Substitute prescribing in heroin addiction

Abstract

Substitute prescribing involves the prescription in a controlled environment of a pharmaceutically manufactured medication to replace illicit or harmful drug use, as part of a broader package of psychosocial interventions to minimise withdrawal symptoms and assist an individual to gradually reduce drug misuse and/or the harms associated with high-risk using.

The problem

Department of Health (DOH) data demonstrates that the number of patients presenting to primary care with drug-related problems has increased significantly over the last few years. The increase in polydrug use, often combined with alcohol has made treatment more complex (DOH, 2017). The variety of drugs being used by young people is changing, and the number of young people presenting with heroin problems is falling. However, the most common drug misuse referred for treatment programmes is still heroin (Royal College of General Practitioners (RCGP0, 2011). Alcohol is mentioned in approximately a third of drug misuse deaths annually in England, and heroin-related deaths increasingly involve other substances (Public Health England (PHE), 2017).

PHE recorded 2383 drug misuse deaths registered in England in 2016. This represents an increase of 3.6% on 2015, and is the highest figure on record (PHE, 2017). Deaths involving opioids account for the majority of deaths from drug poisoning. Heroin-related deaths in England and Wales have more than doubled since 2012, to the highest number since records began 20 years ago (PHE, 2017) One key factor leading to an increase in heroin-related deaths is the removal of addiction services from the NHS. These services have now moved almost entirely into the third sector, and GPs no longer have accessible care. A second factor is probably the drive towards abstinence and away from harm reduction. Finally, there has been a fall in the number of GPs managing drug users, due to time pressures and work burden.

In 2014, the estimated annual cost of drug misuse was around £15.4 billion; major contributions being £13.9 billion from drug-related crime and National Health Service costs of around £0.5 billion for treatment of drug misuse (National Treatment Agency, 2014). As Fig. 1 demonstrates, drug-related crime imposes a major cost on both local communities and the national economy. There is good evidence that drug treatment significantly reduces drug-related crime; current figures suggest that for every pound spent on drug treatment to reduce illicit drug use there is a £2.50 saving to society (PHE, 2017).

Figure 1.

Estimated cost of illicit drug use in the UK.

Risk factors in drug misuse

Although drug use is seen in all sectors of society, it is most common in socially deprived areas and in patients who already have poorer health outcomes regardless of whether or not they misuse drugs. Figure 2 identifies risk factors for drug misuse leading to social disadvantage. However, social disadvantage can also lead to drug use and dependence. An example of this is homelessness, which is a complex problem and occurs for a variety of reasons. Many homeless individuals are substance misusers. However, it can be difficult to determine whether substance abuse has led to homelessness or whether this addiction is secondary to homelessness. In addition, risk factors associated with drug misuse often lead to other adverse outcomes such as poor physical or mental health and risky sexual behaviour. Therefore, before considering treatment, it is important for GPs to be aware of the complex psychosocial reasons for drug misuse and dependence.

Figure 2.

Risk factors in drug misuse.

Problems in heroin addiction treatment

Despite success with falling numbers of young people currently developing heroin dependence, the morbidity, mortality and long-term needs of an ageing cohort of patients with long-term heroin dependence problems make treatment increasingly complex. This, in turn, makes coordination of effort between services vital.

Before starting treatment

The journey from chaotic drug use to stable treatment may begin in a variety of ways. Patients may present to a GP with the sole purpose of requesting treatment, or they may present with one of the many physical complications of harmful drug use. Establishing when a patient might benefit from substitute prescribing (as opposed to other harm-reduction strategies) is a challenging, but important, primary care skill. The Orange Book, which gives DOH guidance on management of drug misuse and dependence, offers detailed guidance for clinicians to help support decisions when considering substitute prescribing (DOH, 2017).

Patient assessment

History taking

It is essential to treat any urgent/acute presentation such as overdose and withdrawal. Box 1 describes key elements of the history when assessing a patient presenting with drug misuse.

Box 1.

Key points to cover in history taking.

• What, how much, how taken (route), how often

• Other illegal/none illegal medications?

• Alcohol? Quantity/frequency/pattern of drinking/ symptoms of alcohol dependence? Smoking?

• Previous drug therapies

• Any past accidental/intentional overdoses

• Injection techniques

• Drug-related complications: Abscesses, venous thrombosis, septicaemia, endocarditis, and constipation

• What happens if they do not use?

• Past medical history

• Past/current mental health problems

• Social history: Relationships, housing, family, any crimes/offence/arrests/fines, employment, financial situation – how are drugs funded?

