Twelve-months follow-up of

methadone maintained
patients
with and without
associated
benzodiacepine
Dr. Jos Martnezabuse
Raga
Unidad de Conductas Adictivas del rea 11 de
Valencia (C.S. Corea, Ganda)

Co-Authors
Carlos Knecht, MD
Ana Sabater, PhD
Sara Martinez-Espinosa, MSc
Belen Plaza, MSc

Ackowledgem
ents

Nstor Ramirez, MSc

Rosa de la Poza
Isabel Ruiz
CSISP

Introduction (1)

Benzodiazepines are widely used in a variety of

conditions, particularly anxiety disorders, sleep
disorders, epilepsy, as muscle relaxants, as well as for
alcohol withdrawal.

In anxiety and insomnia, its two major psychiatric

indications, benzodiazepines are only indicated for
short-term-use, due to rapid development of tolerance to
the hypnotic and anxiolytic effects of these medications.

Substance abusers are at particularly high risk to

develop tolerance and dependence to these medications.

Introduction (2)

Polysubstance-dependent individuals frequently selfmedicate with benzodiazepines 1.

Benzodiazepines are often abused to counteract the

unpleasant effects of other drugs of abuse.

Combined with alcohol and heroin may be used to

potentiate its depressant or even for its paradoxical
effects, as described in several reports.

Malcolm RJ. J CLin Psychiatry 2003

Polydrug abusers
Drug misusers tend to take high doses* of
benzodiazepines and become extremely tolerant to the
sedative effects.
They are taken because
They carry their own effects of intoxication which is
valued
They enhance the primary drug
They are used to counter early withdrawal symptoms

* Paradoxical effects at high doses

Up to 90% of attendees at drug misuse treatment centres,

reported use of benzodiazepines over a one-year period, 49% of
these had injected them (Strang et al, 1994).

In comparison to non-abusers they

Were more likely to be single
Have spent time in prison
Be unemployed
Have at least one parent with an addictive or mental disorder
Abuse more cocaine, heroin and cannabis
Have significantly more psychopathology and negative mood
Have significantly more HCV
Report more HIV/HCV risk-taking behaviour
Have an 8 fold likelihood of death

Correlates of benzodiazepine abuse in MMT. A 1 year

prospective study in an israeli clinic (Bleich et al, 1999).

After 1 year of MMT, more BZD abusers were:

Single
Had spent time in prison
Were unemployed
Have at least one parent with an addictive or mental disorder
Ha started using cocaine and heroin earlier
Currently abused more cocaine, heroin and cannabis
Have significantly more psychopathology and negative mood
Have significantly more HCV
Report more HIV/HCV risk-taking behaviour

Benzodiacepine and
methadone

Higher doses of methadone may occur with chronic

abuse of BZD and methadone treatment because
over time BZD inhibit hepatic enzymes that
metabolize methadone 1.

Benzodiacepines may speed up the tolerance to

subjetive as well as to some of the adverse effects
of opiates, such as constipation 2.

Mikolaenko et al. Am J Forensic Med Pathol 2002

2 Freye and Latasch, 2003

The study

The present results are part of a research project we

decided to conduct due to the relative lack of evidence
about the possible correlates of benzodiazepine abuse
with psychosocial, medical, drug abuse and comorbid
psychiatric disorders on treatment outcome in
methadone maintained patients.

Heroin dependent individuals enrolled in a methadone

maintenance programme and attending an outpatient
treatment center for the treatment of patients with
addictive disorders in Valencia, Spain, were included in
this follow-up study.

Aims (1)

Of the 86 heroin dependent patients included

enrolled in 41 (47.7%) were abusing BZD (BZDgroup) and were compared to the 45 patients
(52.3%) who were not taking BZD (non-BZDgroup) when entering treatment in our Unit.

Patients where compared on a series of

sociosociodemographic, substance-related,
comorbid disorders and 12-months cocaine use
outcomes.

Aims (2)
The following research questions were addressed:
1) What is the prevalence of benzodiazepine (BZD)

abuse among patients in a methadone maintainance

programme (MMP) attending an outpatient addictive
disorders unit.
2) Where there differences in sociodemographic,

substance use related, HIV and hepatitis infection at

entering treatment between BZD abusers and nonabusers?

Aims (3)
The following research questions were addressed
(cont.):
3) Do BZD abusers and non abusers differ in rates of

psychiatric comorbidity?
4) Did MM patients, BZD abusers and non-abusers,

have different 3, 6 and 12 month cocaine use and

clinical treatment outcome?

Benzodiazepine
abuse

Benzodiacepine abuse was defined as:

o

Using these drugs without prescription.

Using these drugs for other purposes than for those

originally prescribed.

Using these drugs for longer period then intended

Using these drugs at a dose higher then those

included in the prescribing guidelines.

The setting

The study was conducted at a specialized Addictive

Behaviors Unit (Unidad de Conductas Adictivas), an
outpatient unit for the treatment of patients with an
addictive disorder serving a specific catchment area
in the city of Valencia (Spain).

