Is it possible to treat heroin addicts with severe ...

Regular article Heroin Addict Relat Clin Probl 2014; 16(4): 15-24

Is it possible to treat heroin addicts with severe comorbid benzodiazepines addiction combining enhanced methadone maintenance and clonazepam maintenance treatments? Angelo Giovanni Icro Maremmani 1,2, Silvia Bacciardi 1, Fabio Rugani 1, Luca Rovai 1, Enrico Massimetti 1, Denise Gazzarrini 1, Liliana Dell’Osso 5, Pier Paolo Pani 4, Matteo Pacini 1,3, and Icro Maremmani 1,2,3 1 Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Italy, EU 2 AU-CNS, Association for the Application of Neuroscientific Knowledge to Social Aims, Pietrasanta, Lucca, Italy, EU 3 G. De Lisio Institute of Behavioural Sciences Pisa, Italy, EU 4 Social and Health Services, Health District 8 (ASL 8) Cagliari, Italy, EU 5 Department of Experimental and Clinical Medicine, University of Pisa, Italy, EU

Summary Objective. The aim of this naturalistic (observational) controlled cohort study was to compare the long-term outcomes of treatment-resistant heroin addicts with (HA+BZD) and without (HA-BZD) comorbid benzodiazepine (BZD) severe addiction. Methods. 63 HA-BZD and 14 HA+BZD patients were monitored prospectively along an enhanced methadone maintenance treatment programme (MMTP). HA+BZD patients were treated, also, with clonazepam maintenance treatment (CMT). Results. Survival-in-treatment rates were no different in HA+BZD and HA-BZD patients. HA+BZD patients showed better outcome results than HA-BZD patients. HA+BZD patients needed a higher methadone dosage in the stabilization phase. Conclusions. This study supports the possibility to use methadone maintenance and clonazepam maintenance combination in heroin-addicted patients with comorbid severe BZD dependence. Key Words: Methadone Maintenance; Long-term Outcome; High-threshold Methadone Maintenance Programme; Benzodiazepines; Clonazepam maintenance treatment

1.

Introduction

Benzodiazepine (BZD) use by methadone maintenance treatment (MMT) patients is associated with a more complex clinical picture and may negatively influence treatment outcomes (poorer psychosocial adjustment, higher levels of polydrug use, more risktaking behaviours, less retention in treatment and drug dependent death) [7, 9, 12, 16, 35, 39, 42]. Intermittent benzodiazepine abuse was found to be significantly associated with lower rates of opiate abstinence during methadone maintenance treatment [20]. Benzodiazepine-using methadone maintenance patients are a dysfunctional subgroup of the methadone population, who may require more clinical intervention than other clients [11].

Some authors emphasize the high priority that should be given to stopping benzodiazepine use during [37] or before entering MMT. Others claim that cautious prescribing of benzodiazepines may be beneficial due to the reduction of overall illicit use [12]. The relative safety of BZD use by methadoneor buprenorphine-treated patients has not been systematically examined. BZDs may significantly alter the response to opioid substitution treatment with methadone or buprenorphine. However, BZD had greater peak effects on performance measures (simple reaction time, digit symbol substitution task, and cancellation time) in methadone-treated than in buprenorphine-treated patients [24]. While methadone maintenance treatment (MMT) has been demonstrated to be an effec-

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

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Heroin Addiction and Related Clinical Problems 16(4): 15-24

tive treatment for opiate dependence, its impact on the treatment outcome of other illicit drug abuse is not as clear. Therapeutic approaches for benzodiazepine (BZD) dependence in patients in methadone maintenance treatment (MMT) have met with limited success. Clonazepam detoxification (CDTX) and clonazepam maintenance treatment (CMT) were considered. Maintenance strategy with clonazepam is a useful BZD treatment modality for BZD-dependent MMT patients with a long-term history of abuse and previous attempts at detoxification [46]. The aim of this study was to compare the longterm outcomes of HA-BZD patients and HA+BZD patients co-treated with CMT. We decided to evaluate whether comorbid BZD dependence and concomitant CMT treatment were able to influence methadone treatment outcomes in patients who had previously failed in first-line, low threshold treatment facilities, when those patients were included in a high-threshold, maintenance-oriented, high-dose methadone programme. The hypothesis of the study was that comorbid BZD severe dependence and adjunctive CMT treatment would not affect treatment outcomes if patients with comorbid BZD severe dependence received higher, individualized doses of methadone and that a favourable outcome would be related to long-term on-going treatment (retention). To test this hypothesis, a group of treatmentresistant heroin addicts, with and without comorbid BZD dependence, were followed in a naturalistic approach for a minimum of 0.7 and a maximum of 7.9 years in the context of the maintenance high-threshold, high-dose Pisa methadone programme, using retention in treatment and rates of heroin use as the main end-point parameters. 2.

