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Current issues in the drug treatment of rheumatoid arthritis Volume 17 Number 5 July 2007

Summary This Bulletin discusses some of the current issues in the drug treatment of rheumatoid arthritis (RA) and includes: Diagnosis of early RA When should disease modifying anti-rheumatic drugs (DMARDs) be introduced? Methotrexate safety issues Biologic therapies Combination therapy Monitoring of DMARDs and biologic therapies The place of corticosteroids Corticosteroid-induced osteoporosis

Introduction

Rheumatoid arthritis (RA) is a chronic, progressive, disabling autoimmune disease.^1,2 It is characterised by inflammation of the synovial tissue in joints, which causes pain, swelling and stiffness and can lead to joint destruction.² RA affects between 0.5% and 1% of the population. Approximately 400,000 people in England and Wales have this condition.²

RA often impacts severely on quality of life and it is estimated that 40% of people with RA will stop working within 5 years of diagnosis.² The life expectancy of people with RA is reduced by 5–10 years compared with that of people without the condition, and 35–50% of this excess risk is accounted for by cardiovascular (CV) mortality.¹

Several conditions that commonly occur with RA adversely affect outcomes such as disability and death. The long-term prognosis for people with RA depends not only on how well their joint disease is managed but also on how well co-existing illnesses are addressed. The three co-existing conditions that have the greatest impact on morbidity and mortality in RA are infection (pulmonary infection and generalised sepsis are particular risks), osteoporosis, and CV disease.^3,4

A NICE guideline on the management of RA in adults being developed and is expected to be issued in December 2008.

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Diagnosis of early RA

Early diagnosis is required for appropriate early treatment to control symptoms and delay disease progression. However, it is not always easy. There is no single diagnostic test for RA, and diagnosis relies heavily on history taking and clinical examination and less on investigations.⁵ Useful investigations include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), full blood count, liver function tests, urinalysis, antinuclear antibodies, rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP), and radiology.^4,6 The anti-CCP test is not routinely available in the NHS.⁶

RA usually presents as a gradual-onset, symmetrical arthritis mainly affecting the hands and/or feet. It can present acutely and may also present with large-joint involvement (e.g. shoulders and knees), or with extra-articular or systemic features (e.g. rheumatoid nodules, fever, weight loss).⁴

Typically, a patient with early RA will describe pain, stiffness and swelling of the joints which is worse in the morning and after inactivity. Examination will usually show symmetrical swelling and tenderness of the small joints of the hands and feet (and to a variable extent the larger joints) and the presence of synovitis (i.e. soft tissue swelling in relation to the joint).^4,5

In patients whose symptoms of RA started recently, differential diagnosis should always be considered (see Panel 1).^4,5 For further information regarding diagnosis, refer to the PRODIGY guidance on RA.⁴

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When should DMARDs be introduced?

Currently, early referral for specialist rheumatology opinion (see Panel 2), and early treatment of diagnosed RA with DMARDs to control symptoms and delay disease progression, is the recommended approach.^4,5,7,8 The ‘pyramid’ approach to treatment of RA is no longer advocated. This involved using non-steroidal anti-inflammatory drugs (NSAIDs) initially for symptom relief, and introducing DMARDs only when joint damage was detected.⁹

Paracetamol (with codeine, where needed) and NSAIDs partially relieve pain and stiffness and are particularly useful until a definitive diagnosis of RA is made. If possible, paracetamol (with codeine, where needed) should be used in place of NSAIDs.⁴

Prescribing of NSAIDs should be based on careful consideration of a patient’s condition and risk factors for treatment, particularly with regard to the known effects of NSAIDs on the gastrointestinal and CV systems.¹⁰ If an NSAID is prescribed for a patient with RA, the dose should be reduced and if possible withdrawn when a good response to DMARDs is achieved.⁴ A full discussion of NSAIDs is beyond the scope of this Bulletin.

