Twelve-months follow-up of methadone maintained

patients with and without

associated benzodiacepine abuseDr. José Martínez RagaDr. José Martínez Raga

Unidad de Conductas Adictivas del Área 11 de

Valencia (C.S. Corea, Gandía)

• Carlos Knecht, MD

• Ana Sabater, PhD

• Sara Martinez-Espinosa, MSc

• Belen Plaza, MSc

Co-AuthorsCo-Authors

AckowledgemAckowledgementsents

• Néstor Ramirez, MSc

• Rosa de la Poza

• Isabel Ruiz

• CSISP

● Benzodiazepines are widely used in a variety of Benzodiazepines are widely used in a variety of conditions, particularly anxiety disorders, sleep conditions, particularly anxiety disorders, sleep disorders, epilepsy, as muscle relaxants, as well as for disorders, epilepsy, as muscle relaxants, as well as for alcohol withdrawal.alcohol withdrawal.

● In anxiety and insomnia, its two major psychiatric In anxiety and insomnia, its two major psychiatric indications, benzodiazepines are only indicated for indications, benzodiazepines are only indicated for short-term-use, due to rapid development of tolerance to short-term-use, due to rapid development of tolerance to the hypnotic and anxiolytic effects of these medications. the hypnotic and anxiolytic effects of these medications.

● Substance abusers are at particularly high risk to Substance abusers are at particularly high risk to develop tolerance and dependence to these medications.develop tolerance and dependence to these medications.

Introduction (1)Introduction (1)

● Polysubstance-dependent individuals frequently self-Polysubstance-dependent individuals frequently self-medicate with benzodiazepines medicate with benzodiazepines 11..

● Benzodiazepines are often abused to counteract the Benzodiazepines are often abused to counteract the unpleasant effects of other drugs of abuse.unpleasant effects of other drugs of abuse.

● Combined with alcohol and heroin may be used to Combined with alcohol and heroin may be used to potentiate its depressant or even for its paradoxical potentiate its depressant or even for its paradoxical effects, as described in several reports.effects, as described in several reports.

Introduction (2)Introduction (2)

1 Malcolm RJ. J CLin Psychiatry 2003

Drug misusers tend to take high doses* of Drug misusers tend to take high doses* of benzodiazepines and become extremely tolerant to the benzodiazepines and become extremely tolerant to the sedative effects.sedative effects.

They are taken because They are taken because

• They carry their own effects of intoxication which is They carry their own effects of intoxication which is valuedvalued

• They enhance the primary drugThey enhance the primary drug

• They are used to counter early withdrawal symptomsThey are used to counter early withdrawal symptoms

* Paradoxical effects at high doses* Paradoxical effects at high doses

Polydrug abusersPolydrug abusers

In comparison to non-abusers they In comparison to non-abusers they

• Were more likely to be singleWere more likely to be single

• Have spent time in prisonHave spent time in prison

• Be unemployedBe unemployed

• Have at least one parent with an addictive or mental disorderHave at least one parent with an addictive or mental disorder

• Abuse more cocaine, heroin and cannabisAbuse more cocaine, heroin and cannabis

• Have significantly more psychopathology and negative moodHave significantly more psychopathology and negative mood

• Have significantly more HCV Have significantly more HCV

• Report more HIV/HCV risk-taking behaviourReport more HIV/HCV risk-taking behaviour

• Have an 8 fold likelihood of deathHave an 8 fold likelihood of death

Up to 90% of attendees at drug misuse treatment centres, Up to 90% of attendees at drug misuse treatment centres, reported use of benzodiazepines over a one-year period, 49% reported use of benzodiazepines over a one-year period, 49% of these had injected them of these had injected them (Strang et al, 1994)(Strang et al, 1994)..

After 1 year of MMT, more BZD abusers were: After 1 year of MMT, more BZD abusers were:

• SingleSingle

• Had spent time in prisonHad spent time in prison

• Were unemployedWere unemployed

• Have at least one parent with an addictive or mental disorderHave at least one parent with an addictive or mental disorder

• Ha started using cocaine and heroin earlierHa started using cocaine and heroin earlier

• Currently abused more cocaine, heroin and cannabisCurrently abused more cocaine, heroin and cannabis

• Have significantly more psychopathology and negative moodHave significantly more psychopathology and negative mood

• Have significantly more HCV Have significantly more HCV

• Report more HIV/HCV risk-taking behaviourReport more HIV/HCV risk-taking behaviour

Correlates of benzodiazepine abuse in MMT. A 1 year Correlates of benzodiazepine abuse in MMT. A 1 year prospective study in an israeli clinic prospective study in an israeli clinic (Bleich et al, 1999)(Bleich et al, 1999)..

