The effects of pharmacological treatment with ...



Archives paperSuboxone 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, UK2Bristol Specialist Drug Service, Manor Road, Fishponds, Bristol, BS16 2EW, UK3Psychopharmacology Unit, Social and Community Medicine, University of Bristol Division of Psychiatry, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK4Addiction Research Group, Department of Health Science, University of York, York, YO10 5DD5Neuropsychopharmacology Unit, Imperial College London, Hammersmith Campus, London, W12 0NN, UK*Corresponding author: e-mail: Fergus.Law@awp.nhs.uk ; Tel: 0117-9754840; Fax: 0117-9586569Word count 4763 44413(i.e. too long, must be 3500-4500)References 316Tables 64Figures 2 (8 incl. tables)7Competing 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. AbstractContext: 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 ? g heroin smoked or ? 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 withdrawalIntroductionOpiate 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). 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 receptors in 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 Suboxone combination 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. HYPOTHESESHypothesesInduction 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 cravings and 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. MethodsSubjectsStudy design and patient recruitmentThis 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 ? gram illicit heroin IV or up to ? 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 2? .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 hereInsert Table 2 about hereInduction 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 hereLofexidine 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. Insert table 3 about herePatients were randomisedrandomiszed in blocks of 6 by Reckitt-Benckiser Healthcare (Hull, UK), who also prepared prepackaged boxes of medication for each patient number. For use in emergencies the researchers had access to the allocation code for each patient, which was containedsealed in individual sealed opaque envelopes, but such use was never required. On entry to the trial, patients were allocated the next treatment number available. During detoxification but not during stabilizationstabilisation patients were allowed adjunctive treatment (see table 4) of a single day’s supply (2 days on Saturdays) on request of zopiclone 7.5-15 mg (for night sedation), ibuprofen 400mg qds (for aches and pains), promethazine hydrochloride 10-20 mg qds (for anxiety) and hyoscine butylbromide 20 mg qds (for stomach spasms/cramps). Patients were withdrawn from the study if they failed to attend on 8 consecutive days, if they failed to provide 3 consecutive opiate-free urine samples within 6 weeks of starting the study, and or if they became pregnant (females tested weekly).The mean age, patterns of drug use, and other demographic characteristics are shown in table 3. There were no significant differences between the two groups. Insert table 43 about hereContingency payments:Vouchers from major local food supermarkets (Tesco, ASDA, and M&S) totalingtotalling ?4 per day were issued to promote retention in the study and to encourage study subjectpatients to buy essential food stuffs. Provision of food stuffs was considered important as 25% of patients were mildly anaemic on screening. In addition clients subjectpatients received ?15 for questionnaire completion on the day naltrexone was commenced (end of detoxification), and ?5 for questionnaire completion on the following three days (irrespective of whether the urine sample was opiate positive or negative).MEASURESMeasuresOpiate withdrawal symptoms and cravings:Opiate Withdrawal ScaleSubjective withdrawal symptoms were assessed using the 32 item opiate Gossop Opiate Wwithdrawal Sscale (OWS; refBradley et al., 1987) which asks how strong each symptom had been on a four point scale (not at all = 0; mild = 1; moderate = 2; severe = 3) during the last 24 hours. (Bradley et al 1987). Scores range from 0 to 96 with a higher score indicating worse perceived withdrawal symptoms.Opiate Craving ScaleThe strength of craving over the last 24 hours was assessed by a 6 item scale (Opiate Craving Scale; OCS) that was added to the subjective withdrawal symptom scaleOWS and