelona, Spain, EU
Michael Farrell National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
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Carla Gambarana Department of Molecular and Developmental Medicine, University of Siena, Italy
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Michael Gossop King’s College, University of London, UK, EU
Leift Grönbladh Institute of Addictive Diseases, University Hospital of Uppsala, Sweden, EU
Lars Gunne University of Uppsala, Sweden, EU, [Emeritus]
Herman Joseph Stop Stigma Now; NAMARecovery, New York, NY, USA
Andrej Kastelic Center for Treatment of Drug Addiction, University Hospital, Ljubljana, Slovenia, EU
Michael Krausz St.Paul’s Hospital, University of British Columbia, Canada
Mary Jane Kreek The Rockfeller University, New York, USA
Evgeny Krupitsky St. Petersburg Bekhterev Psychoneurological Research Institute, Saint Petersburg, Russia
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Joyce Lowinson Albert Einstein College of Medicine, The Rockfeller University, New York, USA, [Emeritus]
Angelo GI Maremmani Department of Psychiatry, Northern-West Tuscany Region Local Health Unit, Versilian Zone,
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Robert Newman Baron de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY, USA
Charles P. O'Brien University of Pennsylvania, Phildelphia, USA
Lubomir Okruhlica Centre for Treatment of Drug Dependencies, Bratislava, Slovak Republic, EU
Matteo Pacini Institute of Behavioural Sciences, Pisa, Italy, EU
Mark Parrino American Association for the Treatment of Opioid Dependence, New York, USA
Einat Peles Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
Giulio Perugi Department of Clinical and Experimental Medicine, University of Pisa, Italy, EU
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Marc Reisinger European Opiate Addiction Treatment Association, Brussels, Belgium, EU
Lorenzo Somaini Addiction Treatment Center, Cossato (Biella), Italy, EU
Marlene Stenbacka Karolinska Institute, Stockholm, Sweden, EU
Ambros Uchtenhagen Research Foundation on Public Health and Addiction, Zurich University, Switzerland
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Fabio Rugani School of Psychiatry, University of Naples, Italy, EU
Master in Addictologia, University of Pisa
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Master in Addictologia, University of Pisa
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CONTENTS
Substantial improvement in outpatient opiate-free exits using a novel resource-efficient
lofexidine and buprenorphine-based protocol (‘Detox-in-a-Box’) – a service evaluation study
Radu Iosub, Irmgard Seeger, Fergus Law, Nathan Wallbank, and Jan Melichar 5
Novel approach to predicting the likelihood of sustained abstinence in heroin addicts treated
with naltrexone and naltrexone-behavioural therapy
Jasmina Knežević Tas ić, Maša Karleuša Valkanou, Borislav Đukanović, Dragić Banković, 13
and Vladimir Janjić
Effectiveness of cognitive-behavioural stress management on self-efficacy and risk of relapse
into symptoms of substance use disorders
Kamal Solati and Ali Hasanpour-Dehkordi 25
Exploring predictors of response to methadone maintenance treatment for heroin addiction:
the role of patient satisfaction with methadone as a medication
Saul Alcaraz, Joan Trujols, Núria Siño, Santiago Duran-Sindreu, Francesca Batlle, 35
and José Pérez de los Cobos
Clinical determination of carbohydrate-deficient transferrin (CDT) in alcohol addicts: a
random sample of the general population in Naples, Italy
Luigi Reccia, Rossella Morelli, Serena Boccella, Reginaldo Iovine, Domenico Zaia, 41
Alessandro Crinisio, Aniello Leone, Ida Marabese, Giulio Scala, Francesca Guida,
Domenico Cante, Vito De Novellis, and Luigi Stella
Experience of drug overdose at an urban addiction clinic in Ireland
Tomás Barry, Des Crowley, Aoife Benton, Enda Barron, and Fiona O’Reilly 47
Patterns of prescription drug use and misuse in Spain: The European Opioid Treatment
Patient Survey
Francina Fonseca, Marta Torrens, Magí Farré, Karin E. McBride, Marilena Guareschi, 53
Didier Touzeau, Pierre Villeger, Amine Benyamina, Oscar D’Agnone, Lorenzo Somaini,
Icro Maremmani, and Richard C. Dart
Medicina
delle
Dipendenze
Italian Journal of the Addictions
Organo ufciale della
Società Italiana Tossicodipendenze
P
Luigi Stella
S
Gaetano Deruvo
T
Franco Montesano
C D
Giovanni Addolorato
Ciro D'Ambra
Giovambattista De Sarro
Giuseppe Falcone
Fernando Fantini
Riccardo Gionfriddo
Piergiovanni Mazzoli
Franco Montesano
Fabrizio Starace
Andrea Vendramin
P P
Gian Luigi Gessa
Alessandro Tagliamonte
Gian Paolo Guel
Pier Paolo Pani
Icro Maremmani
C R
Bruno Aiello (Presidente)
Andrea Fuscone (Membro Effettivo)
Patrizia Oliva (Membro Effettivo)
Antonio Barchetta (Membro Supplente)
Domenico Cante (Membro Supplente)
Regular article
Heroin Addict Relat Clin Probl 2017; 19(4): 5-12
5
Corresponding author: Jan Melichar, Consultant Psychopharmacologist, The Glen Hospital, Redland Hill, Bristol, BS6 6UT,
United Kingdom
Phone:+44 1454 615278; Fax: +44 117 9743203; E-mail: janmelichar@gmail.com
Substantial improvement in outpatient opiate-free exits using a novel resource-
efficient lofexidine and buprenorphine-based protocol (‘Detox-in-a-Box’) – a
service evaluation study
Radu Iosub1, Irmgard Seeger1, Fergus Law2, Nathan Wallbank1, and Jan Melichar2, 3
1- Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK
2- Turning Point Drug and Alcohol Services, Wiltshire, UK
3- The Glen Hospital, Bristol, UK
Summary
Background: Due to relatively poor outpatient opiate detox success rates locally and limited access to inpatient opiate
detoxication beds, we introduced a novel two week long structured opiate detoxication regime using ve key princi-
ples: 1) Four outpatient visits over the two week regime. 2) Buprenorphine frontloading: long-acting partial agonist with
less severe withdrawal symptoms. 3) Lofexidine: an α2-adrenoceptor agonist for opiate withdrawal symptoms, with
signicantly less sedation and hypotension than clonidine. 4) “Well-being medication”: symptomatic relief for insomnia,
abdominal symptoms, etc. 5) Naltrexone: offered for relapse prevention. Aims: We assessed the efcacy of this regime
in our outpatients setting (annual numbers coming into treatment 120-150/year) compared to previous years when client-
led opiate replacement dose reduction regimes were used solely. Methods: Electronic patient management software
was used by data analysts to lter our caseload and calculate the number of ‘opiate-free’ discharges yearly 2010 – 2014.
Results: In the rst year after its introduction the number of patients achieving abstinence quadrupled. ‘Detox-in-a-Box’
was rapidly embraced by both key-workers and patients, and continued to prove highly successful over the subsequent
four years leading to a dramatic improvement in the number of patients exiting drug-free from our services. This dramatic
improvement cleared the backlog of highly motivated clients awaiting a detox. Conclusions: Compared to other com-
munity opiate detox strategies used, ‘Detox-in-a-Box’ proved to be a highly efcient, successful, structured and resource
efcient protocol. It continues to be used by services and is gradually being rolled out elsewhere.
Key Words: Rapid community opiate detoxication; buprenorphine; lofexidine
1. Introduction
Opiate dependence has for many decades been
a major challenge for health-care systems, govern-
ments, police forces, social services and societies
across the world [13] and has disabling consequences
for those using opiates illicitly; increasing their risks
of overdose, infection with blood borne viruses, sep-
sis, venous thromboembolism, endocarditis and many
other adverse physical health and social impacts [1,
10, 12, 14, 15].
Although prescribed opiates account for an in-
creasing percentage of opiate dependence in modern
western societies [3], heroin remains the most com-
mon form of illicit opiate misused across the world
and is associated with signicantly more harm com-
pared to prescribed opiates [3, 10, 15, 16].
A UK based study identied heroin as one of
the top three most harmful drugs for both users and
others / society (alongside alcohol and crack cocaine)
[10] and a more recent pan-European study has repli-
cated these results [15].
The treatment of opiate dependence follows
three main steps: stabilisation, safe opiate withdrawal
(detoxication) and relapse prevention (maintenance
of abstinence) [1, 8, 12].
Opiate stabilisation strategies consist of opiate
replacement prescribing (most commonly methadone
- 6 -
Heroin Addiction and Related Clinical Problems 19(4): 5-12
and buprenorphine) with the aim to disconnect the
association between the drug use and changes in the
mental state and personal circumstances [12].
Safe withdrawal from opiates (detoxication)
is achieved through various strategies ranging from
gradual dose reduction of the opiate replacement
(methadone or buprenorphine) over 12 weeks through
to rapid detox protocols – often offered in inpatient
settings.
A Cochrane review [6] published in 2014 com-
pared studies reporting methadone dose reduction and
detoxication with alpha2-adrenergic agonist after
discontinuation of methadone. The duration of treat-
ment was signicantly longer with reducing doses of
methadone. The signs and symptoms of withdrawal
occurred and resolved earlier with alpha2-adrenergic
agonists whereas the chances of completing with-
drawal treatment were similar in both groups [6].
Anecdotally, opiate withdrawal regimes involv-
ing gradual dose reduction have been compared to an
endless “Russian doll” toy game, which is probably
an accurate metaphor to describe the pitfalls of this
technique (Figure 1).
While the intention is to reduce the dose in an
ever decreasing spiral down to zero, often the dose
reduction is followed by an increase and a further
dose reduction, with a never ending circle where the
patient often ends up being on sub-therapeutic opiate
stabilization treatment longer term.
From our experience, patients’ recovery capital
and willingness to progress to abstinence is enhanced
through a range of intense psychosocial interven-
tions offered by care-coordination and key-working.
These create a window of opportunity for successful
detoxication. Patients at this stage of treatment typi-
cally prefer structured and time limited rapid detox
protocols over gradual dose reduction detoxication
where the nal goal is often very distant and out of
sight. Common experience demonstrates that because
of the long duration, dose reduction opiate detoxica-
tion often misses the valuable window of opportunity
created through intense engagement efforts and in-
creases the chances of relapse during detoxication.
A rapid opiate detoxication instead can favourably
utilise bursts of intense motivation and recovery capi-
tal and offers a palpable, in sight outcome.
Buprenorphine is a partial agonist at μ and κ
opioid receptors. That makes buprenorphine less like-
ly to cause respiratory depression compared to full μ
agonists like heroin and methadone. It is also less se-
dating and has a lower risk of overdose, and therefore
it has been regarded as a safer option for both opi-
ate stabilization and detoxication. Buprenorphine
has an established role in opiate detoxication [1, 9,
11, 18, 20] and because of its long half-life and high
receptor occupancy it tends to be associated with a
milder and slower opiate withdrawal compared to
methadone [1, 8, 12].
Chronic opiate use inhibits noradrenaline re-
lease. However noradrenergic neurones adapt to
chronic inhibition and upregulate. Opiate detoxi-
cation triggers a rebound “noradrenaline storm” re-
sponsible for some of the most troublesome opiate
withdrawal symptoms such as tachycardia, sweat-
Figure 1. The ‘ideal’ versus the ‘practice’ of gradual opiate replacement dose reduction detoxication. The
spiral (the ideal) involving gradual dose reduction until zero, versus the never ending cycle (the practice) of
repeated reductions, dose increases and further reductions
- 7 -
R. Iosub et al.: Substantial improvement in outpatient opiate-free exits using a novel resource-efcient lofexidine-based protocol (‘Detox in a Box’)
– a service evaluation study
ing, piloerection, rhinorrhea and shivering. Alpha2-
adrenoceptor agonists (clonidine and lofexidine) are
able to inhibit the “noradrenergic storm” and have
been proven to be useful tools in opiate detoxica-
tion [4, 6, 11, 13, 17, 19]. Clonidine causes more
pronounced cardio-vascular side effects (hypotension
and bradycardia) compared to lofexidine and it is
rarely recommended for use in outpatient settings [1].
Various studies suggest that Lofexidine is more use-
ful than clonidine in rapid opiate detoxication, not
only to counteract withdrawal symptoms, but also in
the treatment of dysphoria and mood changes [5, 7].
1.1 Relapse prevention and maintenance of
abstinence
Relapse prevention involves using psychosocial
interventions aimed at promoting recovery and absti-
nence from drugs by building on the clients’ strengths,
skills and abilities. Alongside these interventions
psychopharmacology also plays an important role in
maintaining abstinence from opiates. Naltrexone is
a μ opioid receptor antagonist. Although it does not
completely alleviate cravings, naltrexone signicant-
ly reduces them [2] hence can play a signicant role
in relapse prevention.
Detoxication is often perceived by patients as
the most difcult part in the treatment of opiate ad-
diction. However experience has demonstrated that it
is instead sustaining recovery and relapse prevention
that is more challenging. The effort required to suc-
cessfully complete an opiate detox has been compared
to climbing a mole hill whereas the effort of sustain-
ing recovery is like climbing a mountain (Figure. 2.)
2. Methods
Back in 2010, South Gloucestershire drug and
alcohol community services introduced a novel 2
week community opiate detox protocol (‘Detox-in-
a-Box’) (Figure 3) which was created to address the
problem of a long backlog of service-users waiting
for a rapid structured opiate detox in a climate of lim-
ited beds availability for a medically supervised rapid
opiate withdrawal.
2.1. Eligibility criteria
‘Detox-in-a-Box’ was offered to highly mo-
tivated opiate dependent patients, who were stable
on maintenance opiate replacement treatment (Bu-
prenorphine – irrespective of the dose or Methadone
up to 30mg daily), with minimal or no on top opioid
use and no major psychiatric or physical health co-
morbidities.
Detox-in-a-Box has four main components:
1. Buprenorphine frontloading
Figure 2. The detox ‘molehill’ and the ‘mountain’ of recovery. The effort required to successfully complete an
opiate detox has been compared to climbing a mole hill whereas the effort of sustaining recovery is like climb-
ing a mountain.
- 8 -
Heroin Addiction and Related Clinical Problems 19(4): 5-12
2. Lofexidine (an α2-adrenoceptor agonist to
address the symptoms caused by the “no-
radrenergic storm”)
3. “Well-being medication” for symptomat-
ic relief for insomnia, anxiety abdominal
symptoms (spasm, diarrhoea, nausea etc.)
and headaches/pain
4. Naltrexone for relapse prevention.
2.1.1. Buprenorphine frontloading
The aim is to switch the “opioid of use” to Bu-
prenorphine – at full blocking dose – at the beginning
of the detox. This process is called frontloading. Due
to its long half-life and high receptor occupancy bu-
prenorphine causes a much milder withdrawal that is
delayed and onsets slower, on or after day 5 of detox.
2.1.2. Lofexidine
Lofexidine is used to alleviate opiate withdraw-
al symptoms which are largely due to the dramatic
increase in the levels of noradrenaline during opiate
withdrawal. Frontloading with buprenorphine means
that lofexidine is not needed until day 5 due to the
milder and slower onset withdrawal and lower doses
can be used with signicantly reduced need for moni-
toring.
Blood pressure measurements: For the past
5 years we have successfully simply monitored the
blood pressure and pulse on day 5 of the detox (when
opioid withdrawals are predicted to start) before and
30min after the rst dose of lofexidine (0.2mg). Of
the nearly 100 patients detoxed by this method, there
have been no major concerns and only minor issues
with blood pressure and pulse, with no patients stop-
ping their detoxication as a result.
2.1.3. “Wellbeing medication” – as required –
These are aimed at other symptoms like insom-
nia, anxiety, abdominal symptoms (spasm, diarrhoea,
nausea etc) and headaches/pain. Our team uses: zopi-
clone 7.5-15mg ON PRN (insomnia); promethazine
hydrochloride 10 - 20mg TDS PRN (anxiety); lopera-
mide 2mg orally after each loose stool (max 16mg/
day) (diarrhoea); hyoscine butylbromide 10-20mg
QDS PRN (abdominal cramps); Buccastem 3mg buc-
cal BD (nausea and vomiting); and ibuprofen 200-
600mg TDS (pain).
2.1.4. Naltrexone
Naltrexone was offered to all patients and if cho-
sen a half dose was given on day 12 (25mg) followed
by 50mg daily thereafter.
The detox programme involves four clinic ap-
pointments with one of the nurse prescribers, on days
1, 5, 7 and 12 (Figure 3).
2.2. Procedure
2.2.1 Day 1
‘Detox-in-a-Box’ is designed to start on Thurs-
days (day 1) with buprenorphine frontloading. Prior
to commencing the detox, patients were asked to time
their opiate use so that opiate withdrawal symptoms
are about to begin around the time of their rst visit
at the detox clinic. The rst buprenorphine 2mg dose
is given in the clinic during the assessment. The total
dose of buprenorphine (8mg on day 1) is split (2mg,
2mg and 4mg) to limit the likelihood of precipitated
withdrawal. The remaining doses for days 1, 2 and 3
are dispensed on day 1 (Figure 3). With this buprenor-
phine front-loading regime withdrawal symptoms are
not expected to occur earlier than day 5, therefore
there is no need for any “well-being medication” and
lofexidine before day 5.
Figure 3. Overview of the ‘Detox-in-a-Box’ prescribing plan
- 9 -
R. Iosub et al.: Substantial improvement in outpatient opiate-free exits using a novel resource-efcient lofexidine-based protocol (‘Detox in a Box’)
– a service evaluation study
2.2.2 Day 5
The rst dose of lofexidine (0.2mg) is given
with blood pressure monitoring before and half an
hour after the rst dose. Lofexidine and “well-being
medication” are then dispensed for days 5 and 6.