● Higher doses of methadone may occur with chronic Higher doses of methadone may occur with chronic abuse of BZD and methadone treatment because abuse of BZD and methadone treatment because over time BZD inhibit hepatic enzymes that over time BZD inhibit hepatic enzymes that metabolize methadone metabolize methadone 11..

● Benzodiacepines may speed up the tolerance to Benzodiacepines may speed up the tolerance to subjetive as well as to some of the adverse effects subjetive as well as to some of the adverse effects of opiates, such as constipation of opiates, such as constipation 22..

Benzodiacepine and Benzodiacepine and methadonemethadone

1 Mikolaenko et al. Am J Forensic Med Pathol 2002 2 Freye and Latasch, 2003

● The present results are part of a research project we The present results are part of a research project we decided to conduct due to the relative lack of evidence decided to conduct due to the relative lack of evidence about the possible correlates of benzodiazepine abuse about the possible correlates of benzodiazepine abuse with psychosocial, medical, drug abuse and comorbid with psychosocial, medical, drug abuse and comorbid psychiatric disorders on treatment outcome in psychiatric disorders on treatment outcome in methadone maintained patients.methadone maintained patients.

● Heroin dependent individuals enrolled iHeroin dependent individuals enrolled in a methadone n a methadone maintenance programme and attending an outpatient maintenance programme and attending an outpatient treatment center for the treatment of patients with treatment center for the treatment of patients with addictive disorders in Valencia, Spain, were included addictive disorders in Valencia, Spain, were included in this follow-up study.in this follow-up study.

The studyThe study

Aims (1)Aims (1)

● Of the 86 heroin dependent patients included Of the 86 heroin dependent patients included enrolled in 41 (47.7%) were abusing BZD (BZD-enrolled in 41 (47.7%) were abusing BZD (BZD-group) and were compared to the 45 patients group) and were compared to the 45 patients (52.3%) who were not taking BZD (non-BZD-(52.3%) who were not taking BZD (non-BZD-group) when entering treatment in our Unit.group) when entering treatment in our Unit.

● Patients where compared on a series of Patients where compared on a series of sociosociosociodemographic, substance-related, sociodemographic, substance-related, comorbid disorders and 12-months cocaine use comorbid disorders and 12-months cocaine use outcomes.outcomes.

The following research questions were addressed:The following research questions were addressed:

1)1) What is theWhat is the prevalence of benzodiazepine (BZD) prevalence of benzodiazepine (BZD) abuse among patients in a methadone maintainance abuse among patients in a methadone maintainance programme (MMP) attending an outpatient addictive programme (MMP) attending an outpatient addictive disorders unit. disorders unit.

2)2) Where there differences in sociodemographic, Where there differences in sociodemographic, substance use related, HIV and hepatitis infection at substance use related, HIV and hepatitis infection at entering treatment between BZD abusers and non-entering treatment between BZD abusers and non-abusers?abusers?

Aims (2)Aims (2)

The following research questions were addressed The following research questions were addressed (cont.)(cont.)::

3)3) Do BZD abusers and non abusers differ in rates of Do BZD abusers and non abusers differ in rates of psychiatric comorbidity?psychiatric comorbidity?

4)4) Did MM patients, BZD abusers and non-abusers, Did MM patients, BZD abusers and non-abusers, have different 3, 6 and 12 month cocaine use and have different 3, 6 and 12 month cocaine use and clinical treatment outcome?clinical treatment outcome?

Aims (3)Aims (3)

● Benzodiacepine abuse was defined as:Benzodiacepine abuse was defined as:

o Using these drugs without prescription.Using these drugs without prescription.

o Using these drugs for other purposes than for those Using these drugs for other purposes than for those originally prescribed.originally prescribed.

o Using these drugs for longer period then intendedUsing these drugs for longer period then intended

o Using these drugs at a dose higher then those Using these drugs at a dose higher then those included in the prescribing guidelines.included in the prescribing guidelines.