Methods

2.1. Design of the study A prospective controlled cohort study was designed in order to evaluate treatment outcome (in terms of retention in treatment, substance use, clinical improvement and general social adjustment) of patients included in a methadone programme, in terms of its relationship to the presence of benzodiazepine (BZD) severe dependence. Treatment-resistant, heroin-dependent patients were divided into two groups – those with (experimental group) and those without (control group) comorbid BZD severe dependence. The experimental group was treated also with clon- 16 -

azepam maintenance treatment (CMT). We excluded patients with an Axis I psychiatric comorbidity (according to the results of SCID interview, to minimize the influence of dual diagnosis on this issue). All 77 consecutive patients were admitted to the programme over an 8-year time period (from January 1995 to May 2003) and followed for up to 8 years. The length of the prospective observation was 2.9 years on average (min. 0.7, max. 7.9); follow-up evaluation was carried out monthly, from the beginning of treatment. All patients gave their written informed consent to the study after the procedure had been fully explained. The pertinent ethics committees, in accordance with internationally accepted criteria for ethical research, approved both the consent form and the experimental procedures. 2.2. Setting The settings of Italian low-threshold facilities for drug addicts and of the Pisa Enhanced Methadone Maintenance Treatment Programme (Pisa-MMTP) were previously discussed [27, 33]. Here we reminder only the concept of “stabilized” patients, as the stabilization of a patient is our main therapeutic goal. After patients at the PisaMMTP have been safely inducted into treatment with methadone, their doses are gradually increased until the point is reached where there is no more than one urine drug screen which is positive for illicit opiates, cocaine, or benzodiazepines in the previous sixty-day period. Once this requirement is fulfilled, the patient is defined as having being “stabilized”, and the dose at which this goal has been accomplished is referred to as the “stabilization dose”. No upper limit for dosage exists. Nevertheless, one time limitation is present in this setting: patients who cannot achieve stabilization within one year end the program, to be transferred to local treatment units. The dosage is increased to reflect the results of urinalyses, and evidence of improvement on social grounds is not enough by itself to justify dose stability as long as the urinalyses stay positive for opiates. Patients are not allowed to raise or lower the dose by themselves. In our clinical practice, BZD dependence was treated, systematically, according to the follow procedure that is very similar to an agonist substitution approach. We started switching the patient from the abused BZD to a slow-onset, long-acting, high potency BZD agonist (clonazepam). As the dosage of the abused benzodiazepine was progressively lowered

AGI Maremmani et al.: Is it possible to treat heroin addicts with severe comorbid benzodiazepines addiction combining enhanced methadone maintenance and clonazepam maintenance treatments?

the clonazepam dosage was progressively raised until the substitution was complete. In this way the patient stopped his primary abuse of BZD without any switch from intoxication to withdrawal states. Then, patients passed through four successive phases: induction, stabilization, maintenance, and, when possible, medication withdrawal. This methodology was recently described by Liebrenz et al. in BZD dependent patients [23]. For more information on this procedure see Maremmani et al. [29] 2.3. Subjects All heroin-dependent patients with comorbid BZD severe dependence or without it, referred to the Pisa-MMT programme during the January 1995-May 2003 period (N=77) were consecutively enrolled in the study, if DSM-IV Axis I psychiatric comorbidity was not present. To be referred to the PISA-MMT programme, patients should have: A diagnosis of heroin dependence according to DSM-IV criteria. Resistance to previous first-line, low-threshold methadone treatment programmes attended at local Addiction Treatment Units: Criteria for treatment resistance included: at least two unsuccessful treatments in the 2-year period before being referred to our programme. Patients had been treated with the standard protocols for heroin dependence (methadone maintenance with dosages up to 100 mg/day), and were discharged because of persisting positivity for opioid metabolites at urinalyses. We selected HA+BZD and HA-BZD patients. HA+BZD patients fulfilled DSM-IV criteria for severe dependence on sedatives, hypnotics or anxiolytics (F13.24). We excluded patients with axis 1 psychiatric comorbidity; Axis II diagnoses were excluded from the study, since a wide range of personality disorders are usually displayed by substances abusers, which makes very difficult to define xis II diagnostic subgroups. 14 patients showed comorbid BZD severe dependence. 10 (71.4%) were males, age ranged between 26 and 38 years. 63 were without comorbid BZD severe dependence. 48 (76.2) were males, age ranged between 20 and 46 years.

