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Archives paper

Suboxone versus methadone and lofexidine in community stabilizationstabilisation and detoxification: A randomized controlled trial of low dose short term opiate-dependent individuals.

1Judy Myles, 2Fergus Law, 3Alison Diaper, 4Simon Coulton,3Jan Melichar, and 5David Nutt. .

1Department of Addictive Behaviour and Psychological Medicine, St George’s Medical School, 6th floor Hunter Wing, Cranmer Terrance, London, SW17 ORE, UK

2Bristol Specialist Drug Service, Manor Road, Fishponds, Bristol, BS16 2EW, UK

3Psychopharmacology Unit, Social and Community Medicine, University of Bristol Division of Psychiatry, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK

4Addiction Research Group, Department of Health Science, University of York, York, YO10 5DD

5Neuropsychopharmacology Unit, Imperial College London, Hammersmith Campus, London, W12 0NN, UK

*Corresponding author:

e-mail: ; Tel: 0117-9754840; Fax: 0117-9586569

Word count 4763 44413(i.e. too long, must be 3500-4500)

References 316

Tables 64

Figures 2 (8 incl. tables)7

Competing interests:

FDL and JKM have been reimbursed by Schering Plough, the manufacturer of buprenorphine, for attending several conferences. FDL has acted as a consultant, on focus groups, market research, and on an advisory board for Schering-Plough, and has been funded as a researcher on a study by Schering-Plough and Reckitt-Benckiser. FDL and JKM have received honoraria from Britannia Pharmaceuticals for speaking at symposia and JKM has received a small unconditional grant from them. FDL is on the UK national faculty of the Quality Patient Care Initiative, funded by Reckitt-Benckiser, and has received honoraria in this role. FDL has acted as a consultant and has been on a focus group for Britannia Pharmaceuticals. FDL has taught the staff of Schering-Plough and Dupont. AMD declares that she has no competing interests. DJN has received speakers fees and grants from RB pharmaceuticals, and Nalpharm, two companies with an interest in the treatment of opioid addiction.

Abstract

Context:Suboxone (buprenorphine/naloxone) and lofexidine (an 2-adrenergic agonist) are medications with utility in the treatment of opiate withdrawal. We report the first randomized controlled trial to compare the effects of these two medications on withdrawal symptoms and outcome during opiate induction/stabilizationstabilisation and withdrawaldetoxification. Objective: We hypothesised no differences during induction/stabilizationstabilisation, but that during the withdrawal detoxification phase withdrawal symptoms would be less severe, peak later and be associated with lower drop-outs during the gradual Suboxone withdrawal than during the methadone/lofexidine withdrawal. Design: A double-blind randomized controlled trial. Setting: The study was conducted in an outpatient satellite clinic of a specialist drug service. Patients: 80 opiate dependent individuals meeting DSM-IV criteria for opiate dependence, using  ½ g heroin smoked or ¼ g heroin injected or  10-30mg methadone, with  3 years of opioid dependency. Interventions: Two short-term opiate treatment programs involving induction and stabilizationstabilisation on methadone 30mg or Suboxone 4mg /1mg, followed by detoxification (where the methadone group was assisted by lofexidine).Main outcome measures: Urine drug screens for opiates, Opiate Withdrawal Scalesubjective level of opiate withdrawal,Opiate Craving Scale, craving for opiates and the Single Dose Opiate Questionnaire. . Results: Contrary to hypotheses, there were no overall differences in positive urine drug screens and dropouts during any phase of the study. During induction/stabilizationstabilisation, withdrawal symptoms subsided more slowly for Suboxone than for methadone/lofexidine, and craving was significantly higher in the Suboxone group. During detoxification withdrawal symptoms were significantly greater and the peak of withdrawal was later for the methadone/lofexidine group than the Suboxone group as predicted. These results during the withdrawal phase were potentially confounded by an apparent non-equivalence of opioid dose during the induction/stabilizationstabilisation phases. Conclusions: Methadone/lofexidine and Suboxone had comparable outcomes during a rapid outpatient stabilizationstabilisation and detoxification.

Key words: Buprenorphine, methadone, lofexidine, suboxone, opiate withdrawal

Introduction

Opiate dependence is a major international health problem with the majority of opiate dependent individuals relapsing to drug use soon after detoxification from opiates (Gossop et al.,1989[DN1]). After assessment, the treatment of opiate dependence involves three phases, namely stabilizationstabilisation, detoxification and maintenance of abstinence, where effective treatment at each phase is critical to the overall success rates of the whole process. There is a growing recognition that during the withdrawal phase the severity of withdrawal symptoms experienced can lead to failure to complete the detoxification (Kosten et al 1985, Rounsaville et al., 1985;,Kanof et al., 1993), with a reduction in the longer term abstinence rates. This has led to an interest in novel pharmacological treatments aimed at reducing the severity of opiate withdrawal, including lofexidine and the different formulations of buprenorphine – Subutex (sublingual buprenorphine) and Suboxone (sublingual buprenorphine/naloxone).