Benzodiazepine Benzodiazepine abuseabuse

● The study was conducted at a specialized Addictive The study was conducted at a specialized Addictive Behaviors Unit (Unidad de Conductas Adictivas), an Behaviors Unit (Unidad de Conductas Adictivas), an outpatient unit for the treatment of patients with an outpatient unit for the treatment of patients with an addictive disorder serving a specific catchment area addictive disorder serving a specific catchment area in the city of Valencia (Spain). in the city of Valencia (Spain).

● On arrival to the Unit, served by a multidisciplinary On arrival to the Unit, served by a multidisciplinary team, patients are thoroughly assessed prior to team, patients are thoroughly assessed prior to deciding the treatment option considered more deciding the treatment option considered more appropriate to their needsappropriate to their needs

The settingThe setting

The sample The sample

BZD Group (n=41) Non-BZD (n=46)

Gender (%male) 61.0 77.8

Race (% white) 95.1 88.9

Educational level (%)

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

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

● All patients had been taking BZD for at least 12-months All patients had been taking BZD for at least 12-months prior to their initial assessment in our Unit.prior to their initial assessment in our Unit.

● Alprazolam was the BZD of choice either alone or with Alprazolam was the BZD of choice either alone or with other BZD in 38 (92.7%) cases.other BZD in 38 (92.7%) cases.

● The mean Diazepam equivalent dose was 73.5 The mean Diazepam equivalent dose was 73.5 ± (SD) ± (SD) 39.6 mg at baseline; 5739.6 mg at baseline; 57.0 .0 ± 34.1 mg at 3-months; 53.7± 34.1 mg at 3-months; 53.7 ± ± 34.7 mg at 6-months and 44.434.7 mg at 6-months and 44.4 ± 35.6 mg at 12 months ± 35.6 mg at 12 months of follow-up.of follow-up.

Benzodiacepine Benzodiacepine abusersabusers

● Patients not taking BZD were significantly more Patients not taking BZD were significantly more likely to have initiated treatment on their own likely to have initiated treatment on their own initiative (77.8% vs. 48.8%; p<0.05) rather than initiative (77.8% vs. 48.8%; p<0.05) rather than family, legal or other external pressures. family, legal or other external pressures.

● Non BZD abusing patients were significantly more Non BZD abusing patients were significantly more likely to be enrolled in full-time employment than likely to be enrolled in full-time employment than BZD patients (62.2% vs 24.4%; p<0.01).BZD patients (62.2% vs 24.4%; p<0.01).

● Individuals in the non-BZD group were significantly Individuals in the non-BZD group were significantly more likely to be single (66.7% vs 39.0%; p<0.05)more likely to be single (66.7% vs 39.0%; p<0.05)..

Baseline characteristics Baseline characteristics (1)(1)

● Patients not taking BZD group were significantly Patients not taking BZD group were significantly more likely not to have a history of more likely not to have a history of legal problemslegal problems (51.1% vs. 25.0%; p<0.02). (51.1% vs. 25.0%; p<0.02).

● Significantly more subjects abusing BZD were Significantly more subjects abusing BZD were HIV+HIV+ (56.1% vs 26.7%; p<0.01).(56.1% vs 26.7%; p<0.01).

● BZD-abusers had significantly higher rates of BZD-abusers had significantly higher rates of VHBVHB infection (86.7% vs 50.0%; p<0.005) and infection (86.7% vs 50.0%; p<0.005) and VHCVHC infection than non-BZD abusing patients (87.9% vs infection than non-BZD abusing patients (87.9% vs 63.4%; p<0.002)63.4%; p<0.002)..

Baseline characteristics Baseline characteristics (2)(2)

● Patients in the BZD group were significantly to have a Patients in the BZD group were significantly to have a comorbid personality disorder (70.7% vs. 20.0%; comorbid personality disorder (70.7% vs. 20.0%; p<0.001):p<0.001):

● Borderline PDBorderline PD was the most common diagnosis: seen in 14 was the most common diagnosis: seen in 14 BZD abusers and 6 non-BZD abusers; followed by.BZD abusers and 6 non-BZD abusers; followed by.

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

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

● Histrionic, Avoidant, Paranoid, DependentHistrionic, Avoidant, Paranoid, Dependent and and Histrionic Histrionic PD PD with 1 case each.with 1 case each.

