Drug treatment of opiate dependence in primary care — an update
Volume 18 Number 2
February 2008

View PDF of Main Bulletin View PDF of Appendix
Introduction How big a problem is opiate misuse? What are the aims and principles of treatment? What is the evidence for maintenance treatment? What is the evidence for detoxification treatment?	But does treatment work in 'real life'? What are the risks of drug treatment? Key resources References Appendix

Summary Opioid dependence is a chronic, relapsing condition associated with significant harms for patients and the wider community. In the broadest sense, the aims of treatment are to reduce the health, social and economic harms that are associated with the misuse of opiates. The available evidence indicates that treatment can lead to substantial improvements in a number of outcomes for many individuals and society. These improvements rely on a multidisciplinary approach using appropriate drugs at sufficient doses to retain patients within treatment programmes, supported by a range of ongoing psychosocial interventions. It is important that all drug misusers are provided with information and advice about harm reduction, both at routine contacts and opportunistically. Drug treatment should only be considered if there is evidence of dependence and tolerance, and at least one positive opiate test. Maintenance treatment is the best option for many individuals in the short, medium and often the long term. Coerced or enforced detoxification is not effective as it leads to relapse, a return to the use of street drugs and the associated risks of overdose, blood-borne viruses, etc. Maintenance treatment Methadone and buprenorphine, using flexible dosing regimens, are both recommended as options for maintenance therapy in the management of opioid dependence. Evidence suggests that methadone maintenance therapy (MMT) is more effective at maintaining patients in treatment than buprenorphine maintenance therapy (BMT). There is little evidence to support the routine use of BMT instead of MMT in terms of other outcome measures such as illicit opiate use whilst on treatment. However, it is generally agreed that there is less risk of opioid overdose associated with the use of buprenorphine than with oral methadone. The decision about which drug to use should be made on a case-by-case basis. If both drugs are equally suitable, methadone should be prescribed as the first choice. Injectable diamorphine and injectable methadone should only be considered for the minority of patients who are genuinely unresponsive to an optimised oral maintenance treatment approach. Close monitoring and regular clinical review are required throughout treatment, and especially during the early stages of treatment and periods of instability. Daily installment prescribing and supervised consumption are useful for ensuring that patients take their treatment as intended and for reducing the diversion of prescribed drugs. Detoxification It is not clear if there is any difference in efficacy between methadone and buprenorphine for opioid detoxification. Either may be offered as the first-line treatment. Risks of drug treatment Methadone carries a risk of QT-interval prolongation, so patients with risk factors (e.g. heart or liver disease, electrolyte abnormalities) and those taking doses over 100mg per day should be carefully monitored. When buprenorphine is initiated, withdrawal symptoms may arise if patients still have opioid drug present in their system. This occurs because buprenorphine has a high affinity for opioid receptors and displaces other opioids, such as heroin or methadone. This gives a rapid reduction in opiate effects because it has less opioid activity. The first dose should therefore be administered when the patient is exhibiting signs of withdrawal, or at least 6-12 hours after the last use of heroin and 24-48 hours after the last use of methadone. Patients should be fully informed of the risks of overdose with the use of prescribed and illicit drugs. They also need to be aware that their previous tolerance to illicit opioids may be lost during detoxification treatment and relapse to illicit drugs may increase their risk of overdose..

Introduction

This Bulletin discusses the evidence in support of the drug treatment of opiate dependence in primary care, with reference to recent National Institute for Health and Clinical Evidence (NICE) guidance and the updated Department of Health-commissioned Drug misuse and dependence: UK guidelines on clinical management, otherwise known as the ‘Orange book’.¹ Psychosocial interventions are an important component of treatment but are beyond the scope of this Bulletin.

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How big a problem is opiate misuse?