2.4. Instruments The following instruments were used to collect data on the variables to be studied: 2.4.1. Drug Addiction History Rating Scale (DAH-RS) (administered at the beginning of treatment) [31].

The DAH-RS is a multi-scale questionnaire comprising the following categories: demographic information, physical health, mental health, substance abuse, treatment history, social adjustment and environmental factors. The questionnaire rates 10 items: physical problems, mental problems, substance abuse, previous treatment, associated treatments, employment status, family situation, sexual problems, socialization and leisure time, legal problems. Items have been constructed in such a way as to ensure dichotomous (yes/no) answers. For more details, see [25, 26, 28, 30, 32]. 2.4.2. Global Assessment of Functioning, DSM-IV-GAF (administered monthly).

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

The CGI considers the severity of the disorder, the degree of the improvement or worsening following the intervention and any adverse reactions [19]. CGI and GAF were administered by the same senior researcher (IM). 2.4.4. Psychiatric Diagnostic Evaluation. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Clinician Version.

This instrument [14] will help clinicians make standardized, reliable and accurate diagnoses, while avoiding the common problem of ‘premature closure' (a premature focusing on one diagnostic possibility). Specifically adapted from the research standard for Axis I structured clinical interviewing for use in clinical settings, the SCID-I covers the DSM-IV diagnoses most commonly seen by clinicians and includes the diagnostic criteria for these disorders with - 17 -


corresponding interview questions. The SCID-I is divided into six self-contained modules that can be administered in sequence: mood episodes; psychotic symptoms; psychotic disorders; mood disorders; substance use disorders; and anxiety, adjustment, and other disorders. Patients were evaluated outside acute phases, for which hospitalization was required, so as to reduce the diagnostic ambiguity between intoxication-related symptoms and spontaneous mental disorders. In case further information emerged on clinical grounds from later interviewing, diagnoses were reviewed. 2.4.5. Toxicological urine analyses (carried out randomly every week during the induction phase and almost every month during the stabilization phase).

The enzyme-multiplied immune technique for opiates was used. 2.5. Procedure Patients were assessed monthly by use of CGI and GAF. Patients who stayed in treatment were assessed at the end of treatment. Among patients with negative outcomes, those who gave up were assessed at the time of treatment interruption, this being the last regular assessment, and not the previous month’s. 2.6. Data analysis Heroin addicted patients with and without co-

morbid BZD severe dependence were compared for demographic and addiction history by means of the chi-square test for categorical variables, and Student's t test for continuous variables. Retention in treatment was analysed by means of the survival analysis and Wilcoxon statistics for comparison between the survival curves. For the purpose of this analysis, the term ”terminal event” refers to patients who left the treatment as a “not stabilized patient” (see the section appearing above entitled “Setting” for details). The toxicological urinalyses were expressed using two indices: PC-CU and TT-CU. PC-CU represents the percentage ratio between urinalyses proving negative for the presence of morphine and the total number of urinalyses carried out for each patient during the treatment period. TS-CU is the percentage ratio between the number of urinalyses testing negative for the presence of morphine and the number of urine analyses that the protocol has envisaged throughout the process. In this case the protocol provided 386 urinalyses (the theoretical maximum number of urine samples per patient, considering a 8 year period). PCCU tends to give a preference to patients who remain “opiate free”, but who terminate the study in advance, for reasons not correlated with the study. TT-CU too considers how long the patient remains in the protocol, but gives less precedence to these patients. These two indices represent the two extremes, and the results tend to balance out. With regard to these parameters, the comparison between the two groups was