Our primary purpose in this study was to compare the efficacy of lofexidine and Suboxone during opiate withdrawal following opiate stabilizationstabilisation on methadone and Suboxone respectively, and secondly to examine the variables which may have impact on this efficacy. Raistrick et al. (2005) have demonstrated non-inferiority of buprenorphine compared with lofexidine in detoxification, but without naloxone. Similar studies of detoxification comparing buprenorphine with clonidine have shown benefit of buprenorphine with respect to less severe withdrawal symptoms and craving over 5-6 days (Ziaaddini et al., 2010; Hussain et al., 2015), an outcome also found with Suboxone over clonidine after 12-13 days detoxification (Ling et al., 2005; Ziedonis et al., 2009).

Studies covering aAAThis study is unusual because it involves all phases of addiction treatment have not been are rarely assessed. The rationale for this including all phases is that success at earlier phases of treatment may influence the outcome at the later stages of treatment. Thus achievement of termination of on top illicit drug use during stabilizationstabilisation is likely to be associated with higher levels of abstinence during detoxification, which is turn is likely to be associated with a reduced relapse rate during follow up. Although the design of the study is somewhat complex,This study is designed to allow assessment of the variables that may influence outcome at the different phases of treatment.

Medications:

Lofexidine, like clonidine, is an alpha-2 adrenergic agonist which is thought to act presynaptically on alpha-2 receptors to block the “noradrenergic storm” that occurs during opiate withdrawal (Gold and Pottash 1981Yu et al., 2008). Lofexidine is preferable to clonidine because it causes less hypotension and sedation (Myles, 1996; Gowing et al., 2003NICE, 2007), due to less potency at the A subtype of the alpha2-adrenoreceptors than clonidine (Herman and O’Brien, 1997). It , and has become the gold standard treatment in the UK since it was licensed for the treatment of opiate withdrawal in 1992 (Akhurst 1999), largely replacing clonidine. As a non-opiate it cannot promote opiate dependence, and avoids the regulatory complexities of prescribing controlled drugs, and can be given to those in whom the level of opiate dependence is uncertain. Alpha-2 adrenergic agonists are interesting in that they demonstrate that the major physical symptoms of opiate withdrawal are due to a downstream effect from the opiate receptors. Lofexidine itself has several side effects such as a dry mouth and mild drowsiness, which can lead to sedation when used with alcohol or other central nervous system depressants. They have also been shown to be relatively ineffective against the mood changes and subjective distress occurring during withdrawal (Jasinski et al 1985, Charney et al 1981, 1982, Washton and Resnick 1982, Loimer et al 1991).

Buprenorphine is a partial mu opioid receptor agonist and a kappa opioid receptor antagonist Nutt DJ (1997) Receptor pharmacology of buprenorphine. Research and Clinical Forums 9-15, and was licensed as an opioid analgesic in the UK in 1978 and for opiate dependence in 1998. It is also licensed for this to treat opiate dependence in France (1996), Australia (2000), Israel and much of Europe (2001) and the USA (2002), among others. The clinical use of buprenorphine in the treatment of opioid dependence, both for stabilizationstabilisation and withdrawal, has been comprehensively reviewed (e.g. by Bickel and Amass, 1 (1995; ), Johnson et al (2003), and Law et al., (20045;) and Kahan et al., (2011). . Buprenorphine has a number of advantages over the full mu receptor agonists such as methadone (Lewis, 1985), and has been extensively studied both in non-dependent opiate users and in users dependent on morphine or methadone. Buprenorphine exhibits a unique profile of effects including a) opioid-agonist activity that promotes treatment compliance (Jasinski et al., 1978, Law et al., 1997; Bickel et al., 1999); b) a long duration of action which allows it to be administered daily or on alternate days at high-doses (above 8 mg; Bickel et al., 1999)); c) a low risk of overdose due to a ceiling on respiratory depressant effect due to its partial agonism (Walsh et al., 1994); d) a slow onset of action with the production of little drug ‘“high’”, which means it is less reinforcing and therefore has a lower abuse liability; e) opioid antagonist like activity which occurs both as it can displace full agonists from the mu receptor, and also as a result of the degree of occupation of mu receptors resulting in a partial blocking of the effects of exogenously administered full mu receptor agonists (Bickel et al., 1988ab); f) cross-tolerance with other mu receptor agonists such that it is similar to methadone in its potential to reduce the use of illicit opiates at doses of < 60-80mg methadone or equivalent; g) high affinity (“stickiness”) for the mu opioid receptor which results in a low level of withdrawal signs and symptoms (Rance and Dickens, 1978) and producing only limited withdrawal symptoms on abrupt termination. This , which may allow a direct transition to naltrexone without the need for an opioid-free period. The low level of withdrawal symptoms with buprenorphine is thought to be due to its long duration of action and its slow dissociation from the opioidate receptorsin conjunction with its high affinity for the mu opioid receptor (Lewis, 1995).