2.2.3 Day 7
Lofexidine and “well-being medication” are dis-
pensed for days 7-12.
Relapse prevention medication is discussed and
naltrexone information leaets are given to the pa-
tient.
2.2.4 Day 12
Lofexidine at reducing doses is dispensed for
days 12-14 together with “well-being medication”
(Figure 3). If the patient elected to start naltrexone, a
half dose of 25mg is given on day 2 and naltrexone is
dispensed until the next review.
3. Results
The total caseload of the service was ltered to
select for opiate dependent patients under our care,
discharged as drug free each year, following a phar-
macological intervention in community (detoxica-
tion) between 2010 and 2014. During this time the
service caseload remained stable (between 120-150
opiate dependent patients per year receiving treat-
ment for opiate dependence).
A total of 93 patients were discharged from our
services as “drug-free” between 2010 and 2014 fol-
lowing detoxication. The female:male ratio was
1:1.65. The rst drug of choice (at point of referral)
was heroin (85%), methadone (5.4%) and other opi-
ates (9.7%); and 50.5% of these patients were docu-
mented to use crack-cocaine as a second drug (at the
point of referral) (Table 1).
‘Detox-in-a-Box’ was rapidly embraced by both
key-workers and patients, and proved highly suc-
cessful over the subsequent four years leading to a
dramatic improvement in the number of patients exit-
ing drug-free from our services. In the rst year af-
ter its introduction the number of patients achieving
abstinence quadrupled. This dramatic improvement
cleared the backlog of highly motivated clients await-
ing for a detox. Subsequent years showed a similar
steady increase in the numbers of those achieving ab-
stinence (Figure 4).
Compared to previous community opiate detox
strategies used by the team, ‘Detox-in-a-Box’ proved
to be a structured and resource efcient protocol (re-
quiring only four routine appointments with a nurse-
prescriber during the 14 days of treatment).
‘Detox-in-a-Box’ samples of qualitative feed-
back received from patients and staff are reported in
Table 2.
4. Discussion
Typically rapid opiate detox programmes are
medically assisted and take place in inpatient units;
such treatment often incurring signicant costs. In
the current nancial climate most Drug and Alcohol
Table 1. Description of characteristics of patients seen in
the South Gloucestershire service (2010-2014)
Demographic N %
Age (at time of
discharge) 18-20 3,23
21-30 24.73
31-40 44.09
41-50 23.66
>50 4.30
Gender Female: Male =
1:1.65
First drug of
choice Heroin 84.95
(at point of refer-
ral)
Unprescribed
Methadone 5.38
Codeine 2.15
Other opiates 7.52
Second drug of
choice
Cocaine Freebase
(crack) 50.54
(at point of refer-
ral) No second drug 25.81
Alcohol 15.05
Diazepam 2.15
Buprenorphine
(prescribed) 2.15
Other 4.30
Table 2. ‘Detox-in-a-Box’ samples of qualitative feed-
back received from patients and staff
‘Detox-in-a-Box’ Feedback Statements
“The shorter detox and use of ‘Bup’ reduced my with-
drawal symptoms.” Detox Service User
“It was easier and less harsh than longer detox pro-
grammes I’ve tried.” Service User
“We found the protocol useful for clients who nd the
nal reductions below 40mls of methadone difcult as
they can switch to buprenorphine.” Nurse Prescriber
“It works really well, is time limited and structured,
gives client reassurance and is easily adjustable if re-
quired.” Rehabilitation Manager
- 10 -
Heroin Addiction and Related Clinical Problems 19(4): 5-12
services are faced with scarce availability of inpatient
detoxication beds and very long waiting times for
the treatment; often missing the window of opportu-
nity of the “peak” in recovery capital created through
engagement, stabilisation and key-working.
To our knowledge ‘Detox-in-a-Box’ is the rst
rapid community based opiate detox protocol which
offers a structured yet resource efcient alternative to
inpatient opiate detox programmes.
Within one year of its implementation, ‘Detox-
in-a-Box’ led to a four-fold increase in the number of
patients being discharged as “drug free”, clearing the
back-log of patients waiting for inpatient treatment. A
sustained increase in the numbers of “drug-free” exits
was demonstrated over the subsequent 4 years.
‘Detox-in-a-Box’ is a structured intervention
which brings a sense of predictability and safety for
both patients and teams, who prefer ‘Detox-in-a-Box’
over slow dose reduction regimes.
Aside from the clear benets of our clients be-
ing more likely to complete their community detox,
we found that by running this model alongside the
existing alcohol detox service, we made better use
of resources – both in terms of facilities and staff.
Having a programme that was time limited – with a
clear beginning, middle and end – also enabled us to
plan aftercare services more effectively. We were also
able to work alongside Mutual Aid groups such as
SMART Recovery and NA, which were an essential
ingredient to the success of the model. We also found
that utilising our existing relationships with our col-
leagues in community pharmacies helped by adding
another layer of support.
It was re-assuring to note that our experience of
having no signicant clinical issues or adverse events
was replicated as the ‘Detox-in-a-Box’ was rolled
out over the past 5 years. In particular the (theoreti-
cal) concerns around hypotension and lofexidine did
not, in practical terms, cause any signicant issues or
problems. A key part of the success of the interven-
tion was due to the fact that it selects service users
who are ready for detoxication (they have already
reduced to 40ml of methadone or are on buprenor-
phine with no on top use).
This protocol was quickly adopted by other ser-
vices locally, including independent residential rehab
units and is in the process of being incorporated into a
variety of national services’ guidelines (2016). Other
services have taken it up, in part, because it offers an
alternative to very slow detoxication protocols and
helps overcome the issue of patients stuck on low
doses due to not having a focussed nal detoxication
pathway, which does not involve inpatient or exces-
sive community input. ‘Detox-in-a-Box’ was seen as
being able to provide an option that re-enthused both
staff, service users and commissioners to make the
most of the scarce community resources now avail-
able to the substance misusing population.
Limitations
‘Detox-in-a-Box’ is an innovative, efcient, two
Figure 4. ‘Detox-in-a-Box’ led to a substantial improvement in outpatient opiate-free exits
- 11 -
R. Iosub et al.: Substantial improvement in outpatient opiate-free exits using a novel resource-efcient lofexidine-based protocol (‘Detox in a Box’)
– a service evaluation study
7. Kahn A., Mumford J. P., Rogers G. A., Beckford H.
(1997): Double-blind study of lofexidine and clonidine
in the detoxication of opiate addicts in hospital. Drug
Alcohol Depend. 44(1): 57-61.
8. Melichar J. K., Daglish M. R., Nutt D. J. (2001):
Addiction and withdrawal--current views. Curr Opin
Pharmacol. 1(1): 84-90.
9. Nutt D. J. (2015): Considerations on the role of
buprenorphine in recovery from heroin addiction from
a UK perspective. J Psychopharmacol. 29(1): 43-49.
10. Nutt D. J., King L. A., Phillips L. D., Independent
Scientic Committee On D. (2010): Drug harms in the
UK: a multicriteria decision analysis. Lancet. 376(9752):
1558-1565.
11. Oldham N. S., Wright N. M., Adams C. E., Sheard
L., Tompkins C. N. (2004): The Leeds Evaluation of
Efcacy of Detoxication Study (LEEDS) project: an
open-label pragmatic randomised control trial comparing
the efcacy of differing therapeutic agents for primary
care detoxication from either street heroin or methadone
[ISRCTN07752728]. BMC Fam Pract. 5: 9.
12. Praveen K. T., Law F., O'shea J., Melichar J. (2012):
Opioid dependence. Am Fam Physician. 86(6): 565-566.
13. Soyka M., Kranzler H. R., Van Den Brink W., Krystal J.,
Moller H. J., Kasper S., Wfsbp Task Force on Treatment
G. F. S. U. D. (2011): The World Federation of Societies
of Biological Psychiatry (WFSBP) guidelines for
the biological treatment of substance use and related
disorders. Part 2: Opioid dependence. World J Biol
Psychiatry. 12(3): 160-187.
14. Tang Y. L., Zhao D., Zhao C., Cubells J. F. (2006): Opiate
addiction in China: current situation and treatments.
Addiction. 101(5): 657-665.
15. Van Amsterdam J., Nutt D., Phillips L., Van Den
Brink W. (2015): European rating of drug harms. J
Psychopharmacol. 29(6): 655-660.
16. Van Amsterdam J P. L., · Henderson G, · Bell J, ·
Bowden-Jones O,· Hammersley R, · Ramsey J, · Taylor
P,· Dale-Perera a, · Melichar J (2015): Ranking the harm
of non-medically used prescription opioids in the UK.
Regulatory Toxicology and Pharmacology 73(3): 999-
1004.
17. Vartak A. P. (2014): The preclinical discovery of
lofexidine for the treatment of opiate addiction. Expert
Opin Drug Discov. 9(11): 1371-1377.
18. Wallen M. C., Lorman W. J., Gosciniak J. L. (2006):
Combined buprenorphine and chlonidine for short-term
opiate detoxication: patient perspectives. J Addict Dis.
25(1): 23-31.
19. Washton A. M., Resnick R. B. (1981): Clonidine in opiate
withdrawal: review and appraisal of clinical ndings.
Pharmacotherapy. 1(2): 140-146.
20. Whelan P. J., Remski K. (2012): Buprenorphine vs
methadone treatment: A review of evidence in both
developed and developing worlds. J Neurosci Rural
Pract. 3(1): 45-50.
week long opiate detoxication protocol. It is careful-
ly tailored for a selected group of patients in commu-
nity settings. Although detoxication is an essential
step in achieving recovery, relapse prevention is the
most important goal in successful recovery. ‘Detox-
in-a-Box’ is most likely to be of benet to two patient
groups: those who have achieved a degree of stability
on opiate replacement therapy and those who invest-
ed – through psycho-social interventions – in building
a solid recovery capital.
A long-term follow up was not possible in the
present study due to its retrospective design. There is
data to suggest that a long duration of opiate misuse
and a high number of previous detoxications are as-
sociated with decreased odds of success in further de-
toxication attempts and so further ‘Detox-in-a-Box’
studies should aim to sub-group analyse and compare
success rates. This will generate useful information to
inform the process of selecting the most appropriate
patients for this intervention.
5. Conclusions
The ‘Detox-in-a-Box’ technique clearly demon-
strates that it is possible for service users to detoxify
safely from opiates in a community setting with little
professional input, compared to other models in use,
and in a way that enthuses both staff and service us-
ers.
References
1. Diaper A. M., Law F. D., Melichar J. K. (2014):
Pharmacological strategies for detoxication. Br J Clin
Pharmacol. 77(2): 302-314.
2. Dijkstra B. A., De Jong C. A., Bluschke S. M., Krabbe
P. F., Van Der Staak C. P. (2007): Does naltrexone affect
craving in abstinent opioid-dependent patients? Addict
Biol. 12(2): 176-182.
3. Fischer B., Patra J., Cruz M. F., Gittins J., Rehm J. (2008):
Comparing heroin users and prescription opioid users in
a Canadian multi-site population of illicit opioid users.
Drug Alcohol Rev. 27(6): 625-632.
4. Fresquez-Chavez K. R., Fogger S. (2015): Reduction
of opiate withdrawal symptoms with use of clonidine
in a county jail. J Correct Health Care. 21(1): 27-34.
5. Gerra G., Zaimovic A., Giusti F., Di Gennaro C., Zambelli
U., Gardini S., Delsignore R. (2001): Lofexidine versus
clonidine in rapid opiate detoxication. J Subst Abuse
Treat. 21(1): 11-17.
6. Gowing L., Farrell M. F., Ali R., White J. M. (2014):
Alpha2-adrenergic agonists for the management of
opioid withdrawal. Cochrane Database Syst Rev. 3:
CD002024.
- 12 -
Heroin Addiction and Related Clinical Problems 19(4): 5-12
Nathan Wallbank has served as a speaker, a consult-
ant and an advisory board member for Britannia Pharma-
ceuticals. Nathan Wallbank is an employee of Avon and
Wiltshire Mental Health Partnership NHS Trust. Nathan
Wallbank owns no stocks and shares. Nathan Wallbank
owns no patents.
Dr Fergus Law has over the last 20 years served as
a speaker, a consultant and an advisory board member
for Alpharma, Britannia/Genus, Bristol-Myers-Squibb,
Dupont, Lundbeck, Reckitt-Benckiser, Schering-Plough,
Servier and has received research funding from Schering-
Plough Ltd and Reckitt-Benckiser Healthcare. Dr Fergus
Law is an employee of Turning Point. Dr Fergus Law owns
no stocks or shares. Dr Fergus Law owns no patents.
Dr Jan K Melichar has served as a speaker, a con-
sultant and an advisory board member for Britannia and
Indivior and as a speaker and a consultant for Lilly, Reck-
itt-Benckiser, Schering-Plough and Britannia and has re-
ceived research funding from Britannia. Dr Jan K Melichar
is Medical Director of DHI, Bath and Ranvier Health Ltd,
Bristol. Dr Jan K Melichar owns stocks and shares in Ran-
vier Health Ltd, Bristol. Dr Jan K Melichar has a patent but
not in this area of medicine.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki –
Ethical Principles for Medical Research Involving Human
Subjects. This study does not require ethics committee ap-
proval because it is a retrospective analysis of the outcomes
of a novel treatment intervention. Implementation and re-
view of outcomes was performed in accordance with the
internal clinical gouvernance regulations and was overseen
by senior clinicians and managers involved in the process.
Received April 10, 2016 - Accepted November 6, 2016
Acknowledgements
The authors would like to acknowledge the contribu-
tion of their colleagues Mr Guy March and Mrs Rebecca
Miles-Smith (data analysts) for their help with caseload
ltering and data analysis.
Role of the funding source
Authors state that this study was nanced with inter-
nal funds. No sponsor played a role in study design; in the
collection, analysis and interpretation of data; in the writ-
ing of the report; and in the decision to submit the paper
for publication.
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
control, including nal responsibility for the decision to
submit the paper for publication.
Conict of interest
Dr Radu Iosub has received conference travel grants
from Deafness Resesarch, UK, The Physiological Society
– UK and Britannia Pharmaceuticals. Over the last 17 years
Dr Radu Iosub has been involved in various research pro-
jects funded by Deutsche Forschungsgemeinshaft (DFG)
in Germany and The Welcome Trust in the UK. Dr Radu
Iosub is an employee of Avon and Wiltshire Mental Health
Partnership NHS Trust. Dr Radu Iosub owns no stocks or
shares. Dr Radu Iosub owns no patents.
Dr Irmgard Seeger has not served as a speaker or a
consultant and/or as an advisory board member, and has
not received research funding. Dr Irmgard Seeger is an em-
ployee of Avon and Wiltshire Mental Health Partnership
NHS Trust. Dr Irmgard Seeger owns no stocks or shares
Dr. Irmgard Seeger owns no patents.
Regular article
Heroin Addict Relat Clin Probl 2017; 19(4): 13-24
13
Corresponding author: Jasmina Knežević Tasić, Clinic for Addiction and Other Psychiatric Disorders, Lorijen Hospital, Tetovska
45, 11000 Belgrade, Serbia.
Phone: +381616717375; E-mail: psyonics@gmail.com
1. Introduction
Heroin addiction is a chronic, progressive and
recurrent disease. The optimal treatment outcome of
total abstinence from opiates is seldom achieved [47,
16, 11]. Some studies have provided evidence that
it is possible to sustain multiannual abstinence from
opiates and opioids as an outcome of heroin addic-
tion treatment [32, 23, 28]. Achieving recovery is a
lengthy process whose dynamics and determing fac-
tors we still do not understand fully [23, 28].
The use of μ- opioid receptor antagonist naltrex-
one (NTX) can help achieve long-lasting abstinence
from opiates [44, 49, 24, 25]. The positive sides of
NTX in sustaining stable abstinence in heroin addicts
include lack of abuse potential and the ability to act
as a strong anti-craving medication, not only for opi-
ates, but also for alcohol and other substances [40,
49, 50, 15, 18, 19, 5]. Furthermore, there is evidence
that the use of NTX signicantly reduces the possi-
bility of death from heroin overdosing [22]. One of
naltrexone’s drawbacks is that it does not promote
self–administration, due to the lack of any agonistic
effect. Retention in treatment and compliance are of
great importance in determining the outcome of ther-
apy [35, 30, 47, 31, 23, 28]. Combining NTX with
a psychosocial treatment increases the chances of
overcoming non-compliance [40, 49]. More speci-
Novel approach to predicting the likelihood of sustained abstinence in heroin
addicts treated with naltrexone and naltrexone-behavioural therapy
Jasmina Knežević Tasić1, Maša Karleuša Valkanou2, Borislav Đukanović3, Dragić Banković4,
and Vladimir Janjić5
1-Clinic for Addiction and Other Psychiatric Disorders, Lorijen Hospital, Belgrade, Serbia
2-“Reverie” Institute of Mental Health, Belgrade, Serbia
3-University of Donja Gorica, Podgorica, Montenegro
4-Faculty of Science of the University of Kragujevac, Kragujevac, Serbia
5-Faculty of Medical Sciences of the University of Kragujevac, Kragujevac, Serbia
Summary
Background: Factors determining heroin addiction treatment outcome have not been studied extensively, despite their
practical and theoretical signicance. It is uncertain whether we are able to predict the odds of sustained heroin absti-
nence, or to inuence the factors that increase the likelihood of recovery. This study has aimed to identify factors that ei-
ther individually or in synergy support sustained multiannual abstinence. Methods: In this translational, ambidirectional
cohort study, we have evaluated two groups of heroin addicts that underwent the same therapeutic procedures but with
different outcomes (133 abstainers and 56 relapsers), using a non-standardized questionnaire to study: a) the history of
addiction, b) motivation for the treatment, c) parental attitudes and control, d) job satisfaction, e) social and emotional
relationships, f) alternative satisfactions, g) use of other substances during treatment and h) treatment characteristics.
