Opioid substitution therapy: Lowering the treatment thresholds

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Review

Opioid substitution therapy: Lowering the treatment thresholds Georgios Kourounis a,b , Brian David Wensley Richards a,b , Evdokia Kyprianou c , Eva Symeonidou c , Minerva-Melpomeni Malliori d , Lampros Samartzis a,b,∗ a

St George’s University of London, Medical School at the University of Nicosia, Agiou Nikolaou Street 93, Engomi, 2408 Nicosia, Cyprus Department of Addiction Psychiatry, Athalassa Psychiatric Hospital, Cyprus Mental Health Services, Leoforos Lemesou 199/2, 1452 Nicosia, Cyprus Cyprus Anti-Drugs Council, Leoforos Lemesou 130, City Home 81, 2015 Strovolos, Cyprus d Department of Psychiatry, School of Medicine, National and Kapodistrian University of Athens, 72, 74, Vassil. Sophias Avenue, 11528 Athens, Greece b c

a r t i c l e

i n f o

Article history: Received 24 July 2015 Received in revised form 2 December 2015 Accepted 21 December 2015 Available online xxx Keywords: OST Opioid Substitution Methadone Buprenorphine Threshold Policy Cyprus Drugs Addiction Heroin Harm reduction

a b s t r a c t Background: Opioid substitution therapy (OST) has been established as the gold standard in treating opioid use disorders. Nevertheless, there is still a debate regarding the qualitative characteristics that define the optimal OST intervention, namely the treatment threshold. The aim of this review is twofold: first, to provide a summary and definition of “treatment thresholds”, and second, to outline these thresholds and describe how they related to low and high threshold treatment characteristics and outcomes. Method: We searched the main databases of Medline, PubMed, PsycInfo, EMBASE, CINAHL and the Cochrane Library. Original published research papers, reviews, and meta-analyses, containing the eligible keywords: “opioid substitution”, “OST”, “low threshold”, “high threshold” were searched alone and in combination, up to June, 2015. Results: Treatment thresholds were defined as barriers a patient may face prior to and during treatment. The variables of these barriers were classified into treatment accessibility barriers and treatment design barriers. There are increasing numbers of studies implementing low threshold designs with an increasing body of evidence suggesting better treatment outcomes compared to high threshold designs. Conclusion: Clinical characteristics of low threshold treatments that were identified to increase the effectiveness of OST intervention include increasing accessibility so as to avoid waiting lists, using personalized treatment options regarding medication choice and dose titration, flexible treatment duration, a treatment design that focuses on maintenance and harm reduction with emphasis on the retention of low adherence patients. © 2016 Published by Elsevier Ireland Ltd.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Treatment accessibility barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.1. Long waiting lists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.2. Inflexible admission criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.3. Limited availability: lack of access through primary care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.4. Cost of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Treatment design barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: Department of Addiction Psychiatry, Cyprus Mental Health Services, Athalassa Psychiatric Hospital, THEMEA building, 1452 Nicosia, Cyprus. Fax: +357 22402281, email: [email protected]. E-mail addresses: [email protected], [email protected] (L. Samartzis). http://dx.doi.org/10.1016/j.drugalcdep.2015.12.021 0376-8716/© 2016 Published by Elsevier Ireland Ltd.

Please cite this article in press as: Kourounis, G., et al., Opioid substitution therapy: Lowering the treatment thresholds. Drug Alcohol Depend. (2016), http://dx.doi.org/10.1016/j.drugalcdep.2015.12.021