Although buprenorphine is thought to be much safer in overdose than full mu opioid agonists such as methadone, it suffers from a number of problems including the ease with which it can be misusedappropriated by dissolving and injecting, meaning that it also needs to be given by supervised consumption. Also in people with recent heroin use , and that it may precipitate withdrawal symptoms, that may be confused with spontaneous withdrawal whose cause may be difficult to determine particularly during induction. Indeed withdrawal discomfort during induction can result from three separate processes (Johnson et al., 1989, Law et al 1997). Firstly, the dose of buprenorphine may be too low resulting in insufficient agonist effects to substitute for other opiate agonists. Secondly, buprenorphine, as a partial agonist, may not fully substitute for full opioid agonists beyond 60-80 mg methadone or equivalent. Thirdly, the dose of buprenorphine may be too high, and as a partial agonist may directly precipitate withdrawal by displacement of the full agonist.

The ease with which buprenorphine can be dissolved and injected hasMisuse of buprenorphine sappropriation led to the development of a combination medication consisting of buprenorphine and naloxone in a 4:1 ratio known as (Suboxone), which was licensed in the USA in 2002 and is designed to reduce misuse of buprenorphine if diverted. When taken sublingually the low bioavailability of naloxone means that suboxone it acts clinically for all intents and purposes like pure buprenorphine. However if injected iv the high bioavailability of naloxone will induce opiate withdrawal symptoms lasting 1-2 hours in those taking full mu opioid agonists, and therefore should act as a detere rent against further injectingons, so and effectively reduce the abuse liability of buprenorphine (Robinson et al 1993, Johnson et al 2003, Mallaret et al 2002Law et al., 2004). This Suboxonecombination may therefore be particularly suitable in clinical practice in situations where supervised consumption is not possible, as for example occurs at weekends when take home doses are required. Isn’t there a recent finnish study that shows this is true in practice?

This formulation of buprenorphine was the one used in this study.

We chose toIn our study we compared 4mg/1mg Suboxone with 30mg methadone based on the results of a previous results study where we transferred patients from opiate dependent individuals from 30mg methadone directly onto 4mg buprenorphine 20-24 hours after their methadone dose (Law et al., 1997), and found no dysphoria or precipitated withdrawal. Buprenorphine given to tolerant individuals caused no detectable agonist effects or drug ‘high’, but patients reported feeling ‘good’ effects, and it waswas ‘liked’and well tolerated. The lack of drug ‘high’ in combination with significant positive effects and minimal negative effects theoretically makes buprenorphine an excellent substitution agent, with the positive effects promoting compliance and the lack of early reinforcing effects and side-effects minimising both psychological reinforcement to the addiction and reasons for dropping out.

HYPOTHESESHypotheses

Induction and stabilizationstabilisation hypotheses:

There will be no significant differences between the two groups in terms of subjective withdrawal symptoms, opiate cravings, opiate negative urine tests or drop-out from treatment.

Detoxification hypotheses:

The Suboxone group will have a lower proportion of opiate positive urine tests during detoxification, and in addition the Suboxone group should be associated with lower levels of subjective withdrawal symptoms, opiate cravingsand drop-outs from treatment than the methadone/lofexidine group. We hypothesised the peak level of withdrawal will be lower and occur later for the Suboxone group than the methadone/lofexidine group.

Methods

SubjectsStudy design and patient recruitment

This study was conducted over an 18 month period from June 1998 to December 1999 inclusive in the city of Bristol UK, in an outpatient satellite clinic of a specialist drug service. Eighty opiate-dependent individuals who fulfilled DSM-IV criteria (APA, 1994) at that time were recruited from GPprimary care, hospital and voluntary sector services and were randomized into a double-blind study comparing the efficacy of two short-term opiate treatment programs consisting of opiate induction/stabilizationstabilisation followed by detoxification.