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Early intervention with DMARDs
Joint damage occurs early in the course of RA, and is largely irreversible.³ The early introduction of DMARDs in RA is now a widely accepted approach. One systematic review (three randomised controlled trials [RCTs], n=336) and one additional RCT (n=38) found that introducing DMARDs early significantly improved radiological progression, swollen joint counts, and quality of life scores at 12 to 60 months compared with delayed treatment.¹¹

The two year results of the BeSt study, which compared four different initial treatment strategies, have recently been published.¹² Patients with early active RA (n=508) were randomised to sequential DMARD monotherapy, step up combination therapy, initial combination therapy with tapered high dose prednisone, or initial combination therapy with infliximab. Treatment adjustments were made every three months to achieve low disease activity.

In this setting of tight disease control, initial combination therapies seemed to provide earlier clinical improvement and less radiological evidence of progression of joint damage. However, all treatment strategies eventually showed similar clinical improvements. After two years, 79% of patients in all groups achieved the goal of low disease activity and 42% of patients were in clinical remission.¹² A more detailed discussion on the results from this study can be found in the section on combination therapy.

There is also some evidence from a small 18-month study that a strategy using DMARDs to provide sustained, tight control of disease activity in RA improves outcomes.¹³

Guidelines recommend that DMARDs should be started in patients with RA (by a specialist) as soon as possible once the diagnosis is confirmed.^4,5,8 The aim should be to try to achieve remission.^8,14

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Which DMARD?
Traditional DMARDs include sulfasalazine, methotrexate, intramuscular gold (sodium aurothiomalate), oral gold (auranofin), penicillamine, and hydroxychloroquine. Azathioprine, cyclophosphamide and ciclosporin also have disease-modifying activity. However, they are usually reserved for people unresponsive to other DMARDs, due to the risk of serious adverse effects.⁴ There is some evidence showing the effectiveness of minocycline in RA. However, minocycline is not licensed for treating RA in the UK,⁴ and it is not used routinely.

DMARDs all reduce joint inflammation, with similar efficacy to each other, but they can all cause toxicity.¹¹ Therefore, monitoring is essential.⁴ Although DMARD prescriptions are usually initiated by a specialist, they are often monitored in primary care under a shared care arrangement with the local rheumatology service, using a protocol.⁴ The enhanced service arrangements in general practice support this approach, since it has been shown that the incidence of side-effects can be reduced significantly if this monitoring is carried out in a well-organised way, close to the patient’s home.¹⁵

Leflunomide is a newer DMARD, which seems to be as effective as methotrexate or sulfasalazine at improving inflammation and function. However, its long-term effects are unclear and it is more expensive than options such as methotrexate or sulfasalazine.^11,16 In 2001, the European Agency for the Evaluation of Medicinal Products (EMEA) issued a public statement on leflunomide which described reports of rare cases of severe liver injury, including cases with fatal outcome, during treatment.¹⁷

The use of leflunomide is increasing. In 2005–06, leflunomide accounted for approximately 5% of the total DMARD items prescribed in general practice in England, and approximately 44% of the cost.¹⁸

SIGN guidelines recommended sulfasalazine and methotrexate as the DMARDs of choice due to their more favourable efficacy/toxicity profiles.⁵ In 2005–06, methotrexate accounted for approximately 72% of the total DMARD items prescribed in general practice in England.¹⁸

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Methotrexate safety issues

Oral methotrexate is a safe and effective medication if taken at the right dose and with appropriate monitoring. However, between 1993 and 2002, the National Patient Safety Agency (NPSA) was notified of 137 patient safety incidents in England associated with the use of oral methotrexate, including 25 deaths and 26 cases of serious harm.¹⁹ Two thirds (67%) of these incidents involved prescribing the wrong frequency of dose of the tablets, 19% were due to a lack of, or poor monitoring of therapy, and 7% because of misidentification of the tablets by professionals or patients.¹⁹

The NPSA published a patient safety alert in July 2004 which aimed to reduce the harm caused by oral methotrexate.¹⁹ This identified a series of actions for NHS acute trusts, primary care organisations and local health boards in England and Wales to be carried out by March 2005 (see Panel 3).