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3.2.1. Lack of individualization in treatment design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2.2. Lack of pluralism in medication options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2.3. Limited duration of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2.4. Zero tolerance approach, focus on abstinence from drug use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2.5. Supervision upon drug administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2.6. Adjuvant obligatory psychosocial intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction Opioid substitution therapy (OST) combined with psychosocial interventions is the most common treatment for opioid dependence in Europe, with over half of opioid users undergoing substitution treatment (EMCDDA, 2012a,b, 2015a,b). This practice is supported by available evidence, establishing OST as the most effective pharmacological treatment for patients suffering from opioid addiction (Amato et al., 2005; De Maeyer et al., 2010; Farré et al., 2002; WHO/UNODC/UNAIDS, 2004). Based on the principles of psychopharmacology, OSTs are far more effective than non-pharmacological approaches in retaining patients and in maintaining patient abstinence from heroin and other illicit opiates as OSTs reduce craving, death due to criminal behavior and overdose, tolerance and withdrawal symptomatology, and HIV risk behaviors (EMCDDA, 2012b; Lawrinson et al., 2008; Mattick et al., 2009; Weber et al., 2009; WHO, 2009; EMCDDA, 2015a,b). According to findings, regarding the epidemic spread of HIV in Greece and Romania, limited access to substitution treatment is one of the main factors that appears to correlate with this trend (EMCDDA, 2012a,b). According to the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA, 2012a,b, 2015), best practices in the treatment of drug addiction include: (1) OST combined with psychosocial support; an approach which increases staying in treatment, reduces morbidity and mortality (Davstad et al., 2009). (2) Methadone and buprenorphine are both recommended pharmacological treatments, with Heroin-Assisted Treatment (HAT) recommended for patients who previously failed methadone treatment attempts (Blanken et al., 2010a). (3) OST is strongly recommended for pregnant women dependent on opioids. (4) OST and provision of clean needles for preventing HCV and HIV infections in IV drug users, as IV drug users who are receiving OST, show less risky behaviors and they inject less. Those patients who continue to inject drugs take less risks when participating in a needle and syringe exchange program or utilizing drug consumption rooms. (5) OST is particularly important in prison as it reduces opioid use, IV drug use, violence and withdrawal symptoms. OST greatly reduces mortality among drug users, which is particularly important when drug users are released from prison and in immediate need of finding continuity of treatment in the community (Degenhardt et al., 2014; Hedrich et al., 2012). However, despite the evidence supporting OST treatments (Amato et al., 2005; Davstad et al., 2009; Gibson et al., 1999; WHO/UNODC/UNAIDS, 2004), the published literature is not yet clear on what the optimal OST clinical framework is. This knowledge would be of great benefit for policy makers and treatment providers in order to promote effective interventions. Most importantly, the availability of OST treatment, within an effective framework, would contribute towards the improvement of users’

quality of life and life expectancy (Chang et al., 2015; Feelemyer et al., 2014; Nosyk et al., 2011). The variables which determine the clinical framework of OST treatments are known as treatment thresholds. The term “treatment threshold” is used to describe the barriers a patient may face prior to and during their treatment. These barriers affect treatment outcomes and overall prognosis (Stöver, 2011). Treatment thresholds can be classified into treatment accessibility barriers and treatment design barriers. Treatment accessibility barriers are ones that make it more difficult for drug users to commence OST treatment and include highly selective or inflexible intake criteria, long waiting lists, lack of access through primary care, and the cost of the treatment (Deering et al., 2011; Stöver, 2011). Treatment design barriers are ones that make it more difficult for patients who have commenced OST treatment to remain in treatment and include inflexible discharge policies, no individualization of treatment, no patient choice on medication and dose, short or limited duration of treatment, zero tolerance OST approaches, close supervision of patients on administration of medications, frequent urine testing, lack of confidentiality and anonymity, and lack of adjuvant psychosocial intervention or obligatory counselling sessions as a prerequisite to continue the treatment (Deering et al., 2011; Stöver, 2011). Lowering the treatment threshold is necessary in order to overcome treatment barriers and improve OST quality characteristics (Table 1). OST is considered a typical intervention for reducing harm in patients suffering from opioid addiction in the community (Amato et al., 2005; Degenhardt et al., 2015; Gowing et al., 2011a,b; Humber et al., 2011; Larney et al., 2014, 2015a, 2012; Rivlin et al., 2013). Harm reduction services are usually characterised as “high threshold” or “low threshold” (Mofizul Islam et al., 2013). The differentiation is made on the basis of variables which include: accessibility, waiting lists, access through primary care, quality standards, cost of treatment, minimum age requirements, anonymity, gender, individualisation of treatment, choice of OST drug and dose, duration of treatment, zero tolerance approaches, supervision upon drug administration, and adjuvant psychosocial interventions. A harm reduction service could be of low or high threshold, with most low-threshold services oriented towards harm reduction (Mofizul Islam et al., 2013). In contrast to high-threshold services for drug users, low-threshold services for drug users are defined as those that do not impose abstinence from drug use as a condition of service use, in contrast to high-threshold services (Gjersing and Bretteville-Jensen, 2013). Low threshold services also aim to reduce other documented barriers to service access (Mofizul Islam et al., 2013). In current literature, the term OST is mainly used in a midterm or long-term maintenance or relapse prevention contexts (Dennis et al., 2014; Stöver and Michels, 2010), despite the fact that the common OST drugs, such as buprenorphine and methadone, are