Table 1. Significant differences in clinical and addiction history aspects of heroin addicts with and without comorbid benzodiazepine dependence at treatment entry. Heroin Addicts Without BZD With BZD Dependence Dependence N=63 N=14 Chi/T p N° Mental Status Altered Areas (M±sd) -5.97 0.000 3.26±2.0 6.28±1.6 Consciousness (N(%)) 0 (0.0) 2 (14.3) 9.24 0.031 Depression (N(%)) 37 (58.7) 13 (92.9) 5.85 0.015 Sleep (N(%)) 29 (46.0) 11 (78.6) 4.85 0.028 Excitement (N(%)) 21 (33.3) 11 (78.6) 9.65 0.002 Violence (N(%)) 19 (30.2) 11 (78.6) 11.28 0.001 Suicidality (N(%)) 5 (7.9) 5 (35.7) 7.82 0.005 Delusions (N(%)) 3 (4.8) 4 (28.6) 7.85 0.005 Hallucinations (N(%)) 0 (0.0) 3 (21.4) 14.04 0.000 Concomitant use of cannabinoids 61 (96.8) 11 (78.6) 6.28 0.012 Social and leisure, unsatisfactory (N(%)) 34 (54.0) 12 (85.7) 4.80 0.036 Elapsed time from 1st use to 1st treatment 9.90±6.7 5.07±3.7 2.59 0.012 (years) (M±sd) 5.54±0.6 5.07±0.7 2.33 0.041 CGI-Severity of illness (M±s)

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made using Student’s t-test. Regarding clinical global impressions and social adjustment outcomes, univariate and multivariate statistical procedures have been used for cross-sectional evaluation and repeated measures analysis of variance for longitudinal evaluations. The statistical tests were considered significant at the level of P < 0.05.

age of heroin first contact, age of heroin continuous use, dependence length (months), age of 1st treatment, elapsed time from 1st contact to continuous use. Using Cox regression life table statistics, stepwise forward (Wald) method, (chi-square=5.17 df 1 p=0.023) better retention rate was found for patients with satisfactory social leisure time (p=0.027).

3.

3.2. Outcomes

Results

3.1. Baseline evaluation (at the beginning of the treatment) On the basis of DAH-RS-collected information, no differences were observed, at the beginning of treatment, between heroin addicts with and without comorbid BZD severe dependence regarding gender (males, females), civil status (single, no-single), education (less than 8 years, more than 8 years), occupation (student, white collar, blue collar, unemployed), welfare benefit (yes, no), income (poor, adequate), living (alone, in family). Table 1 reports significant clinical and addiction history differences between heroin addicts with and without comorbid BZD severe dependence of the sample. Heroin addicts with comorbid BZD severe dependence seemed to indicate a greater number of altered mental status areas. They showed greater frequency of consciousness alterations, depressive states, sleep disturbances, excitement states, violence episodes also with suicidality, delusions and hallucination. No differences were found on insight, memory disturbances, anxious states and eating disorders. Heroin addicts with comorbid BZD severe dependence seemed to have with greater frequency unsatisfactory social and leisure time. Their elapsed time from 1st heroin use to the 1st treatment was longer, but severity of illness (heroin addiction) at treatment entry was less severe. Concomitant use of cannabinoids was less frequent. Patients belonging to the two groups did not differ significantly on somatic complications, work, family problems, romantic concerns, legal problems, poly-abuse (more than 3 substances), past unsuccessful treatments, general social adjustment (according to DSM-IV GAF values), frequency of heroin intake (unfrequent, daily or more), modality of use (stable, unstable), periodic self-detoxification, stage of heroin dependence (stage 1 and 2, stage 3), antecedents (without stressors, with bio-psychosocial stressors),