scored in the same way by summing the items. . The 6 items were: desires to use opiates (e.g. heroin, methadone); sudden urges to score or use opiates; feeling you couldn’t resist opiates (if they were offered); finding yourself making plans to use opiates; desires or urges for other drugs (not opiates). The score ranged from 0 to 18 with higher scores indicating a higher level of craving.Urine ScreeningUrine samples were assessed using the Biocell Surescreen (Derby, UK) immunological cassettes for opiates only. Urine samples were assessed in the week prior to completion of detoxification.Physiological measures.Blood pressure and heart rate was measured daily for the first two weeks of induction/stabilizationstabilisation and the first 3 weeks of withdrawal. These were measured after 5 minutes in a resting position using a Dinamap Compact TS (Critikon, UK).Patient perceived treatment effects.These were measured using the Single Dose Opiate Questionnaire (ref?) which asked ‘How the drug treatment has made you feel over the past 24 hours?’ The 6 items chosen were ‘high’, ‘any drug effect’, ‘good effect’, ‘bad effect’, ‘sick’ and ‘like’. In addition these items were supplemented with ‘normal’. These items were scored using a Visual Analogue Scale, 100mm in length anchored with the labels ‘Not at all’ and ‘Extremely’. Power calculations and data analysisWe estimated that the difference in opiate positive urine samples during the withdrawal stage would be of the order of 30% (60% in the methadone/lofexidine group and 30% in the Suboxone group). Using this difference in proportions at 80% power, a significance level of 0.05 using a two-tailed test requires approximately 40 subjectpatients in each group. Analysis was conducted using an intention-to-treat paradigm. For time series data a mixed model analysis was adopted using the PROCMIXED module of SAS version 7. Within the mixed model approach covariates included in the model included the baseline value of the outcome variable, severity of dependence at baseline, the outcome of the urine screen for each time-point and whether the patient had received adjunct medication. Data was represented as adjusted means and standard errors, the mean difference between the groups and standard errors and the significance value. Treatment drop- outs were analysed using Chi-square.ResultsThe flow of patients through the study is illustrated in the CONSORT diagram (figure 1). 90% of patients completed the first two weeks of induction, and 58% completed stabilizationstabilisation by providing 3 consecutively opiate clean urines within 6 weeks of study entry. Of those who completed stabilizationstabilisation, 96% completed the detoxification phase.Figure 1 about hereInduction/stabilizationstabilisation phaseThe mMain outcomes from the induction/stabilizationstabilisation phase are reported in table 54. No significant differences between the groups were observed for subjective withdrawal symptoms, proportion of negative urine samples, heart rate, diastolic and systolic blood pressure, ‘How high’, ‘Drug effects’, ‘Good drug effects’, ‘Bad drug effects’, ‘How sick’ or ‘Like’ on the Single Dose Opiate Questionnaire. The mMethadone/lLofexidine group had significantly lower scores on the Opiate Craving Scale (mMean difference -3.5; p = 0.02) and higher scores on the ‘Normal’ dimension of the Single Dose Opiate Questionnaire (mMean difference 10.1; p=0.01) than the Suboxone group. Of the 80 patients randomiszed 72 successfully completed the induction phase (37 in the mMethadone/ lLofexidine group and 35 in the Suboxone group). There were no differences in the numbers successfully completing induction or stabilizationstabilisation between the groups.Insert table 5 about hereWithdrawal Detoxification phaseThe mMain outcomes from the withdrawal detoxification phase are reported in table 65. There were no significant differences observed between the groups in terms of reported craving, proportion of negative urine samples, systolic or diastolic blood pressure. The methadone/lofexidine group had significantly worse levels of subjective withdrawal symptoms (Mean difference 2.7; p < 0.01) and higher heart rates (Mean difference 7.9; p=0.01) than the Ssuboxone group.Insert table 6 about hereThe peak level of withdrawal symptoms occurred at day 8 for the methadone/lofexidine group with