In June 2006, a further patient safety alert was issued.²⁰ This alert stated that 18% of NHS organisations in England had not reported having fully implemented the actions from the 2004 alert. Between July 2004 and June 2006, the NPSA received 165 reports of patient safety incidents involving oral methotrexate, two of which led to the patients’ deaths. Of these 165 incidents, 151 happened after the July 2004 alert was issued. Better compliance with this alert might have prevented 37% of the incidents.²⁰

The 2006 alert reinforces and updates the action points from the previous alert. The 2006 alert should be referred to for full details, and is available from www.npsa.nhs.uk/alerts.²⁰

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Biologic therapies

Biologic therapies include the tumour necrosis factor (TNF) alpha inhibitors, (etanercept^▼, infliximab^▼ and adalimumab^▼), rituximab and anakinra.^3,4,21 These new therapies are generally reserved for people who do not respond adequately to conventional DMARDs.^4,11,21

TNF-alpha inhibitors block the effects of TNF-alpha, a mediator of inflammation.⁴ NICE guidance on etanercept and infliximab for the treatment of RA was issued in March 2002.²² This technology appraisal advises that etanercept or infliximab (infliximab only in combination with methotrexate) are recommended as treatment options for adults with active RA who have not responded well to treatment with at least two DMARDs, including methotrexate. Only a consultant rheumatologist should prescribe etanercept or infliximab and provide follow-up and monitoring of treatment. NICE recommends that these drugs should be prescribed in accordance with the relevant sections of the guidelines that have been produced by the British Society for Rheumatology (BSR). The BSR guidelines for prescribing TNF-alpha inhibitors in adults with RA were updated in 2005.²³ NICE recommends that the decision to continue therapy should be based on how the patient’s condition is progressing and how well the drugs are working. Sequential use of etanercept and infliximab is not currently recommended.²²

NICE guidance is currently being reviewed, and the update includes adalimumab. A Final Appraisal Determination (FAD) was issued in November 2006 (see Panel 4).¹⁴ There were six appeals against the recommendations in the FAD and these were heard in April 2007. Although individual appeals were dismissed, the appeal panel advised that the appraisal committee should review the evidence regarding use of a second TNF-alpha inhibitor where there had been no response to a first TNF-alpha inhibitor. As a result of this, the publication date for the final guidance is unknown. The recommendations within the FAD may change and, until the final guidance is published, the existing 2002 NICE guidance on etanercept and infliximab is still in force.

Within the FAD, the NICE appraisal committee concluded that studies demonstrated the efficacy of adalimumab, etanercept and infliximab in a range of populations with RA. There were some differences in efficacy endpoints reported for the three agents in the individual RCTs, but the populations included in the trials were not necessarily comparable. There was no compelling evidence to distinguish between the TNF-alpha inhibitors on the basis of clinical effectiveness.¹⁴

Rituximab was licensed in July 2006 for use in combination with methotrexate for the treatment of adult patients with severe active RA who have had an inadequate response or intolerance to other disease modifying anti-rheumatic drugs, including one or more TNF-alpha inhibitors.^21,24 It has a different mechanism of action from the TNF-alpha inhibitors and is a monoclonal antibody that depletes the B cell population.²⁵

A recent review concluded that rituximab is an effective therapy in patients who have disease refractory to TNF-alpha inhibitors.²¹ NICE is currently developing a technology appraisal on rituximab for the treatment of RA. The FAD has recently been published²⁵ and is available at www.nice.org.uk. Recommendations in the FAD do not yet constitute NICE guidance.