The chi square analysis was used to determine specic signicant factors that act individually. Binary logistic regression
provided a mathematical model of the synergistic effects of signicant factors. Results: The study found a new variable,
an ‘abstinence marker’, which was dened by the synergistic effect of the following factors: a) use of tramadol before
treatment (p = 0.011), b) non-use of benzodiazepines (p = 0.001), c) length of naltrexone use (p <0.0005), d) non-use of
cannabis (p = 0.002), e) non-compulsive exercise (p = 0.009), and f) employment and job satisfaction (p <0.0005) during
recovery. Conclusions: This study reports a mathematical model that predicts multiannual sustained abstinence as an
outcome of heroin addiction treatment.
Key Words: Heroin addiction; treatment outcome; naltrexone; abstinence
- 14 -
Heroin Addiction and Related Clinical Problems 19(4): 13-24
cally, in naltrexone-behavioural therapy (BNT), NTX
is used in combination with evidence–based treat-
ments, including motivational interviewing, cognitive
behavioural relapse prevention, voucher incentives
and network therapy. BNT may contribute to the pa-
tient’s genuine motivation for treatment [4, 5, 27, 11,
38, 49].
1.1. Impact of use of other psychiatric medications
and substances on heroin addiction treatment
Heroin addicts often substitute heroin with
available opiates and non-medically used prescription
opioids for practical or psychological reasons [17,
51]. Examples of these substitutes include tramadol
(TRM), ‘poppy cocoon tea’, methadone, buprenor-
phine, codeine and morphine. To better understand
their impact on addiction treatment, we need to elu-
cidate the signicance of a substitute choice. The an-
tidepressive, anxiolytic and antipsychotic properties
of opiates as a pharmacological category have been
widely recognized by the scientic community. More
specically, it does seem that TRM is able to provide
a strongly antidepressant effect, compared with other
opioids, since it also suppresses the reuptake of ser-
otonin and norepinephrine. In addition, the anti-de-
pressant effects of TRM have been shown in animal
models of depression and in several preclinical stud-
ies, so leading to it being increasingly considered as
a suitable therapy for depression treatment [52, 55].
The impact of using other substances during re-
covery from heroin addiction on the treatment out-
come has been explored in many studies. Those stud-
ies suggest the negative impact of related substance
abuse on the clinical presentation of heroin addicts.
In particular, cocaine abuse has shown to increase the
likelihood of psychiatric disorders and to lower the
subject’s awareness of his/her own psychopathology
[6]. Similarly, it has been shown that heroin addicts
may mask heroin use with alcohol abuse, so con-
tinuing addiction patterns that may be disguised as
remission [39]. Among those other substances, can-
nabis has been studied the most extensively, as its
abuse is frequent among opiate addicts even during
their recovery [40, 14]. Clinicians are often faced by
the dilemma of whether to insist on abstinence from
all substances during the treatment of opiate addicts,
or to tolerate the use of substances such as nicotine
and cannabis [33]. Several studies have shown that
the use of cannabis impedes heroin addiction treat-
ment or produces worse outcomes [54, 1], and results
in a 27% reduction in the odds of abstinence from
drug and heavy alcohol use [33]. In contrast, other
studies, e.g. Saxon et al. [42], showed that patients
using cannabis were less likely to use other psycho-
active substances. Additionally, in some studies, e.g.
Epstein and Preston [14], the use of cannabis did not
have an impact on the duration or outcome of heroin
addiction treatment [10, 12, 14]. Other studies have
suggested that the use of cannabis may increase the
odds of a patient staying in treatment and sustain-
ing abstinence [40, 42]. It has also been reported that
cannabis use correlates positively with retention in
treatment and taking naltrexone [40, 12]. Studies by
Wasserman et al. and Aharonovich [1, 54] indicated
the worse outcome of treatment of opiate addicts who
had been abusing cannabis.
Interactions between cannabinoid and opioid
systems are being focused on by research goups. The
study of Haney M. et al. shows that naltrexone main-
tenance decreases self-administration and the subjec-
tive effects of cannabis [19].
Although some studies found no correlation be-
tween the heavy use of benzodiazepine (BZ) and ei-
ther treatment abandonment or successful abstinence
[8], Stella et al. showed that the use of prazepam in
the early abstinence of patients treated with NTX re-
duced symptoms such as dysphoria, while increasing
the odds of sustaining abstinence [48]. Similarly, in
the study of Hubbard and Marsden the largest num-
ber of relapses was found in the group of addicts that
used heroin alone [21]. Given these contradictory re-
ports, the present study includes variables related to
the abuse and misuse of substances other than hero-
in before the treatment and during heroin addiction
treatment and recovery.
1.2. Impact of behavioural and environmental factors
on heroin addiction treatment
A famous study by Alexander et al. [3] named
“Rat Park” showed the signicance of environmentsl
factors, suggesting that the use of heroin is a choice
that a “happy rat” would not make [3]. This revolu-
tionary study showed that rats found in an inspiring
environment that offers different types of comfort,
would not choose heroin, unlike rats that found them-
selves in an uninspiring environment [2]. Although
clinical experience suggests that employment itself
and satisfaction with one’s job are signicant factors
in developing healthy lifestyle habits during recovery,
there are too few studies on the correlation between
employment and successful long-term abstinence.
Silverman et al. found that employment is a signi-
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J. Knežević Tasić et al.: Novel approach to predicting the likelihood of sustained abstinence in heroin addicts treated with naltrexone and
naltrexone-behavioural therapy
cant factor in sustaining the abstinence of cocaine ad-
dicts and that a job serves as an additional protective
agent [46]. Furthermore, De Fulio et al. conrmed
that an adequate monetary compensation, if coupled
with the employer’s request for abstinence, increases
an addict’s chance of sustaining abstinence [13].
Physical activity may be regarded as a behav-
ioural factor that signicantly improves the quality of
life and chances of recovery from heroin addiction
[20] and there are an increasing number of studies on
the neurobiological basis of this phenomenon. Meta-
analysis of 22 randomized control trials conducted
from 1990 to 2013 showed that physical activity
might increase the abstinence rate, signicantly more
so in the case of illegal drug addicts than in the case
of alcohol and nicotine addicts [53]. The study found
that moderate and intense aerobic exercise, and mind-
body exercise both contribute to a positive addiction
treatment outcome. Possible mechanisms by which
physical activity affects the possibility of a relapse
include its effect on glutamatergic and dopaminergic
signalling and chromatin remodelling in reward path-
ways [26]. In addition, exercise seems to have a sig-
nicant effect on specic molecular systems regulat-
ing neuroplasticity [7, 37, 38]. Specically, sustained
cardio training leads to a long-lasting increase in the
level of Brain Derived Neurotrophic Factor (BDNF)
in the hippocampus of experimental animals. This
leads to adult hippocampal neurogenesis and syn-
aptogenesis, and the enhancement of learning and
memory [37, 38]. Higher production of BDNF in the
hippocampus exerts a long-lasting therapeutic effect
by removing the damage done to nerve cells by con-
tinuous substance abuse [37, 7, 26, 53].
Though benecial in reducing craving and risk
for relapse, exercise might have no effect or even
lead to harmful effects, depending on the intensity,
frequency, type and especially timing of practice dur-
ing the treatment of heroin addiction [26]. Exercise, if
initiated at a late stage during abstinence may mimic
the effect of substance use. It may lead to further in-
creases in dopaminergic and glutamatergic signalling,
causing the enhancement rather than the attenuation
of drug seeking. Forced exercise, particularly at high
intensity levels, may actually enhance drug seeking in
response to drug use [26].
In this study we hypothesize that it is possible
to develop the mathematical model to investigate the
relationship that signicant factors have to sustained
abstinence. This formula can then be used to predict
the success of the treatment, manipulate given fac-
tors to optimize therapeutic interventions and raise
the likelihood of achieving the desired treatment out-
come.
2. Methods
2.1. Sample
This ambidirectional cohort study used a stable
patient population of 189 heroin addicts treated in the
Lorijen Hospital clinic for at least 24 months. The
experimental group consisted of 133 heroin addicts
with uninterrupted, continuous abstinence from hero-
in and all other opiates and opioids lasting from 24 to
126 months. It should be noted that at the time of the
study, nearly half of the participants (45%) had been
abstinent for 3 to 10.5 years. The control group con-
sisted of 56 relapsers who had been treated for more
than 24 months, but who failed to stabilize abstinence
and sustain it for more than 6 months. Participants
were mostly men (159 men and 30 women), aged 25
to 40. The two groups were equal in terms of sociode-
mographic data and addiction history.
2.2. Instruments
On the basis of our clinical experience and rel-
evant data from the professional literature, we devel-
oped the questionnaire consisting of 136 questions
and three types of variables: interval, binary and cat-
egorical, divided into the following thematic areas:
a) sociodemographic variables, b) addiction history,
c) motivation for treatment, d) parental attitude and
control during treatment, e) employment and job sat-
isfaction, f) social and emotional relations, g) alterna-
tive satisfactions, h) NTX use, i) type and duration
of psychotherapy, j) abuse and dependence on other
substances, and behavioural addictions, and k) mar-
riage and parenthood after the treatment began. All
respondents lled in the questionnaire following the
same instructions and under the supervision of the
clinical psychologist.
All participants underwent the same diagnostic
procedures: 1) psychiatric and physical assessment,
2) standard laboratory analyses, and 3) standard ther-
apy procedures including: a) hospital detoxication
and amelioration of the opiate withdrawal syndrome
using clonidine, lorazepam and other symptomatic
medications, b) induction of NTX (rst day 25 mg,
second day 50 mg) and continuing NTX therapy un-
der the supervision of a signicant other, and c) indi-
vidual psychotherapy treatment (BNT) two times per
week. Experimental variables were duration of NTX
- 16 -
Heroin Addiction and Related Clinical Problems 19(4): 13-24
use and time spent in the psychotherapeutic setting.
Abstinence control was performed clinically, at a
frequency suitable for the treatment stage. The treat-
ment programme envisaged regular checks on opiate
and opioid use through urine screening in the clinic
– twice a week during the rst three months (cor-
responding to the frequency of psychotherapy ses-
sions), and once a week during the next three months.
From the sixth to the twelfth month, urine screening
was performed once every two weeks, during each
check-up. During the second and third year, it was
performed once a month, each time a patient came for
a check-up and naltrexone prescription. Afterwards, it
was performed once every three months. Signicant
others (companions in treatment) were instructed to
perform home screening in any case when there was
a doubt based on the appearance and behaviour of the
patient. After the rst year of abstinence, when the
visits to the clinic became less frequent, they were
invited to perform home screening regularly once
every two weeks. Abstinence was also assessed when
selecting patients for the study, through a psychiat-
ric evaluation, inspection of the patient’s medical re-
cords, auto- and heteroanamnestic data (from signi-
cant others) and control screening of urine for opiates
and opioids.
2.3. Data analysis
We applied descriptive statistical measures:
arithmetic mean, standard deviation, median, quar-
tiles, frequencies and percentages. The Mann-Whit-
ney test was used to compare the mean values of
variables for the two populations. The correlation
between categorical variables was assessed using the
chi square test for contingency tables. The impact
of assessed variables on abstinence was determined
by using univariate and multivariate binary logistic
regression. We used ROC curves to assess whether
a variable may indicate abstinence, after determin-
ing the optimal value, sensitivity and specicity of
each variable. Data were processed in the SPSS pro-
gramme.
3. Results
Binary logistic regression conrmed our hy-
pothesis that there are factors that inuence one’s
ability to sustain abstinence from heroin. This same
method was used to develop the mathematical model
of synergy between signicant factors that, taken to-
gether, make up what we have named our ‘abstinence
marker’. In accordance with the aim of the research,
we determined a variety of protective factors and their
percentage occurrence.
Male sex was predominant both in the group
of abstainers (82.7%) and in the group of relapsers
(87.5%). The mean age of the abstainers was 32.4
± 4.69 years, and of the relapsers was 31.20 ± 4.89
years. The average length of education of abstainers
was 12.87 ± 2.13, and of relapsers was 12.27 ± 2.03
years. The average age at which participants started
experimenting with psychoactive substances was 17
years and with opiates 19.6 years for both groups.
The ndings of this study indicate that the fac-
tors showing a signicant relationship with the treat-
ment outcome included: a) the use of other psycho-
active substances (TRM, BZ and cannabis), before,
during and after treatment, b) therapy factors (use of
NTX and duration of psychotherapy treatment), and
c) behavioural factors such as sports, employment
and job satisfaction. The chi square test showed a
correlation between the treatment outcome and the
factors studied.
As seen in Table 1, multivariate binary logistic
regression identied the cluster of factors that, when
acting in synergy, contribute to multiyear abstinence
as an outcome of heroin addiction treatment. Absti-
nence is largely determined by the use of TRM before
treatment (p = 0.011), non-use of a BZ during recov-
ery (p = 0.001), prolonged use of NTX (p < 0.0005),
non-use of cannabis in large doses (p = 0.002), not
exercising compulsively (p = 0.009) and job satisfac-
tion (p < 0.0005).
Furthermore, we found that a participant taking
TRM with heroin prior to treatment had a nearly 4
times better chance of sustaining abstinence (odds
ratio for TRM use was 3.858 [range 1.367-10.890]).
In contrast, taking benzodiazepines was found to de-
crease vefold the chance of sustained abstinence
(odds ratio 0.183 [0.066-0.510]). Participants with
frequent cannabis use proved to have around 2 times
less chance of sustaining abstinence (odds ratio 0.530
[0.353-0.794]). NTX use was identied as a signi-
cant factor, with each new month of NTX use increas-
ing the chance of sustaining abstinence by around
13.7% (odds ratio 1.137 [1.076-1.202]). So too cat-
egories of job satisfaction (highly unsatised, unsatis-
ed, partially satised, and satised) had a signicant
impact on the outcome, with each successive listed
category that implies an improvement in job satisfac-
tion improving the odds for sustaining abstinence by
around 62% (odds ratio 1.619 [1.240-2.113]).
The chi square test conrmed the inverse cor-
- 17 -
J. Knežević Tasić et al.: Novel approach to predicting the likelihood of sustained abstinence in heroin addicts treated with naltrexone and
naltrexone-behavioural therapy
relation between the use of TRM if taken in paral-
lel with heroin before treatment and abstinence (p =
0.003). More specically, 17.9% of patients taking
TRM side by side with heroin relapsed, compared
with 39% of patients who did not take TRM, so dem-
onstrating that addicts using TRM have signicantly
higher chances of achieving sustained abstinence
once they start the treatment. As expected, the chi
square test showed that addicts who use BZ during
treatment have a statistically lower chance of achiev-
ing sustained abstinence (Table 2).
Our results indicate that there is a complex re-
lationship between cannabis use and sustaining ab-
stinence. More specically, a signicantly higher
percentage of patients not taking cannabis were ab-
stainers (87.3%) than relapsers (12.7%). This dif-
ference in outcome was still demonstrable in groups
whose use was rare or occasional (62% vs 38%),
whereas the chances of achieving abstinence dimin-
ished with frequent or daily use of cannabis (Table 3).
It was shown that frequent cannabis use signicantly
(p < 0.0005) reduced the chances of sustaining absti-
nence and of becoming abstinent by approximately
50% (Odds ratio was 0.530 [0.353-0.794]).
As shown in Tables 1 and 4, NTX use and the
duration of its use signicantly affect the treatment
outcome and success in sustaining abstinence (odds
ratio was 1.137 [1.07- 1.202]). There were 72.8% and
43.8% of abstainers in the two groups of patients –
the rst using and the second not using NTX (Table
4). The difference in the mean value of the length of
NTX use between abstainers and relapsers was statis-
tically signicant (p <0.0005). Abstainers used NTX
for 16.13 ± 7.85 and relapsers for 6.22 ± 12.77 months
on average. Moreover, the results showed that a pa-
tient’s sex is not correlated with NTX use (p = 0.080),
as 89.9% of male and 100% of female participants
used NTX. Importantly, the duration of NTX use was
identied as one of the abstinence markers (area =
0.776, p <0.0005, sensitivity of 71.0% and speci-
city of 73.2%). Cut-off was identied at 7.5 months,
indicating that NTX should be used for at least that
long to achieve the maximum therapeutic benet. It
was also found that each new month of NTX use in-
Table 1. Factors predicting sustained heroin abstinence
Univariate binary regression Multivariate binary regression
Variable Odds ratio p Odds ratio p
Use of TRM before treatment 2.947 (1.490-5.830) 0.002 3.858 (1.367-10.890) 0.011
BZ during recovery 0.426 (0.316-0.574) < 0.0005 0.183 (0.066-0.510) 0,001
Months of NTX taking 1.123 (1.072-1.177) < 0.0005 1.137 (1.076-1.202) < 0.0005
Cannabis during recovery 0.585 (0.450-0.761) < 0.0005 0.530 (0.353-0.794) 0.002
Exercise during recovery 0.326 (0.142-0.748) 0.008 0.228 (0.075 -0.693) 0.009
Clearly set goals 3.400 (1.525-7.580) 0.003
Job satisfaction during recovery 1.487 (1.242-1.781) < 0.0005 1.619 (1.240-2.113) < 0.0005
Cocaine during recovery 0.535 (0.382 – 0.748) < 0.0005
Loss of behavioural control as a
motivation for treatment 0.485 (0.257-0.917) 0.026
Socialization during heroin abuse 1.604 (1.318-1.953) < 0.0005
Type of psychotherapy 1.153 (1.004-1.325) 0.044
Duration of psychotherapy 1.591 (1.259-2.010) < 0.0005
Gambling during recovery 5.773 (2.044-16.303) 0.001
Parenthood during recovery 1.452 (1.071-1.969) 0.016
Unemployment during recovery 0.277 (0.144-0.533) < 0.0005
Clear goals, unreached 3.497 (1.814-6.739) < 0.0005
Antidepressants during recovery 0.478 (0.250-0.915) 0.026
Table 2. Use of benzodiazepine among abstainers and relapsers
Abstainers Relapsers p
Did not use BZ 63 (88,7%) 8 (11.3%) < 0.0005
Used BZ 70 (59,3%) 48 (40.7%)
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Heroin Addiction and Related Clinical Problems 19(4): 13-24
creased the chance of a successful outcome by 13.7%.
