Guidance

Oral methadone and buprenorphine: recommendations

Published 27 December 2024

Applies to England

Introduction

Opioid substitution treatment (OST) is proven to reduce harm to people who are dependent on opioids. In 2007, the National Institute for Health and Care Excellence (NICE) technology appraisal Methadone and buprenorphine for the management of opioid dependence (TA114) made the following recommendations:

Methadone and buprenorphine (given as a tablet or a liquid) are recommended as treatment options for people who are opioid dependent.

A decision about which is the better treatment should be made on an individual basis, in consultation with the person, taking into account the possible benefits and risks of each treatment for that particular person. If both drugs are likely to have the same benefits and risks, methadone should be given as the first choice.

Different people will need different doses of methadone or buprenorphine. People should take methadone or buprenorphine daily in the presence of their doctor, nurse or community pharmacist for at least the first 3 months of treatment and until they are able to continue their treatment correctly without supervision.

Treatment with methadone or buprenorphine should be given as part of a support programme to help the person manage their opioid dependence.

In 2017, Drug misuse and dependence: UK guidelines on clinical management (the Orange Book) developed these recommendations further and in more depth, as well as taking into account changes in clinical practice since 2007. It also referenced the NICE clinical guideline Drug misuse in over 16s: opioid detoxification (CG52).

Since these guidance documents were published, there have been 3 main changes which meant that an update was necessary:

• our knowledge base (research evidence, data and clinical experience) has grown, and so has the availability of different buprenorphine formulations
• we have more evidence that engagement with OST is associated with reduced mortality across a range of conditions
• the arrival of potent illicit synthetic opioids in the UK has reinforced the importance of engaging and retaining greater numbers of opioid dependent people in treatment

These changes led to the Department of Health and Social Care (DHSC) convening a clinical expert group to consider the evidence and clinical experience to advise DHSC on recommendations for England to supplement the Orange Book. This guidance on the choice between, and use of, methadone and buprenorphine in OST is the first output of that work. We will update it in 2025 to include guidance on the use of buprenorphine long-acting injection in treatment.

NICE has confirmed that except for the recommendations on the duration of supervised consumption, this guidance does not significantly differ from its TA114 and CG52. Since these documents were published, clinical practice and guidance has already established greater flexibility than was recommended in 2007.

Recommendations

The Orange Book remains the main reference document for treating people dependent on opioids, based on the NICE drug misuse guidance. However, the clinical expert group has made the following recommendations to DHSC, where it has reviewed published evidence and clinical experience, and believes practice could change. DHSC has accepted these recommendations and used them to form this guidance.

In this guidance, ‘oral’ is used as shorthand for formulations that are swallowed or allowed to dissolve in the mouth.

Buprenorphine and methadone must be available

All treatment systems must have buprenorphine and methadone available as treatment options.

In most circumstances, you should offer patients a choice of medication, methadone or buprenorphine.

You should discuss the risks and benefits of each treatment option with the patient.

Where you do not consider one treatment option suitable, you should explain the reason why to the patient.

Rapid prescribing should be available

All appropriate patients in every locally-commissioned drug treatment system should have access to rapid prescribing, including on their first day in the service.

Decisions about supervised consumption should be based on assessment

You should base decisions about supervised consumption of OST medication on an individualised assessment of benefits and risks to the patient and the community. You should do this for each medication and dispensing option. You should also do this assessment in collaboration with the patient.

You should consider balancing the risk of a patient dropping out of treatment and continuing illicit drug use, against the risk to the patient of unsupervised dispensing of medication.

If a patient is prescribed methadone, you should consider keeping the usual requirement for methadone supervision at the start of treatment and ongoing supervision until the patient achieves stability, in line with the Orange Book.

If the patient is prescribed buprenorphine, you should consider:

• providing take-away doses for the initial dose at the start of treatment, to allow the patient to take buprenorphine when they experience significant withdrawal symptoms and to divide doses where appropriate
• unsupervised medication from the start of treatment, subject to an appropriate assessment of the benefits and risks - in appropriate circumstances this can be up to 7 days of oral buprenorphine

When to offer buprenorphine before methadone

You should offer buprenorphine in preference to methadone if:

• you are concerned that the patient may have a low or uncertain level of opioid tolerance
• you are concerned about the patient’s use of other prescribed sedatives and of non-prescribed drug or alcohol consumption (you should advise patients that there is a risk of fatal oversedation regardless of which form of OST medication is prescribed)
• the patient has significant comorbid cardiac or respiratory disease
• a supervised consumption option does not exist, for example in rural areas
• the patient has significant issues with mobility (whether due to physical or psychiatric illness) that prevents them attending a pharmacy regularly

Methadone may still be a viable option in each of these scenarios, after you consider the benefits and risks.

In-person assessments for OST

You should usually assess a patient for OST in person. If this is not possible, you can carry out much of the assessment remotely. But you should usually conduct biological testing for non-prescribed substance use, and carry out a physical examination, before a patient starts treatment. For more information, see guidance on Substance misuse: providing remote and in-person interventions.