Anakinra inhibits the activity of interleukin-1, a mediator of inflammation.⁴ NICE guidance on anakinra for RA was issued in November 2003.² This concluded that, on the balance of its clinical benefits and cost-effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study.²

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Combination therapy

Even with early treatment with DMARD monotherapy, many patients continue to have progressive disease. Therefore, combinations of drugs with different modes of action are sometimes used.⁶

Combination therapy is generally initiated using a ‘step up’ approach. Most patients are treated initially with DMARD monotherapy and are monitored closely to assess response. A second DMARD is added if they do not respond.⁶ The ‘step down’ approach is an alternative, whereby a combination of treatments is started early in the disease. Treatment can then be reduced once the disease is controlled.⁶

As described briefly earlier, the two year results of a study which compared four different initial treatment strategies have recently been published.¹² Patients with early active RA (n=508) were randomised to sequential DMARD monotherapy, step up combination therapy, initial combination therapy with tapered high-dose prednisone, or initial combination therapy with infliximab. Treatment adjustments were made every three months on the basis of the DAS to achieve low disease activity (DAS < 2.4).

The primary endpoints were functional ability, as measured by the Dutch Health Assessment Questionnaire (HAQ), and Sharp-van der Heijde score for radiographic joint damage. Clinical remission (defined as DAS < 1.6) was a secondary efficacy endpoint.¹²

The study found that, in this setting of tight disease control, initial combination therapies seemed to provide earlier clinical improvement and less radiological evidence of progression of joint damage, but all treatment strategies eventually showed similar clinical improvements.¹² At two years, there was no significant difference in the mean improvement in HAQ score between the groups (0.7, 0.8, 0.9, 0.9, respectively, P=0.257). After two years, 79% of patients in all groups achieved the goal of low disease activity (overall, P=0.554), and 42% of patients were in clinical remission (overall, P=0.690).¹²

An accompanying editorial suggested that if clinicians have the flexibility to change therapy and have a clear treatment goal, all patients achieve similar disease control, regardless of their originally assigned treatment.²⁶ It is currently not possible to determine which patients will respond to which treatment strategy at disease onset.²⁶ In addition, costs of the different strategies vary widely,²⁶ and there is an increased potential for adverse events with combination therapy.

In conclusion, although we do not fully understand the potential consequences of a delay in achieving treatment goals with initial monotherapy,²⁶ the current practice of treating most patients initially with DMARD monotherapy seems sensible. Disease activity should be monitored closely to assess response and treatment adjustments should be made as appropriate on an individual basis.

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Monitoring of DMARDs and biologic therapies

Sources of information regarding monitoring of DMARDs and biologic therapies include individual summaries of product characteristics,²⁷ guidelines produced by BSR,^23,28 and PRODIGY guidance.²⁹ The PRODIGY guidance includes a summary of the recommendations for monitoring for adverse effects from DMARDs and biologic therapies, (Table 1). The full guideline should be consulted for further detail.²⁹

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The place of corticosteroids

Systemic use of corticosteroids is controversial due to the relative lack of evidence, the potential for disease flare on cessation, and concerns over adverse effects.⁹ Corticosteroids may be useful as a ‘bridging treatment’, while waiting for DMARDs to take effect, or for short-term treatment of a flare of RA in a person with established disease. They are an option that may be considered alongside symptomatic therapies such as paracetamol and NSAIDs⁴

For ‘bridging treatment’ (specialist advice required), intra-articular corticosteroids may be considered for localised disease, and systemic corticosteroids for more generalised disease. Intramuscular corticosteroids may be preferred to oral treatment, as this allows control of the dosage and duration of treatment.⁴

A disease flare in a patient with established RA may indicate that their treatment needs adjusting. Therefore, referral should be considered. For a monoarticular flare, if appropriate, an intra-articular corticosteroid injection will often give rapid relief of symptoms. Intra-articular corticosteroid injections should always be administered by an appropriately skilled person. Systemic corticosteroids can be considered for a monoarticular flare if intra-articular injection is not possible, or for a polyarticular flare. Intramuscular corticosteroids may be preferable to oral treatment.⁴