It is presumed that the absence of exercise, em-
ployment and, especially, job satisfaction has a strong
impact on abstinence. According to our results ab-
sence of exercise (p = 0.009) and job satisfaction (p
<0.0005) both contribute signicantly to sustaining
abstinence. Job satisfaction, along with the duration
of NTX treatment, was found to be one of the most
important factors that allow sustained abstinence to
be achieved (Table 1).
Using binary logistic regression we identied
coefcients that express the contribution of each sig-
nicant factor on the treatment outcome (Table 5).
These coefcients were applied in the following for-
mula to dene the new variable called by us the ‘ab-
stinence marker’:
the abstinence marker = exp(sum)/(1+
exp(sum))·100, whereby
sum = 3.267 + 1.350 · a - 1.689 · b + 0.129 · c –
0.636 · d – 1.477 · e + 0.482 · f.
Our ability to fully identify an applicable absti-
nence marker conrms the existence of a specic set
of factors that, taken together, may be considered a
predictor of sustained abstinence. The values for this
marker range from 0 to 100. This variable is a robust
marker of abstinence (area = 0.838, p <0.0005). The
optimal cut-off for predicting abstinence is 74, with
a sensitivity of 86.8%, and a specicity of 85.5%.
The difference in the mean value of the new variable
between abstainers and relapsers is statistically sig-
nicant (p <0.0005). In our study the mean value of
the abstinence marker in relapsers was 30.66 (range
11.94-48.03), and in abstainers it was 93.83 (range
82.74-98.45).
The value of the abstinence marker was sig-
nicantly correlated with abstinence (p <0.0005)
(odds ratio was 1.062 [range 1.046-1.079]) and the
increase in the value of this variable by 1 was found
to increase the chances of abstinence by 6.2%. The
Hosmer–Lemesh test shows that the variable absti-
nence marker shows a good t with abstinence (i.e.,
it is effective in predicting the chances of a patient
becoming abstinent). By applying the values of the
abstinence marker to our patient population, we were
able to conrm an excellent correlation. For exam-
ple, the calculated value of this marker for a patient
in our study who was abstinent is 99.75, implying
that the chance of him/her being abstinent is as high
as 99.75%. In contrast, the value of this marker in a
patient who was not abstinent was 4.16, indicating a
chance of achieving abstinence as low as 4.16%.
4. Discussion
This study identied signicant factors affecting
heroin addiction treatment outcome and constructed a
mathematical model for the synergistic effect of these
factors, with the aim of selecting a reliable abstinence
marker. Individual factors that proved to be signi-
cant in sustaining abstinence include the use of TRM
as a heroin substitute before treatment, non-use of BZ
during treatment, absence of the extensive use of can-
nabis, longer use of NTX, physical activity and job
satisfaction.
This study shows that TRM use before treatment
tends to compensate for the lack of heroin or, in cases
of self-medication, increases fourfold the chance of
Table 3. Cannabis use among abstainers and relapsers
Abstainers Relapsers p
No use of cannabis 69 (87.3%) 10 (12.7%)
0.015
Rare use of cannabis 24 (61.5%) 15 (38.5%)
Occasional use of cannabis 23 (62.2%) 14 (37.8%)
Frequent use of cannabis 10 (47.6%) 11 (52.4%)
Daily use of cannabis 5 (50.0%) 5 (50.0%)
Table 4. Naltrexone use among abstainers and relapsers
Abstainers Relapsers p
Did not use NTX 7 (43.8%) 9 (56.3%) 0.015
Used NTX 126 (72.8%) 47 (27.27%)
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J. Knežević Tasić et al.: Novel approach to predicting the likelihood of sustained abstinence in heroin addicts treated with naltrexone and
naltrexone-behavioural therapy
azepines might reect an unbalanced opioid debt and
post-withdrawal symptomatology not alleviated by
naltrexone. The possible explanation for the negative
effect of prolonged BZ use on achieving sustained
abstinence may be related to a BZ-induced fall in
cognitive activity, the acquisition of new knowledge,
and ongoing psychological development. We may
presuppose that a negative correlation with achieving
sustained abstinence through the intensive use of can-
nabis is due to effects identical to those seen with BZ.
Results of our study partly conrmed the nd-
ings of recent studies that the moderate use of can-
nabis increases the likelihood of sustained abstinence
[40, 42, 43, 10, 12, 14]. On the other hand, another
of our ndings was that frequent cannabis use during
treatment halves the chance of sustaining abstinence
longer than two years, which is in line with ndings
by Mojarrad and co-workers [33], Wasserman and
co-workers [54] and Aharonovich and co-workers
[1]. Unlike these previous studies, we stratied our
patients according to the intensity of marijuana use,
and this lack of differentiation might be the reason
for the apparent discrepancy between various studies.
Opiate withdrawal syndrome (WS) is a result
of hyperactivity in locus coeruleus (LC). By inhibit-
ing LC, cannabinoids reduce the hyperactivity of the
sympathetic nervous system in opiate WS [43], so it
is possible that moderate cannabis use in early absti-
nence helps reduce subacute WS, but also hyperexcit-
ability and insomnia related to NTX use. In the latter
course of treatment, the more substantial risks related
to cannabis abuse include amotivational syndrome
and contacts with dealers, which lower the chance of
qualitative changes during the treatment. Specically,
learning new coping skills and developing mature
intrapsychic patterns require adequate and persistent
motivation and intact cognitive abilities.
Clinical and animal studies indicate numerous
interactions between the opioid and endocannabi-
noid systems. Activating cannabinoid CB1 receptors
a heroin addict achieving sustained abstinence for
longer than two years, while the alternative in the
form of other opiates and opioids instead of heroin
(e.g., methadone, poppy cocoon tea) before the start
of treatment did not act as a protective abstinence fac-
tor. TRM is a synthetic opioid with weak agonistic
effects on μ-opioid receptors. Owing to its opioid ef-
fect, TRM has antidepressive, anxiolytic and antipsy-
chotic properties. TRM also suppresses the reuptake
of serotonin and norepinephrine, thus causing an an-
tidepressant effect similar to that of venlafaxine [52,
55]. Clinical experience shows that TRM is ‘a drug
of choice’ for depressed and socially anxious people.
It may also be presupposed that previous experience
with TRM – a factor that alleviates both the with-
drawal syndrome and the accompanying emotional
disturbances (such as depression and social anxiety)
– served as an encouragement for the new treatment
and induced more optimism in heroin addicts about
the success of their recovery. Due to the weak agonis-
tic effect on μ-opioid receptors, TRM suppressed the
craving and compulsion of heroin addicts, while the
antidepressant effect encouraged their determination
to seek better solutions, as well as healthier and more
efcient ways to combat addiction [23, 29].
The study showed that BZ abuse leads to a ve-
fold reduction in the chance of sustaining opiate ab-
stinence for longer than two years. This contradicts
the study by Stella and co-workers [48] according to
whom the medical use of prazepam during the early
abstinence of patients treated with NTX helped re-
duce dysphoria and other symptoms, while raising
the chances of sustaining abstinence. It also contra-
dicts the results of the study by Hubbard and Marsden
[21], which found that the largest number of relapses
were those among addicts who used heroin alone.
The reason for discrepant results between these two
studies may lie in the fact that the rst study evalu-
ated the effect on early abstinence. The long-term
use of a partially cross-tolerant drug such as benzodi-
Table 5. Factors signicantly affecting heroin addiction treatment outcome
Variable Symbol Coefcient
Use of TRM before treatment a 1.350
Use of BZ during recovery b -1.698
Months of NTX use c 0.129
Use of cannabis during recovery d -0.636
Exercise during recovery e -1.477
Job satisfaction during recovery f 0.428
Constant 3.267
- 20 -
Heroin Addiction and Related Clinical Problems 19(4): 13-24
ery from addiction can be explained by their shared
ability to weaken the will, psychic tone and cogni-
tive abilities during treatment, while these convergent
forms of impediment disrupt the learning process.
The concomitant use of BZ and cannabis has an addi-
tional anxiolytic effect through the interaction of the
cannabinoidergic and the GABAergic systems [34].
Use of NTX over a sufciently long period can be the
factor that connects this cluster through its effect on
cannabis use [19].
5. Conclusions
The conclusion will give prominence to the fac-
tors that are likely to have a signicant impact on the
chances of achieving sustained abstinence. The syn-
ergistic effect of these factors is of particular impor-
tance, and can be expressed in a mathematical model.
The ndings reported in this study have impor-
tant implications for addiction treatment. What is vi-
tal to treatment success is being able to keep NTX,
provided it is used in sustaining abstinence, as long
as possible in the treatment, to cover a period of at
least 7.5 months. Substances that maintain cognitive
decline, such as BZ, and regular cannabis use to the
extent that it impedes everyday life and mental activ-
ity, should be avoided. The psychotherapeutic setting
should support gaining new experiences, psychologi-
cal awakening, and cognitive activity, while encour-
aging emotional content that leads to activation of the
overall psychological apparatus, as opposed to inner
numbness. Regular sports activities should be incor-
porated early into addiction treatment plans, but more
studies are needed to elucidate their effects on the lat-
er stages of abstinence. An excercise plan should be
monitored closely in order to avoid the substitution of
activities that have benecial effects on recovery with
an excessive and compulsive physical activity.
Finally, patients undergoing heroin addiction
treatment should be encouraged to seek a job if pos-
sible, as it brings not only a new structure of time, but
also a sense of achievement and inner satisfaction.
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submit the paper for publication.
Conict of interest
All authors declare no conict of interest.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki -
Ethical Principles for Medical Research Involving Human
Subjects. This study has ethics committee approval. All pa-
tients gave their informed consent to the anonymous use of
their clinical data for this independent study.
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this case, the Corresponding Author accepted our service.
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Acknowledgements
None
Role of the funding source
Authors state that this study was nanced with inter-
nal funds. No sponsor played a role in study design; in the
collection, analysis and interpretation of data; in the writ-
ing of the report; and in the decision to submit the paper
for publication.
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
Received April 18, 2016 - Accepted August 29, 2016
Regular article
Heroin Addict Relat Clin Probl 2017; 19(4): 25-34
25
Corresponding author: Ali Hasanpour-Dehkordi, Assistant Professor, Department of Medical and Surgical Nursing, Shahrekord
University of Medical Sciences, Shahrekord, Iran.
Phone: 00989133830205; Email: alihassanpourdehkordi@gmail.com
Effectiveness of cognitive-behavioural stress management on self-efficacy and
risk of relapse into symptoms of substance use disorders
Kamal Solati1 and Ali Hasanpour-Dehkordi2
1- Department of Psychiatry, Modeling in Health Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
2- Nursing and Midwifery Research Centre, Department of Medicine and Surgery, Faculty of Nursing and Midwifery, Shahrekord
University of Medical Sciences, Shahrekord, Iran
Summary
Background: Substance use disorders (SUDs) lead to serious problems, including health disorders, and social and oc-
cupational complications. Relapse prevention plays an important role in treating affected individuals. Aim: The present
study was conducted to study the effects of cognitive-behavioural stress management (CBSM) on self-efcacy and relaps-
es into a form of SUD. Methods: The present semi-experimental study was conducted on 40 individuals enrolled from
addiction rehabilitation centres; they were matched on the basis of demographic characteristics and randomly assigned to
two groups, labeled “case” and “control” group, respectively, each comprising 20 members. The questionnaires, which
covered demographic data, self-efcacy, and the Relapse Prediction Scale, were distributed to the participants. After a
pretest had been administered to the two groups, eight sessions of 60 minutes (two sessions a week) were held to provide
CBSM training to the case group only. The test was then readministered immediately afterwards, and again two months
after the completion of training and after all the data had been analysed using SPSS 17. Results: Analysis of covariance
indicated a signicant difference in self-efcacy and relapse showing SUD symptom recurrence; this emerged from the
comparison between the case and control groups for pretest and post-test, and for pretest and follow-up (p>0.001). Con-
clusion: CBSM training contributes positively to increasing self-efcacy and lowering the risks of relapse into once again
showing SUD symptoms. In the light of these ndings, the training approach adopted can be recommended as a way to
resolve SUDs.
Key Words: Self-efcacy; cognitive-behavioural stress management; relapse
1. Introduction
Chronic disorders have an impact on psycholog-
ical, social and economic states [20, 21]. Substance
use disorders (SUDs) are particularly signicant in
terms of morbidity and mortality, and they lead to
exorbitant costs for the community [13, 28, 41]. Sub-
stance abuse appears to reduce longevity and increase
the risk of chronic diseases, while also resulting in
the disintegration of families, the loss of jobs, and
the abuser falling victim to violence that will then
require intervention and prevention [25]. Approxi-
mately 69,000 individuals worldwide are estimated
to die every year because of opioid abuse [12]. From
a behavioural viewpoint, addiction includes forced in-
volvement in a behaviour (such as drug or substance
abuse), craving or innate motivation and desire – a
state dominated by an appetitive urge that is experi-
enced immediately before engagement in that behav-
iour, which then leads to a decline in the individual’s
control over his/her behaviour, and the continuation
of engagement in the behaviour despite the adverse
consequences for that individual [17].
Several complicated factors contribute to the
use of substances, in some cases even to the use of
a particular category of substances; these factors
may be physical, behavioural, and/or cognitive. As
a result, non-pharmacological approaches such as
psychosocial interventions, namely cognitive-behav-
ioural therapy (CBT), could be used to treat substance
abuse [42, 47]. In addition, CBT could be developed
in such a way that it becomes stress management-
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Heroin Addiction and Related Clinical Problems 19(4): 25-34
based, and can hence be applied to the disorders asso-
ciated with addiction and dependency [35]. Cognitive
behavioural stress management (CBSM) as a psy-
chological intervention has led to improved physical
and psychological functions in patients with chronic
disease [1, 7, 24, 38]. What is more, CBSM could
be effective in increasing psychological and social
adaptability [14, 43], motivation and coping skills in
individuals with substance abuse [19, 34, 46]. Psy-
chological interventions work through relieving stress
for assessment, recovering stress and reducing mental
anxiety by affecting the arousal of autonomic systems
(such as heart rate and galvanic response) and neu-
roendocrine activity (such as the reduced secretion of
cortisol) [9, 45].
One of the factors that could contribute to re-
ducing stress and enhancing quality of life is an in-
crease in self-efcacy through training interventions
[22]. Self-efcacy is a term that refers to the compe-
tence of an individual taking on hard or novel kinds
of work, and the ability to cope with an urgent and
specic situation [10, 30]. Self-efcacy leads to better
results in coping with new conditions. On the other
hand, it alters attitudes to life and leads to increased
self-esteem, job performance, social and psychologi-
cal status, and health promotion [27]. There is a rela-
tionship between earlier performance and subsequent
performance that is heavily mediated through self-
efcacy [29]. Results of other studies have shown
that people who have both the necessary skills and
strong self-efcacy are likely to mobilize the energy
needed to successfully deal with situations involving
high risks of drinking or drug use. Self-efcacy leads
to success in all aspects of life and greatly reduces the
risk of relapse [26]. Various studies have shown that
self-efcacy is a predictor of treatment outcome and
relapse. In some cases, self-efcacy has been found
to predict the quantity of alcohol or drugs consumed
[23]. Other studies have indicated that, although self-
efcacy could contribute to the treatment of SUDs,
further major studies are still needed [29]. One study
demonstrated that self-efcacy could play a greater
role than previously thought in the prevention of drug
and substance abuse [8].
All psychological principles and techniques that
aim to prevent and reduce the symptoms of relapse
can lead to positive outcomes if they are correctly im-
plemented by experts in addiction centres. Relapse is
a challenge to be faced in treating addiction, and a
prerequisite to achieving successful results in addic-
tion centres. Relapse prevention is a long-term task
and is considered an essential part of any cognitive-
behavioural framework [6, 25].
Although CBT is thought to be effective in
treating addiction, some studies have reported that it
has resulted in fewer positive outcomes to substance
abuse treatment than other approaches, so further
studies are needed [15]. SUD is caused by a variety
of psychological factors, and many investigations
are needed to study all the psychological layers that
actually contribute to its incidence. Meanwhile, as
SUD has become one of the most signicant forms
of psychosocial damage and could easily destabilize
the basis of personal, family, and cultural life while
also jeopardizing the dynamism of the workforce in a
country, the study of SUD and the contribution made
by psychological interventions to its treatment and
prevention should be further highlighted. In view of
these considerations, the present study has been car-
ried out to study the effects of CBSM on self-efcacy
and the relapse of addicts into showing symptoms of
an SUD; these addicts had all been referred to the Or-
ganization of Rehabilitation-afliated addiction with-
drawal centres in south Tehran.
2. Methods
2.1. Sample
The present semi-experimental study included
two groups: the case group, and the control group.
Sampling was done according to the principles of
clustered randomization. For this purpose, eight of
16 camps afliated with the Organization of Reha-
bilitation to which opioid-dependent men aged over
18 years referred for withdrawal were selected, after
which 40 individuals who were matched by demo-
graphic characteristics were enrolled from the select-
ed camps and randomly assigned to the two groups,
“case” and “control” group, each comprising 20
members.
