Elsevier

Drug and Alcohol Dependence

Volume 187, 1 June 2018, Pages 278-284
Drug and Alcohol Dependence

Full length article
A cluster-analytic profiling of heroin-dependent patients based on level, clinical adequacy, and patient-desired adjustment of buprenorphine dosage during buprenorphine-naloxone maintenance treatment in sixteen Spanish centers

https://doi.org/10.1016/j.drugalcdep.2018.02.020Get rights and content

Highlights

  • Buprenorphine (BUP) dose is crucial in BUP-Naloxone treatment of heroin use disorder.

  • We ran cluster analysis based on BUP dosage, including: level, adequacy, adjustment.

  • The 4-cluster solution was the most suitable and was easily interpretable.

  • Three clusters with adequate BUP dosage showed comparable clinical condition.

  • The Inadequate/Adjusted Moderate Dosage cluster presented poorer clinical condition.

Abstract

Background

Buprenorphine dosage is a crucial factor influencing outcomes of buprenorphine treatment for heroin use disorders. Therefore, the aim of the present study is to identify naturally occurring profiles of heroin-dependent patients regarding individualized management of buprenorphine dosage in clinical practice of buprenorphine-naloxone maintenance treatment.

Methods

316 patients receiving buprenorphine-naloxone maintenance treatment were surveyed at 16 Spanish centers during the stabilization phase of this treatment. Patients were grouped using cluster analysis based on three key indicators of buprenorphine dosage management: dose, adequacy according to physician, and adjustment according to patient. The clusters obtained were compared regarding different facets of patient clinical condition.

Results

Four clusters were identified and labeled as follows (buprenorphine average dose and percentage of participants in each cluster are given in brackets): “Clinically Adequate and Adjusted to Patient Desired Low Dosage” (2.60 mg/d, 37.05%); “Clinically Adequate and Adjusted to Patient Desired High Dosage” (10.71 mg/d, 29.18%); “Clinically Adequate and Patient Desired Reduction of Low Dosage” (3.38 mg/d, 20.0%); and “Clinically Inadequate and Adjusted to Patient Desired Moderate Dosage” (7.55 mg/d, 13.77%). Compared to patients from the other three clusters, participants in the latter cluster reported more frequent use of heroin and cocaine during last week, lower satisfaction with buprenorphine-naloxone as a medication, higher prevalence of buprenorphine-naloxone adverse effects and poorer psychological adjustment.

Conclusions

Our results show notable differences between clusters of heroin-dependent patients regarding buprenorphine dosage management. We also identified a group of patients receiving clinically inadequate buprenorphine dosage, which was related to poorer clinical condition.

Introduction

In the European Union, the non-medical use of opioids continues to be relatively rare (0.4% of the adult population), with heroin accounting for around 80% of the new opioid-related demands of treatment (EMCDDA, 2017a). At the national level, five countries account for more than three quarters of the estimated high-risk opioid users (France, Germany, Italy, Spain, and United Kingdom). In Spain, high-risk opioid use decreased between 2007 and 2015, but heroin remains as the main substance linked to serious adverse health and social consequences (EMCDDA, 2017b). Until January 2010, methadone was the only opioid agonist with proven efficacy to treat heroin use disorder that was available in Spain. Since then, the combination of buprenorphine (BUP) and naloxone (NAL) in a 4:1 ratio is also available to treat heroin dependence.

Dosage of opioid agonist maintenance treatment for heroin use disorder is a key factor that influences treatment outcomes. Regarding BUP maintenance treatment, a meta-analysis of 21 randomized clinical trials (RCT) recommended administering >16–32 mg/d of BUP to better retain patients in treatment (Fareed et al., 2012). In addition, according to a narrative review of laboratory studies, blockade of average doses of abused opioids may require <20% of mu-opioid receptor availability, which may entail single daily BUP doses >16 mg for most individuals (Greenwald et al., 2014).

Whether all patients have to receive BUP ≥ 16 mg/d is controversial. On one hand, the ratio of patients who relapsed in 32 Italian addiction treatment centers decreased as the daily induction dose of BUP increased: Over half of all treatments induced with 2 mg of BUP relapsed, whereas only 20% of those with 10 mg, and 10% of those with 16 mg did so (Leonardi et al., 2008). On the other hand, a positive relationship between BUP dosage and opioid use was found in 11 USA treatment programs where clinicians tailored the BUP induction dosage to the patient’s current condition (Hillhouse et al., 2011). In this study, those patients receiving BUP 8 mg/d, in comparison to patients receiving BUP 24 mg/d, had lower rate of continued opioid use during the induction phase and, more importantly, reported less severe drug use at baseline. These results of Hillhouse et al. (2011) could be explained by the fact that RCTs are usually not designed to determine the minimum effective dose or to individualize opioid dosage (Trafton et al., 2006), both cornerstones of clinical practice. According to this explanation, the main question concerning optimization of opioid dosage should not be focused on dosage level but on dosage adequacy, in order to achieve treatment goals with each patient (González-Saiz, 2004).

