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: Fergus.Law@awp.nhs.uk ; Tel: 0117-9754840; Fax: 0117-9586569

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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.

2

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

3

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

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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). 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 detoxificationwithout 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).

5

Studies covering aAAThis study is unusual because it involves all phases of addiction

treatment 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

6

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

7

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,

8

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

9

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 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.

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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?

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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

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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).

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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.

Insert table 3 about here

Patients 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

14

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 here

Contingency 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

15

on the following three days (irrespective of whether the urine sample was opiate positive

or negative).

MEASURESMeasures

Opiate withdrawal symptoms and cravings:

Opiate Withdrawal Scale

Subjective 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 Scale

The 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 Screening

Urine 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.

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Physiological measures.

Blood pressure and heart rate was measured daily for the first two weeks of

induction/stabilisation 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 analysis

We 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.

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Results

The 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 here

Induction/stabilizationstabilisation phase

The 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

18

were no differences in the numbers successfully completing induction or

stabilizationstabilisation between the groups.

Insert table 5 about here

Withdrawal Detoxification phase

The 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 here

The 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 here

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Use 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.

Discussion

Suboxone and lofexidine are two medications with different mechanisms of action which

have utility in the treatment of opiate withdrawal. In this pragmatic Rrandomised

CcControlled tTrial of uncomplicated cases, Overall 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

20

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

21

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/stabilisation 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

22

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.

23

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.

SUMMARYSummary

Both 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.

24

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.

25

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32

Table 1: Interventions

Medications Psychological interventions

Suboxone group Methadone/

-lofexidine group

Both groups identical (non-

manualised)

Induction and

stabilizatio

nstabilisation

phase (2-6

weeks)

4mg/1mg

Suboxone*

No prn PRN

medications

30mg methadone*

No prn PRN

medications

1. Reassurance during induction

2. 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 vouchers

Detoxification

phase (2½ .5

weeks)

Gradual

Suboxone

withdrawal plus

prn PRN

medications

(hypnotic,

analgesic,

anxiolytic,

antispasmodic)

Lofexidine assisted

methadone

withdrawal

plus 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/½/0.5mg Suboxone or 15mg methadone on day 1 if appropriate

33

Table 2: Characteristics of patients on entry to treatment

Variable Methadone/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]

Heroin 2.8 [1.5, 3.0] [2.0] [2, 3]Amphetamines 0 [0, 0] [0] [0, 0]Cannabis 0.11 [0, 1] [0.07] [0, 0.53]Crack cocaine 0 [0, 0.04] [0] [0, 0.04]Tranquilisers 0 [0, 0.125] [0] [0, 0]Alcohol 0.02 [0, 0.58] [0.05] [0, 0.97]Tobacco 12.5 [10, 20] [15] [10, 17.8] Opiate Treatment Index polydrug use score

5 [3, 6] [5] [3, 5]

*missing data for 1 individual in each arm

34

Table 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

detox

Suboxone group Methadone and lofexidine group

Number of active Suboxone

(2/0.5mg) tablets with number

of placebo tablets in brackets

Active Methadone (1mg/ml)

plus placebo methadone

(ml) dose in brackets

Lofexidine dose

in mg (regular

plus PRN dose)

0 2 (+0) 30 (+ 0) 0.0 + 0.0 PRN

1 1.5 (+0.5) 20 (+ 10) 0.4 + 0.8 PRN

2 1.5 (+0.5) 15 (+ 15) 0.8 + 0.8 PRN

3 1.5 (+0.5) 10 (+ 20) 1.2 + 0.8 PRN

4-7 1 (+1) 0 (+ 30) 1.6 + 0.8 PRN

8 0.5 (+1.5) 0 (+ 30) 1.6 + 0.8 PRN

9 0.5 (+1.5) stop 1.6 + 0.8 PRN

10 0.5 (+1.5) 1.6 + 0.8 PRN

11 0 (+ 2) 1.6 + 0.8 PRN

12 0 (+ 2) 1.2 + 0.8 PRN

13 0 (+ 2) 0.8 + 0.8 PRN

14 0 (+ 2) 0.4 + 0.8 PRN

15 0 (+ 2) 0.0 + 0.8 PRN

16 0 (+ 2) 0.0 + 0.8 PRN

17 Stop stop

35

Table 3 – Characteristics of subjects on entry to treatment

Variable Methadone/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]