Opium was considered as the used substance
under study, hence its use as the inclusion criterion.
Other inclusion criteria were having good physical
health and volunteering to withdraw. Abuse of and/
or simultaneous addictions to other substances were
considered as exclusion criteria.
2.2. Instruments
In this study, a three-section questionnaire was
used. The rst section consisted of the items on demo-
graphic characteristics and the second was dedicated
to the Sherer and Adams Self-Efcacy Scale [40].
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K. Solati & A. Hasanpour-Dehkordi: Effectiveness of cognitive-behavioural stress management on self-efcacy and risk of relapse into symptoms of
substance use disorders
This scale consists of 17 ve-point Likert items
offering choices ranging from fully agree to fully
disagree. To investigate the reliability of the scale,
we administered it to 30 individuals who were not in-
cluded in the nal study and the reliability coefcient
was calculated as being 0.738 by using Cronbach’s
alpha. Three psychologists were asked to examine the
scale’s validity and the precision of translation of the
items. The third section of questions had the aim of
examining relapses into symptoms of various SUDs.
To examine the level of desire for the chosen sub-
stance, Wright’s Relapse Prediction Scale (RPS) was
used [5]. This scale consists of two subscales, temp-
tation and desire, measured by 47 four-point Likert
items. As with the Sherer and Adams Self-Efcacy
Scale, the validity and reliability of RPS were meas-
ured and the reliability coefcient was derived as be-
ing 0.806 and 0.860 for temptation and desire, respec-
tively, and then conrmed.
2.3. Procedure
Prior to intervention, the tests of interest to
us were administered to both groups, after which
eight in-group sessions of 60 minutes (two sessions
a week) were held to train the case group in CBSM
techniques. The educational content of sessions in-
cluded: concepts and denitions of stress and anxi-
ety, skills to be applied in achieving stress relief and
coping with daily stress, modication of maladaptive
cognitive assessments using cognitive restructuring,
promotion of the skills of interpersonal and commu-
nication conict resolution through self-expression
and anger management, and increase in access to and
use of social support networks through enhanced in-
terpersonal and communication skills. Between ses-
sions, the participants were given assignments.
The test was readministered to both groups im-
mediately, and again two months after completion of
training (follow-up).
2.5. Data analysis
The data were analysed by applying SPSS 17
and then using descriptive statistics, the Kolmogorov-
Smirnov test, test of equality of variances, and analy-
sis of covariance (ANCOVA).
3. Results
The participants were mainly under 40 years.
The educational level of most of the participants in
both groups reached the high school certicate. The
demographic characteristics of the participants are
summarized in Table 1.
Our ndings indicated that CBSM was effective
in increasing self-efcacy as recorded in opioid-ad-
dicted individuals in the post-test and follow-up (Ta-
ble 2a, 2b).
Kolmogorov-Smirnov test conrmed the hy-
pothesis of self-efcacy normality (p>0.05). This
test also conrmed the normal distribution of self-
efcacy scores in the two groups. More clearly, this
hypothesis indicated that the difference between the
mean self-efcacy scores in the two groups before
the intervention was zero, while any difference was
Table 1. Demographic characteristics of participants in case and control groups
Frequency (%) in case
group
Frequency (%) in control
group
Age (yr) 30 and under 9 (45%) 7 (35%)
31-40 6 (30%) 7 (35%)
41-50 5 (25%) 6 (30%)
Education Guidance school certi-
cate 5 (25%) 4 (20%)
High school certicate 8 (40%) 9 (45%)
Associate degree 4 (20%) 3 (15%)
BA/BSc 3 (15%) 3 (15%)
MA/MSc 0 (0%) 1 (5%)
Duration of substance
abuse (yr) 1-4 7 (35%) 8 (40%)
5-8 9 (45%) 6 (30%)
Over 9 4 (20%) 6 (30%)
- 28 -
Heroin Addiction and Related Clinical Problems 19(4): 25-34
due to random enrollment of the participants. This
test and Levene’s test, which indicated that that there
was equality of variances in the two groups, should
always be conducted before ANCOVA so that they
can be utilized if the mean values and variances in the
two groups are normal.
In addition, Levene’s test conrmed the homo-
geneity of the variances in the two groups.
Our ndings indicated that CBSM was effective
in decreasing the incidence of relapses into showing
the symptoms of an SUD (temptation) in opioid-ad-
dicted individuals in post-test and follow-up (Table
3a, 3b).
Kolmogorov-Smirnov test conrmed the hy-
pothesis of temptation normality (p>0.05). In ad-
dition, Levene’s test conrmed the homogeneity of
the variances in the two groups (p>0.05). ANCOVA
indicated a signicant difference in the incidence
of relapse into showing SUD symptoms (tempta-
tion) between the case and control groups for pretest
and post-test, and again for pretest and follow-up
(p>0.001). It can therefore be concluded that CBSM
was effective in lowering the risk of relapse into SUD
symptoms (temptation).
Our ndings indicated that, in the post-test and
follow-up (Table 4a, 4b), CBSM proved to have been
effective in lowering the frequency of relapse into
SUD symptoms (desire for the chosen substance) in
individuals addicted to opioids.
Kolmogorov-Smirnov test conrmed the hy-
pothesis of desire for substance normality (p>0.05).
Similarly, Levene’s test conrmed the homogeneity
of the variances in the two groups (p>0.05).
ANCOVA indicated a signicant difference in
the frequency of relapse into symptoms of an SUD
(desire for substance) between case and control
Table 2b. Results of ANCOVA* on self-efcacy in pretest and post-test, and pretest and follow-up in case and
control groups
Source of change Total
square Df Mean
square FLevel of sig-
nicance
Eta
square
Test
power
Pretest
and post-
test
Pretest 81.67 1 81.67 26.32 0.01 0.42 0.99
Group member-
ship 381.30 1 381.30 120.91 0.001 0.76 0.99
Pretest
and
follow-up
Pretest 0.27 1 0.27 0.00 0.92 0.01 0.05
Group member-
ship 632.21 1 632.21 21.99 0.001 0.37 0.99
* Analysis of covariance
Table 3a. Mean (and SD*) scores of decrease in relapse of SUDs** symptoms (temptation) in pretest, post-test,
and follow-up in case and control groups
Variable Group Test Mean SD Minimum Maximum
Temptation
Case
Pretest 120.25 26.30 109 131
Post-test 116.40 6.62 105 124
Follow-up 116.25 6.70 105 123
Control
Pretest 121.30 5.99 111 130
Post-test 121.75 6.11 110 132
Follow-up 121.75 5.63 111 130
* Standard deviation; ** Substance use disorders
Table 2a. Mean (and SD*) scores of self-efcacy in pretest, post-test, and follow-up in case and control groups
Variable Group Test Mean SD Minimum Maximum
Self-efcacy
Case
Pretest 60.58 3.03 56 62
Post-test 66.75 1.58 58 66
Follow-up 68.40 6.83 58 66
Control
Pretest 60.80 2.89 56 61
Post-test 60.55 2.81 57 62
Follow-up 60.45 3.05 56 61
* Standard deviation.
- 29 -
K. Solati & A. Hasanpour-Dehkordi: Effectiveness of cognitive-behavioural stress management on self-efcacy and risk of relapse into symptoms of
substance use disorders
groups for pretest and post-test, and again for pretest
and follow-up (p>0.001). It may therefore be con-
cluded that CBSM was effective in lowering the risk
of relapse into SUD symptoms (such as desire for the
chosen substance).
4. Discussion
The present study was conducted to study the ef-
fects of CBSM on self-efcacy and the risk of relapse
into the presence of SUD symptoms. The ndings
demonstrated the efcacy of CBSM training on im-
proved self-efcacy with regards to SUDs. Similarly,
a clinical trial study demonstrated that the group un-
dergoing intervention acquired a higher coping self-
efcacy after 10 weeks of antiretroviral medication
compliance training and CBSM training [2].
In the study of Cruess et al. on CBSM and HIV-
infected men, CBSM not only could be effective on
mood and depression symptoms, but also caused im-
provements in the self-efcacy of the patients [11].
As an explanation of the efcacy of CBT, it could
be argued that individuals’ assessment of their own
abilities to cope with stress is important. Although
this assessment may and/or may not be in accordance
with reality and one’s real capabilities, one’s percep-
tion of capabilities is a main determinant in coping
with difculties. If individuals feel incapable and lose
Table 4b. Results of ANCOVA* on decrease in relapse of SUDs** symptoms (desire for substance) in pretest
and post-test, and pretest and follow-up in case and control groups
Source of change Total
square Df Mean
square FLevel of sig-
nicance
Eta
square
Test
power
Pretest and
post-test
Pretest 749.51 1 749.51 64.69 0.01 0.63 0.99
Group mem-
bership 306.33 1 306.33 26.44 0.001 0.41 0.99
Pretest and
follow-up
Pretest 397.61 1 397.61 26.35 0.01 0.41 0.99
Group mem-
bership 628.78 1 628.78 21.95 0.01 0.37 0.99
* Analysis of covariance; ** Substance use disorders.
Table 3b. Results of ANCOVA* on decrease in relapse of SUDs** symptoms (temptation) in pretest and post-
test, and pretest and follow-up in case and control groups
Source of change Total
square Df Mean
square FLevel of sig-
nicance
Eta
square
Test
power
Pretest
and post-
test
Pretest 749.63 1 749.63 42.43 0.001 0.54 0.99
Group member-
ship 309.52 1 309.52 17.91 0.001 0.32 0.98
Pretest
and
follow-up
Pretest 533.41 1 533.41 25.11 0.01 0.41 0.99
Group member-
ship 216.66 1 216.66 12.07 0.001 0.24 0.92
* Analysis of covariance; ** Substance use disorders.
Table 4a. Mean (and SD*) scores of decrease in relapse of SUDs** symptoms (desire for substance) in pretest,
post-test, and follow-up in case and control groups
Variable Group Test Mean SD Minimum Maximum
SUDs relapse
Case
Pretest 115.40 6.43 100 123
Post-test 110.20 5.25 100 117
Follow-up 100.00 5.27 100 116
Control
Pretest 115.10 5.67 101 121
Post-test 115.50 5.86 102 124
Follow-up 114.55 4.74 102 123
* Standard deviation; ** Substance use disorders.
- 30 -
Heroin Addiction and Related Clinical Problems 19(4): 25-34
self-condence, they will be unable to overcome dif-
culties, despite all the coping skills they may have
acquired. In this sense, self-efcacy may be strongly
inuenced by individual beliefs, attitudes, and ac-
complishments.
The results of the present study showed that
there was a relationship between self-efcacy and re-
lapse, so that, irrespective of the degree of increase in
self-efcacy, recurrence was reduced. Another study
showed that self-efcacy was a factor contributing to
the withdrawal of drug use and the chances of relapse
[23]. Those researchers also found that decreases in
daily self-efcacy predicted a relapse into smoking
[18].
This study demonstrated that self-efcacy could
affect patients’ behaviours and attitudes in a variety
of ways.
Many studies have reported a relationship be-
tween self-efcacy and subsequent drinking in terms
both of quantities consumed and relapses into drink-
ing. Self-efcacy predicted the frequency and volume
of drinking, and the chances of a relapse into drinking.
Moreover, self-efcacy was strongly associated with
the level of subsequent alcohol consumption [29]. In
the present study, CBSM was effective in lowering
the risk of a relapse into showing SUD symptoms
(temptation). Consistently with this nding, a pilot
study on CBSM and individuals suffering from an
SUD indicated that stress-induced craving and stress
in the group undergoing intervention both fell, while
self-efcacy improved signicantly as compared with
the control group after three weeks in primary assess-
ments. In addition, the resistance of individual par-
ticipants to desire for the chosen substance increased
[3]. Another study demonstrated the potential useful-
ness of CBSM in preventing SUDs and relapses [31].
Although some studies have recommended the com-
bination of CBT with other approaches to enhance
treatment and the prevention of relapse into SUDs
[39], other studies on treatment for SUDs and relapse
prevention have indicated that cognitive therapies, in
particular CBT, cannot be considered a comprehen-
sive approach, and the interventions conducted so far
have failed to cause considerable variations in desire
for the chosen substance [16, 35]. Relapse is a com-
plicated and multifactorial agent of substance abuse,
and may be caused by an inappropriate lifestyle, un-
healthy nutrition and social relationships, even inac-
tivity. The factors of the strengthening of self-efcacy,
neutralization of the sources of stress, and relaxation
techniques could all play a role in relapse prevention
[37]. On the other hand, the ndings could be affected
by the quality of the intervention that was being stud-
ied and the duration of follow-up, so inevitably lead-
ing to inconsistent ndings.
Obviously, social background and support con-
tribute greatly to treating and preventing relapse into
addiction [33, 44]. CBSM has partly been developed
on the grounds that it is based on cognitive social
learning, relapse prevention theory, and stress man-
agement [4, 14, 32, 36], the use of which alongside
coping skills comprises an integrated, appropriate
programme for dealing with the complications arising
from substance abuse; as a result, the improvements
achieved may be greater than those obtained by other
kinds of psychological intervention.
If each of the above factors, and other related
ones, are not considered and/or monitored during in-
terventions, the ndings may be compromised and
positive outcomes due to interventions will be seen
only during treatment rather than follow-up. This
could lead to the failure of programmes developed
for the correction and quitting of substance abuse,
and even become confounding factors in the ndings.
What is more, the inconsistent ndings of previous
studies could be attributed to inefcient thinking and
coping styles, as these could lead individuals toward
resuming the use of opioids. Recurrence is a multi-
factorial phenomenon that can be inuenced by in-
appropriate lifestyle and diet, physical inactivity,
inappropriate social relationships, and, collectively,
biopsychosocial, spiritual factors. Consequently, all
these factors should be considered in this regard.
5. Conclusions
CBSM training contributes positively to increas-
ing self-efcacy and lowering the risks of relapse into
symptoms of SUDs. One may therefore recommend
the implementation of training programmes based
on this therapeutic approach in rehabilitation camps
and centres to enhance self-efcacy in addicted indi-
viduals, to prevent any relapse into SUD symptoms
through proper implementation and necessary follow-
up, and thus minimize the chances that treatment will
fail.
It would not be correct to generalize the nd-
ings of this study to other SUDs. The method of data
gathering by self-measurement further limits any
form of generalization of the ndings. Future stud-
ies can be recommended to compare CBT with other
well-known therapeutic approaches applied in treat-
ing SUDs.
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This research project was funded with grant
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K. Solati & A. Hasanpour-Dehkordi: Effectiveness of cognitive-behavioural stress management on self-efcacy and risk of relapse into symptoms of
substance use disorders
Ethics
Authors conrm that the submitted study was
conducted according to the WMA Declaration of
Helsinki - Ethical Principles for Medical Research
Involving Human Subjects. All patients gave their in-
formed consent to the anonymous use of their clinical
data for this independent study.
Note
It is the policy of this Journal to provide a free
revision of English for Authors who are not native
English speakers. Each Author can accept or refuse
this offer. In this case, the Corresponding Author ac-
cepted our service.
Received May 16, 2016 - Accepted October 10, 2016
Contributors
Kamal Solati contributed to research design,
and the acquisition, analysis and interpretation of the
data, and Ali Hasanpour Dehkordi drafted the paper,
revised it critically, and approved the nal version
that was submitted.
Conict of interest
There are no conicts of interest.
Regular article
Heroin Addict Relat Clin Probl 2017; 19(4): 35-40
35
Corresponding author: Saül Alcaraz, PhD, Addictive Behaviours Unit, Department of Psychiatry, Hospital de la Santa Creu i Sant
Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain, EU
E-mail: salcaraz@santpau.cat
Exploring predictors of response to methadone maintenance treatment for
heroin addiction: the role of patient satisfaction with methadone as a medication
Saul Alcaraz1, Joan Trujols1,2, Núria Siñol1, Santiago Duran-Sindreu1,2, Francesca Batlle1,
and José Pérez de los Cobos1,2,3
1-Addictive Behaviours Unit, Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant
Pau (IIB Sant Pau), Barcelona, Spain, EU
2-CIBER de Salud Mental (CIBERSAM), Madrid, Spain, EU
3-Departament de Psiquiatria i Medicina Legal, School of Medicine, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del
Vallès), Spain, EU
Summary
Background: Patients’ degree of dissatisfaction with methadone is correlated with their response to methadone mainte-
nance treatment (MMT), as patients who do not interrupt compulsive use of substances during MMT are less satised with
methadone than their counterparts who do. Aim: To examine the satisfaction of heroin-dependent patients with metha-
done as an independent predictor of response to MMT. Methods: Participants (n = 185) were heroin-dependent patients
who had been receiving MMT for at least the previous three months. Of these, 152 were considered non-responders due
to current substance use disorders (SUD) requiring inpatient detoxication treatment, and 33 were considered respond-
ers due to sustained full remission of SUD. Satisfaction with methadone as a medication was measured with the Scale to
Assess Satisfaction with Medications for Addiction Treatment – methadone for heroin addiction (SASMAT-METHER).
The SASMAT-METHER subscales assess three domains: Personal Functioning and Well-Being; Anti-Addictive Effect
on Heroin; and Anti-Addictive Effect on Other Substances (e.g., cocaine). We also evaluated other possible predictors
of response to MMT: sociodemographic variables, heroin use, use of non-opioid substances, MMT characteristics and
patients’ views on methadone dose adjustment. Differences between non-responders and responders were tested indi-
vidually; only those variables that reached statistical signicance (p ≤ .05) were included in a subsequent binary logistic
regression analysis. Results: On the regression model, two factors were independently associated with the likelihood of
non-response to MMT: 1) a low level of satisfaction with the Anti-Addictive Effect (of methadone) on other substances
and 2) current benzodiazepine treatment. Conclusions: Our results suggest that heroin-dependent patients’ degree of
satisfaction with methadone may be an independent predictor of MMT response. Prospective studies are now needed to
conrm this nding.