a peak value of 29.0. The peak level of withdrawal symptoms for the Ssuboxone group occurred later at day 12 with a peak value of 23.1 (see figure 2).Insert figure 2 about hereUse of PRN medications was increased for analgesic and antispasmodic in the methadone/lofexidine group compared with the Suboxone group, but were similar for the hypnotic and anxiolytic medications (see table 4). A total of 44 patients successfully completed the withdrawal detoxification phase (23 in the mMethadone/ lLofexidine group and 21 in the Suboxone group). There were no statistical differences between the numbers who completed withdrawal detoxification between the groups.DiscussionSuboxone and lofexidine are two medications with different mechanisms of action which have utility in the treatment of opiate withdrawal. In this pragmatic RRrandomised CcControlled tTrial of uncomplicated cases, oOverall both medications appeared to be well tolerated overall,. B with both produceding the same proportion of opiate negative urine samples during detoxification, and both were effective at reducing opiate withdrawal symptoms, and both were associated with surprisingly similar outcomes during induction and /stabilizationstabilisation and detoxification. There were no significant differences in detoxification completion rates although the sample sizes are rather small at this point (methadone/lofexidine, n=9 (23%); Ssuboxone, n=7 (18%)). We had predicted a significant difference between the two drugs, as noted in trials of clonidine (Ling et al., 2005; Hussain et al., 2015). It may be that this difference was minimized by the study itself, by intensive therapeutic input with a dedicated staff team involving daily contact and crisis intervention, focused weekly counselingcounselling and contingency management. We are unclear the extent to which these findings would generalize to clinical settings with less intensive psychosocial support, and it is possible that larger differences between the two treatments would be detected in a clinical rather than a research setting. We are aware that patient preference is forefront in clinical healthcare planning in the UK and it is possible different outcomes may have been found if patients were able to choose their own treatment, however the double-blinding, psychosocial support and contingency management would negate this effect.Throughout stabilizationstabilisation subjects patients on Suboxone reported higher levels of craving, and felt less ‘normal’ than those on methadone/lofexidine. These findings cannot be explained by precipitated withdrawal symptoms in the Suboxone group, and the most likely explanation is that the agonist doses used were not equivalent, and that a higher dose of Suboxone, such as 6mg/1.5mg, would have been clinically equivalent to 30mg methadone. Indeed, a recent study by Wright et al. (2011) comparing 8-4mg sublingual buprenorphine with 30mg methadone found comparable abstinence rates after 8 days detoxification. This non-equivalence could have potentially confounded the findings during the withdrawal phase of the study, but there is no evidence from the drop-out rates that this occurred. It is also not possible to say with any certainty that stabilizationstabilisation on Suboxone takes a few days longer than that on methadone, if equivalent doses are were being compared. Precipitated withdrawal would have increased withdrawal (and drop-outs) on induction exclusively in the Suboxone group, but in this study we minimized this effect by inducing subjectpatients at 100% of the dose required to cover their withdrawal symptoms (which in almost all cases, apart from 4 subjectpatients, was the full stabilizationstabilisation dose), and enforcing a time interval of 12 hours for heroin and 20 hours for methadone since last dose. We relied on patient history to ascertain the time interval since the last dose, and the dose of heroin used (although prescribed methadone doses could be precisely qualified).The issue of equivalent doses between buprenorphine and methadone has been long debated (Law et al., 20045), and as no difference in illicit drug use was detected, it may be that the equivalent dose to ameliorate withdrawal symptoms is different from the dose needed to stop on-top illicit opiate use. This study assumed the dose equivalence of 4mg of buprenorphine was equivalent