• Unsafe sexual practices

• Pregnancy

• Blood-borne virus (BBV) screening?

• Assess risk, both to selves and to others

Examination

When examining patients with suspected or confirmed drug misuse, GPs must have an awareness of specific conditions that can occur in this patient population (Box 2). Examination is required to confirm addiction and assess for any complications due to this addiction. Assessment of respiratory, cardiovascular and other systems, according to the history or presenting symptoms can identify subtle complications of drug misuse and signs of withdrawal (Table 1). Assessment should include measurement of weight, height and blood pressure. Injection sites should be examined if the patient is a current or past injecting drug user. It may be necessary to bring the patient back for a longer appointment in order to complete this assessment.

Table 1.

Signs of opiate withdrawal.

Objective signs of opiate withdrawal	Subjective signs of opiate withdrawal
• Yawning • Coughing • Sneezing • Runny nose • Lachrymation • Raised blood pressure • Increased pulse • Dilated pupils • Cool, clammy skin • Diarrhoea • Nausea • Fine muscle tremor	• Restlessness • Irritability • Anxiety (The signs listed above may also be useful objective signs) • Sleep disorders • Depression • Drug-craving • Abdominal cramps

Source: DOH (2017).

Box 2.

Physical problems that present more commonly in illicit drug users.

• Injection site abscess and vascular damage

• Skin or lip ulcers

• Infective endocarditis

• Thromboembolic disease

• Hepatitis and HIV

• Tuberculosis

• Intestinal and dermatological parasites

• Drug-induced cardiomyopathy and accelerated atherosclerosis

• Malnutrition, anorexia and anaemia

Source: Booker (2012b).

Investigations

The patient’s history, risks, symptoms and physical signs should guide investigations. As a broad guide, these should include: blood tests for (full blood count, liver, thyroid and renal function, hepatitis B and C and human immunodeficiency virus (HIV); urinary dipstick; pregnancy testing and electrocardiogram (ECG). Blood samples may be difficult to obtain from intravenous drug users, and hospital phlebotomy may be required. On no account should patients take their own blood. Drug testing should be performed before prescribing substitute therapy; this should be urine testing in the first instance.

GP role

GPs play a key role in the management of patients with opioid addiction. There is specific RCGP guidance to help primary care clinicians and others in the use of substitute medication for opioid dependence when prescribing for maintenance or detoxification. Management of patients receiving substitute-prescribing regimes involves a multidisciplinary approach. Effective communication channels between the GP, social care, other services providing treatment and the patient’s allocated key worker are essential. In the UK, substitute prescribing is generally organised into tiers of care (Table 2). This organisation structure was presented in further detail by Booker (2012a).

Table 2.

A tiered approach to management of drug dependence and treatment.

Tier	Description of service
1. Non-specific general service	General advice, for example provided by GPs under general services contract or the probation or housing services
2. Open access services	Harm-reduction advice and information, drop-in services, services providing needle exchange, immunisations or BBV screening.
3. Community services	Specialist community drug teams, drug dependency units or day treatment services. May also include GPs prescribing under shared care agreements
4. Specialist residential or highly specialist services	Inpatient units undertaking supervised detoxifications, residential rehabilitation units or forensic services and secure environments

Reproduced from Booker (2012a).

A joint decision is usually made between the patient and their GP about where treatment should be delivered, either primary care, shared care or a tier 3 or 4 service. In addition to supporting patients attending drug treatment services, GPs and pharmacists play a vital role supporting patients who opt to receive their drug treatment in primary care. In these cases, the GP or a drug worker (supporting the GP in a shared care arrangement) assumes the responsibility of being the patient’s keyworker. Shared responsibilities will often include compliance monitoring and ensuring continuity of care. A shared care worker is likely to focus on monitoring progress with treatment goals, formulating a holistic treatment plan and ensuring multidisciplinary discussion when appropriate. If the shared care worker is a prescribing nurse, responsibility for the prescribing can also be delegated.

The GP is usually responsible for both filling any gaps in care and co-ordinating its delivery (as with all patients). It is important that the GP is aware of any local protocols and policies concerned with treatment of drug users. If these are not followed, the reasons for this should be clearly documented in the notes. Consideration of substitute prescribing alone is not a safeguarding risk. However, if patients’ drug use is putting others at risk, they are chaotic drug users, are using a variety of drugs or becoming involved in criminal activity, then it may be necessary to inform social services. Patients with a higher number of risk factors are usually more appropriately managed in a higher-tier service.