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Table 1 Qualitative characteristics of high threshold and low threshold treatment designs as our classification of treatment barriers. Qualitative characteristics Treatment accessibility barriers

Treatment design barriers

High threshold treatment design

Low treatment threshold design

Waiting lists Admission criteria Point of access Cost of treatment Treatment design Medication options Duration of treatment Relapse policies

Long Inflexible Strictly specialist care Cost to patient Universally the same for all patient groups Standard and limited Limited Zero tolerance approach

Drug administration Adjuvant psychological treatment

Supervised only Obligatory

Short or absent Flexible General practitioners and office based care No cost to patient Individualized according to the patient Flexible and pluralistic Unlimited Relapses expected and treated as part of the OST Take-home therapies Voluntary or absent

also used in short-term detoxification interventions (Pilling et al., 2007). This review aims to contribute a definition and summary of OST thresholds, based on the available literature to date, so as to be able to create a common ground for future comparison of low and high threshold OST designs. Furthermore, we aim to use these definitions and summary of barriers to outline how these barriers relate to low- vs high-threshold treatment characteristics and outcomes. The results of this review will be important for policy makers and health care providers when allocating resources and investing in the provision of cost-effective harm reduction measures and treatment for opioid dependence. 2. Methods 2.1. Search strategy Studies were identified and screened by searching main electronic databases (Medline, PubMed, PsycInfo, CINAHL EMBASE, and the Cochrane Library) for original published research papers, reviews, and meta-analyses, containing the eligible keywords: “opioid substitution”, “OST”, “low threshold”, “high threshold”, alone and in combination, up to September, 2015. We also manually reviewed the reference lists of included studies for relevant citations that may not have been found by searching with our keywords. We did not review dissertations and conference proceedings. 2.2. Inclusion and exclusion criteria We searched for papers that compared or observed high versus low threshold characteristics in the stated interventions as primary or secondary endpoints. Comparison or observational study endpoints that we searched for were: ease of accessibility, pluralism in treatment options, tailor-made treatment plan, inclusion of psychosocial care, non-judgemental approach, dose of medication, frequency of urine testing, and duration of the treatment. Articles excluded were ones in which there were comparisons between buprenorphine and methadone without a mention on treatment strategies, other than the OST drug of choice. In total 149 articles were screened and 51 were selected after screening. An additional 36 articles were selected after hand searching the bibliographies of retrieved articles and published reviews. 3. Results 3.1. Treatment accessibility barriers Treatment accessibility barriers are those that make it more difficult for drug users to commence OST treatment. These barriers include highly selective or inflexible intake criteria, long waiting