On arrival to the Unit, served by a multidisciplinary

team, patients are thoroughly assessed prior to
deciding the treatment option considered more
appropriate to their needs

The sample
BZD Group (n=41)

Non-BZD (n=46)

Gender (%male)

61.0

77.8

Race (% white)

95.1

88.9

Basic reading skills

17.1

11.1

Basic Education (EGB)

51.2

53.3

High School degree

29.3

28.9

Higher degree

2.4

6.7

Age (mean)

33.9 5.7

34.0 6.1

Age of first heroin use use (mean)

18.5 3.7

19.8 4.7

Educational level (%)

Benzodiacepine
41abusers
of the 86 patients (47.7%) were abusing BZD when
entering treatment.

All patients had been taking BZD for at least 12-months

prior to their initial assessment in our Unit.

Alprazolam was the BZD of choice either alone or with

other BZD in 38 (92.7%) cases.

The mean Diazepam equivalent dose was 73.5 (SD)

39.6 mg at baseline; 57.0 34.1 mg at 3-months; 53.7
34.7 mg at 6-months and 44.4 35.6 mg at 12 months of
follow-up.

Baseline characteristics
(1)
Patients not taking BZD were significantly more

Patients not taking BZD were significantly more

likely to have initiated treatment on their own
initiative (77.8% vs. 48.8%; p<0.05) rather than
family, legal or other external pressures.

Non BZD abusing patients were significantly more

likely to be enrolled in full-time employment than
BZD patients (62.2% vs 24.4%; p<0.01).

Individuals in the non-BZD group were significantly

more likely to be single (66.7% vs 39.0%; p<0.05).

Baseline characteristics
(2)

Patients not taking BZD group were significantly

more likely not to have a history of legal problems
(51.1% vs. 25.0%; p<0.02).

Significantly more subjects abusing BZD were HIV+

(56.1% vs 26.7%; p<0.01).

BZD-abusers had significantly higher rates of VHB

infection (86.7% vs 50.0%; p<0.005) and VHC
infection than non-BZD abusing patients (87.9% vs
63.4%; p<0.002).

Comorbid psychiatric
disorders

Patients in the BZD group were significantly to have a

comorbid personality disorder (70.7% vs. 20.0%;
p<0.001):

Borderline PD was the most common diagnosis: seen in 14

BZD abusers and 6 non-BZD abusers; followed by.

Antisocial PD: in 16 BZD abusers and 2 non-BZD abusers;

Schizoid PD: in 2 BZD abusers and 2 non-BZD abusers; and

Histrionic, Avoidant, Paranoid, Dependent and Histrionic PD

with 1 case each.

Methadone dose at entering treatment and 36- and 12-months of follow-up in BZD (n=41)
and non-BZD abusers (n=45)
120

110
Methadone dose

100

(baseline)
90

Methadone dose
(3 months)

80

Methadone dose
(6 months)

70
Methadone dose
60

(12 months)
BZD

Non-BZD

BZD abusers had significantly higher Methadone dose at

baseline (p=0.009), at 3-months (p=0.004), 6-months
(p=0.005), and 12-months (p=0.011) of follow-up.

Cocaine use outcome at 3-, 6- and 12months of follow-up

There were no significant differences between the two

groups in cocaine use outcomes at 3-, 6-, or 12 months
of follow-up.

34.1% of BZD abusers and 31.1% of non-abusers

remained cocaine abstinent at 3-months of follow-up,
while 36.6% and 42.2% of BZD abusers and non-abusers
stayed abstinent at 6-months of follow-up. At 12 months
of follow-up, 48.7% patients in the BZD-group and
62.2% in the non-BZD group were abstinent of cocaine.

CGI scores at 3-, 6- and 12months of follow-up

Severity of Illness subscale of CGI: patients in

the BZD group had significantly worse scores at
3-months (p=0.005), 6-months (p=0.017) and 12months (p=0.006) of follow-up than individuals
not taking BZD.

Global improvement subscale of CGI: in

contrast, there were no significant differences at
any of the follow-up assessments between both
groups.

Conclusions (1)

It was not surprising that Alprazolam was the BZD of

choice considering that this is the most commonly
prescribed benzodiacepine in Spain.

In addition, short-life BZD are associated with more

reinforcing effects and higher abuse potential.

Flunitracepam and alprazolam have been associated

with increased euphoria in methadone-maintained
subjects in experimental setting.

Conclusions (2)

Among patients included in this follow-up study, BZD

abuse appeared to be associated with overall worse
substance related and sociodemographic characteristics
and higher comorbid disorders.

These factors have been often associated with worse

treatment outcome in patients with a variety of substance
use disordr diagnoses.

Among patients included in this follow-up study, BZD

abuse was associated with an overall worse clinical
outcome, despite the lack of differences in cocaine use.

Conclusions (3)

Caution must be used when prescribing BZD to

patients with a current SUD, particularly those in
MMT.

Furthermore, MM patients ought to be screened for

BZD as part of the routine assessment.

Patients abusing BZD may represent a subgroup of

methadone-maintained patients in need of more
pharmacological and psychological treatment needs.

Thank you for

your attention