Comorbid psychiatric Comorbid psychiatric disordersdisorders

Methadone dose at entering treatment and Methadone dose at entering treatment and 3- 6- and 12-months of follow-up in BZD 3- 6- and 12-months of follow-up in BZD (n=41) and non-BZD abusers (n=45) (n=41) and non-BZD abusers (n=45)

Non-BZDBZD

120

110

100

90

80

70

60

Methadone dose

(baseline)

Methadone dose

(3 months)

Methadone dose

(6 months)

Methadone dose

(12 months)

● BZD abusers had significantly higher Methadone dose at BZD abusers had significantly higher Methadone dose at baseline (p=0.009), at 3-months (p=0.004), 6-months baseline (p=0.009), at 3-months (p=0.004), 6-months (p=0.005), and 12-months (p=0.011) of follow-up(p=0.005), and 12-months (p=0.011) of follow-up..

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

● There were no significant differences between the two There were no significant differences between the two groups in cocaine use outcomes at 3-, 6-, or 12 months groups in cocaine use outcomes at 3-, 6-, or 12 months of follow-upof follow-up..

● 34.1% of BZD abusers and 31.1% of non-abusers 34.1% of BZD abusers and 31.1% of non-abusers remained cocaine abstinent at 3-months of follow-up, remained cocaine abstinent at 3-months of follow-up, while 36.6% and 42.2% of BZD abusers and non-while 36.6% and 42.2% of BZD abusers and non-abusers stayed abstinent at 6-months of follow-up. At 12 abusers stayed abstinent at 6-months of follow-up. At 12 months of follow-up, 48.7% patients in the BZD-group months of follow-up, 48.7% patients in the BZD-group and 62.2% in the non-BZD group were abstinent of and 62.2% in the non-BZD group were abstinent of cocaine.cocaine.

● Severity of Illness subscale of CGI:Severity of Illness subscale of CGI: ppatients in atients in the BZD group had significantly worse scores at the BZD group had significantly worse scores at 3-months (p=0.005), 6-months (p=0.017) and 12-3-months (p=0.005), 6-months (p=0.017) and 12-months (p=0.006) of follow-up than individuals months (p=0.006) of follow-up than individuals not taking BZD. not taking BZD.

● Global improvement subscale of CGI:Global improvement subscale of CGI: in in contrast, there were no significant differences at contrast, there were no significant differences at any of the follow-up assessments between both any of the follow-up assessments between both groups.groups.

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

● It was not surprising that Alprazolam was the BZD of It was not surprising that Alprazolam was the BZD of choice considering that this is the most commonly choice considering that this is the most commonly prescribed benzodiacepine in Spain.prescribed benzodiacepine in Spain.

● In addition, short-life BZD are associated with more In addition, short-life BZD are associated with more reinforcing effects and higher abuse potential.reinforcing effects and higher abuse potential.

● Flunitracepam and alprazolam have been associated Flunitracepam and alprazolam have been associated with increased “euphoria” in methadone-maintained with increased “euphoria” in methadone-maintained subjects in experimental setting.subjects in experimental setting.

Conclusions (1)Conclusions (1)

● Among patients included in this follow-up study, BZD Among patients included in this follow-up study, BZD abuse appeared to be associated with overall worse abuse appeared to be associated with overall worse substance related and sociodemographic characteristics substance related and sociodemographic characteristics and higher comorbid disorders.and higher comorbid disorders.

● These factors have been often associated with worse These factors have been often associated with worse treatment outcome in patients with a variety of treatment outcome in patients with a variety of substance use disordr diagnoses.substance use disordr diagnoses.

● Among patients included in this follow-up study, BZD Among patients included in this follow-up study, BZD abuse was associated with an overall worse clinical abuse was associated with an overall worse clinical outcome, despite the lack of differences in cocaine use. outcome, despite the lack of differences in cocaine use.

Conclusions (2)Conclusions (2)

● Caution must be used when prescribing BZD to Caution must be used when prescribing BZD to patients with a current SUD, particularly those in patients with a current SUD, particularly those in MMT.MMT.

● Furthermore, MM patients ought to be screened for Furthermore, MM patients ought to be screened for BZD as part of the routine assessment.BZD as part of the routine assessment.

● Patients abusing BZD may represent a subgroup of Patients abusing BZD may represent a subgroup of methadone-maintained patients in need of more methadone-maintained patients in need of more pharmacological and psychological treatment needspharmacological and psychological treatment needs..

Conclusions (3)Conclusions (3)

Thank you forThank you foryour attentionyour attention