Heroin 2.8 [1.5, 3.0] [2.0] [2, 3]Amphetamines 0 [0, 0] [0] [0, 0]Cannabis 0.11 [0, 1] [0.07] [0, 0.53]Crack cocaine 0 [0, 0.04] [0] [0, 0.04]Tranquilisers 0 [0, 0.125] [0] [0, 0]Alcohol 0.02 [0, 0.58] [0.05] [0, 0.97]Tobacco 12.5 [10, 20] [15] [10, 17.8] OTI polydrug use score 5 [3, 6] [5] [3, 5]

*missing data for 1 individual in each arm

Figure 1: CONSORT diagram

36

CONSORT DIAGRAMEn

rollm

entE

nrol

men

t Assessed for Eligibility (n = 111)

Excluded (n = 23) Failed to attend appt offered (n = 23)

Randomized (n = 80)

Allo

catio

n Allocated to Suboxone (n = 40) Received intervention (n = 40)

Allocated to mMethadone/lofexidine (n = 40) Received intervention (n = 40)

Trea

tmen

t and

follo

w-u

p

Completed 2 week induction (n = 35) Lost to follow-up (n = 5)

Completed 2 week induction (n = 37) Lost to follow-up (n = 3)

3 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) Discontinued intervention (n = 2)

3 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) Discontinued intervention (n = 2)

Completed 3 week gradual Suboxone reduction (n = 21) Lost to follow-up (n = 0) Discontinued intervention (n = 0)

Completed 3 week lofexidine assisted methadone withdrawal (n = 23) Lost to follow-up (n = 1) Discontinued intervention (n = 1 due to pregnancy)

Completed 12 week follow-up (n = 7) Lost to follow-up (n = 14)

Completed 12 week follow-up (n = 9) Lost to follow-up (n = 14)

Ana

lysi

s All 40 included in analysis All 40 included in analysis

37

38

Table 43: Use of adjunctive medications during detoxification

Suboxone group Methadone/Llofexidine group

% Pts

subjectpatient

used

medication

Mean

no. days

used

Median

%

of use

Range

of

values

% Pts

subjectpatient

used

medication

Mean

no.

days

Pts

used

Median

% of

use

Range

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%

39

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 urines

Physiological measures:

Pulse rateDiastolic blood pressureSystolic blood pressure

Single Dose Opiate Questionnaire:

How highDrug effects

Good drug effectsBad drug effectsHow sick effects

LikeHow normal

Methdone/ Lofexidine

(n=40)

Suboxone(n=40)

Difference favouring Methadone/ Lofexifine

group

Mean (SE) Mean (SE) Mean (SE) 95% CI

17.5 (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; 12.5

2.67; 17.6**

* significant at 0.05 level** significant at 0.01 level

40

Table 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 urines

Physiological measures:

Pulse rateDiastolic blood pressureSystolic blood pressure

Methdone/ Lofexidine

(n=37)

Suboxone(n=35)

Difference favouring Methadone/ Lofexifine

group

Mean (SE) Mean (SE) Mean (SE) 95% CI

16.7 (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; 0.1

2.0; 13.8**-4.6; 3.8

-12.8; 3.0

* significant at 0.05 level** significant at 0.01 level

41

Figure 21: Adjusted subjective withdrawal scores (OWS) by group during the withdrawal detoxification phase

Adjusted subjective withdrawal by trial arm - detoxification phase

0

5

10

15

20

25

30

35

1 3 5 8 10 12 15 17 19

Day

Subj

ectiv

e w

ithdr

awal

Methadone/ LofexidineSuboxone

42