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30 November 2011

Final Concord seminar (ever): life beyond maintenance ...

"The Exit Strategy Part 2: Is there life after methadone?"

Tuesday December 7 2010 saw the final Dependency Seminar at Concord Hospital, which concluded with a presentation of native flowers and thanks to Andrew Byrne, whose energy and organizing skills whose energy and organizing skills kept the Concord Seminars going over more than a decade. The series continues in similar format and new venue, at Royal Prince Alfred Hospital.

Nick Lintzeris and Richard Hallinan presented an overview of published evidence about duration of opioid substitution treatment (OST), withdrawal and reduction regimens, "cycling in and out of treatment", the relative ease of reductions for methadone and buprenorphine and other matters.

Key points:

People come off OST in numerous ways, the most common methods are simply jumping off, and gradual reductions.

The issue of exit from OST should be discussed openly at the time of treatment induction.

There should be a shared understanding of when coming off treatment is likely to be successful, and clear milestones for achieving this.

Abstinence from problematic substance use, and psychosocial stability are generally preconditions for coming off OST.

Psychoeducation is important to allay inappropriate fears about coming off treatment.

Patients need to understand that their body takes time to adjust (reverse neuroadaption to opioids) - it's not just a matter of "the methadone getting out of my system”.

A flexible menu of options for coming of treatment should be offered, as well as after care.

There is no evidence that transfer from methadone to buprenorphine improves the chances of sustainably coming off OST, but it is one of the menu of options.


A common complaint about opioid substitution treatment (OST) is that there is "no exit strategy". People talk of liquid handcuffs, and critics claim OST just keeps people addicted forever.

How should the health professionals respond to a request for reductions toward abstinence? Is there any evidence to guide professional practice?

Richard Hallinan began by pointing out that people come off OST all the time, with retention rates varying from 40-70% after 12 months. Some "jump off" treatment, others use shorter or longer tapers of methadone or buprenorphine, or accelerated withdrawal regimens. But many or most of these people return to OST. There is a common pattern of cycling in and out of treatment, particularly with buprenorphine.

RH proposed to discuss "exit" from OST in terms of coming off treatment "sustainably". In the absence of an agreed definition he proposed a working definition: “sustainable exit” means not needing to return to OST.

Sadly, there is very little evidence for how this be best done. Korner and Waal (2005) reviewed the issue of reductions off MMT and found studies heterogenous, poorly described, methods and results extremely various. A total of 1900 people in 14 studies were followed up for 1 to 24 months after reductions off MMT, with reductions ranging over periods up to 7 months, with sustained periods of abstinence achieved by 33%, ranging from 22% to 86%.

Interestingly the 86% figure comes from Andrew Byrne's 9-year follow up published in 2000.

RH proposed some preconditions for sustainably coming off OST. There should be:
• no current injecting drug use nor problematic other substance use (otherwise there is a likelihood of relapse, or "swapping the witch for the bitch", ie substituting other drugs);
• no "chemical coping" with life stresses;
• psychosocial stability, including stable mental health (no uncontrolled mood or anxiety disorders) and stable housing; and
• no uncontrolled chronic pain.

As to when to start reducing off OST, RH proposed there should usually be 3-6 months since last problematic opioid use, and since last injecting drug use. The journey of reductions doesn't really begin until you achieve a probationary period of abstinence. Every time a person in OST injects, they are resetting the "trip meter" on their journey.

Should the reductions by a fixed or physician determined protocol, or flexible patient determined protocol with room to rest on the way? The small number of published benefit shows no clear benefit for physician regulation.

How fast should reductions be? 10% per 3-4 days (as for example at the residential facility WHOS MTAR: see Concord Summary from 2005), or 10% per week, or per month? Senay et al (1977) randomised MMT patients to 3% or 10% weekly reductions, and those reducing by the slower protocol did clearly better on a number of measures.

Should reductions be linear (straight down) or inverse exponential (landing like an aeroplane)? Strang and Gossop (1990) compared linear with inverse exponential reductions and found no benefit for the latter: perhaps because the reductions were completed within 10 days. One's impression is that most physicians and patients elect smaller dose reductions as their dose gets smaller.

Many people describe having "hit a wall" during attempts at methadone reductions, often after 4 or 5 successful dose reductions, and actually increased their dose again after that.

RH suggested one way of understanding the phenomenon of "hitting a wall" during reductions: consider the pattern of symptom recovery from one reduction, and then imagine what happens when you add more reductions.

Previous studies from the Maudsley showed symptoms peaking at the very end of both 10 and 21 day methadone reductions protocols, and declining slowly (and apparently inverse exponentially!) after that, persisting in a long "tail" up to 40 days (Gossop et al 1987, 1989).

Thus, after early rapid improvement of symptoms from one dose reduction, a person may be tempted to add another reduction, even though the "tail" of symptoms from the previous reduction persists. If enough "tails" accumulate, one is left with significant symptoms with no sign of improvement day to day: "hitting a wall".