Around 1% of people aged 15–64 years in the UK are estimated to be using illicit drugs in a chronic, potentially damaging way.² Of those seeking help for their drug use in 2004/5, around 75% reported opiates as their main problem drug.³ Heroin (diamorphine) was the main opiate of misuse in 64% of people presenting for treatment and, of these, 21% reported crack cocaine and 4% reported cocaine as adjunctive drugs of misuse. Heroin and crack or cocaine misuse is increasingly common among those presenting for treatment in England.³

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Mental health problems such as depression, anxiety, and suicidal thoughts are also common in drug misusers. A study in London indicated that around 75% of drug services users in 2001/2 experienced these kinds of problems.³ People with both a mental health and substance misuse diagnosis have increased rates of service utilisation, poorer levels of social functioning and, generally, appear to have poorer outcomes.³

The number of drug-related deaths has decreased since its peak in 2000. However, in 2003 there were still over 1400 deaths, of which 55% were associated with heroin or morphine and 20% with methadone.² Overall, the mortality risk of people dependent on heroin is estimated to be around 12-times that of the general population.⁴

Social problems for individuals and the wider community
Social problems associated with drug misuse include marital and relationship breakdown, unemployment, homelessness, and child neglect, which often results in children being taken into the care system. Many opiate-dependent people also resort to crime to support their drug use.⁴ In 1996 it was estimated that half of all recorded crime was drug related, with associated costs to the criminal justice system in the UK of £1 billion per annum.⁴ Between a half and two-thirds of people in prison are reported to be problem drug users.²

What is happening in primary care?
Survey data indicate that GPs have become increasingly involved in treating opiate misusers.⁵ In addition, prescribing data from England indicate that methadone instalment prescribing by GPs and nurses in 2006 was double that in 2001, while instalment prescribing by hospitals and clinics grew at a much lower rate over the same period.⁶ This reflects the increasing involvement of primary care health professionals in the management of drug misusers.

The advent of non-medical prescribing and recent changes in controlled drugs regulations have created opportunities for other primary/ community-based healthcare professionals to take wider responsibilities for the management and care of drug misusers. A range of guides on the current and future roles of these professionals, and on commissioning substance misuse services, has been produced (see Resources).

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What are the aims and principles of treatment?

In the broadest sense, the aims of treatment are to reduce the health, social and economic harms to individuals, communities and society that are associated with the use of drugs.³

It is important that all drug misusers are provided with information and advice about harm reduction, both at routine contacts and opportunistically. Harm reduction is concerned with preventing infections, overdose and drug-related death. Examples include advice about access to sterile needles and syringes, safer injecting techniques, minimising the risk of overdose, safe sex, and immunisation against hepatitis A and B, and tetanus.^1,9

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What is the evidence for maintenance treatment?

The NICE technology appraisal of methadone and buprenorphine for the management of opioid dependence, published in January 2007,^4,13 assessed the effectiveness of these agents in terms of a number of outcomes where evidence was available. The quality of the included studies was generally moderate to good, but it is important to note that there are some limitations in the extent to which they reflect current UK practices. ¹³

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Evidence suggests that fixed-dose MMT helps retain patients in maintenance treatment programmes and also leads to improved outcomes for patients on treatment compared with placebo or no treatment (e.g. lower rates of self-reported opioid use, mortality, HIV risk behaviour and criminal activity) (see Appendix).⁴ This appears to be particularly so with higher doses of MMT than lower doses. Although lower doses of MMT may be appropriate for some patients, there have been concerns that MMT doses used in Britain are sub-optimal, with average doses less than 50mg/day and only around a quarter of patients receiving over 60mg/day.¹⁵ This could potentially be a contributing reason for patients withdrawing from treatment and relapsing to illicit opiate use. The evidence supports a usual maintenance dose range of 60-120mg/day. However, this presents a clinical dilemma, particularly when initiating methadone, because deaths have been associated with methadone doses as low as 40mg,¹⁶ or even 20mg,¹ daily.

Buprenorphine vs. methadone maintenance treatment
Buprenorphine is a partial agonist/antagonist of opioid receptors and is claimed to provide less euphoric and less sedating effects than full opioid agonists such as diamorphine or methadone. It has a high affinity for opioid receptors, which reduces the impact of illicit opiates by preventing these drugs from occupying opioid receptors, and gives it a prolonged duration of action at higher doses.⁴ There is limited randomised controlled trial (RCT) evidence that administering sublingual buprenorphine solution twice or three-times a week has comparable efficacy as daily dosing,¹⁷ but this needs confirming in larger trials that use sublingual tablets, as used in practice. As with MMT, buprenorphine maintenance treatment (BMT) is significantly superior to placebo/no treatment in retaining patients in treatment at all doses used in RCTs, and higher fixed doses of BMT are more effective than lower fixed doses.⁴ However, comparisons of BMT against MMT are more informative.