to 30mg methadone based on our previous work (Law et al., 1997) and the finding that 2mg buprenorphine resulted in more withdrawal than 30mg methadone (Bickel et al., 1988b, reviewed in Jasinski and Preston 1995). Although previous research studies did appear to find equivalence at the doses of buprenorphine used in this study, these earlier studies used mainly ethanol based solution of buprenorphine which has a higher bioequivalence than the sublingual tablet (Strain et al., 2004). During the induction/stabilizationstabilisation phase the withdrawal symptoms gradually subsided over two weeks, which was contrary to expectation and clinical experience that withdrawal symptoms typically subside within 2 to 3 days. In fact after the two weeks of induction the level of withdrawal symptoms were still 50% above the level they would fall to prior to the withdrawal detoxification phase, indicating that 2 weeks failed to provide a sufficient period for the withdrawal symptoms to subside to a low level. This conflict between clinical experience and the withdrawal data isare difficult to explain, but one potential explanation is that some patients were using larger amounts of opiates than they reported using prior to entry into the study. During induction negative effects appeared temporarily on day 1 to 3, and waswhich were associated with an increase in feeling sicknauseous. As these effects occurred only after the second and subsequent doses of Suboxone, it is thought unlikely to be due to precipitated withdrawal which typically peaks following the first dose of buprenorphine. Even though plasma levels of buprenorphine would be building up towards steady state during the first few days, the reduced levels of the opiate used prior to treatment means that precipitated withdrawal is a very unlikely explanation (apart from those who had previously been taking methadone). The data therefore suggest that a temporary increase in nausea may have occurred on Suboxone induction.In terms of the withdrawal detoxification phase, the shape of the withdrawal curves (fig 1.) are very similar except that the methadone/-lofexidine had itsgroup showed a peak on day 8 extending above the other Suboxone curve. There was a significant difference in subjective withdrawal between the groups with the Suboxone group reporting a lower level of withdrawal effects, supporting the conclusions of the recent Cochrane review of buprenorphine (Gowing et al., 2009). Dropouts were similar between the groups at the end of the withdrawal detoxification phase. Delayed withdrawal with fewer subjective effects with buprenorphine compared with lofexidine agrees with the trial findings of Raistick et al. (2005) after 1 week detoxification.The cardiovascular effects during withdrawal showed systolic blood pressure effects were marked during the first week on lofexidine, but appeared to resolve rapidly and did not elicit clinically relevant symptoms. Other studies have not found such marked cardiovascular effects (Bearn et al., 1996), which may be because we waited a minimum of 5 minutes before taking measurements in our patients in order to improve the accuracy of our measurements. SUMMARYSummaryBoth Suboxone and methadone/lofexidine are surprisingly similar in terms of termination of illicit drug use, withdrawal symptoms and drop-outs during stabilizationstabilisation and withdrawaldetoxification. In general during stabilizationstabilisation patients subjects treated with methadone reported feeling betterfewer negative effects than those treated with Suboxone, and vice versa during detoxificationand had treatment retention was higher on methadone., while during withdrawal they reported feeling better and treatment retention was higher on Suboxone. Results indicate Suboxone may produce a delayed but more comfortable detoxification compared with lofexidine, and lofexidine may be advantageous for expediting detoxification but with less comfort than Suboxone. The novel study design used is particularly useful at looking at addiction treatment as a whole, and may be especially relevant to the identification of factors relevant to the different phases of addiction treatment. Acknowledgements: We are grateful for the hard work of the study staff, Tess Raybould, Swindapal Singh and Emma Cockerill, the cooperation of the other staff of the clinic in which