A Cochrane systematic review (10 studies, n=320) compared short-term treatment (5 days to two weeks) with low-dose oral corticosteroids (equivalent to 15mg prednisolone daily or less) with placebo or NSAIDs in patients with RA.³⁰ Prednisolone had a statistically significantly greater effect than placebo on joint tenderness, pain and grip strength. Prednisolone also had a statistically significantly greater effect than NSAIDs on joint tenderness and pain, but not grip strength. The review concluded that prednisolone in low doses, not exceeding 15mg daily, may be used intermittently in patients with RA, particularly if the disease cannot be controlled by other means.³⁰ Adverse effects were poorly described. However, the risk of adverse effects seemed acceptable.³⁰

There is some limited evidence showing that longer-term treatment (approximately six months) with corticosteroids (prednisone [or a comparable corticosteroid preparation] at a mean dosage of < 15mg/day) in RA appears to be superior to placebo and comparable to treatment with aspirin or chloroquine in improving some common RA disease activity measures (e.g. joint tenderness). However, long-term use is associated with considerable adverse effects e.g. hypertension, osteoporosis and diabetes.^11,31 Further investigation is needed to carefully weigh the relative effectiveness of corticosteroids against their adverse effects.³¹

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Corticosteroid-induced osteoporosis

Osteoporosis is a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fracture. Aside from postmenopausal osteoporosis, the most common secondary cause of osteoporosis is that due to the long-term use of oral corticosteroids.³² The higher the dose of corticosteroid, the higher the risks of fracture.³² However, increased risk is seen even at daily doses of prednisolone less than 7.5mg.^32,33 It is also important to recognise that RA increases the risk of osteoporosis even in the absence of corticosteroid therapy.⁴

Guidelines for the management of corticosteroid-induced osteoporosis were published by the Bone and Tooth Society, National Osteoporosis Society and the Royal College of Physicians in 2002.^33,34 In patients either committed to long-term oral corticosteroids or who have been exposed to long-term oral corticosteroid treatment for three months or more, osteoporosis prophylaxis is recommended if patients are aged 65 years or over, or aged under 65 years with a history of a previous fragility fracture. In the absence of a prior fragility fracture in those aged under 65 years, a bone mineral density (BMD) test is recommended and osteoporosis prophylaxis should be considered where the T-score is –1.5 standard deviation (SD) or lower.^4,32,33

A Health Technology Assessment (HTA) on corticosteroid-induced osteoporosis has been published recently.³² Only risedronate and calcidiol (unlicensed in the UK) were shown to have significant effects on reducing vertebral fracture risk, but neither had significant effects on non-vertebral fracture risk.³²

Several patient assessment algorithms were tested. The HTA found that the age threshold at which treatment was recommended in the above guideline (age 65 years or more) was not cost-effective. Also, the use of a T-score threshold of –1.5 SD in patients without a prior fragility fracture was not cost-effective.³²

The HTA concluded that the following strategy would be appropriate in patients receiving long-term corticosteroids. Patients with a prior fragility fracture would be eligible for treatment, as would individuals aged 75 years or more, irrespective of BMD. At other ages, patients without prior fractures would be eligible for treatment if the T-score was –2.0 SD or less on BMD testing. With this strategy, 47% of the corticosteroid treated population would be eligible for treatment. There are resource implications with this strategy since BMD tests would be required in 64% of the corticosteroid treated population, which is greater than that suggested by the current guidance.³²

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References

1. The National Institute for Health and Clinical Excellence. Rheumatoid arthritis. Draft scope for consultation. November 2006. Accessed from www.nice.org.uk on 10/05/07
2. The National Institute for Clinical Excellence. Anakinra for rheumatoid arthritis. Technology Appraisal No 72. November 2003. Accessed from www.nice.org.uk on 10/05/07
3. O’Dell. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004;350:2591–602
   