Additional training, for example RCGP certificates in substance misuse are highly beneficial for any GP interested in becoming involved with substitute prescribing. For GPs with a special interest, the role in patient management may be slightly different and involve more of a general oversight of treatment. The pharmacist’s and GP’s roles should be documented clearly in the treatment plan.

Substitute prescribing

There are two different substitute-prescribing strategies: maintenance prescription and detoxification prescription. Maintenance regimes involve using the prescribed drug as an on-going replacement to reduce and stop the use of illicit opioids. Detoxification regimes use the replacement drug with a reducing dose until all opioid use is stopped. Maintenance and detoxification are part of the same spectrum, and evidence supports maintenance as a route to abstinence for many patients (RCGP, 2011). The two strategies are not mutually exclusive and may be used at different points in a patient’s treatment journey.

Treatment plans should be individualised for each patient, taking account of their medical and psychosocial needs, as well as their personal treatment goals. Goals will vary from reduction in drug use, reducing high-risk practices (e.g. femoral injecting), switching to a substitute drug or total abstinence from all medication including substitute medications. While a patient is receiving treatment, their goals may change as other lifestyle changes occur and this requires regular monitoring and input. A keyworker is vital in exploring a patient’s treatment goals and reviewing these goals and the whole treatment process is a constant dynamic assessment of risk and benefit. Some patients view these goals as milestones in their recovery. It is important to understand that a proportion of patients will continue to use the illicit drug while in treatment; this may still represent progress, but needs on-going review.

Benefits of substitute prescribing

Substitute prescribing should only be considered if the patient is dependent on the drug and motivated to change their lifestyle (DOH, 2017). This requires counselling, support and encouragement, alongside the medical treatment and not just medication alone. It is therefore suggested that substitute prescribing is used in conjunction with psychosocial interventions. However, many IAPT services refuse to accept intravenous drug users, and there are long waiting lists for any counselling services. Hence, substitute prescribing is generally commenced while waiting for additional counselling services. Treatment can provide a useful tool to engage and motivate individuals to address their own personal and individual physical and mental health needs.

Both methadone and buprenorphine (sometimes referred to by one of the more common trade names ‘Subutex’) are ‘clean’ pharmaceutical drugs that reduce and eventually replace illicit, often contaminated street drugs that may be mixed with a variety of other chemicals. The aim of substitute prescribing is to reduce the harm to the patient by decreasing the amount of heroin used and to reduce the risks associated with it (such as unsafe sexual practices, overdose and infection with blood-borne viruses). By breaking the cycle of drug abuse, the patient is able to alter their lifestyle and improve their physical and mental wellbeing.

Maintenance treatment versus detoxification

Methadone and buprenorphine have been found to be equally effective at treating opioid dependence alongside a package of care that encompasses psychosocial support (National Institute for Health and Care Excellence (NICE), 2007). Both medications can be used for maintenance or detoxification programmes. The choice between detoxification and maintenance treatment is not easy; there are many factors to consider, and the decision should be patient-led. The patient should be presented with evidence and allowed to choose either at their first assessment or at any other time during their treatment process. The RCGP (RGCP, 2011) suggests that patients should be able to move between these two aspects of treatment, but preparation for detoxification is essential. Figure 3 depicts the possible prescribing routes with methadone or buprenorphine.

Figure 3.

Prescribing routes for methadone and buprenorphine.

Maintenance treatment is for those patients whose goal is to stop using illicit opioids but who are not yet able to achieve complete abstinence from all opioids. In some people it may take years to achieve complete abstinence from all illicit drugs. Maintenance treatment regimes have a strong evidence base and this often forms the first step towards detoxification and abstinence (RCGP, 2011). For maintenance treatment, current evidence suggests that methadone is more likely to retain patients in treatment, however, the RCGP argues that evidence comparing the efficacy of methadone and buprenorphine in preventing illicit opioid misuse is mixed (RCGP, 2011). If both drugs are equally suitable, then NICE 9200) states that methadone is still considered to be the ‘gold standard’. It is important to consider patient preference and past experiences with the medications when choosing the most suitable drug, and to check for any potential interactions with any other regularly prescribed medications. Patients must be regularly reviewed during maintenance treatment, and medication must be part of a social and psychological support programme. Supervised consumption is usually required. Guidance in NICE (2007) recommends that consumption of methadone and buprenorphine are supervised daily for at least 3 months.