Evidence suggests that fixed and flexible dose MMT is more effective at maintaining patients in treatment than BMT and there is little evidence to support the routine use of BMT instead of MMT in terms of other outcome measures such as illicit opiate use whilst on treatment (see Appendix).⁴ The potential for less frequent dosing with BMT than MMT in some patients may be useful, but currently, only limited data support this concept.

Pooled RCT data show no significant difference in the rate of serious adverse events with MMT compared with BMT.⁴ Although it is generally agreed that there is less risk of opioid overdose associated with the use of buprenorphine than with oral methadone,¹ when buprenorphine is used in combination with alcohol and/or other central nervous system (CNS) suppressants (e.g. benzodiazepines) there is still a major risk of overdose.^1,18

NICE guidance recommends that the decision about which drug to use should be made on a case by case basis. Although methadone is cheaper than buprenorphine, and if both drugs are equally suitable it should be prescribed as first choice, there may be clinical reasons why buprenorphine is preferable for an individual person. History of opioid dependence and commitment to a particular long-term management strategy should be taken into account, together with an estimate of the risks and benefits of each treatment.⁴

Why not use injectable diamorphine (heroin) or methadone for maintenance treatment?
There have been reports of successful clinical experience with injectable diamorphine maintenance treatment.¹⁹ However, the published evidence base for this approach is weak (see Appendix).²⁰ A Cochrane systematic review was unable to draw any definitive conclusions about the overall effectiveness of diamorphine compared with MMT or other substitution treatments in terms of retaining patients in treatment, reducing the use of illicit drugs, reducing criminal activity or improving health and social functioning.²¹

In addition to the weak evidence base, injectable maintenance programmes are associated with additional operational and financial issues to oral maintenance programs. Injectable diamorphine may need to be used two or three times a day, seven days a week¹⁹ and supervised use may prove to be a burden on the patient and on service providers. It has been estimated that injectable maintenance treatment may be 5-15 times more expensive to provide than oral maintenance treatment. It therefore needs to be targeted appropriately to avoid a negative impact across other substance misuse services.²⁰ In its guide to the use of injectable diamorphine and injectable methadone in 2003, the National Treatment Agency for Substance Misuse recommended that they should only be considered for a minority of patients who are genuinely unresponsive to an optimised oral maintenance treatment approach.²⁰

What is the evidence for detoxification treatment?

A NICE clinical guideline, published in July 2007, reviewed the evidence supporting the available pharmacological approaches to opioid detoxification (see Panel 2 and Appendix).^22,23 It concluded that methadone and buprenorphine both appeared to be effective in comparison with other detoxification treatments such as α2-adrenergic agonists (e.g. lofexidine, clonidine) plus other opioid agonists. However, further studies are required to identify if there are any differences between use of buprenorphine or methadone for detoxification.²³ Both are recommended as first-line treatments for opioid detoxification.^22,23 Keeping patients fully informed about different aspects of detoxification appears to have some effect in improving completion rates and minimising reported withdrawal severity.²³

Several small studies have assessed the length of the detoxification period with methadone. They have found that neither a long methadone taper (up to 70 days) nor a fairly short programme (14 days) was any better than a standard 21-day taper.²³

The Royal College of General Practitioners produced a guide to buprenorphine in 2004, which suggested there is increasing consensus among experienced clinicians that buprenorphine may be better suited to those who wish to detoxify. This opinion was based on the assumption that withdrawal from buprenorphine is easier, and transition to naltrexone can be achieved earlier, than with methadone.¹⁸ However, more studies are needed to confirm this.²⁴

Lofexidine and clonidine are α2-adrenergic agonists that act to reduce the noradrenergic hyperactivity seen in opioid withdrawal (e.g. piloerection, sweating, runny nose).²³ NICE found no difference in completion of detoxification between clonidine and lofexidine, but clonidine was associated with higher levels of hypotension.²³

Naltrexone should only be administered under adequate supervision to people who have been fully informed of the risk of side effects and the risk of fatal respiratory depression if they attempt to overcome the effects of naltrexone with opiates.¹²