Adequate doses for oral buprenorphine

When inducting a patient onto buprenorphine, you should provide an adequate initial dose.

The Orange Book recommends a dose between 4 and 8 milligrams (mg) on the first day in most cases.

There are clinical scenarios where it may be appropriate to prescribe a lower dose, such as concerns about tolerance, comorbid substance use or lung disease. There are also scenarios where it may be appropriate to prescribe more than 8mg of buprenorphine on the first day.

Usually, the patient should return the following day for further assessment, and an increase in dose of up to a further 8mg if required.

Prescribing the optimal dose

You should prescribe patients the optimal dose of OST medication that supports them to reduce or stop non-prescribed opioid use and remain in treatment.

You should assess patients before each incremental change in dose of OST medication, whether they are prescribed methadone or buprenorphine. You can carry out this assessment remotely if you think it is appropriate, after you consider the risks and benefits.

Appropriate monitoring of the patient

For all patients, whether their OST is supervised or unsupervised, they should be appropriately monitored. This includes regular reviews and the opportunity to check the patient’s self-reported history with the results from random drug tests.

At these reviews, you should consider the benefits and risks of the current dispensing regimen, and change it if appropriate.

If the patient shows evidence of not benefitting from unsupervised buprenorphine or methadone dosing, you should consider reintroducing supervised consumption. Or, if appropriate, you could consider switching to long-acting injectable buprenorphine (guidance to follow in 2025).

Evidence for the patient not benefitting can include:

• instability
• ongoing regular non-prescribed drug use
• excessive alcohol use
• deterioration of functioning
• diversion of prescribed medication

Considerations for take-away doses

If you believe the patient is suitable for take-away doses, you should:

• assess dangers to children or vulnerable adults in the home from OST medication
• provide a lockable box to store the medication, if necessary and unless the patient chooses to provide one

You should also consider whether the patient is at risk of coercion to divert their medication.

Safe transfer of prescribing between settings

Services need to ensure that there are smooth arrangements for safe transfer of prescribing between settings, to make sure there is no break in prescribing of OST due to service factors. This includes circumstances such as:

• changes to service provision, including opening hours
• when the patient moves home
• release from prison
• admission to and discharge from hospital

In these situations, there should be appropriate communication between settings before a patient is transferred.

Evidence for recommendations

The above recommendations are based on evidence considered by the clinical expert group. It includes the following research, grouped into relevant areas.

Difference in fatal overdose risk

Research has suggested a reduced risk of overdose with buprenorphine over methadone but there are significant concerns about confounding factors and risks of bias in the analysed studies (Sordo and others, 2017; Lim and others, 2023).

The clinical expert group considered these studies, and looked at other sources of information, including data relevant to England and clinical experience. A cohort study in primary care of buprenorphine and methadone in England suggested reduced mortality in people prescribed buprenorphine instead of methadone (Hickman and others, 2018).

National Drug Treatment Monitoring System (NDTMS) data shows that about 70% of patients on OST in England are prescribed methadone and about 30% prescribed buprenorphine. However, the Office for National Statistics report Deaths related to drug poisoning in England and Wales showed that in 2023 there were 709 deaths involving methadone, compared with 46 deaths involving buprenorphine. This difference in mortality has remained at least tenfold for each of the past 10 years.

The difference in safety profile between methadone and buprenorphine was reflected during the COVID-19 pandemic, when supervised dispensing regimens were necessarily relaxed. There was a significant increase in methadone deaths but no corresponding increase in buprenorphine deaths (Aldabergenov and others, 2022).

Differences in pharmacology

There are differences in pharmacology between methadone and buprenorphine. As a partial agonist and antagonist, buprenorphine is reported to have a ‘ceiling effect’, in both human and preclinical studies (before clinical trials in humans), meaning that above a certain point, buprenorphine does not generate any more respiratory depression (Walsh and others, 1994; Dahan, 2006).

There is no evidence that methadone, as a full agonist, has a ceiling effect and higher doses are more likely to lead to respiratory suppression (Corkery and others, 2004). Both methadone and buprenorphine show considerable inter-individual variation (differences in behaviours between members of a population) in plasma levels at any given dose (Kuhlman Jr and others, 1996; Eap and others, 2002).

Multiple studies have shown the increased risk of mortality from methadone compared with buprenorphine during the induction phase (Kimber and others, 2015; Sordo and others, 2017; Hickman and others, 2018).

The clinical expert group thought that these differences in pharmacology and risk allow for a quicker induction onto a therapeutic dose of buprenorphine than can be safely achieved with methadone.

Risks of non-prescribed use

Non-prescribed use of OST medication, from diverted prescribed medication, is a concern.