Key Words: Satisfaction with medication; methadone; heroin addiction; substance use disorder.
1. Introduction
As a group, heroin-dependent patients benet
from methadone maintenance treatment (MMT),
which has been shown to reduce heroin use [8] and,
potentially, to help decrease the use of non-opioid
substances such as cocaine [5]. As with any treatment,
the individual response of heroin-dependent patients
to MMT varies. In terms of heroin and/or non-opioid
substance use, Morral and colleagues [9] identied
three natural proles of response to MMT, including
two groups of patients characterized by a clear versus
scant reduction in substance use, respectively, while
an intermediate group gave a mixed response.
Various predictors of response have been ex-
amined in an effort to identify any variables that
would maximize response to MMT. In most cases,
however, patients’ perspective towards MMT is lit-
tle considered; rather, the focus has been on objec-
tive patient- or MMT management-related features,
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Heroin Addiction and Related Clinical Problems 19(4): 35-40
such as gender [7], use of non-opioid substances [3],
and methadone dose administered [2]. The likelihood
remains that patients’ perspectives are probably rel-
evant factors associated with MMT response and they
should be taken into consideration, given that they
both inuence and are inuenced by MMT outcomes.
For instance, a negative attitude towards methadone
might negatively impact MMT outcomes through low
adherence to this treatment.
Patients’ satisfaction with the treatment received
is a perspective that at least partly depends on how
closely their expectations match the actual experi-
ence: when there is a gap, satisfaction is likely to be
lower [16]. In a previous study, we found that the lev-
el of patients’ satisfaction discriminated between two
extreme groups of non-responders and responders to
MMT [12]. Based on these ndings, we hypothesized
that their satisfaction with methadone as a medication
for the treatment of heroin addiction could predict
MMT response. In our previous study, non-respond-
ers felt less satised than responders with regard to
the compatibility of methadone with their personal
functioning and well-being, and they also reported
feeling less satised with the perceived anti-addictive
effects of methadone on heroin and non-opioid sub-
stances.
The aim of the present study was to explore the
role of heroin-dependent patients’ satisfaction with
methadone as an independent predictor of response
to MMT in terms of compulsive substance use. We
assessed several dimensions of satisfaction, includ-
ing the effects of methadone on personal function-
ing and well-being, and the anti-addictive effects of
methadone on heroin and non-opioid substance use.
In addition, we evaluated the predictive capacity of
several common clinical variables including sociode-
mographic variables, use of heroin, use of non-opioid
substances, pharmacological treatment, including
methadone administration, and patients’ views on
methadone dose adjustment. Our hypothesis was that
patient satisfaction with methadone, among those
other predictive variables, would be a factor indepen-
dently associated with the likelihood of non-response
to MMT. The results presented in this study extend
the ndings presented in [12].
2. Methods
2.1. Sample
Inclusion criteria included age ≥18 years, fulll-
ment of DSM-IV [1] criteria for heroin dependence,
and having received MMT for at least the previous 3
months. Patients with mental disorders that could hin-
der clinical assessments and those with poor Spanish
language prociency were excluded. Non-responders
to MMT were dened as those with current substance
use disorders (SUDs) requiring inpatient detoxica-
tion treatment due to the compulsive use of heroin
and/or non-opioid substances. All non-responders
were voluntarily admitted to a detoxication unit for
assistance in interrupting the use of non-prescribed
substances while continuing on MMT. Responders to
MMT were dened as those who met criteria for SUD
in sustained remission (other than tobacco use disor-
der) according to DSM-IV. All responders were re-
cruited through convenience sampling at a methadone
clinic. Our sample included 152 non-responders and
33 responders. The total sample consisted primarily
of males (73.5%), with an average age of 40.34 years
(SD = 7.23).
The study protocol was approved by the Institu-
tional Review Board of Santa Creu i Sant Pau Hospi-
tal. All patients were enrolled at the Santa Creu i Sant
Pau Hospital. No monetary compensation was of-
fered to participants. Participants signed an informed
consent form to declare their voluntary participation
in the study. The survey began in February 2007 and
ended in March 2012.
2.2. Candidate predictors of MMT response: data
collection and assessments
Candidate predictors included sociodemo-
graphic variables (age, gender, years of education);
heroin use (age at onset, time of use, and main route
of administration); history of non-opioid substance
use (alcohol, non-prescribed benzodiazepines, can-
nabis, cocaine, and tobacco); characteristics of MMT
(lifetime duration, number of MMT episodes, cur-
rent daily dose, split dosage, take-home doses, and
[R]-methadone plasma levels); current treatment with
other medications (antidepressants, antivirals, benzo-
diazepines, and others); satisfaction with methadone
as a medication; and patients’ views on methadone
dose adjustment.
Patient satisfaction with methadone was meas-
ured with the Scale to Assess Satisfaction with
Medications for Addiction Treatment-methadone for
heroin addiction (SASMAT-METHER; [11]). This is
a self-reported 17-item scale that assesses the over-
all experience (current or previous) with methadone
treatment. The questionnaire includes three subscales:
1) Personal Functioning and Well-Being, 2) Anti-Ad-
- 37 -
S. Alcarez et al.: Exploring predictors of response to methadone maintenance treatment for heroin addiction: the role of patient satisfaction with
methadone as a medication
dictive Effect on Heroin, and 3) Anti-Addictive Effect
on Other Substances. SASMAT-METHER items are
evaluated using a 5-point Likert scale (1 = terrible,
2 = generally unsatisfactory, 3 = mixed, 4 = gener-
ally satisfactory, 5 = excellent). SASMAT-METHER
scores are obtained by averaging item scores.
In terms of patients’ views on regulation of
methadone dose, we assessed two variables: 1) ad-
justment of the methadone dose desired by patients,
and 2) perceived participation in methadone dose reg-
ulation. These variables were evaluated using a meth-
od described in detail elsewhere [13, 17]. Briey, ad-
justment of the methadone dose desired by patients
was assessed using the Visual Analogue Scale of
Methadone Dose (VAS-MD). Perceived participation
in dose regulation was evaluated by asking two ques-
tions (the range of response categories is presented
in brackets): 1) ‘Are you informed about the changes
your centre’s staff make with regard to your metha-
done dose?’ (1 = never to 5 = always); 2) ‘Do you
think that your opinion inuences your centre’s staff
members to modify the methadone dose you take?’ (1
= no to 5 = a great deal).
The (R)-methadone plasma concentrations were
determined by capillary electrophoresis-ultraviolet
detection after a liquid-liquid extraction of samples
with tert-butylmethylether, a procedure previously
described by Fonseca and colleagues [6].
2.3. Data analysis
Possible differences between non-responders
and responders were individually tested using χ2 tests
(categorical variables) or t-tests (continuous vari-
ables). Variables that differed signicantly between
non-responders and responders at a bivariate level
(p ≤ .05) were entered in a binary logistic regression
model to identify the factors independently associated
with the likelihood of compulsive use of substances.
Binary logistic regression analyses were performed
with a forward stepwise procedure (entry criterion p
< 0.05, removal criterion p > 0.10).
3. Results
Regarding heroin use, average age at onset of
use was 20.87 years (SD = 6.93) and the main routes
of administration were injection (67%), snifng
(21.6%), and inhalation (11.4%). Participants had
been on MMT for an average of 128.19 months (SD
= 78.78), and were receiving an average methadone
dose of 73.30 mg/d (SD = 68.96). It should be noted
that comparisons between non-responders and re-
sponders have been reported in detail elsewhere [12].
The following characteristics were found to discrimi-
nate between non-responders and responders (Table
1): years of education; history of use of cocaine and
non-prescribed benzodiazepines; number of MMT
Table 1. Binary logistic regression model of variables associated with compulsive substance use during MMT.
Variables B Wald χ2P-value OR 95%CI
Years of education -0.179 2.418 0.120 0.836 0.667-1.048
History of non-prescribed benzodiazepine
usea0.530 0.704 0.402 1.699 0.492-5.868
History of cocaine use 0.349 0.177 0.674 1.418 0.279-7.199
Number of MMT episodes 0.509 1.978 0.160 1.664 0.818-3.384
Split methadone dosage -1.050 2.422 0.120 0.350 0.093-1.313
Take-home methadone doses -8.286 0.087 0.768 0.000 0.000-2.299E+20
Antidepressant treatment 0.694 0.750 0.387 2.003 0.416-9.647
Benzodiazepine treatment 1.749 5.848 0.016 5.749 1.393-23.727
Personal functioning and well-beingb-0.228 0.141 0.707 0.797 0.243-2.613
Anti-addictive effect on heroinb-0.501 0.652 0.419 0.606 0.179-2.046
Anti-Addictive effect on other Substancesb-1.074 6.167 0.013 0.341 0.146-0.797
Perceived information regarding methadone
dose changes -0.400 0.578 0.447 0.671 0.239-1.879
Perceived inuence on methadone dose
changes -0.495 1.695 0.193 0.610 0.289-1.284
a History of non-prescribed benzodiazepine use was dened as use without a prescription at least twenty times in a life-
time.
b Subscale of the Scale to Assess Satisfaction with Medications for Addiction Treatment – methadone for heroin addiction
(SASMAT-METHER).
B: logistic coefcient; CI: condence interval; MMT: methadone maintenance treatment; OR: odds ratio.
- 38 -
Heroin Addiction and Related Clinical Problems 19(4): 35-40
episodes; split methadone dosage; take-home privi-
leges allowed with methadone doses; antidepressant
and benzodiazepine treatments; all the SASMAT-
METHER subscale scores; perceived information
regarding methadone dose changes; and perceived
inuence on methadone dose changes. As Table 1
shows, the statistically signicant predictors in the lo-
gistic regression model (Hosmer and Lemeshow test:
χ2(8) = 4.828, P = 0.776; Nagelkerke’s R2 = 0.562)
were current benzodiazepine treatment (OR = 5.749;
95%CI 1.393-23.727) and the SASMAT-METHER
score on satisfaction with the Anti-Addictive Effect
on Other Substances (OR = 0.341; 95%CI 0.146-
0.797).
4. Discussion
In the present study we have explored the role
of heroin-dependent patient satisfaction with metha-
done as a medication in functioning as a potential
independent predictor of response to MMT in terms
of compulsive substance use. We also assessed a set
of other potential predictive variables, including age,
gender, years of education, use of heroin and non-
opioid substances, characteristics of MMT (e.g., daily
dose of methadone) and other pharmacological treat-
ments, and patients’ views on methadone dose adjust-
ment. We found that two factors were independently
associated with non-response to MMT: 1) patient sat-
isfaction with Anti-Addictive effects (of methadone)
on non-opioid substances and 2) current benzodi-
azepine treatment.
Our assumption was that patient satisfaction
with methadone would prove to be a signicant pre-
dictor of response to MMT, but we did not formulate
a hypothesis as to which dimensions of SASMAT-
METHER would be involved in this relation. We
found a negative association between the likelihood
of being a non-responder and scores on the subscale
'anti-addictive effects' on non-opioid substances.
This association suggests that the discrepancy be-
tween expectations about the anti-addictive effects of
methadone on non-opioid substances and the actual
experience was stronger in non-responders than in
responders. In non-responders, we surmise that the
clinical staff may have raised expectations about the
anti-addictive effects of methadone on non-opioid
substances by managing methadone administration
contingent on non-opioid substance use. This possi-
bility suggests that staff members should make every
effort to clarify the limitations of methadone with re-
spect to its ability to reduce non-opioid substance use.
In this way, it may be advisable to bring expectations
more closely in line with reality, thereby reducing the
degree of dissatisfaction expressed with methadone.
It seems likely that the persistent or increased use of
non-opioid substances after starting MMT, a phenom-
enon that has been described in some patients [15,
18], may also be signicantly related to the low level
of satisfaction with methadone in non-responders.
The positive association between benzodi-
azepine treatment and non-response to MMT ob-
served in our study could be explained by the fact
that non-responders could be suffering from higher
psychological distress than responders. In this sense,
the prescription of benzodiazepines in the context of
MMT has been considered inappropriate [4] given
the undesired interactions reported between benzodi-
azepine misuse and methadone (e.g., overdose; [10,
14]). Interestingly, non-prescribed benzodiazepine
use has been associated with MMT dropout, whereas
prescribed benzodiazepine treatment has not [18].
This suggests that the consequences of benzodi-
azepine treatment and benzodiazepine misuse in the
context of MMT may be quite different.
Limitations
The main limitation of this study is its cross-
sectional design. Accordingly, we were unable to
elucidate whether the low level of satisfaction with
the anti-addictive effects of methadone and benzo-
diazepine treatment preceded or were subsequent to
non-response to MMT. As a result, the results of this
study do not allow us to make any denitive recom-
mendations on the best way to improve MMT re-
sponse. The cross-sectional design of our study also
prevented us from examining whether patients’ char-
acteristics prior to MMT (e.g., severity of substance
use disorders) accounted both for patients’ degree
of satisfaction with methadone and their response to
MMT.
5. Conclusions
The results obtained in this study suggest that
the degree of satisfaction with methadone expressed
by heroin-dependent patients may be a key clinical
variable in the assessment of MMT response, and we
believe that this novel nding warrants further re-
search (preferably a prospective study) to strengthen
its reliability.
- 39 -
S. Alcarez et al.: Exploring predictors of response to methadone maintenance treatment for heroin addiction: the role of patient satisfaction with
methadone as a medication
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Acknowledgements
The authors are grateful to the patients who kindly
participated in the study and to Vanessa García, Saiko Al-
lende, and Isabel Blásquiz for their secretarial support. The
authors want to thank Bradley Londres for proofreading
the manuscript.
Role of the funding source
Funding for this study was provided by grant
PI06/0531 from Fondo de Investigación Sanitaria, Instituto
de Salud Carlos III (Spanish Ministries of Economy and
Competitiveness, and Health, Social Services and Equal-
ity). Funding sources had no role in the study design, col-
lection, analysis or interpretation of the data, writing the
manuscript, or the decision to submit the paper for publica-
tion.
Contributors
JP, JT and SA conceptualized the study. FB and SD
selected the participants. NS performed data collection. JT
and NS undertook the statistical analyses. SA wrote the
rst draft of the manuscript. JP and JT revised it critical-
ly. All authors contributed to and have approved the nal
manuscript.
Conict of interest
José Pérez de los Cobos has received grant support
for research and educational activities from RB Pharma-
ceuticals Ltd, a subsidiary of Indivior PLC. RB Pharma-
ceuticals had no knowledge of this study. All other authors
declare no nancial interests or potential conicts of inter-
- 40 -
Heroin Addiction and Related Clinical Problems 19(4): 35-40
Note
It is the policy of this Journal to provide a free re-
vision of English for Authors who are not native English
speakers. Each Author can accept or refuse this offer. In
this case, the Corresponding Author accepted our service.
Received April 26, 2016 - Accepted October 20, 2016
est directly or indirectly related to this work.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki -
Ethical Principles for Medical Research Involving Human
Subjects. This study has ethics committee approval. All pa-
tients gave their informed consent to the anonymous use of
their clinical data for this independent study.
Regular article
Heroin Addict Relat Clin Probl 2017; 19(4): 41-46
41
Corresponding author: Vito de Novellis, Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second
University of Naples, 80138 Naples, Italy, EU
Phone +39(0)815665878; Fax +39(0)815667503; e-mail: vito.denovellis@unina2.it
Clinical determination of carbohydrate-deficient transferrin (CDT) in alcohol
addicts: a random sample of the general population in Naples, Italy
Luigi Reccia1, Rossella Morelli1, Serena Boccella2, Reginaldo Iovine1, Domenico Zaia3,
Alessandro Crinisio4, Aniello Leone4, Ida Marabese2, Giulio Scala5, Francesca Guida 2,
Domenico Cante6, Vito De Novellis2, and Luigi Stella7
1-Department of Laboratory Medicine ASL Napoli 2 Nord, Frattamaggiore (province of Naples), Italy, EU
2-Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy, EU
3-Health Department ASL Naples 2 North, Frattamaggiore (province of Naples), Italy, EU
4-School of Medicine, Second University of Naples, Naples, Italy, EU
5-Department of Anaesthesiology, Surgery and Emergency, Second University of Naples, Naples, Italy, EU
6-Addiction Treatment Service ASL Naples 2 North, Acerra (province of Naples), Italy, EU
7-Addiction Treatment Service of Somma Vesuviana (province of Naples) ASL Naples 3 South, Torre del Greco (Naples), Italy, EU
Summary
Background. Alcoholism has become one of the main medical and social problems in Western society. Among different
indicators, carbohydrate-decient transferrin (CDT) can be considered the main marker in both clinical and forensic en-
vironments for alcohol addicts. Aim. The present study aims to report an accurate estimate of CDT levels in a sample of
chronic alcoholic subjects, while comparing that with a control group. Methods. We administered the CDT dosage to 993
subjects from a random sample of the general population and in patients from the Addiction Treatment Service (SERT,
double diagnosis in two different samples of population in Naples). Among them, 423 belonged to a ‘random’ sample
from the control group and 570 alcohol addicts indicated as the Chronic Alcoholic group. To this end, serum CDT levels
in both groups were measured by high-performance liquid chromatography (HPLC). Results. The analyses from the dif-
ferent groups revealed signicantly higher percentages of CDT levels in the Chronic Alcoholic group than in the control
group. Conclusions. Our ndings add new data on CTD dosage in a signicant sample of the territory pertaining to the
Local Health Authority within Naples known as ASL Napoli 2 North.