In clinical practice, a BUP dose range of 2–16 mg/d is often reported (Daulouède et al., 2010; Springer et al., 2010; Piralishvili et al., 2014). In fact, Vicknasingam et al. (2015) stated that, in Malaysia, 70% of patients had prescribed BUP doses in the range of 2–4 mg/d and 79% of patients reported taking daily BUP doses ≤ 2 mg. The reasons given by physicians to justify prescribing opioid doses lower than those recommended in experimental studies are heterogeneous. Possibly, the most important reason is that some heroin-dependent patients are responsive to low opioid agonist doses (Mino et al., 1998; Trafton et al., 2006; Hillhouse et al., 2011; Bizzarri et al., 2016). Other reasons could be: Physicians’ fears of overdose fatalities, low patient acceptance of the long-term maintenance treatment approach, break-down in the communication between physicians and patients concerning dose adjustment, and reduction of side effects (Lin and Detels, 2011). Regarding the perspective of patients, they play a significant role in adjusting the eventual maintenance dose of opioid agonists, such as methadone (Somogyi et al., 2014). In Spain, a considerable proportion of heroin-dependent patients (35–54%) desired to adjust their methadone doses downward (Pérez de los Cobos et al., 2005, Pérez de los Cobos et al., 2016; Trujols et al., 2017). Reasons given by heroin-dependent patients to reduce their methadone dosage include: lack of control in treatment, concerns about methadone dependence, desire to avoid adverse effects, and shame and stigma associated with methadone treatment (Sanders et al., 2013).

In keeping with the proposal of a group of European experts (Maremmani et al., 2016), the present cross-sectional study aims at identifying subgroups of heroin-dependent patients with potential for improved outcomes through optimized BUP dosage. To accomplish this objective, we performed a cluster analysis based on three key indicators of individualized BUP dosage management: current dose, adequacy according to clinicians, and adjustment according to patients. The groups identified were compared in terms of substance use, severity of heroin dependence, satisfaction with BUP-NAL as a medication, BUP-NAL adverse side effects, and psychological adjustment.

Section snippets

Participants

The study included participants meeting the following inclusion criteria: (a) age ≥ 18 years old, (b) fulfillment of DSM-5 (American Psychiatric Association, 2013) criteria for heroin use disorder, (c) BUP-NAL maintenance treatment for at least the previous 3 months, and (d) no changes introduced in the BUP dose during the week prior to assessment. Furthermore, patients were not included if they met the following exclusion criteria: (a) presence of any mental disorder that could hinder patient

Descriptive statistics

A total of 325 patients participated in the process of data collection in our study (González-Saiz et al., 2018; Pérez de los Cobos et al., 2017). Taking into account that 9 of them did not meet the inclusion criteria, the final sample included 316 participants (see flow-chart in Figure A of the Supplementary Materials). Descriptive analyses show that the final sample did not differ from the initial sample in terms of socio-demographic data.

The participants included in the final sample were

Discussion

The present research is based on a cross-sectional survey conducted during usual clinical practice of BUP-NAL maintenance treatment in 16 Spanish centers. Data were obtained during the stabilization phase of BUP-NAL maintenance treatment and were analyzed to develop profiles of heroin-dependent patients regarding BUP dosage management. Patients were grouped using a cluster analysis based on three key indicators of BUP dosage management: dose, adequacy according to physician, and adjustment

Funding

This work was supported by the Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau-IIB Sant Pau through an unrestricted grant from Indivior España S.L. (former RB Pharmaceuticals Ltd). Views expressed here are those of the authors and do not necessarily represent those of the funding source.

Conflict of interest

José Pérez de los Cobos and Francisco Gonzalez-Saiz have received grant support for research and educational activities from Reckitt-Benckiser. All other authors declare no financial interests or potential conflicts of interest directly or indirectly related to this work.

Contributors

JPC and FGS are the principal investigators for the Buprenorphine-Naloxone Survey Project. JPC, JT and NS specifically developed the design and methods of data collection. NS trained the psychologists who administered the surveys and SA built the database. SA performed the statistical analyses. JPC, SA and JT wrote the manuscript. FGS and EVM helped to revise the manuscript. All authors have approved the final manuscript.

Acknowledgements

We are grateful to the patients who kindly participated in the study and to Amalia García and Gerard Soriano who performed the surveys together with Saül Alcaraz. We would also like to thank Saiko Allende and Isabel Blásquiz for their secretarial support. The Buprenorphine/Naloxone Survey Group includes (in addition to the authors above mentioned) the following authors. Andalusia: Salvador Zambrano (Centro de Tratamiento Ambulatorio Torreblanca, Sevilla); Catalonia: Francina Fonseca, Marta

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