Studies in England have shown that most methadone deaths occur in people who are not in OST (Aldabergenov and others, 2022). Internationally, in West Virginia, USA, a study of methadone deaths revealed that 67% of them were non-prescribed (Weimer and others, 2011), with similar findings in Norway (Clausen, 2014). A study in England and Scotland found a significant reduction in methadone mortality after introducing supervised consumption (Strang and others, 2010).

Given the difference in pharmacological profiles, the clinical expert group thought that the risk of diverted buprenorphine was less than the risk of diverted methadone.

International experience

International comparisons can be problematic given that drug use and drug treatment systems often depend on national culture. However, experience in France suggests that buprenorphine can be prescribed with fewer dispensing restrictions (such as supervised dispensing and daily collection) than methadone, without increasing the mortality rate from buprenorphine diversion (Auriacombe and others, 2004).

The USA has a long history of allowing significant take-home doses of buprenorphine from the start of treatment (SAMHSA, 2021) but has not seen a large number of buprenorphine-related deaths (Tanz and others, 2023).

Finland has had a different experience. There, buprenorphine is the main opioid implicated in drug-related deaths, although rarely as an isolated substance. Most buprenorphine deaths in Finland are among people not prescribed buprenorphine by treatment services (Mariottini and others, 2024).

Increasing the numbers in treatment

Using the reports Adult substance misuse treatment statistics: 2022 to 2023 and Estimates of opiate and crack use in England, we estimate that English treatment services currently engage a little under half (47%) of the opioid dependent population in treatment each year. People who are not in treatment are at increased risk of fatal overdose.

A main goal of the English treatment system is to expand access to OST. Evidence suggests inadequate take-away doses of buprenorphine from the start of treatment is a reason for patients dropping out of treatment (Meinhofer and others, 2019). Another of the reasons stated by patients for not engaging in treatment is the restrictions of, and stigma surrounding, supervised consumption of medication (Wakeman and Rich, 2018; Scott and others, 2023).

The clinical expert group considered that buprenorphine’s better safety profile allows guidance on supervised consumption to be relaxed for some people. The arrival of long-acting forms of buprenorphine allows others to avoid supervised dispensing of medication entirely.

Retention in treatment

Oral buprenorphine has been shown to retain fewer patients in treatment than oral methadone (Sordo and others, 2017; Hickman and others, 2018; Lim and others, 2023). Being in treatment protects against mortality and morbidity in opioid-dependent populations, and methadone has been shown to retain patients for longer in treatment than buprenorphine (Degenhardt and others, 2023). The expert group thought that this improved retention in treatment with methadone helped offset the increased mortality associated with methadone induction and diversion, described in the ‘Differences in pharmacology’ section above.

The arrival of several forms of long-acting buprenorphine, with a growing evidence base of improved retention, may change that balance. This type of buprenorphine has reported higher rates of retention in treatment than oral buprenorphine (Farrell and others, 2022; Marsden and others, 2023). Buprenorphine long-acting injection will be covered in the second part of this guidance, which we will publish in 2025.

Therapeutic dose

Evidence has suggested that a therapeutic dose of OST medication is in the range of:

• 60mg to 120mg a day of methadone (Faggiano and others, 2003)
• 8mg to 16mg (and up to 32mg) a day of buprenorphine (Fareed and others, 2012; Mattick and others, 2014)

Data from the NDTMS shows that some patients continue to use non-prescribed opioids when receiving doses of methadone and buprenorphine at or below these therapeutic doses. The Orange Book states that these patients should be offered a higher dose. Clinical experience from the expert group suggests that some patients stop non-prescribed opioid use if they are on lower doses than the above therapeutic doses, and in these circumstances do not need a higher dose.

More recent evidence suggests that a patient’s dose of buprenorphine should be individually tailored to achieve optimal stability, retention in treatment, and stop non-prescribed opioid use (Chalabianloo and others, 2024).

For methadone, the significant inter-individual variation affecting the ratio of plasma concentration to dose has already been covered in the ‘Differences in pharmacology’ section above. Factors affecting inter-individual variation include genetic differences, gender, obesity and associated medication.

Buprenorphine induction

Initial doses of buprenorphine of 4mg or less have been associated with patients dropping out of treatment (Samples and others, 2018; Meinhofer and others, 2019). The clinical expert group noted that, from their clinical experience, there are many reports of underdosing with buprenorphine and slow induction regimes that take significant time to reach an optimal dose.

Clinical expert group

The clinical expert group members are listed below. DHSC provided the group’s secretariat.

Dr Michael Kelleher (chair), South London and Maudsley NHS Foundation Trust and DHSC

Daniel Ahmed, Cranstoun

Dr Prun Bijral, Change Grow Live

Dr David Bremner, Turning Point

Dr Nicola Kalk, South London and Maudsley NHS Foundation Trust

Professor John Marsden, King’s College London and DHSC

Martin McCusker, Lambeth service user council

Graham Parsons, Waythrough

Soyar Sherkat, Central and North West London NHS Foundation Trust

Professor Sir John Strang, National Addiction Centre

Dr Roya Vaziri, Waythrough

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