Patients need to understand that their body takes time to adjust (reverse neuroadaption to opioids) - it's not just a matter of "the methadone getting out of my system", as many people imagine.

RH suggested reduction of 10% of the current dose (ie inverse exponential), every 3-4/weeks, resting whenever necessary, with the prescriber "pulling on the reins", as patients are often keen to reduce more quickly.

How long would it take to get off methadone at this rate? From 200mg methadone there are about 31 reductions. For example: 200mg - 180 - 165 - 150 - 135 - 120 - 110 - 100 - 90 - 80 - 70 - 62.5 - 55 - 50 - 45 - 40 - 35 - 32.5 - 30 - 27.5 - 25 - 22.5 - 20 - 17.5 - 15 - 12.5 - 10 - 8 - 6 - 4 - 2 - 0.

At 3 weeks between reductions, that’s 93 weeks to come off 200mg. Compare that with reductions from 100mg (24 reductions = 72 weeks) or from 50mg (19 reductions = 57 weeks).

The bottom end reductions take most of the time.

To put that in perspective, RH referred to a study from The Redfern Clinic (Hallinan et al 2006) which found each 50mg of increased methadone dose doubled the odds of not using heroin, the same odds achieved by staying an extra 34 months on MMT at the same dose.

Thus a higher dose may get people on the road to reductions much sooner, more than compensating for the modest increase in time required for reductions.

Of course, at some point people have to jump off (otherwise the frog would never reach the wall). Some people jump at 10mg. One patient of the Byrne surgery continued on 1mg methadone/day for many months.

Is coming off buprenorphine maintenance any easier?

Although there is some evidence for the superiority of buprenorphine for opioid withdrawal management (Gowing et al 2009), there is no published evidence to demonstrate sustainable reductions off maintenance pharmacotherapy are easier or quicker with buprenorphine, nor any evidence that transfer from MMT to buprenorphine with subsequent reductions is more effective than reductions off methadone maintenance (though it is feasible: Breen et al 2003). Top end buprenorphine reductions may be particularly easy where the daily dose exceeds receptor saturation (typically above 16 mg/day).

RH's advice is: don't transfer from methadone to buprenorphine for the sake of it; don't transfer to buprenorphine if methadone reductions are going well; but if the methadone dose is no longer "holding" 24 hours, there is a reasonable chance buprenorphine will last better. Methadone to buprenorphine transfer doesn't always succeed, and it can be disappointing to end up on 32mg buprenorphine when transferring from 25mg of methadone!

Nick Lintzeris advised us to take much of what RH had said with a grain of salt!

People come off OST every which way, is the long and short of it. His rule of thumb is that 1/3 of people find coming off MMT easy and 1/3 find it very difficult.

Breen et al (2003) found a majority of people on low dose methadone maintenance randomized to buprenorphine based reductions lasting up to 16 weeks managed to reduce to zero, but only 31% were abstinent from opiates a month later. The published evidence for long-term benefit of “rapid opioid detoxification” is equivocal at best (see seminar summary of The Exit Strategy Part 1).

NL pointed out that although many people would like to come off OST, many are daunted by the prospect; as are their care providers. A large cross-sectional study of MMT clients found only 17% had interest, confidence and good prospects for methadone reductions. Clinic staff and doctors were less optimistic about post-withdrawal outcomes than patients. (Lenné et al 2001).

NL also cited a recent study "Should I stay or should I go?" Coming off methadone and buprenorphine treatment. (Winstock et al 2010), showing high levels of interest and low levels of confidence in coming off OST; interest being higher in people who had been on treatment longer. Surprisingly, the most common method previously used was jumping off treatment (though perhaps that is why they were back in treatment). The idea of physician regulated-reductions was more popular among clients than patient-regulated.

But it is true that we have little research to guide us. We were reminded of the historical context: the first days of MMT in which the opioid treatment was seen as replacement in a neurochemical deficiency syndrome, with the expectation that the treatment would be long term, followed by a swing toward low dose and limited duration treatment in the 1990s. As evidence showed inferior results for lower doses and shorter treatments, by the middle years of this decade the swing was back to higher doses and longer treatment.

The fight to establish a person's right to stay on OST, if they need and want to, may have overshadowed considerations about how to end the treatment. It is particularly telling that one of the measures of treatment success in opioid pharmacotherapy is RETENTION in treatment.

NL pointed out that little is known about the long term consequences of opioid pharmacotherapy on physical health, as the patient cohort ages: 16% of OST patients in Australia are over the age of 50, and as they grow older, there will be increasing problems with other medical illnesses, medication interactions, transport and mobility issues, and the cost of continuing supervised dosing.