Buprenorphine with naloxone (Suboxone®^▼)
Suboxone is a sublingual tablet containing buprenorphine and the opioid receptor antagonist naloxone. When taken sublingually as intended, the naloxone is inactivated or is only absorbed at a dose which is insufficient to provoke withdrawal symptoms. However, if it is abused (e.g. by being crushed and intravenously injected), withdrawal effects occur. The combination tablet is therefore intended to provide the same therapeutic benefit as buprenorphine, while preventing or reducing the liability for abuse.¹ In a four-week RCT, (n=323) Suboxone demonstrated similar efficacy and safety to buprenorphine.²⁵ However, it is unclear whether it offers any advantages over buprenorphine alone and there are currently no published trials comparing Suboxone with methadone. In February 2007, the Scottish Medicines Consortium recommended its use in Scotland should be restricted to those in who methadone is not suitable and buprenorphine is considered appropriate.²⁵ Clinical experience with Suboxone is so far extremely limited in the UK and it is too early to indicate its place in therapy.¹

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But does treatment work in ‘real life’?

Evidence from cohort studies suggests that many of the treatment benefits seen in clinical trial settings may also be seen in the practice setting. The National Treatment Outcomes Research Study was a prospective study that followed over a thousand problem drug users initially enrolled in 54 residential or community treatment programmes in the UK in 1995.²⁶ This showed that, after four to five years of treatment, rates of abstinence from illicit opioids were increased (e.g. from 6% at base-line to 35% at 4-5 years for patients receiving methadone in the community setting) and frequency of drug use was reduced (e.g. daily opiate use fell from 62% to 20% in community methadone patients). In all study participants, injecting behaviours were improved (rates of injecting fell from 60% at baseline to 37%, and rates of sharing equipment fell from 14% to 5%), and rates of criminal involvement were reduced (from 61% in the three months before baseline vs. 20-28% at 4-5 years).²⁶

Not all patients responded to treatment. About one fifth of the cohort continued to use heroin on a daily basis throughout the follow-up period, and after five years, about 40% of the residential and community programme enrolees were still using heroin at least once a week. Nonetheless, the results demonstrated that treatment of people with serious and long-term drug misuse problems resulted in important benefits to individuals and to society (e.g. reductions in drug use and problem behaviours such as criminal activity). It should be noted that these positive outcomes arose from access to, and often extensive input from, drug misuse services.²⁶ Psychosocial support is an important component of the management of opiate dependence, as outlined in the NICE clinical guideline published July 2007.⁷

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What are the risks of drug treatment?

Prescribing drugs for opioid-dependent drug misusers requires a balance between achieving an effective and appropriate dose of medication, responding to the patient's need for appropriate treatment to retain them in treatment and minimising the risk of overdose.¹ Prevention of diversion and abuse of prescribed drugs are also key.

The risks of toxicity with methadone are increased during the first two weeks of treatment, especially if alcohol and/or other CNS suppressants are being used concurrently.¹ Methadone has a long and variable half-life that can lead to accumulation and delayed toxicity, often after several days of treatment. It is therefore essential that methadone induction starts with low doses (e.g. 10-30mg daily), and continues with slow titration (increases of 5-10mg daily and no more than 30mg over a week). Doses can continue to be increased incrementally up to a total of 60-120mg daily or when the patient reports feeling comfortable and no longer using illicit heroin. It may take several weeks to reach the desired dose¹ and, due to a risk of QT-interval prolongation, patients with risk factors (e.g. heart or liver disease, electrolyte abnormalities), and those taking doses over 100mg per day, should be carefully monitored.²⁷ In patients with risk factors, or in case of concomitant treatment with drugs that have a potential for QT-prolongation, electrocardiogram (ECG) monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation. ECG monitoring is also recommended in patients without risk factors before dose titration above 100mg per day and at seven days after titration.²⁸

Buprenorphine induction involves starting with a low dose (4-8mg daily), followed by rapid up titration. As with methadone, there is a risk of toxicity if CNS suppressants are also being taken. Withdrawal symptoms may be precipitated if patients still have opioid drug present in their system at the time buprenorphine is commenced, which may deter patients from continuing with treatment. Precipitated withdrawal occurs because buprenorphine has a high affinity for opioid receptors and displaces other opioids, such as heroin or methadone. This gives a rapid reduction in opiate effects because it has less opioid activity.¹⁸ The first dose of buprenorphine should therefore be administered when the patient is exhibiting signs of withdrawal, or at least 6-12 hours after the last use of heroin and 24-48 hours after the last use of methadone. For most patients, effective maintenance treatment with buprenorphine requires doses in the range of 12-16mg daily.¹