lists, lack of access through primary care, and the cost of the treatment. 3.1.1. Long waiting lists. Lengthy waiting times for substitution treatment can be a significant barrier to treatment access (Adamson and Sellman, 1998; Riksheim et al., 2014). Low threshold designs are characterized by absent or short waiting lists, as compared to high threshold designs, which increase the barriers to treatment access and are thus characterized by long waiting lists. Increased service accessibility and decreased waiting time could increase the effectiveness of OST interventions (Adamson and Sellman, 1998). Older, high threshold programs were usually characterized by long waiting times. This was mainly due to strict and inflexible admission criteria rather than a lack of resources. When treating addiction, waiting lists were believed to serve a treatment function on their own, by changing patients’ perspectives of treatment. Timely entry into treatment is associated with the effectiveness of opioid substitution maintenance therapy (WHO/UNODC/UNAIDS, 2004). Waiting lists have been gradually been made substantially shorter (Riksheim et al., 2014). Increased accessibility could take the form of shortening the waiting lists, offering OST to patients without access to the health care system, the use of flexible admission and discharge criteria, and avoiding involuntary discharge of patients due to either low adherence or parallel use of illicit drugs or other medications. 3.1.2. Inflexible admission criteria. Admission criteria are identified potential barriers to OST treatment access and commencement. In their attempt to reduce the barriers to access of treatment, low threshold treatment designs have flexible admission criteria (Mofizul Islam et al., 2013). Old, high-threshold OST programmes would admit only chronic, adult patients who had failed in abstinence-oriented programs. There is increasing evidence for lowering the age threshold and including adolescents in OST programs (Levy et al., 2007). A recent study also found the main factors that play a role in accessibility: among both female and male patients, Caucasian ethnicity and daily injecting heroin use were associated with decreased time to methadone initiation, while in females, pregnancy was associated with more rapid treatment initiation (Bach et al., 2015). 3.1.3. Limited availability: lack of access through primary care. The patient’s point of access within a health care provision system is an identified potential barrier in the treatment accessibility barriers group. Low threshold designs are ones that are characterized by their availability in primary care settings, as compared to high threshold designs which are characterized by OST treatments being offered through secondary and tertiary care specialist services. An important way to increase accessibility is to increase the availability of substitute treatment. This should happen not only in the special OST setting, but also in general hospital and office-

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based settings in the public and private practice sectors. This can be achieved by increasing the number of addiction psychiatrists who provide OST (Murphy et al., 2014). Treatment in office-based settings could expand access to OST in a less stigmatizing environment than specialized clinics, where patients arrive en masse for their doses. Office-based treatment would also further enable care of comorbidities such as HIV, hepatitis C, and psychiatric illnesses. In Canada great increases in access to methadone treatment were observed following the implementation of office-based treatment in 1996. For instance, the number of clients receiving methadone in British Columbia rose from 2,800 in 1996 to 13,000 in 2012. In Ontario the increase was from 700 to nearly 30,000 (Gunderson and Fiellin, 2008; Luce and Strike, 2011; Nosyk et al., 2013). Some countries also chose to offer OST training and support to primary health care practitioners who in turn deliver OST in their offices, significantly reducing the lack of access through primary care (Bell et al., 2002). Psychiatric comorbidity has also been found to be associated with decreased level of treatment (Murphy et al., 2014). It has been suggested that patients with drug addiction, who are also suffering from additional mental disorders, show increased retention to treatment when both mental disorders are treated in the same treatment centre: ease of access, results in increased adherence to treatment (Prodromou et al., 2014). Chronic but stable patients in OST can benefit by receiving treatment in the primary care setting, whereas more severe and/or unstable patients with comorbidities may need a more specialized tertiary addiction psychiatry setting. 3.1.4. Cost of treatment. The financing of OST is another identified barrier in the group of treatment accessibility barriers. Low threshold OST interventions are characterized by their attempts to provide OST at no cost to the patient, in contrast to high threshold OST designs which include a cost to the patient. Evidence also suggests that when OST services are of no cost, there is an associated increase in treatment retention (Booth et al., 2004). Financial barriers may limit access and continuity of treatment for disadvantaged people, whose cases are often the most complex to treat. The cost of OST is small compared to the disease burden of the population of untreated patients suffering from addiction. Government sponsorship of OST would potentially increase the retention rates of lower income OST program recipients (Shepherd et al., 2014). 3.2. Treatment design barriers Six groups of treatment design barriers which make it more difficult for drug users to remain in OST treatment were identified. These barriers include absence of individualization of treatment, absence of patient choice regarding medication and dose, limited duration of treatment, zero tolerance OST programs, close supervision of medication administration, lack of confidentiality and anonymity, and lack of adjuvant psychosocial intervention or obligatory counselling sessions as a prerequisite for treatment continuation. 3.2.1. Lack of individualization in treatment design. The level of flexibility in treatment design poses a treatment design barrier. In terms of treatment design, low threshold OST treatments are characterised by their flexibility in design, as compared to high threshold OST treatments, which are strict and inflexible. Addicted patients have their own biopsychosocial needs. Because opioid addiction is a chronic relapsing and remitting mental disorder, individualization of the treatment is the standard approach. This was not the case until recently (Waal, 2007). OST used to be offered in an abstinence-oriented approach (Mofizul Islam et al., 2013), in the context of behavioural group therapy