the study took place especially Des Collins, and also the pharmacy staff of the Bristol Royal Infirmary. We would also like to thank Britannia Pharmaceuticals for providing both the lofexidine and lofexidine placebo free of charge. This study was funded by Reckitt-Benckiser Heathcare and Schering-Plough Pharmaceuticals. ReferencesAmerican Psychiatric Association (APA). (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn (Washington, American Psychiatric Association).Akhurst, J.S. (1999). The use of lofexidine by drug dependency units in the United Kingdom. European Addiction Research 5, 43-49.American Psychiatric Association (APA). (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn (Washington, American Psychiatric Association).Bearn, J., Gossop, M., Strang, J. (1996). 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Outpatient opiate detoxification with clonidine.J Clin Psychiatry. 1982 Jun;43(6 Pt 2):39-41Table 1: InterventionsMedicationsPsychological interventionsSuboxone groupMethadone/-lofexidine groupBoth groups identical (non-manualised)Induction and stabilizationstabilisation phase (2-6 weeks)4mg/1mg Suboxone* No prn PRN medications30mg methadone*No prn PRN medications1. Reassurance during induction2. Daily supervised consumption (with counselingcounselling as appropriate)3. Weekly 1 hour counselling (MI and RP focused on terminating on top use, crisis intervention and problem solving for life problems)4. Contingency management with shopping vouchersDetoxification phase (2? .5 weeks)Gradual Suboxone withdrawal plus prn PRN medications (hypnotic, analgesic, anxiolytic, antispasmodic)Lofexidine assisted methadone withdrawalplus prn PRN medications (hypnotic, analgesic, anxiolytic, antispasmodic)1. Daily supervised consumption (with counselingcounselling as appropriate)2. Weekly 1 hour counselling (MI and RP focused on terminating on top use, crisis intervention and problem solving for life problems)3. Contingency management with shopping vouchers*2mg/?/0.5mg Suboxone or 15mg methadone on day 1 if appropriateTable 2: Characteristics of patients on entry to treatmentVariableMethadone/Lofexidine(n = 40)Suboxone(n = 40)Mean age (SD)23.0 yrs(5.9)23.2 yrs(5.1)Female: n (%)14(35%)9(22.5%)Prior number of substitution treatments: mean (SD)*1.1(1.6)1.2(1.5)Prior number of detoxification treatments: median [IQR]*1[1, 3]2[1, 4]Number of clean years: median [IQR]*0[0, 0]0[0, 0.2]Years of heroin use: median [IQR]*2.5[2, 4]3[2, 4]Injecting heroin: n (%)*26(66.7%)28(71.8%)Smoking heroin: n (%)*39(100%)36(92.3%)Drug use (Average number of uses/amount): median[IQR]Heroin2.8[1.5, 3.0][2.0][2, 3]Amphetamines0[0, 0][0][0, 0]Cannabis0.11[0, 1][0.07][0, 0.53]Crack cocaine0[0, 0.04][0][0, 0.04]Tranquilisers0[0, 0.125][0][0, 0]Alcohol0.02[0, 0.58][0.05][0, 0.97]Tobacco12.5[10, 20][15][10, 17.8]Opiate Treatment Index polydrug use score5[3, 6][5][3, 5]*missing data for 1 individual in each armTable 32: Detoxification regime for the two patient groups. Note that the methadone/lofexidine group also had Suboxone placebo, and the Suboxone group had both methadone and lofexidine placebo (not tabulated). Day of detoxSuboxone groupMethadone and lofexidine groupNumber of active Suboxone (2/0.5mg) tablets with number of placebo tablets in bracketsActive Methadone (1mg/ml) plus placebo methadone (ml) dose in brackets Lofexidine dose in mg (regular plus PRN dose)02 (+0)30 (+ 0)0.0 + 0.0 PRN11.5 (+0.5)20 (+ 10)0.4 + 0.8 PRN21.5 (+0.5)15 (+ 15)0.8 + 0.8 PRN31.5 (+0.5)10 (+ 20)1.2 + 0.8 PRN4-71 (+1)0 (+ 30)1.6 + 0.8 PRN80.5 (+1.5)0 (+ 30)1.6 + 0.8 PRN90.5 (+1.5)stop1.6 + 0.8 PRN100.5 (+1.5)1.6 + 0.8 PRN110 (+ 2)1.6 + 0.8 PRN120 (+ 2)1.2 + 0.8 PRN130 (+ 2)0.8 + 0.8 PRN140 (+ 2)0.4 + 0.8 PRN150 (+ 2)0.0 + 0.8 PRN160 (+ 2)0.0 + 0.8 PRN17StopstopTable 3 – Characteristics of subjects on entry to treatmentVariableMethadone/Lofexidine(n = 40)Suboxone(n = 40)Mean age (SD)23.0 yrs(5.9)23.2 yrs(5.1)Female: n (%)14(35%)9(22.5%)Prior number of substitution treatments: mean (SD)*1.1(1.6)1.2(1.5)Prior number of detoxification treatments: median [IQR]*1[1, 3]2[1, 4]Number of clean years: median [IQR]*0[0, 0]0[0, 0.2]Years of heroin use: median [IQR]*2.5[2, 4]3[2, 4]Injecting heroin: n (%)*26(66.7%)28(71.8%)Smoking heroin: n (%)*39(100%)36(92.3%)Drug use (Average number of uses/amount): median[IQR]Heroin2.8[1.5, 3.0][2.0][2, 