If a patient is ready for complete abstinence from all opioids, then they can undergo detoxification. This can occur in a community or inpatient setting, and the patient and their clinical response should control the reduction rate. If a patient is new to treatment, they can be offered reduction with either buprenorphine or methadone. If the patient has been receiving methadone or buprenorphine as maintenance therapy, then current RCGP guidance (RCGP, 2008) states that detoxification should usually be performed using the same medication. RCGP guidance also makes it clear that detoxification should be supported by aftercare and relapse prevention, as the risk of relapse is high (RCGP, 2008). Detoxification should be undertaken in the community unless the patient has already failed in previous attempts at community detoxification, has comorbid medical or psychiatric conditions that require hospital admission, has comorbid polydrug use (e.g. benzodiazepines, alcohol) or has social circumstances that prevent community detoxification (e.g. homelessness). In such situations inpatient detoxification is preferred.

Methadone

Methadone was developed in Germany between 1937 and 1939 by Gustav Ehrhart and Max Bockmühl. In 1947, it was approved for use in the United States as a pain reliever for a variety of conditions, and was eventually found to be useful in treating narcotic addictions. It acts as a full opioid agonist. Methadone eases opioid withdrawal symptoms and once optimal doses are reached it blocks the effects of additional opioids and alleviates craving. This can effectively reduce, and often eliminate, the need to acquire illicit opioid drugs.

There is a risk of overdose during induction with methadone. This risk is increased with high doses, rapid induction, if the patient is also using alcohol or benzodiazepines, and if the patient has low opioid tolerance. The usual starting dose of methadone is 10–30 mg or 10–20 mg if tolerance is low or unknown. It should only be prescribed as a 1 mg in 1 ml oral solution. Common maintenance doses are in the region of 60–100 mg. The usual advice is to ‘start low’ and ‘go slow’; it can take 2–4 weeks to achieve the optimal dose. Potential drug interactions (especially with antidepressant, antipsychotic or antiretroviral medications) should be considered prior to initiating methadone.

Bupernorphine

In 1999, buprenorphine (‘Subutex’) was licensed in the UK as a treatment for opioid dependence. It is a semi-synthetic opioid that is derived from the morphine alkaloid thebaine. It is a mixed agonist antagonist and its primary action is as a partial opiate agonist. It partially activates mu opioid receptors; therefore, it produces less euphoria, sedation and respiratory depression than other opioids such as heroin, methadone or morphine. However, it produces sufficient opiate effects to prevent or alleviate opioid withdrawal, including craving. It prevents additional opioids occupying receptors, and acts as an opioid antagonist. Thus, it produces opioid responses while also reducing the effect of additional heroin, methadone or morphine. When commencing buprenorphine, it must be started as far after use of heroin as the patient can tolerate to avoid precipitated withdrawal. The patient should therefore ideally be starting to withdraw slightly before taking the first dose.

The maintenance dose of buprenorphine is 8–32 mg daily, but the blockade dose that reduces the effects of additional opioids is maximal above 16 mg daily. Buprenorphine is available as 0.4 mg, 2 mg and 8 mg sublingual tablets. Patients should be warned about the serous risks of attempting to ‘overcome’ the blocking effect by using large doses of on-top opiates, particularly during initiation and/or titration phases.

As buprenorphine is highly soluble, there is potential for it to be misused and injected. This has led to the introduction of buprenorphine and naloxone combined preparations (Suboxone®). When buprenorphine/naloxone is taken sublingually, the absorption of naloxone is negligible and the full opiate effect of buprenorphine is experienced. However, if the tablet is injected, the patient will experience the opiate antagonist effect of naloxone, which would precipitate withdrawal from opiates (RCGP, 2011). This is rarely used in the UK.

Side effects of methadone and buprenorphine

Most side effects are those typical of all opioids, and include nausea, vomiting, constipation and drowsiness. Dry mouth, sweating, and decreased libido may also occur. Side effects are usually worse in the first few days of treatment. Larger doses of methadone produce respiratory depression and hypotension. However, due to its antagonistic effects, buprenorphine does not have these effects. Headache is a common side-effect with buprenorphine. In addition, evidence demonstrates that some patients report clouding of the mind with methadone whereas others report a clear mind with buprenorphine (RCGP, 2011). When undertaking substitute prescribing it is important to consider the contraindications and precautions as described in the RCGP (2011) guidance (Box 3).

Box 3.

Indications, contraindications and precautions to consider when prescribing methadone or buprenorphine.