interventions, or other forms of obligatory rehabilitation (Waal, 2007). All patients were obligated to follow the same “program rules”—or the “the therapeutic community’s rules,”—and inevitably they were often involuntarily discharged or “kicked out” of the programs, mainly due to use of illegal drugs during the treatment period. Also, older high-threshold services used the same treatment plan and low dose regimen for all patients. Recent evidence suggests increased efficacy with highly individualized OST approaches (Connock et al., 2007; Torrens et al., 1996; Waal, 2007). A recent meta-analysis on dosing strategy, found that retention was greater with flexible-dose strategies than with fixed-dose strategies (Bao et al., 2009). The poorly stabilized or “difficult” patients required even more flexibility in terms of dosing and take home strategies, and this group may indeed be more effectively managed under a flexible low threshold strategy (Coppel, 2005b). 3.2.2. Lack of pluralism in medication options. Medication options, or the lack thereof, in the treatment of OST patients is an additional identified treatment design barrier. In this case, low threshold OST designs are characterised by a pluralism of medication options, in contrast to high threshold OST designs characterised by standardized and/or limited medication options. According to World Health Organisation (WHO) guidelines for the pharmacological treatment of opioid dependence, the choice of treatment for an individual should be based on a detailed assessment of the treatment needs and appropriateness of treatment to meet those needs, incorporating individual preferences and past treatment experiences (WHO, 2009). Our findings suggest that there is no single best medication choice for use in OST, even though methadone and buprenorphine show a greater effect compared to other opioid choices. Methadone and buprenorphine, the two most effective and, therefore, popular OST options, show similar efficacy in terms of keeping the patients in maintenance treatment, away from drug use, and decreasing drug use morbidity and mortality (Farré et al., 2002; Gibson et al., 2008). For shorter, detoxification-only interventions, the effectiveness of buprenorphine and methadone were also found to be comparable (Wright et al., 2011). While, methadone and buprenorphine are both recommended pharmacological treatments, Heroin-Assisted Treatment (HAT) is recommended for patients who have failed previous methadone treatment attempts (Blanken et al., 2010a,b). A recent prospective cohort study found that retention rates increased and total population under treatment tripled over 10 years, together with the increase of buprenorphine availability, when over the same time frame the percentage of OST patients increased from 16% to 50% of the whole (Riksheim et al., 2014). This cannot fully be attributed to replacing methadone with buprenorphine as there are many other changes in OST culture during this period making treatment more attractive, with the most important being the establishment of a non-judgemental therapeutic culture, less stigma attached to addicted patients undergoing substitution treatments, and a shift in clinicians’ focus from total abstinence through detoxification to harm reduction through maintenance. The optimal dose of the opioid substitute should be tailormade and differ between patients, to account for differences in severity of addiction, chronicity, main substance of dependence, method of administration, potency of main opioid used, tolerance acquired, and idiosyncratic reasons. There is evidence that treatment retention and number of days without relapse are prolonged in higher doses of the substitute due to increased treatment adherence (Booth et al., 2004; Fareed et al., 2012; Johnson et al., 2000). The higher doses of the substitute and the individualization of the treatment are each independently associated with better retention in the opioid substitution maintenance treatment (Bao et al., 2009).