Key Words: Alcoholism; carbohydrate-decient transferrin; drug addicts
1. Introduction
Alcohol abuse has become one of the major is-
sues in the Western world, bringing with it medical
and social consequences as well as forensic implica-
tions [21, 22]. The car crashes arising from this prob-
lem are notoriously the leading cause of deaths due
to this form of addiction, and more than a quarter of
those accidents involve an underage drinking driver
[3, 4]. Indeed, in Italy the mortality rate due to road
accidents caused by the use of ethanol is estimated
to be between 30% and 50% [5]. Moreover, about
10% of the subjects monitored by general practition-
ers have alcohol-related diseases and as many as 10%
of hospital admissions are ascribed to the high con-
sumption of alcoholic drinks [6].
Because of its high diagnostic sensitivity and
specicity, in the last few decades, carbohydrate-
decient transferrin (CDT) has been indicated as the
most specic biomarker of chronic alcohol abuse [4,
5, 7, 15, 23, 32, 43]. Since the year 2007, all the meth-
odological guidelines for protein quantication have
been validated, too (IFCC-WGCDT) [18, 21, 25, 28,
29, 50, 51].
CDT consists of different transferrin isoforms
that have an isoelectric point (IP) ≥ 5.7, named
asialoTf, monosialoTf, and disialoTf, which, con-
sidered as a group, account for less than 2% of total
transferrin [4]. Alcohol consumption above 60-80 g/
die (amount contained in 500-850 ml of wine, in 1-2
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Heroin Addiction and Related Clinical Problems 2017; 19(4): 41-46
litres of beer or 130-220 ml of hard liquor) for 10-15
days is generally associated with an increase in con-
centrations of CDT in the serum (>2%) [39]. Indeed,
several scientic reports have shown an enhancement
in the concentration of CDT in moderate consumers
of alcohol, although the gures recorded remained
within the limits for normal concentrations [30, 39].
Moreover, the blood concentration of CDT – which
has a short mean half-life (7 to 14 days) – declines
signicantly over time for abstinent patients [26].
The mechanism responsible for the increase in
serum CDT levels in alcohol-abusing patients has
not yet been dened. It has, however, been suggested
that ethanol intake may lower the activity of glyco-
protein glycosyltransferase enzymes, referred to as
sialyltransferase (ST), galactosyltransferase (GT),
and N-acetylglucosaminetransferase (N-AGT); these
are predominantly found in hepatic Golgi complexes,
which are responsible for the addition of sialic acid
and other carbohydrates to the transferrin polypeptide
chain via glycosylation [45].
The aim of the present study has been to report
an accurate estimate of the CDT levels, measured by
HPLC, present in a sample of chronic alcoholic sub-
jects, while comparing them with those of a control
group.
2. Methods
2.1. Sample
993 subjects were recruited for CDT dosage at
the Toxicology Laboratory in Frattamaggiore (prov-
ince of Naples) from February 8, 2013 to May 7, 2015.
Out of this total of 993, 423 belonged to a ‘random’
sample from the control group while the remaining
570 were chronic alcoholic subjects. In greater detail,
the subjects related to the rst category include peo-
ple who had taken the CDT dosage as part of the nec-
essary procedures for obtaining a gun license, adopt-
ing a child, taking part in a public competition or for
any of a variety of job tasks required by law 81/03 (ex
626/94), and also other people who had been banned
from driving for infringing the terms of trafc law
186. The second group consisted of chronic alcoholic
subjects who were consuming alcohol in combination
with drugs, or patients under detoxication therapy
and a small number of cirrhotic patients awaiting a
liver transplantation. The diagnosis was performed
through laboratory assessments and diagnostic imag-
ing by specialists. The analysis and the ofcial docu-
ments are preserved in the toxicology laboratories
reported above.
2.2. Laboratory assessment
The analysis of serum CDT from serum matrix
constituents and from non-CDT isoforms requires the
use of at least one of various techniques that include
immunometric [4], High Performance Liquid Chro-
matography (HPLC) liquid chromatography [1, 8, 19,
20, 27, 28, 35, 40, 41, 47, 48], mass spectrometromet-
ric (LC-MS) [4, 12, 13, 14, 31, 49, 50] or capillary
electrophoretic methods [33, 34], selecting the spe-
cic charges and IPs of CDT and non-CDT isoforms
[16, 27, 31, 48]. The CDT levels were measured by
the routine method called READY-PREP % CDT
by HPLC (Bio-Rad) consisting in a two dual-piston
pump system, a thermostated (20°C) 100-sample
auto sampler with a column compartment (35° C),
and a dual wavelength (460 nm and 690 nm) detec-
tor. The system was connected to the CDM software
(Bio-Rad). Before analysis, the samples were pre-
treated by 30-min incubation with a ferrous and dex-
tran sulphate solution, followed by 10-min (10,000 g)
centrifugation, for both iron saturation and lipid pre-
cipitation. The Tf fractions were separated using an
ion-exchange column (600 tests) protected by a guard
column (100 tests). The absorbance of the ferrous
iron–Tf complex was measured as 460 nm; the sec-
ondary 690 nm wavelength was used for background
noise reduction. The area of each Tf glycoform peak
following baseline integration from disialo- to pen-
tasialo transferrin was measured, too. The hexasialo
transferrin peak was not integrated; asialo transfer-
rin n, when present, was integrated into a separate
baseline mode. The area of each identied peak was
expressed as the ratio of its surface to the total under-
peak area. The total analysis time was ∼10 min.
2.3. Data analysis
Data were expressed as % CDT values. Each
point represents the mean of the total subjects per
year of different groups. Student’s t test was applied
to analyse statistical differences between the control
and Chronic Alcoholic groups. P value <0.01 was
considered statistically signicant.
3. Results
CDT analysis revealed a signicant difference
in the protein levels between the Chronic Alcoholic
and the control groups. More specically, the rst
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L. Reccia et al.: Clinical determination of carbohydrate-decient transferrin (CDT) in alcohol addicts: a random sample of the general population
in Naples, Italy
(Chronic Alcoholic) group showed a higher percent-
age of CDT levels in the years 2012, 2013 and 2014
(1.90%, 1.82% and 2.36%, respectively), as com-
pared with the second (control) group (0.95%, 1.2%
and 0.98% respectively) (Table 1).
The mean values for serum CDT in those three
years were 1.04% and 2.02% (p<0.01) in the control
and Chronic Alcoholic subjects, respectively. The
level of statistical signicance between groups was
determined by using the Student t test. Figure 1 shows
the percentages of CDT values for the all durations of
observation (over those three years).
4. Discussion
Several markers have been proposed for the
objective diagnosis of the various forms of alcohol
abuse; of the markers currently available, CDT meas-
urement has been considered the most reliable of
those that have been identied as valid both in the
eld of forensic medicine [2, 9, 10, 13, 17, 18, 34,
36, 37, 38, 46] and in that of occupational medicine
[24, 42]. Thus, the purpose of this study was not to
validate the diagnostic test, but to include new data
on CTD dosage in a signicant sample of the territory
pertaining to the Addiction Treatment Service run by
the local authorities named ASL Napoli [Naples] 2
Nord. In particular, our ndings indicate that the me-
dium levels of the biochemical marker for alcohol-
related abuse was around 1% in the control group,
and this value remained constant until the end of the
experiment. By contrast, the Chronic Alcoholic group
showed CDT values that were initially double in size
(2%), and that seemed to increase proportionally over
the years. The explanation for this discrepancy may
be attributed to the improved use of this marker both
Table 1. Summary of Clinical Studies of CDT as a Marker of Alcohol Abuse in Control and Alcoholics groups
Year CDT% mean Min values Max values P-value
Controls 2013 0.95 0.3 4.0 <0.01
2014 1.20 0.8 2.6 <0.01
2015 0.98 0.5 1.6 <0.01
Alcoholics
2013 1.90 0.5 22.8 <0.01
2014 1.82 0.6 11.5 <0.01
2015 2.36 0.6 14.8 <0.01
Figure 1. Bar graphs showing the % CDT values among 993 patients, divided as follows: 423 selected as a
“random” sample of the general population (Control Group), and the other 570 from the Addiction Treatment
Service (Group of Alcoholics). Each point represents the mean ± S.E.M of the total subjects per year of each
group being examined. P values <0.01 were considered statistically signicant (Student t test).
- 44 -
Heroin Addiction and Related Clinical Problems 2017; 19(4): 41-46
in initial diagnosis and pharmacological therapy.
In patients receiving detoxication therapy, we
found that CDT levels were reduced by 30% in the
rst phase of the experiment, and then fell even fur-
ther until the observation ended. On the basis of the
data previously reported [4, 11, 19, 28, 30, 32, 39,
40], these results demonstrate the high reliability of
our measurements both in terms of specicity and
sensitivity.
Moreover, the nding that the mean maximal
value in the control group was around 1%, and re-
mained constant for the whole duration of the meas-
urements, suggests that the cut-off levels of CDT
should be reassessed to minimize false negatives at
the screening analysis.
In our analysis, we excluded data derived from
carriers of genetic variants, as the number of subjects
involved was less than 0.4% of the total sample of
subjects analysed.
Our data conrm previous ndings [4, 8, 16, 23,
28, 32, 39, 40, 44, 45] that showed the high reliability
and specicity of CDT analysis, which by now can
be considered a marker of chronic high alcohol in-
take, as well as of drinking habits that imply potential
health and safety risks [4]. For these reasons, CDT
measurement is the most widely used and success-
ful test in the medical and forensic environments, so
leading to a shift in the type of test requested by these
users, rather than by the Addiction Treatment Service.
As reported in the present study, we found high-
er percentages for CDT levels in the Chronic Alco-
holic group than in the control group, but it must be
added that the mechanism responsible for this differ-
ence still needs to be claried.
5. Conclusions
In light of the improved use of CDT as clinical
marker both in initial diagnosis and pharmacological
therapy in alcohol addicts, our data have added new
information on CTD dosages in a signicant sample
of the territory pertaining to the Addiction Treatment
Service named “ASL Napoli [Naples] 2 Nord”.
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45. Sillanaukee P., Strid N., AllenJ.P., R.Z. Litten R.Z.
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Acknowledgements
None.
Role of the funding source
Authors state that this study was nanced with inter-
nal funds. No sponsor played a role in study design; in the
collection, analysis and interpretation of data; in the writ-
ing of the report; and in the decision to submit the paper
for publication.
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
control, including nal responsibility for the decision to
submit the paper for publication.
Conict of interest
All authors have no conict of interest.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki -
Ethical Principles for Medical Research Involving Human
Subjects. This study does not require ethics committee ap-
proval because the study describes a meta-analysis, thus
ethics committee approval and informed consent were not
required.
Note
It is the policy of this Journal to provide a free re-
vision of English for Authors who are not native English
speakers. Each Author can accept or refuse this offer. In
this case, the Corresponding Author accepted our service.
Received May 24, 2016 - Accepted November 6, 2016
Short Report
Heroin Addict Relat Clin Probl 2017; 19(4): 47-52
47
Corresponding author: Dr Tomás Barry, Centre for Emergency Medical Science, School of Medicine, University College Dublin,
Ireland
E-mail: tomas.barry@ucd.ie
Experience of drug overdose at an urban addiction clinic in Ireland
Tomás Barry1, Des Crowley2, Aoife Benton3, Enda Barron3, and Fiona O’Reilly3
1 - Centre for Emergency Medical Science, School of Medicine, University College Dublin, Ireland.
2 - The Thompson Centre, Dublin, Ireland.
3 – North Dublin GP Training Scheme, Ireland.
Summary
Background: Drug overdose is a signicant health problem that carries with it potentially fatal consequences. Over-
dose prevention and management strategies should be a key concern for settings that provide services to drug users and
in particular to opioid injectors. The service user perspective is an important consideration in overdose prevention and
management. Aim: To examine the experience of drug overdose among service users at a single addiction clinic, and thus
inform future overdose prevention and management strategies. Methods: An anonymous census of all service users at a
single urban addiction clinic was conducted in order to establish the experience of personal or witnessed drug overdose
within the preceding year. Following this census, questionnaire-based interviews were conducted to examine the service
user experience of drug overdose in greater detail. Results: A census response rate of 96% (216) was achieved. Eighteen
service users participated in a follow up questionnaire-based interview. Almost one-third of service users (31%) had either
witnessed or personally experienced an overdose in the previous year. A quarter of the population (25%) had witnessed
but not experienced an overdose. Service users who were interviewed, were willing to intervene in overdose situations
but many were unaware of the opiate antidote naloxone. Conclusions: A signicant proportion of service users at this
single clinic had recent experience of drug overdose. Overdose prevention and management strategies are relevant to this
population. Training and equipping addiction clinic service users for overdose management may save additional lives.
Key Words: Substance related disorders; Overdose Education; Naloxone Distribution.
1. Introduction
Ireland’s current population stands in the region
of 4.75 million people [4]. Of this there are about
twenty thousand problem opiate users [10] with ap-
proximately half of this group accessing opiate re-
placement therapy, primarily in the form of metha-
done [7]. In Ireland opiate replacement therapy is
provided by specialist addiction clinics and also by
qualied general practitioners working within the
community medicine setting [5]. Unfortunately, Ire-
land experiences a high rate of fatal drug overdose,
with many cases involving individuals who are prob-
lem opiate users [8]. In Ireland in 2013, more people
died due to drug overdose than in road trafc acci-
dents (249 vs 190) [8, 14]. Despite this observation,
road safety has become an established national prior-
ity whereas little action has been taken on the issue of
death due to drug overdose [3]. A recent and welcome
development in Ireland is the roll out of a naloxone
demonstration project. This project investigates the
feasibility of making the opiate antagonist naloxone
available in the community where overdose is likely
to occur [11]. Naloxone is an established treatment in
the setting of opiate overdose, with the World Health
Organisation recommending its availability for at risk
populations [23]. Take home naloxone programmes
have been shown to reduce overdose mortality in the
community and are associated with a low rate of ad-
verse events [12].
Previous research has demonstrated a high prev-
alence of both personal and witnessed drug overdose
among patients attending addiction services [17].
The presence of peer witnesses at an overdose event,
potentially creates an opportunity for interim emer-
gency management while awaiting the arrival of the
- 48 -
Heroin Addiction and Related Clinical Problems 19(4): 47-52
emergency services [19]. In the future, in Ireland, it
is hoped such interim emergency management would
routinely involve both basic life support measures
and peer naloxone administration. Recently pub-
lished data from Ireland showed that over 40% of
people who died in circumstances where heroin was
implicated were not alone at the time of drug taking
[8]. This suggests that there may be potential to save
additional lives if peers are empowered and equipped
to act. In order to support appropriate peer interven-
tion during overdose, it is necessary to gain an un-
derstanding of the experience of and attitudes toward
overdose among the population of problem opiate us-
ers concerned. This study was conducted to establish
the prevalence of personal and witnessed overdose in
a population attending a single addiction clinic, and to
explore the beliefs and attitudes of this group toward
drug overdose and its management. The results are
hoped to inform peer overdose response strategies.
The setting for this study was the Thompson Centre
[9], a drug treatment clinic in inner city Dublin oper-
ated by the Health Services Executive.
2. Methods
An anonymous, self-administered census was
distributed to all 224 service users attending the
Thompson Centre over a two-week period in June
2015. The census examined only whether the service
user had experienced or witnessed drug overdose
within the preceding year. No demographic informa-
tion was collected at this stage.
A convenience sample of service users with per-
sonal or witnessed experience of overdose within the
preceding year were recruited to complete a research-
er administered follow up questionnaire containing
both open and closed questions. Eighteen of a poten-
tial total of sixty seven service users who reported
personal or witnessed experience of overdose within
the preceding year took part. All eighteen service
users were of Irish nationality and most were male
(14/18). Age prole of this group ranged from 22 to
52 years of age, with a median age of 38.
The questionnaire was developed in conjunc-
tion with the local clinical team, national experts in
the area of drug treatment and overdose prevention
and a drug service user representative group. Minor
changes were made following initial pilot of the ques-
tionnaire in early July 2015. Recruitment of partici-
pants continued over the following one-month period.
Posters outlining the research project were displayed
in the clinic and information concerning the research
was made available in advance of recruitment. As
patients of the clinic attended for review or to col-
lect their weekly or fortnightly prescription, the study
was highlighted and they were invited to participate.
Study Information leaets were made available to pa-
tients who expressed an interest in participation, and
a formal consent form was completed by those ser-
vice users who agreed to participate in the question-
naire component. The questionnaire contained 57 in-
dividual questions organised around sections related
to demographics, education, employment, criminal
and drug history as well as specic components that
concerned personal and/or witnessed experience of
drug overdose as relevant.
The questionnaire was administered by the prin-
cipal investigator and by research assistants who were
not employees of the addiction clinic. Where appro-
priate the questionnaire specied categorical answers,
allowing a box to be ticked relevant to the answer pro-
vided. Space for comment and/or clarication was in-
cluded routinely. Where an open question was asked,
space was provided to allow the participants response
to be recorded in detail. Quantitative data was ana-
lysed using descriptive statistics. Qualitative data was
categorised and themes were identied. Ethical ap-
proval for this study was granted by the Irish College
of General Practitioners, Ethics Committee prior to
the initiation of data collection.
3. Results
Of the 224 clinic attenders, a high proportion
(96%) completed the two-question census. Almost
one third of service users (31%) had either witnessed
or personally experienced an overdose in the preced-
ing year. One quarter (25%) had witnessed but not
experienced an overdose, 3% had experienced but not
witnessed an overdose while a further 3% had both
experienced and witnessed an overdose.