Indications • Opioid dependence • Informed consent to treatment

Absolute contraindications • Non-opioid-dependence, unless using low-dose buprenorphine for people coming out of prison to prevent relapse • Allergy or proven intolerance to methadone or buprenorphine

Relative contraindications • Severe liver disease, however, in many cases, with careful monitoring of liver function the benefits will outweigh the risks • Age under 16 years, except on specialist advice • Unlicensed for breast-feeding mothers. Pregnancy is not a contraindication under the UK Medicines and Healthcare products Regulatory Agency licence, but carries a special warning

Cautions Extra caution should be exercised and benefits and risks assessed when prescribing methadone or buprenorphine in the following situations: • Concurrent use of other sedating drugs or medications: Full agonists and especially methadone have been associated with sedation, respiratory depression and coma when used in conjunction with central nervous system (CNS) depressants such as alcohol, benzodiazepines, barbiturates, neuroleptics and tricyclic antidepressants. Monoamine oxidase inhibitors need to be avoided with methadone, due to the potential risk of CNS hyperexcitation. This occurs with buprenorphine, but with much less effect. However, both alcohol and benzodiazepine use is common in those requesting opioid treatment and should not be regarded as an absolute contraindication • Medical conditions complicating opioid use: Should be used cautiously in individuals with recent head injury, acute abdominal conditions, or severe respiratory, hepatic or renal disease • Patients suffering with chronic pain: Where opioid analgesia is indicated, patients should normally be given appropriate doses of additional opioid analgesia on top of that required for the management of dependence • People with severe mental illness: This group may have limited capacity to provide informed consent • Medications that affect methadone levels: Some medications have a significant effect on methadone levels; for example, rifampicin may require a doubling or trebling of methadone dose and can precipitate severe withdrawal. Methadone is excreted more rapidly by urine acidifiers, e.g. ascorbic acid, so can significantly reduce methadone levels. Urine alkalinisers, such as sodium bicarbonate, reduce excretion and so may increase methadone levels • Transfer of patients on more than 30 mg of methadone to buprenorphine: This is more likely to be associated with precipitated withdrawal and should only be attempted after consultation with a specialist or experienced prescriber • History of cardiac arrhythmias or abnormal ECG: Caution is needed when using methadone

Reproduced from RCGP (2011), with permission.

The role of the pharmacist and supervised consumption

There should be a good relationship between the prescriber of substitute medications and the pharmacist issuing the medication. The patient should be introduced to the pharmacist and the pharmacist should be able to feedback to the prescriber if there are concerns about compliance with treatment.

Supervision of consumption by an appropriate professional provides the best guarantee that a medicine is being taken as prescribed. This involves medication being dispensed daily at the pharmacy and then taken in the presence of the pharmacist who provides confirmation that the dose has been administered. This ensures both compliance and the safety of the patient in the higher-risk induction period of treatment (Booker, 2012a). Strang et al. (2010) presents evidence that after the introduction of supervised consumption in England and Scotland, methadone-related deaths reduced fourfold.

The principal reason for using supervision is to ensure the safety of the patient and to minimise the risk of toxicity; it should not be used punitively, but can be helpful if there are genuine concerns about continued treatment engagement. The level of supervision should be risk-based for individual patients. It is important that prescribers are familiar with the opening hours of the local pharmacies that the patient can access, so as to find the most suitable location for that patient. It is important to remember that some patients may require access to a pharmacy that is open 7 days a week in order to receive 7-day supervision (DOH, 2017).

Usually, supervision is carried out for 3 months, however, the duration of supervision is calculated on an individual basis based on patient circumstances and compliance; some patients may require shorter or longer durations of supervision. If treatment is failing, or there are signs of a return to more chaotic engagement, supervision can be reintroduced and conversely, supervision can be relaxed if a patient is making good progress.

If a patient fails to collect their prescription for three consecutive days, guidelines such as those of the RCGP (2011) and the DOH (2017) suggest that the pharmacist should refuse to dispense the medication and the patient should be re-referred to the prescriber for review.

Monitoring

It is important for the GP or key worker to undertake regular drug testing. If screens are repeatedly negative this is good evidence that relaxing treatment may be possible. If repeated positive results are obtained alongside decreased attendance at appointments, this is an indicator that the patient may need to be more closely monitored and supervised.