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3.2.3. Limited duration of treatment. The duration of OST treatment is another identified potential treatment design barriers. Low threshold OST designs are characterized by an open-ended duration of therapy, whereas high threshold OST designs are characterised by a set deadline or limit to the duration of therapy. The body of evidence suggests that the optimal duration of treatment depends on the patient, as is the case for most medical interventions. Patients may start OST with different therapeutic goals, after a formal clinical evaluation. Possible goals include fast or slow detoxification, and maintenance periods ranging from shortterm to life-long. The optimum duration of the treatment may involve long-term or even lifelong medication use (Kleber, 2007; Kraus et al., 2011; Woody, 2015). According to recent guidance on OST duration, the optimum duration of maintenance is unclear, but may involve long-term or even lifetime medication use (Kraus et al., 2011). In most cases, treatment is required for a long period or even for the rest of patient’s life (Kleber, 2007). Authors, in order to focus on life expectancy and quality of life, explain and underline that “such long-term care which is common to many medical conditions, should not be seen as a failure of treatment but as a cost-effective way to prolong life and improve quality of life” (Kraus et al., 2011). Also, a recent report by the UK’s Advisory Council of the Misuse of Drugs (ACMD, 2014) concluded that the evidence does not support the case for imposing a blanket time limit on OST treatment for heroin users, and this approach is not advised by the ACMD. Taking into account that each patient has his own biopsychosocial needs, guidance suggest that OST should not be time limited (Kraus et al., 2011; Torjesen, 2014). Retention to treatment is a therapeutic goal for patients with chronic addiction to opioids, as it is correlated with opportunities for treatment of severe infectious diseases, therefore improving prognosis (Roux et al., 2009). There is also evidence that maintenance treatment, is more effective than detoxification, in terms of suppressing heroin use (Amato et al., 2005). 3.2.4. Zero tolerance approach, focus on abstinence from drug use. The level of abstinence required by a patient to remain in OST treatment is another one of the identified treatment design barriers. Low threshold interventions are characterised by their expectance and planning of treatment of relapses within the design of the OST program. High threshold interventions frequently have a zero tolerance policy, which imposes abstinence from drug use as a condition for service use. The therapeutic culture of the clinic’s staff affects the quality of the doctor-patient relationship, which in low threshold setting is based on a non-judgemental approach to the patient, focused on treatment retention (Coppel, 2005b). Decreasing the risk for severe infection is an example of harm reduction intervention in patients addicted to opioids. Attitudes toward OST are crucial in preventing and reducing community HIV transmission (Bachireddy et al., 2011; Nosyk et al., 2015; Polonsky et al., 2015), and preventing hepatitis C (Larney et al., 2015b; Maher et al., 2015; Treloar et al., 2013). As a recent study suggests, the risk of acquiring HIV infection for patients in maintenance treatment is markedly reduced (Woody et al., 2014). It is also well documented that you can reduce the risk for HIV, merely by lowering the threshold in the already available OST facilities. The availability of OST treatment has an obvious effect in reducing the harm particularly in vulnerable population groups such as those of prisoners (Larney et al., 2014, 2015a) and pregnant women (Amato et al., 2012, 2011, 2008). Older, high-threshold OST used regular and frequent urine testing as a form of strict follow-up of patients’ adherence to treatment. In the low-threshold approach there is no need for frequent urine testing. Nevertheless, most OST services prefer to perform regu-