NL proposed that the issue of an exit from treatment should be discussed openly at the time of treatment induction. There should be a shared understanding of when coming off treatment is likely to be successful, and clear milestones for achieving this.P Psychoeducation is important to allay inappropriate fears about coming off treatment and a flexible menu of options for coming of treatment should be offered, as well as after care. Clearly we need more research on this subject.

There were two cases presented:

Hugh, 47 yo, was already 20 years on MMT, and his last heroin many years ago, though he continued weekly to monthly cocaine use. His highest previous MMT dose was 170mg and current dose 110mg. Previous reductions had stalled at 80mg, several times. He had decided he would never be able to get his dose under 80mg.

Detailed history revealed morning anxiety, butterflies in stomach especially when attending for supervised doses at 8am (take-home doses he consumed at 5am). Anxiety interfered with his work, sometimes feels afraid to go out. Hugh used occasional diazepam to assist with this, mainly on days of supervised dosing. On examination pre-dose Hugh had huge pupils and a pulse of 94. He was visibly anxious.

Hugh was offered a trial of low dose fluvoxamine 25mg mane, increased to 50mg/day with considerable improvement in his anxiety. Advised that methadone reductions would fail while his cocaine use continued, he indeed ceased cocaine use. At time of writing his methadone dose had reached 15 mg by logarithmic reductions over 2 years. Reductions were supported by PRN dispensing of small numbers of diazepam tabs 5mg*4 at a time, though he has now ceased these.

Discussion centred on the use of fluvoxamine to reduce methadone clearance in rapid metabolisers (with care needed that toxicity doesn't develop). One colleague reported a case of acute opioid withdrawal in a methadone patient who suddenly stopped their fluvoxamine.

The second case was Domel, whose first MMT was at age 26. He was a heroin smoker of 8 years. Though he continued THC heavily, he ceased heroin quickly with methadone dose at 85mg and reduced to 35mg methadone by 1 year into treatment. He transferred to 16 mg buprenorphine, with further reductions to 4mg within 5 months, and to 1.2mg by 10 months. However further reductions were limited by restless and cramped legs when his dose was late, feeling nauseous in the morning before dose, unable to cope if he missed a day's dose.

He reached 0.2 mg/day by 16 months, and 0.1mg (using "Temgesic" tablets) by 24 months into BMT. Despite the cost and inconvenience of continuing treatment, he was not prepared to jump off buprenorphine. At his physician's insistence he finally ceased buprenorphine a year later with assistance of clonidine, paracetamol, ibuprofen, leg and back stretches, and mirtazepine to assist with sleep. He remains opioid abstinent 12 months later.

Discussion centred on the possibility that Domel's symptoms were psychological (which neither he nor his physician believed), the difficulty of low-end reductions, and the unavailability of buprenorphine/naloxone in tablets less than 2mg buprenorphine.

Selected references

Breen CL, Harris SJ, Lintzeris N, Mattick RP, Hawken L, Bell J, Ritter AJ, Lenné
M, Mendoza E. Cessation of methadone maintenance treatment using buprenorphine: transfer from methadone to buprenorphine and subsequent buprenorphine reductions. Drug Alcohol Depend. 2003 Jul 20;71(1):49-55.

Byrne A. Nine-year follow-up of 86 consecutive patients treated with methadone in general practice, Sydney, Australia. Drug Alcohol Rev 2000;19:153 - 8.

Gossop M, Bradley B, Phillips GT. An investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21-day in-patient methadone detoxification procedure. Addict Behav. 1987;12(1):1-6.

Gossop M, Griffiths P, Bradley B, Strang J. Opiate withdrawal symptoms in response to 10-day and 21-day methadone withdrawal programmes. Br J Psychiatry. 1989 Mar;154:360-3.

Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002025. ..... "Buprenorphine may offer some advantages over methadone, at least in inpatient settings, in terms of quicker resolution of withdrawal symptoms and possibly slightly higher rates of completion of withdrawal."

Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis. Drug Alcohol Depend. 2006 Feb 1;81(2):129-36.

Kornor H, Waal H. From opioid maintenance to abstinence: a literature review. Drug Alcohol Rev. 2005 May;24(3):267-74.

Lenné M, Lintzeris N, Breen C, Harris S, Hawken L, Mattick R, Ritter A. Withdrawal from methadone maintenance treatment: prognosis and participant
perspectives. Aust N Z J Public Health. 2001 Apr;25(2):121-5.

Senay EC, Dorus W, Goldberg F, Thornton W. Withdrawal from methadone maintenance. Rate of withdrawal and expectation. Arch Gen Psychiatry. 1977 Mar;34(3):361-7.

Strang J, Gossop M. Comparison of linear versus inverse exponential methadone reduction curves in the detoxification of opiate addicts. Addict Behav. 1990;15(6):541-7.

Winstock AR, Lintzeris N, Lea T. "Should I stay or should I go?" Coming off methadone and buprenorphine treatment. Int J Drug Policy. 2010 Oct 16. [Epub ahead of print]