Warning signs that treatment is ceasing to be effective

Frequently decisions must be made about what action to take if a patient is no longer gaining benefit from their substitute regime. Decisions should be made based on a calculated assessment of risk to both the patient and staff and should also maintain the integrity of the treatment programme. DOH (2017) guidance details how to progress and respond if a patient is showing signs of no longer responding to treatment. This includes establishing the reason for failure to progress with the patient and then optimising treatment. This can be done by: optimising drug doses; increasing the intensity of support available; increasing supervised consumption; switching medications; and introducing additional psychological techniques such as motivational interviewing (DOH, 2017).

Common scenarios encountered in treatment failure

Reassessing the benefit of treatment interventions is the key to successful management in opioid addiction. A variety of scenarios may be encountered when a patient ceases to respond to treatment. These include: additional opiate misuse alongside substitute prescribing; crack cocaine and cocaine misuse on top of an opioid prescription; and alcohol or benzodiazepine misuse in addition to an opioid (DOH, 2017). In this situation GPs should feel confident to have an open and honest discussion with the patient about the suitability of continuing substitute prescribing. There are specific DOH (2017) guidelines available detailing suitable responses to these scenarios. Alternative treatment options may include inpatient detoxification or stopping treatment altogether.

Discharge from treatment and support to prevent relapse

After a patient has completed a programme of drug addiction and substitute prescribing, they still require support to prevent relapse. A large proportion of patients may relapse. If the patient relapses they will need quick access to help, support and further treatment. Prevention of relapse may be aided by the provision of a package of aftercare including psychosocial support. Some patients may be deemed high risk and require a greater package of support than others following discharge from a treatment programme. Support from a GP is vital to help maintain health, as is support from social care to improve access to employment, housing and education when required. There are a number of schemes that patients can access in order to help integration back into the community (DOH, 2017). Patients can also be signposted to support from Narcotics Anonymous, Alcoholics Anonymous and SMART Recovery groups.

KEY POINTS

The number of patients presenting to primary care with drug-related problems has increased significantly in recent years and GPs play a key role in the management of patients with opioid addiction

Substitute prescribing is important, but only part of a treatment jigsaw

Methadone and buprenorphine are equally effective at treating opioid dependence, and both can be used for maintenance or detoxification treatment regimes

When choosing a substitute prescribing regime it is important to consider the individual goals of each patient

GPs must be aware of the ‘warning signs’ that substitute treatment is ceasing to be effective

GPs must be mindful of any safeguarding or safety issues when managing patients who misuse opioids

Footnotes

Acknowledgement

I would like to thank Dr Matthew Booker for his help with the writing of this article under the InnovAiT ‘buddy’ scheme.

References

Booker M (2012a) The primary care management of substance misusers. InnovAiT 5(7): 384–392. DOI: 10.1093/invait/ins103.

Booker M (2012b) The assessment of substance misusers. InnovAiT 5(7): 375–383. DOI: 10.1093/innovait/ins069.

DOH (2017) Drug misuse and dependence. UK guidelines on clinical management. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/673978/clinical_guidelines_2017.pdf (accessed 7 January 2019).

National Treatment Agency (2014) Why invest? How drug treatment and recovery services work for individuals, communities and society. Available at: https://webarchive.nationalarchives.gov.uk/20140727020135/http://www.nta.nhs.uk/uploads/whyinvest2final.pdf (accessed 4 January 2019).

NICE (2007) NICE Technology appraisal guidance 114: Methadone and buprenorphine for the management of opioid dependence. Available at: www.nice.org.uk/guidance/ta114 (accessed 4 January 2019).

NICE (2017) Clinical knowledge summary: Opioid dependence. Available at: https://cks.nice.org.uk/opioid-dependence (accessed 4 January 2019).

PHE (2017) Guidance: Health matters: Preventing drug misuse deaths. Available at: www.gov.uk/government/publications/health-matters-preventing-drug-misuse-deaths/health-matters-preventing-drug-misuse-deaths (accessed 4 January 2019).

RCGP (2011) Guidance for the use of substitute prescribing in the treatment of opioid dependence in primary care. Available at: www.rcgp.org.uk/-/media/Files/SMAH/RCGP-Guidance-for-the-use-of-substitute-prescribing-in-the-treatment-of-opioid-dependence-in-primary-care-2011.ashx?la=en (accessed 17 December 2018).

Strang J, Hall W, Hickman M, et al. (2010) Impact of supervision of methadone consumption on deaths related to methadone overdose (1993-2008): Analyses using OD4 index in England and Scotland. BMJ 341: c4851. DOI: 10.1136/bmj.c4851.