3]Amphetamines0[0, 0][0][0, 0]Cannabis0.11[0, 1][0.07][0, 0.53]Crack cocaine0[0, 0.04][0][0, 0.04]Tranquilisers0[0, 0.125][0][0, 0]Alcohol0.02[0, 0.58][0.05][0, 0.97]Tobacco12.5[10, 20][15][10, 17.8]OTI polydrug use score5[3, 6][5][3, 5]*missing data for 1 individual in each armFigure 1: CONSORT diagramCONSORT DIAGRAMEnrollmentEnrolmentAssessed for Eligibility (n = 111)2426970-17907000Excluded (n = 23) Failed to attend appt offered (n = 23)23964902114550089154021145500Randomized (n = 80)AllocationAllocated to Suboxone (n = 40)93916522669500 Received intervention (n = 40)Allocated to mMethadone/lofexidine (n = 40)111252023304500111061522098000 Received intervention (n = 40)Treatment and follow-upCompleted 2 week induction (n = 35) Lost to follow-up (n = 5)9601201397000 Completed 2 week induction (n = 37) Lost to follow-up (n = 3)11315705588000 948690-388620003 consecutively opiate negative urine samples in an additional 0-4 week stabilizationstabilisation (n = 21) Failed to stabilise (n = 9) Lost to follow-up (n = 9)9601202006600093916524003000 Discontinued intervention (n = 2) 1129665-398145003 consecutively opiate negative urine samples in an additional 0-4 week stabilizationstabilisation (n = 25) Failed to stabilise (n = 9) Lost to follow-up (n = 5)116014521971000 Discontinued intervention (n = 2)Completed 3 week gradual Suboxone reduction (n = 21) Lost to follow-up (n = 0)9505952216150092964016383000 Discontinued intervention (n = 0) 1129665-40576500Completed 3 week lofexidine assisted methadone withdrawal (n = 23) Lost to follow-up (n = 1) Discontinued intervention (n = 1 11696708445500 due to pregnancy)Completed 12 week follow-up (n = 7) Lost to follow-up (n = 14)95059573025009010652476500 1129664-35814100Completed 12 week follow-up (n = 9) Lost to follow-up (n = 14)1169670635000011582405334000 Analysis All 40 included in analysis All 40 included in analysisTable 43: Use of adjunctive medications during detoxificationSuboxone groupMethadone/Llofexidine group% Pts subjectpatients used medicationMean no. days usedMedian % of useRange of values % Pts subjectpatients used medicationMean no. days Pts usedMedian % of useRange of values Zopiclone(hypnotic)100%70.5%71.4%7-86%96%67.7%64.3%0-86%Promethazine(anxiolytic)90%50.3%50.0%0-86%96%53.8%64.3%0-86%Ibuprofen(analgesic)90%33.5%28.6%0-69%92%42.5%35.7%0-86%Hyocine Butylbromide(antispasmodic)86%25.7%21.4%0-62%92%34.2%35.7%0-64%Table 54: Mean (SE) and Mean difference (SE) between the groups for main outcomes during the stabilizationstabilisation phase.Subjective withdrawal (OWS)Opiate Craving (OCS)Proportion of opiate negative urinesPhysiological measures:Pulse rateDiastolic blood pressureSystolic blood pressureSingle Dose Opiate Questionnaire:How high Drug effectsGood drug effectsBad drug effectsHow sick effectsLikeHow normalMethdone/ Lofexidine(n=40)Suboxone(n=40)Difference favouring Methadone/ Lofexifine groupMean (SE)Mean (SE)Mean (SE)95% CI17.5 (2.1)5.1 (0.6)0.3 (0.0)75.3(1.4)65.5 (1.2)113.8 (1.9)20.2 (3.1)30.8 (3.4)49.5 (3.4)17.8 (2.7)17.4 (3.0)57.7 (3.3)61.2 (2.6)20.3 (2.2)7.1 (0.6)0.2 (0.4)76.6 (1.4)66.5 (1.2)117.2 (1.9)20.1 (3.1)26.9 (3.4)45.9 (3.4)25.2 (2.8)19.4 (3.0)54.4 (3.2)51.1 (2.6)-2.8 (3.0)-3.5 (0.7)0.1 (0.0)-0.8 (2.0)-1.1 (1.7)-3.4 (2.10)0.1 (4.4)4.0 (4.8)3.5 (4.8)-7.5 (3.9)-2.0 (4.2)3.3 (4.6)10.1 (3.7)-8.9; 13.21-3.5; -0.38*-0.3; 0.2-4.8; 3.2-4.6; 2.3-8.7; 2.0-7.6; 8.7-5.7; 13.6-6.1; 13.1-15.2; 0.2-10.4; 6.3-5.9; 12.52.67; 17.6*** significant at 0.05 level** significant at 0.01 levelTable 65: Mean (SE) and Mean difference (SE) between the groups for main outcomes during the withdrawal detoxification phase.Subjective withdrawal (OWS)Opiate Craving (OCS)Proportion of opiate negative urinesPhysiological measures:Pulse rateDiastolic blood pressureSystolic blood pressureMethdone/ Lofexidine(n=37)Suboxone(n=35)Difference favouring Methadone/ Lofexifine groupMean (SE)Mean (SE)Mean (SE)95% CI16.7 (1.9)3.1 (0.6)0.8 (0.1)87.6 (2.0)67.0 (1.4)113.5 (2.6)14.0 (2.0)3.1 (0.6)0.8 (0.1)79.7 (2.1)67.4 (1.5)118.4 (2.8)2.7 (2.8)0.0 (0.9)0.0 (0.1)7.9 (2.9)-0.4 (2.1)-4.9 (3.9)3.0; 8.3**-1.7; 1.8-0.2; 0.12.0; 13.8**-4.6; 3.8-12.8; 3.0* significant at 0.05 level** significant at 0.01 levelFigure 21: Adjusted subjective withdrawal scores (OWS) by group during the withdrawal detoxification phase ................
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