The inclusion criteria were that subjectpatients had to be aged 16-65 years of either gender with a current primary diagnosis of DSM-IV opiate dependence (APA, 1994), currently self-administrating prescribed or illicit opioids opiates equivalent to 10-30mg methadone orally (i.e. up to ¼ gram illicit heroin IV or up to ½ gram smoked/chased), and with a history of opioid dependency of  3 years in total (excluding periods of abstinence). The exclusion criteria included other drug dependencies sufficient to warrant another DSM-IV diagnosis (apart from caffeine, nicotine and cannabis), high suicide risk and/or warranting hospital admission, clinically significant physical or psychiatric disease, living with others dependent on illicit opiates, taken benzodiazepines in the last 5 days, pregnant or lactating, or of child bearing potential and not using a reliable method of contraception.
can we say how we did the clinical assements to eliminate other psychiatric disorders ? did we use a formal interview or rating scale?

The purpose of limiting the amount of opiate used prior to entry into the study was to ensure that precipitated withdrawal did not occur on the suboxone arm?, that the stabilizationstabilisation dose given should be sufficient to cover the opiate use, and that the length of withdrawal with the two regimes would be similar. The purpose of imposing an upper limit on the length of the opiate dependency was to restrict the client patient population to those who would not require residential rehabilitation, but whose abstinence could be supported by naltrexone - I wonder if we should say more explicitly thast this was also an aim o fht larger study – to see how easy it would be to get people onto naltrexone ?and counselling. [will we report this as a separate paper then?]

All patients were assessed by a medical and psychiatric history and underwent a physical examination and screening blood tests (U&Es, LFTs, FBC, and plasma viscosity). Patients attended daily (except Sundays and Bank Holidays) for 2-6 weeks of stabilizationstabilisation, followed by 2½ .5 weeks of detoxification (see table 11 for details). The study protocol and procedures were approved by the Bath Research Ethics Committee and all patients gave written informed consent.

The mean age, patterns of drug use, and other demographic characteristics are shown in table 23. There were no significant differences between the two groups.

Insert Table 1 about here

Insert Table 2 about here

Induction occurred at the full stabilizationstabilisation dose of 30mg methadone or 4mg/1mg Ssuboxone, except in 4 subjectpatients who were induced at half the maximum dose because of their low level of opiate use. The first dose of opiate medication was given  12 hours after the last use of heroin or other short acting opioid (Bickel and Amass, 1995), and  20-24 hours after the last dose of methadone (Law et al., 1997). If patients’last use of opioid had been less than these times, induction was delayed until later in the day, or they were asked to return the following day. All opiate doses were given once daily in the morning by supervised consumption (except on Sundays and Bank holidays in which case they were dispensed as a take out the previous day). Withdrawal doses are given in table 32 below, which shows that in the methadone/lofexidine group that the active methadone was terminated on day 3, and active lofexidine was given regularly for 14 days and then as required for a further 3 days. In the Suboxone group the active buprenorphine was reduced by 1mg every 3 or 4 days and terminated on day 10 from a dose of 1mg. Matched placebos were given to maintain blinding. Both the methadone and methadone placebo was obtained from Martindale Pharmaceuticals Ltd (Romford, UK), and were mixed with 50% by volume raspberry syrup (Thornton and Ross Ltd, Huddersfield, UK) immediately prior to dispensing to mask any minor taste difference. Suboxone and placebo was provided by Reckitt-Benckiser Healthcare (Hull, UK), and lofexidine and placebo by Britannia Pharmaceuticals Ltd (Redhill, UK).

Table 2 about here

Lofexidine doses were given in four equal divided doses daily with only the first dose of the day being supervised. Adjunctive medication was issued daily as required and consumption was not supervised. Suboxone and lofexidine tablets were split where necessary before dispensing them to the patient using a tablet splitter (W+W Medsystems, Huddersfield, UK), both to provide the correct dose and also when appropriate to give the impression that the daily dose was remaining constant. Patients qualified for progression from the stabilizationstabilisation to the withdrawal detoxification phase when they had provided 3 consecutive urine samples which were clear of illicit opiates (samples taken 3 times a week on Mon., Wed., Fri.). Urine samples were checked for temperature by hand touch immediately after production, and if felt to be suspect were temperature checked (Dinamap TS temperature probe). If below the acceptable temperature, this sample was considered void and a further sample was requested. Any urine sample considered void or missing was treated as a positive sample.