Of the 18 service users who participated in the
follow up questionnaire-based interview, all had left
school between eleven and sixteen years of age. Half
of this group (50%) described themselves as home-
less. Age of rst illegal drug use ranged from eight to
thirty-eight years of age with a median age of fteen
years old. In fty percent of individuals, the rst ille-
gal drug taken had been cannabis. Age of rst heroin
use ranged from eleven years of age to thirty eight
years of age with a median age of sixteen. Most of
those interviewed (83%) reported a past history of
prison incarceration.
Six respondents reported that they had experi-
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T. Barry et al.: Experience of drug overdose at an urban addiction clinic in Ireland
enced a personal overdose within the preceding year.
These overdoses occurred both at residential loca-
tions and public places. Two respondents reported
that they had experienced an intentional drug over-
dose, thus attempting suicide. Only two of six indi-
viduals reported that they had attended the hospital
following overdose and neither reported receiving
any assistance with their drug problem or advice on
preventing future overdose.
Respondents were asked to explain how they
would recognize an overdose. They identied a range
of factors, which they considered to be associated
with an overdose situation. These factors frequently
included: depressed or absent breathing, a decreased
level of consciousness, a change in skin color and evi-
dence of drug taking such as apparent paraphernalia
associated with heroin use.
Fourteen of the eighteen respondents reported
witnessing a drug overdose within the preceding year.
In all but one of these cases, an ambulance was called.
None of these fourteen individuals reported having
concerns about seeking help in such a situation. Thir-
teen participants reported assisting the overdosed cas-
ualty in some way. This included remaining with, re-
assuring and monitoring the overdose victim, putting
the overdose victim in the recovery position and also
performing cardio pulmonary resuscitation. Of note,
some form of cardio pulmonary resuscitation (CPR)
had been performed by more than half of individuals
(57%) who had witnessed an overdose. This group
had performed chest compressions, rescue ventila-
tions or a combination of both during overdose situa-
tions. Only four service users who participated in the
interview reported that they had heard of the opiate
antagonist naloxone. When naloxone was explained
to service users, 14 reported that they would be happy
to administer it to a fellow drug user who had suffered
an overdose, 2 reported being unsure with the remain-
ing 2 did not answer this question.
4. Discussion
The census component of this study achieved a
substantial response rate and establishes the problem
of drug overdose as relevant to and encountered by
this inner city, addiction clinic population. The fol-
low up interview component explores the content of
service user overdose experience, and the attitudes of
this population, however is limited by the number of
participants involved.
The census component would suggest 67 poten-
tial service users with experience of overdose within
the preceding year of which only 18 participated in
the follow up interview. It is possible that the group
of service users who took part might be those more
willing to intervene in overdose situations. Alterna-
tively it may be that the brief and anonymous nature
of the census component was more acceptable to ser-
vice users, while a face to face more time consum-
ing questionnaire based interview tool may have been
regarded with suspicion, or considered inconvenient.
Ultimately, while the results of the follow up sur-
vey cannot be considered representative of the clinic
population, the data obtained provides an important
insight into service user experience of and attitude
toward overdose, on which further study is recom-
mended.
Peer drug users have a key role in preventing fa-
tal overdose by virtue of the fact that this group is well
placed to identify unintended drug reactions that en-
danger the drug user [6]. Our study participants iden-
tied depressed or absent breathing, a decreased level
of consciousness, a change in skin color and evidence
of drug taking paraphernalia as factors that can sig-
nify overdose. These factors are physiologically and
pragmatically plausible. Previous studies have shown
that drug users who witness drug overdose are will-
ing to intervene and often report undertaking rst aid
type actions, although not all actions are appropriate
or benecial [17, 16, 2]. The respondents in our study
reported willingness to provide assistance to drug us-
ers in overdose situations. Indeed many reported al-
ready having rendered rst aid to an overdosed drug
user. Elsewhere fear of repercussion in summoning
statutory assistance has been reported as a barrier to
overdose response [1, 13, 15]. This nding was not
mirrored in our study. Furthermore it is striking that
over half of the group who had witnessed drug over-
dose in the year preceding this study had performed
some form of cardiopulmonary resuscitation. This
study did not however establish the thought process
that prompted the initiation of CPR, the quality of
CPR or how the respondents had acquired knowledge
of CPR techniques.
Naloxone is an evidence based, effective over-
dose treatment with a favourable safety prole. De-
spite the potentially lifesaving properties of this drug
and its relevance to this population, only a minority of
this study’s respondents were aware of this antidote.
Take home naloxone has been promoted since the
1990’s [18] and many countries now facilitate take
home naloxone programs as a component of wider
overdose prevention and management strategies [20].
In addition to having obvious benets for individuals
- 50 -
Heroin Addiction and Related Clinical Problems 19(4): 47-52
suffering drug overdose, peer overdose management
training and naloxone provision can also have ben-
ets for the rescuer. Overdose management training
has been associated with the development of a new
social role, increased condence and the promotion
of feelings of heroism and pride [21]. Furthermore, it
has been associated with a decrease in personal drug
use [22]. The fact that these addiction clinic service
users were unaware of naloxone supports the asser-
tion that Ireland remains behind the curve on this is-
sue. It is possible that lives are being lost unnecessar-
ily as a result.
5. Conclusions
In keeping with international experience, ser-
vice users at this single addiction clinic are likely to
witness drug overdose and are willing to intervene.
The provision of structured overdose response train-
ing and access to naloxone should be urgently con-
sidered in an effort to reduce overdose related deaths.
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T. Barry et al.: Experience of drug overdose at an urban addiction clinic in Ireland
Acknowledgements
The authors wish to acknowledge the input of the
service user group who participated in this study and the
assistance of staff at the Thompson Centre, without whom
this research project would not have been possible.
The authors also wish to acknowledge the service
user representative group who assisted with study instru-
ment design.
Finally the authors wish to acknowledge the group of
doctors completing specialist training in general practice
who assisted with data collection for this study.
Role of the funding source
No external funding received.
Contributors
All authors were involved in all stages of this research
project from design through to submission for publication.
Conict of interest
All authors declare no conict of interest.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki -
Ethical Principles for Medical Research Involving Human
Subjects. This study has ethics committee approval. All pa-
tients gave their informed consent to the anonymous use of
their clinical data for this independent study.
Received August 22, 2016 - Accepted September 20, 2016
Short communication
Heroin Addict Relat Clin Probl 2017; 19(4): 53-56
53
Corresponding author: Icro Maremmani, Department of Specialty Medicine, Santa Chiara University Hospital, Via Roma, 67,
56100, PISA, Italy, EU
Phone: +39 050 993045; E-mail: icro.maremmani@med.unipi.it;
1. Introduction
Governments and public health organizations
worldwide have become increasingly aware of drug
abuse-related issues and eager to receive systemati-
cally collected surveillance data that may assist in
the formulation and consolidation of their plans to
address this emerging epidemic. The non-medical
use of prescription opioids is a major public health
issue, both because of its overall high prevalence and
because of marked increases in associated morbid-
ity and mortality [1,2]. Through the coordinated re-
search efforts of the Italian-based Association for the
Application of Neuroscientic Knowledge to Social
Aims (AU-CNS), Denver Health Rocky Mountain
Poison and Drug Center (RMPDC) in the U.S.A., and
Patterns of prescription drug use and misuse in Spain: The European Opioid
Treatment Patient Survey
Francina Fonseca 1,2,3, Marta Torrens 1,2,3, Magí Farré 2,3,4, Karin E. McBride 5
Marilena Guareschi 6, Didier Touzeau 7, Pierre Villeger 8, Amine Benyamina 9,
Oscar D’Agnone 10, Lorenzo Somaini 11, Icro Maremmani 6,12, and Richard C. Dart 5,13
1-Hospital del Mar Institute of Neuropsychiatry and Addictions, Barcelona, Spain
2-IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain
3-Universitat Autònoma de Barcelona, Barcelona, Spain
4-Germans Trias i Pujol-IGTP University Hospital, Badalona, Spain
5-Denver Health Rocky Mountain Poison & Drug Center (RMPDC), Denver, USA
6-Association for the Application of Neuroscientic Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy, EU
7-Clinique Liberté, Bagneux, France
8-Laboratory of Toxicology, University Hospital, Limoges, France
9-Paul Brousse Hospital, Villejuif, France
10-Institute of Brain Behaviour and Mental Health, University of Manchester
11-Addiction Treatment Centre, Local Health Unit, ASL BI, Biella, Italy
12-Department of Specialty Medicine, Santa Chiara University Hospital, Pisa, Italy
13-University of Colorado-Denver School of Medicine, Aurora, USA
Summary
Aim: The present study aims to evaluate the patterns of prescription drug misuse in a medication-assisted treatment centre
(MAT) in Spain. Methods: Launched in October 2014, this study is based on patient self-report data collected at treatment
programme intake past 90-day use and injection history for European market prescription opioids, prescription stimulants,
prescription cannabinoids, heroin, and other prescription drugs, as well as basic demographic information, treatment
history, and health care worker status. Results: A total of 101 surveys have been collected so far in Spain (69% males,
42±10 years). The main drugs reported at intake were heroin (51%), cocaine (26%), cannabis (11%), amphetamines (4%),
benzodiazepines (3%), prescription opioids (3%), in addition to other substances (3%). The main routes of administration
were smoking (34%), injection (30%), snorting (27%), and oral consumption (7%), while 2 subjects used transdermal
patches (2%). A majority of subjects (63%) were abusing more than one substance. Conclusions: Initial data show that,
in Spain, there is widespread concomitant abuse of prescription drugs, mainly benzodiazepines, prescription opioids and
cannabis. A thorough knowledge of drug use patterns can provide information that will be useful in developing effective
forms of prevention and treatment.
Key Words: Prescription opioids; prescription drugs; European survey
- 54 -
Heroin Addiction and Related Clinical Problems 19(4): 53-56
European opioid treatment programme physicians, a
pilot study was previously launched which provided
for proof of concept of the feasibility of an interna-
tional drug surveillance system which will be pre-
sented in this study [3].
The present study aims to systematically obtain
data on prescription drug misuse in France, Germa-
ny, Italy, the United Kingdom, Norway and Spain.
In this report we present the patterns of prescription
drug misuse in a medication-assisted treatment centre
(MAT) in Spain, and the clinical characteristics that
have been shown to depend on the primary drug re-
portedly consumed prior to intake.
2. Methods
Patients aged 18-65 entering MAT were sur-
veyed at treatment programme intake, and self-
reported their use and injection history over the
previous 90 days for European market prescription
opioids, prescription stimulants, prescription cannab-
inoids, heroin, and other prescription drugs, as well
as basic demographic information, treatment history,
and health care worker status. Data collected from
October 2014 through May 2016 are presented here.
Descriptive statistics are presented. Comparisons de-
pending on the primary drug at intake were performed
by implementing the Chi-Square test and independent
ANOVA measures combined with SPSS.
3. Results
In all, 101 surveys have been collected in Spain
(69% males, 42±10 years) for the time period speci-
ed. The main drugs reported at intake were: heroin
(51%), cocaine (26%), cannabis (11%), ampheta-
mines (4%), benzodiazepines (3%), and prescrip-
tion opioids (3%), in addition to other substances
(3%). The main route of administration was smoking
(34%), injection (30%), snorting (27%), and oral con-
sumption (7%), while 2 subjects reported misuse of
transdermal patches (2%). A majority (63%) of these
subjects (63%) abused more than one substance; the
main characteristics of the sample are shown in Table
1.
Subjects presented differences that depended on
the primary drug reported by them at intake; those
who named heroin as primary drug showed a higher
level of intravenous and polysubstance use and lower
age at rst treatment. Conversely, patients with pre-
scription opioids as primary drug of use were older
than the rest (Table 2).
Table 1. Main characteristics of the selected sample
N= 101
Males n (%) 70 (69)
Mean age of participants (SD) 42 (10)
Country/Continent of Birth; numbers
(with % values)
Spain
Other European (EU)
Other European (non-EU)
North Africa
Sub-Saharan Africa
America
Asia
Other
73 (72)
12 (12)
5 (5)
4 (4)
2 (2)
2 (2)
2 (2)
1 (1)
Health Workers, number (with % value) 5 (5)
First treatment, n (%) 31 (31)
Age at rst treatment, mean (SD) 32 (11)
Primary Drug, numbers (with % values)
Heroin
Cocaine
Cannabis
Amphetamines
Prescription Opioids
Benzodiazepines
Other
51 (51)
27 (27)
11 (11)
4 (4)
3 (3)
3 (3)
3 (3)
Route of administration of main drug;
numbers (with % values)
Smoking
Injection
Snorting
Oral consumption
Sublingual consumption
Dermal
34 (34)
30 (30)
27 (27)
7 (7)
1 (1)
2 (2)
Source of primary drug, numbers (with %
values)
Dealer
Friend/Relative
Prescription
Stolen
Other*
80 (79)
9 (9)
4 (4)
1 (1)
7 (7)
More than one substance, number (with %
value) 63 (63)
Other substances used, numbers (with %
values)
Benzodiazepines
Cannabinoids
Methadone
Codeine
Tramadol
Buprenorphine
Morphine
Fentanyl
Heroin
Methylphenidate
Amphetamines (street)
Pregabalin
Gabapentin
Other
41 (41)
34 (34)
9 (9)
7(7)
4 (4)
3 (3)
2 (2)
1 (1)
1 (1)
4 (4)
4 (4)
2 (2)
1 (1)
2 (2)
SD: Standard deviation; *Cannabis clubs
- 55 -
F. Fonseca et al.: Patterns of prescription drug use and misuse in Spain: The European Opioid Treatment Patient Survey
4. Discussion and conclusions
Initial data show that, in Spain, there is a ma-
jor problem associated with heroin use. Abuse of and
addiction to prescription opioids remains, but only
as a minor problem often associated with the use of
heroin.
Concomitant abuse of prescription drugs is
mainly associated with benzodiazepines and canna-
bis.
A thorough knowledge of drug use patterns can
provide information that is likely to be useful in de-
veloping effective prevention and treatment.
Limitations
Limitations of the EUROPAD Program includes
self-reporting, sampling bias, and utilization of a pa-
per-based survey, which limits the amount of infor-
mation collected and permits noncompliant responses
(e.g. selection of more than one answer to a question
that requests only one answer be provided). However,
a similar program in the United States yields around
an 80% participation rate, therefore minimizing the
anticipated sampling bias.
Additionally, because data are self-reported,
results for prescription cannabinoids may include
reports for illicit cannabis. The survey questionnaire
used for data collection has since been updated to
separate pharmaceutical cannabinoids from illicit
cannabis.
References
1. Ofce of the President of the United States (2011)
Epidemic: responding to America’s prescription drug
abuse crisis. Washington, DC: Ofce of National Drug
Control Policy. (http://www.whitehouse.gov/sites/
default/les/ondcp/policy-and-research/rx_abuse_plan.
pdf )
2. Paulozzi LJ (2012). Prescription drug overdoses: a
review. J Safety Res. 43: 283-289.
3. Maremmani I, Somaini L, Deruvo G, Maremmani
AGI, Touzeau D, Walcher S, Fonseca F, Bacciardi S,
Guareschi M, Green JL, McBride K, Dart RC (2016).
Opioid misuse in the 30 days prior to entering Agonist
Opioid Treatment in four European Countries. A pilot
study. Heroin Addict Relat Clin Probl 18: 43-52.
Acknowledgements
None
Role of the funding source
The study was funded by Denver Health Rocky
Mountain Poison and Drug Center, located in Denver
(CO), USA and implemented by the Association for the
Application of Neuroscientic Knowledge to Social Aims
(AU-CNS), Pietrasanta, Lucca, Italy, on behalf of European
Opiate Addiction Treatment Association (EUROPAD).
Supported in part by grant from Instituto de Salud
Carlos III – FEDER-Red de Trastornos Adictivos
RD16/0017/0010.
Contributors
FF, MT and FM were involved in the study design.
All authors had full access to the survey data and analyses,
and interpreted the data, critically reviewed the manuscript
and had full control, including nal responsibility for the
Table 2. Main characteristics of the sample depending on the main drug reported at intake
Heroin
N=51
Cocaine
N=26
Cannabis
N=11
BDZs
N=3
Rx opioids
N=3
Other
N=7 p
Males: numbers (%
values) 39 (77) 16 (59) 7 (64) 0 2 (67) 7 (100) 0.033
Age, mean (SD) 43 (10) 40 (8) 36 (13) 40 (16) 55 (8) 45 (9) 0.044
Main route by which
administered; numbers
(with % values)
Smoking
Injection
Snorting
Oral route
Sublingual
Dermal
13 (26)
28 (55)
10 (20)
0
0
0
9 (33)
1 (4)
16 (60)
0
0
0
11 (100)
0
0
0
0
0
0
0
0
3 (100)
0
0
0
0
0
1 (33)
0
2 (67)
1 (17)
1 (17)
1 (17)
3 (32)
1 (17)
0
<0.001
Age at rst treatment,
mean values (SD) 28 (10) 34 (9) 34 (15) 35 (18) 48 (4) 39 (13) 0.005
More than 1 substance;
numbers (% values) 36 (70) 16 (60) 3 (27) 2 (67) 3 (100) 3 (43) 0.044
SD: Standard deviation
- 56 -
Heroin Addiction and Related Clinical Problems 19(4): 53-56
- Ethical Principles for Medical Research Involving Hu-
man Subjects. This study has pertinent ethics committee
approval.
Note
It is the policy of this Journal to provide a free re-
vision of English for Authors who are not native English
speakers. Each Author can accept or refuse this offer. In
this case, the Corresponding Author accepted our service.
decision to submit the paper for publication.
Conict of interest
Authors declared no conict of interest linked to this
paper.
Ethics
Authors conrm that the submitted study was con-
ducted according to the WMA Declaration of Helsinki
Received and accepted May 24, 2016
© Icro Maremmani
Tender is the Night in the Medina - Tunis, Tunisia, February 2009