12 (19.0%) HA-BZD and 4 (28.6%) HA+BZD patients completed their rehabilitation programme and left the treatment, or were referred to another programme as a “stabilized patient”. Thirty-two (50.8%) HA-BZD and 6 (42.9%) HA+BZD patients had failed to achieve stabilization within a year, or relapsed into heroin use during the programme, so they were terminated and referred to their local treatment services. None of the patients were dismissed for violence; none gave up the treatment for side effects; none were imprisoned nor hospitalized. Nineteen (30.2%) HABZD and 4 (28.6%) HA+BZD patients were “stabilized” and were still in treatment at the end of the period of observation. These differences were not statistically significant (chi square 0.65, df=2, p=0.720). The CGI severity of illness and the DSM-IV GAF (global assessment of functioning) showed different significant trends in our patients. HA+BZD patients reported, at the end-point evaluation, lower severity of illness (1.96±0.9) than HA-BZD patients (3.07±0.8). Time effect (F=1816.51; df=1; p=0.000), time-group effect (F=19.23; df=1; p=0.000) and time-outcome effect (F=40.42; df=1; p=0.000) were significant. Timegroup differences were not related to the outcome (F=0.52; df=1; p=0.472). At the end-point evaluation HA+BZD reported a better social adjustment (76.93±6.8) than patients HA-BZD (70.35±9.3). Time effect (F=310.43; df=1; p=0.000), time-group effect (F=5.25; df=1; p=0.025) and time-outcome effect (F=5.88; df=1; p=0.018) were significant. Time-group differences were not related to the outcome (F=0.09; df=1; p=0.756). 3.3. Retention in treatment The cumulative proportion of HA-BZD patients surviving at the end of the observational period was 0.44. The proportion for HA+BZD patients was 0.58. The higher, but not statistical significant (p=0.082) survival rate for patients with comorbid BZD severe - 19 -


Table 2. Survival in methadone maintenance treatment of 77 treatment-resistant heroin dependent patients with and without BZD dependence. Cumulative Number Interval Number Number of Proportion Withdrawing start time Entering Terminal Surviving at During (Years) Interval Events End of Interval Interval BZD dependence BZD dependence BZD dependence BZD dependence No Yes No Yes No Yes No Yes 0 63 14 4 0 24 1 0.61 0.93 1 35 13 3 0 4 4 0.53 0.64 2 28 9 5 1 1 0 0.51 0.64 3 22 8 2 0 3 1 0.44 0.58 4 17 7 2 1 0 0 0.44 0.56 5 15 6 2 0 0 0 0.44 0.56 6 13 6 3 0 0 0 0.44 0.56 7 10 6 10 6 0 0 0.44 0.56 Overall Comparison, Wilcoxon statistics = 3.01 df=1 p=0.082

dependence was due to the greater number of subjects who stayed in treatment rather than to a difference in the number of patients who left the programme with a positive outcome (detoxified after a period of methadone maintenance or referred, once stabilized, to other programmes), as the latter parameter was not modified by the presence or absence of comorbid BZD severe dependence (Table 2). 3.4. Medications On average, HA+BZD patients needed a higher methadone dosage in the stabilization phase (190.73±103.4 mg/day) compared with HA-BZD patients (105.73±40.7 mg/day). This difference was statistically significant (F=9.52; p=.000). No differences were observed according to the outcome (F=0.12; p=0.724) and according to the group-outcome effect (F=2.41; p=0.124). The dose of clonazepam ranged between 6 and 12 mg/day at the start of the treatment. During stabilization phase the dose was not exceeding 6 mg/day. 3.5. Urinalyses On average, 76.05% of samples tested negative for morphine. In patients who left the programme with a positive outcome the PC-CU index was 91.00±4.3; in patients with a negative outcome, it was 62.13±9.2; in patients still in treatment, it was 88.65±4.6. These differences were statistically significant (F=73.67; df=2; p=0.000) when comparing positive and negative outcome, but not between patients who left the

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programme with positive outcome and patients still in treatment (p=0.342). No differences were observed between patients without and with comorbid BZD severe dependence (F=0.44; p=0.509). The group-outcome interaction was not significant, either (F=0.18; p=0.813). The TT-CU index revealed differences (F=53.31; df=2; p=0.000) between different outcomes: positive (0.36±0.2), negative (0.07±0.0), still in treatment (0.67±0.2). Differences were observed also between patients with (0.47±0.3) and without (0.28±0.3) comorbid BZD severe dependence (F=13.81; df=1; p=0.000). The group-outcome interaction was not significant (F=2.44; df=2; p=0.094). In summary, differences were found regarding urinalyses for morphine between patients with and without comorbid BZD severe dependence only when we considered a long-term result index (TT-CU). 4.