Patients need to be fully informed of the risks of overdose with the use of prescribed and illicit drugs. They also need to be aware that their previous tolerance to illicit opioids may be lost during detoxification treatment and relapse to illicit drugs may increase their risk of overdose.^1,9

Close monitoring and regular clinical review are required throughout treatment, and especially during the early stages and periods of instability. NICE recommends supervised daily administration of methadone and buprenorphine for at least three months, which should be relaxed only when the patient's compliance is assured.⁴ Daily instalment prescribing and supervised consumption are useful for ensuring patients take their treatment as intended and reducing the diversion of prescribed drugs.¹ Buprenorphine can be more difficult to supervise than methadone as the sublingual tablets can take 5-10 minutes to dissolve under the tongue.²⁹ Steps to reduce the time, such as crushing the tablets beforehand, introduce a range of legal issues that need to be considered. Such measures should not be undertaken without appropriate clinical governance approval and protocols.¹

Conclusion

Opioid dependence is a chronic, relapsing condition associated with significant harms for patients and the wider community. Detoxification is rarely successful and long term maintenance treatment is often the most appropriate approach. The currently available evidence suggests that treatment can lead to substantial improvements in a number of outcomes for many individuals and society (e.g. retention in treatment, reduction in illicit opioid use, reduction in criminal activity). This relies on a multidisciplinary approach using appropriate drugs at sufficient doses to retain patients within treatment programmes, supported by a range of ongoing psychosocial interventions.

There have been several recent changes to the legislation governing the prescribing and supply of controlled drugs. All those involved in substance misuse services need to be aware of the current legislation and ensure that best practice guidelines are being followed (see Resources section, Panel 3).

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References

1. Department of Health and the devolved administrations. Drug Misuse and Dependence: UK Guidelines on Clinical Management. London: Department of Health (England), the Scottish Government, Welsh Assembly Government and Northern Ireland Executive. September 2007. Accessed from www.nta.nhs.uk/areas/Clinical_guidance/clinical_guidelines/docs/clinical_guidelines_2007.pdf on 30/11/07
   
2. Department of Health. United Kingdom drug situation: annual report to the European Monitoring centre for Drugs and Drug Addiction 2005. United Kingdom Focal Point on Drugs. 2005. Accessed from http://www.dh.gov.uk/prod_consum_dh/groups/ dh_digitalassets/@dh/@en/documents/digitalasset/dh_4126966.pdf on 30/11/07
   
3. Independent Expert Working Group. Drug misuse and dependence — guidelines in clinical management: update 2007. Consultation draft. June 2007. Accessed from http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_update_june_2007.pdf on 31/11/07
   
4. National Institute for Health and Clinical Excellence. Methadone and buprenorphine for the management of opioid dependence. Technology Appraisal No. 114. January 2007. Accessed from: http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11606 on 30/11/07
   
5. Strang J, Sheridan J, Hunt C, et al. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Br J Gen Pract 2005;55:444–51
   
6. NHS Business Services Authority. Quarterly prescribing data. December 2001 to March 2006
   
7. National Institute for Health and Clinical Excellence. Drug misuse: psychosocial interventions. Clinical Guideline No. 51. July 2007. Accessed from: http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11812 on 30/11/07
   
8. National Treatment Agency for Substance Misuse. The Treatment Outcomes Profile (TOP). 2007. Accessed from: http://www.nta. nhs.uk/areas/outcomes_monitoring/default.aspx on 30/11/07
   
9. CKS. Opioid dependence (Prodigy Guidance) Clinical Knowledge Summaries Service. July 2006 [updated March 2007]. Accessed from http://cks.library.nhs.uk/opioid_dependence/view_whole _guidance on 30/11/07
   
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12. National Institute for Health and Clinical Excellence. Naltrexone for the management of opioid dependence. Technology Appraisal No. 115. January 2007. Accessed from http://www.nice.org.uk/ guidance/index.jsp?action=byID&o=11604 on 5/12/07
    
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27. Commission on Human Medicines. Risk of QT interval prolongation with methadone. Current Problems in Pharmacovigilance 2006;31:6. Accessed from http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2023859&ssTargetNodeId=368 on 5/12/07
    
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33. Minozzi S, Amato L, Vecchi S, et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD001333. DOI: 10.1002/14651858.CD001333.pub2
    

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