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lar urine testing. About 70% of patients who are under treatment receive regular urine testing and this has not been changed significantly over the years (Riksheim et al., 2014). High threshold OSTs use regular urine testing not only for the purpose of increasing adherence to treatment, but also in order to avoid diversion, namely injection of the substance or resale on the black market. Despite the fact that diversion is to some extend inevitable (Nielsen et al., 2015), the costs of this diversion are outweighed by the benefits from expanding OST: improvement of health and social integration, and reduction of fatal overdoses, needle sharing, and criminal arrests due to heroin use (Coppel, 2005a). 3.2.5. Supervision upon drug administration. The extent of supervision required by the OST treatment design poses yet another identified treatment design barrier. Low threshold programmes are characterised by a lower level of supervision of drug administration, even the use of take-home medication. By comparison, high threshold programmes supervise drug administration and discourage take-home medication. The level of supervision of the patient by the staff in OST services differs across settings. High threshold programs use closer supervision during administration; therefore take-home therapies are used less often. On the other hand, low threshold approaches more often utilize take-home therapies along with weekly visits in the outpatient clinic. A third strategy used is unsupervised, office-based treatment settings, which do not require supervision other than the regular follow-up visit, and may not implement regular urine tests. These very different treatment strategies, when tailored to patients, have been found to play an important role in retention to treatment. Take-home treatment or office-based treatment may be used from the beginning, or may be started later in the course of the treatment, after the patients have stabilised. A recent study involving a large patient sample found that take-home therapy is very effective in terms of retention rates. Even higher rates of effectiveness were seen when take-home therapy was used in previously stabilised patients, namely those with negative urine tests (Gerra et al., 2011). Some patients subgroups are receiving more unsupervised doses, especially those who are older, currently employed without a prison history, and undergoing treatment for longer period (Larance et al., 2014). Stable patients with good adherence to treatment could benefit by unsupervised prescription of OST preparations, especially with the combination of buprenorphine plus naloxone, which is safe and has a small diversion potential (Mauger et al., 2014). A study on the safety of opioids found that most opioid related fatalities were not related to filled prescriptions of maintenance drugs, but instead were related to the use of illegal, non-prescribed opioid preparations (Wikner et al., 2014). Office based OST is considered safe and effective (Kraus et al., 2011). Illicit use of opioid substitution drugs may be less harmful than previously assumed (Bretteville-Jensen et al., 2015). 3.2.6. Adjuvant obligatory psychosocial intervention. Another identified treatment design barrier is the extent, presence and orientation of adjuvant psychosocial interventions for the patients in OST treatments. Low threshold OST designs are characterized by allowing and motivating patients to participate in adjuvant psychosocial treatment on a voluntary basis. On the other hand, high threshold OST designs often require patients to participate in rehabilitating interventions. According to WHO guidelines for the pharmacological treatment of opioid dependence, psychosocial support should be offered routinely in association with pharmacological treatment for opioid dependence; however patients should not be denied agonist maintenance treatment even if they refuse such adjuvant support (WHO, 2009). A prior study suggests that the addition of psychoso-