Discussion

We examined treatment retention and outcomes for treatment-resistant, methadone-maintained patients with and without comorbid BZD severe dependence. We observed that: Groups differed at baseline in terms of number of altered mental status areas, frequency of unsatisfactory social and leisure time, elapsed time from 1st heroin use to 1st treatment, severity of illness (heroin addiction), concomitant use of cannabinoids. These data are in agreement with the observations of Drake et al. [11] regarding the belonging of MMT patients with BZD dependence to a dysfunctional group. However, the differences we found did not appear to


be related to the better retention or better outcome of the patients with concomitant BZD severe dependence. HA+BZD showed similar retention rate than HA-BZD; they showed no differences in rates of opiate-negative urine specimens and when using a long-term result index they showed better result; they required higher doses of methadone than patients without comorbid BZD severe dependence. The outcome and the retention rate in therapy of our treatment-resistant patients with or without comorbid BZD severe dependence did not differ from that of long-term standard MMT programmes [5, 10, 13, 22, 41, 43]. The main difference between our programme and standard Italian MMT lies in the amount of methadone administered during the stabilization phase; this ranges from 80 to 400 mg/day in our protocols and from 40 to 100 mg/day in standard protocols. A possible explanation for the need for these relatively higher doses in patients who have previously been unresponsive to standard treatments may be related to a pharmacokinetic and/or pharmacodynamic mechanism. Methadone is metabolized in the liver by the P450 cytochrome system and, more specifically, by the CYP3A4 isoform, which is involved in the metabolism of over 50% of the medical agents [8, 15]. The wide inter-individual variability [3, 21, 40, 44, 45, 47] recorded, and the fact that CYP3A4 can be induced by several active principles [18, 36], may explain why a number of patients are under-medicated if a standard dose of methadone is used. Unfortunately we did not measure plasma methadone levels in our patients during the stabilization phase, so we cannot determine whether the doses used were necessary to maintain a proper therapeutic window or to control an underlying underestimated psychopathology. In selecting our patients only Axis I psychiatric disorders were taken into consideration, but the existence of a minor form of psychopathology in the other patients concealed under the main addictive symptoms cannot be excluded sustaining a low degree of compliance with therapies [4, 6, 17, 38]. However, patients were followed up for 3 years on average, and diagnoses were subject to revision whenever further clinical evidence or retrospective information was gathered – a factor that reduces the likelihood of false absence of dual diagnosis patients. Moreover, the duration of addiction was such as to make it improbable that subjects rated as without dual diagnosis had a silent psychiatric history. The availability of significant others was itself extremely helpful in increasing the

level of diagnostic accuracy. In addition, we found that the outcome of MMT patients with or without dual diagnosis is the same in the short [34] and long term [33]. The high GAF score values recorded for our patients with comorbid BZD severe dependence and without hospitalizations throughout the treatment period showed that these subjects were simultaneously compliant both with MMT requirements and with the specific benzodiazepine therapy adopted. Additional medication (we used systematically clonazepam) for the treatment of benzodiazepine abuse – medication not completely changed by the need to treat addiction – may partly explain the more positive outcomes obtained in our comorbid patients, which cannot be attributed exclusively to the effects of methadone. A lack, whether of appropriately flexible methadone doses and/or of specific medications given in association with methadone treatment for these patients, could have been responsible for the conflicting results obtained by other researchers, who reported that benzodiazepine and alcohol abuse were linked to worse treatment outcomes (retention in treatment) [7, 9, 12, 16, 39, 42]. In addition psychotherapeutic support provided by our team and the high therapeutic pressure of our programme could have been responsible for better results [2]. In any case, the incisiveness of our study was limited by several factors, such as the observational nature of the protocol, the impossibility of evaluating a follow-up in the case of the patients who dropped out, and the multiple interference caused by interindividual variability (personality traits and their neurobiological correlates), the clinical setting and the temporary use of adjunctive medications. 5.

Conclusions

This study supports the possibility to use methadone maintenance and clonazepam maintenance combination in heroin-addicted patients with comorbid severe BZD dependence. References 1. A.P.A. (1994): Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. American Psychiatric Association, Washington. 2. Amato L., Minozzi S., Davoli M., Vecchi S. (2011): Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 9: CD005031. 3. Änggård E. (1974): Disposition of Methadone in - 21 -


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Received January 27, 2014 - Accepted July 22, 2014 - 23 -