4. CKS. Rheumatoid arthritis (PRODIGY Guidance). Clinical Knowledge Summaries Service. Last revised July 2005. Accessed from www.cks.library.nhs.uk on 10/05/07
5. Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. SIGN guideline No. 48. December 2000. Accessed from www.sign.ac.uk on 10/05/07
6. Anon. Combination therapy for early rheumatoid arthritis. Drug Ther Bull 2006;44:81–5
7. Kennedy T, McCabe C, Struthers G, et al. BSR guidelines on standards of care for persons with rheumatoid arthritis. Rheumatology 2005;44:553–6
8. Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the management of rheumatoid arthritis (The first 2 years). Full guideline available online via the summary document (Rheumatology 2006;45:1167–9). Accessed from http://rheumatology.oxfordjournals.org/ on 04/04/07
9. Austen S. Developments in the treatment of rheumatoid arthritis. National Prescribing Centre/UK Drug Information Pharmacists Group. May 2000
10. Duff G, Chairman, Commission on Human Medicines. Safety of selective and non-selective NSAIDs. Letter to Health Professionals. October 2006. Accessed from www.mhra.gov.uk on 27/04/07
11. Emery P, Suarez-Almazor M. Rheumatoid arthritis. Clinical Evidence. Search date July 2002. Accessed from www.clinicalevidence.com on 27/04/07
12. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis. Ann Intern Med 2007;146:406–15
13. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263–9
14. The National Institute for Health and Clinical Excellence. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. Final Appraisal Determination. November 2006
15. National enhanced service. Provision of near-patient testing. Accessed from http://www.dh.gov.uk/en/Policyandguidance/Organisationpolicy/
    Primarycare/Primarycarecontracting/GMS/DH_4125637 on 03/05/07
16. NHS Business Services Authority. Drug Tariff. March 2007. TSO London
17. The European Agency for the Evaluation of Medicinal Products. EMEA Public statement on leflunomide (ARAVA) – severe and serious hepatic reactions. March 2001
18. Personal Communication. Prescription Pricing Division. NHS Business Services Authority. January 2007
19. National Patient Safety Agency. Reducing the harm caused by oral methotrexate. Patient Safety Alert 03. July 2004
20. National Patient Safety Agency. Improving compliance with oral methotrexate guidelines. Patient Safety Alert 13. June 2006
21. London New Drugs Group. Rituximab for rheumatoid arthritis. APC/DTC Briefing Document. September 2006
22. The National Institute for Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis. Technology Appraisal Guidance No 36. March 2002. Accessed from www.nice.org.uk on 10/05/07
23. Ledingham J, Deighton C on behalf of the British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNF-alpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157–63
24. Summary of Product Characteristics. MabTheraq. Accessed from http://emc.medicines.org.uk on 09/05/07
25. The National Institute for Health and Clinical Excellence. Rheumatoid arthritis (refractory) – rituximab. Final Appraisal Determination. July 2007. Accessed from www.nice.org.uk on 10/07/07
26. O’Dell JR. The BeSt way to treat early rheumatoid arthritis? Ann Intern Med 2007;146:459–60
27. Summaries of Product Characteristics. The electronic medicines compendium. Available at: http://emc.medicines.org.uk/
28. The British Society for Rheumatology. National Guidelines for the monitoring of second line drugs. July 2000
29. CKS. Monitoring people on disease-modifying drugs (DMARDs) (PRODIGY Guidance). Clinical Knowledge Summaries Service. Last revised July 2005. Accesed from www.cks.library.nhs.uk on 04/04/2007
30. Gotzsche PC, Johansen HK. Short-term low-dose corticosteroids vs placebo and nonsteroidal anti-inflammatory drugs in rheumatoid arthritis. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.:CD000189. DOI: 10.1002/14651858.CD000189.pub2
31. Criswell LA, Saag KG, Sems KM, et al. Moderate-term, low-dose corticosteroids for rheumatoid arthritis. Cochrane Database of Systematic Reviews 1998, Issue 3. Art. No.: CD001158. DOI: 10.1002/14651858.cd001158
32. Kanis JA, Stevenson M, McCloskey EV, et al. Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis. Health Technology Assessment 2007;11:1–258
33. Bone and Tooth Society, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis. A concise guide to prevention and treatment. London: RCP, 2002
34. Bone and Tooth Society, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. London: RCP, 2002

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