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cial interventions to the treatment plan could not only increase the cost, but may also increase the OST effectiveness, as it can improve adherence and retention to treatment, reduce the risk of harm and facilitate patients’ change over time (Johns, 1994). This is reinforced by more recent evidence showing that the addition of psychosocial therapy adds to the overall effectiveness of substitution treatment programmes. However, research evidence indicates that counselling is important for those who need it, but can be counter-productive if mandated (WHO, 2004). It is not clear if and how psychosocial support is associated with OST effectiveness. A recent study found that in a low-threshold buprenorphine or methadone maintenance setting, psychosocial support is associated with less no-shows, reduced social and family problems and reduced severity of mental health disorders (Hesse and Pedersen, 2007). There is also some evidence that higher number of contacts within the OST clinic is associated with retention in the treatment (Booth et al., 2004). Substitution treatment alone may be effective for a minority of patients, whereas for the majority of patients the addition of psychosocial care has been associated with increased efficacy (McLellan et al., 1993). The addition of psychosocial intervention to the OST may be more important when the treatment population consists of adolescents that are addicted to opioids (Levy et al., 2007). Despite some evidence for the importance of adding psychosocial support in OST service, there is no clear evidence as to the grade of effectiveness of the addition of psychosocial interventions in the OST intervention. A recent meta-analysis found that adding psychological support to maintenance treatments could improve the number of participants’ abstinent at follow up, but no difference was found for any other outcome measures, including mortality (Amato et al., 2008). Also, this well conducted meta-analysis found no statistically significant differences between different psychological interventions for contingency approaches, contrary to all expectations (Amato et al., 2008). In the updated version of this Cochrane meta-analysis authors concluded that the inclusion of psychological treatment in OST is desirable in terms of increased clinical effectiveness (Amato et al., 2011).

nence from illicit drugs is not imposed as a condition for service use. It also means that the therapist personalizes treatment options regarding medication choice, dosing titration, and treatment duration. In addition, close supervision of therapy administration is discouraged. A low threshold OST program also encourages adjuvant psychosocial interventions for rehabilitation, but only on a voluntary basis for the patient. It is important going forward, as quantitative data is added to the body of evidence that both clinicians and policy-makers strive for a patient-centred approach as part of their OST programs. This narrative review is based on published evidence regarding OST methodology and effectiveness. For the purposes of this study, this poses a strength, as the findings are seen across a wide span of time and across a large volume of literature. However, the available studies found in the literature used variable methods and operational definitions of terms. This heterogeneity in the literature posed limitations, because a direct, standardized, between-studies comparison was not possible. As a narrative review, this article also retains some of the inherent characteristics of this kind of research methodology (Green et al., 2006), namely the strength of the qualitative integration and critical interpretation of different studies, but the lack of arithmetical comparisons and quantitative results. Future quantitative research is required to effectively compare the different OST methodologies. Furthermore, research investigating which OST treatment characteristics are the most important in patient outcomes should also be performed in order to better guide policy makers and service providers. Conflict of interest No conflict declared. Role of the funding source Nothing declared. Contributors

4. Conclusion In this review, we defined treatment thresholds as a term used to describe the barriers a patient may face prior to and during their OST treatment. We then used this definition to classify the identified barriers from the literature into treatment accessibility barriers and treatment design barriers. The list of identified barriers are summarised in Table 1. Based on these thresholds, our findings show an increased effectiveness of low threshold OST treatment designs. Accessibility barriers have to be lowered in order to increase the effectiveness of OST services. In order to increase patients’ accessibility, an OST service has to set flexible intake criteria to eliminate or decrease waiting lists and offer immediate access to the treatment. Additionally, accessibility is enhanced with increased availability, especially in the primary care setting, and by providing OST treatment at no cost to the patient. Treatment design is also critical for improving patient access, treatment retention, and consequently increased treatment effectiveness, In order to keep patients in treatment and avoid discharges against medical advice, a flexible admission and discharge policy setup is important. The theoretical background of the therapist affects his or her clinical approach to the patient and consequently the patient’s approach towards OST; therefore, practical issues of accessibility are very important. A low-threshold approach is focused on harm reduction and recovery, not on total abstinence, which remains a desirable but unnecessary factor. This means that patients’ absti-

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Please cite this article in press as: Kourounis, G., et al., Opioid substitution therapy: Lowering the treatment thresholds. Drug Alcohol Depend. (2016), http://dx.doi.org/10.1016/j.drugalcdep.2015.12.021