Professor Blair H. Smith explains how the NICE guideline on neuropathic pain provides much needed advice on the pharmacological treatment of this condition in primary care
  • Neuropathic pain, caused by a lesion or disease in the nervous system, is common, distressing, and generally under-treated in primary care
  • Although there are many different causes of neuropathic pain, they generally respond to the same treatments, and these are different from standard analgesics used in nociceptive pain
  • First-line treatment is with amitriptyline (duloxetine in painful diabetic neuropathy) or pregabalin
  • Second-line treatment is with a swap or combination of the first-line treatments
  • Third-line treatment should consider the use of tramadol, but also include specialist referral
  • Doses should be consistent with the British National Formulary, and be titrated up to maximum tolerated dose
  • Ongoing review is important, particularly during titration
  • Referral should be considered at any stage if treatment is not working, or in the event of particular distress
  • Good communication between GPs, specialists, and patients is essential

In March 2010, the National Institute for Health and Care Excellence (NICE) published a clinical guideline outlining the best pharmacological treatments for adults with neuropathic pain who are being treated in non-specialist healthcare settings.1 Although the recommendations can be followed in hospital clinics other than pain or neurology clinics, they are most likely to be of the greatest benefit in primary care settings. The treatment of neuropathic pain in this context represents an important, but probably underestimated problem.

The NICE guideline uses the best available evidence on the effectiveness, cost effectiveness, and adverse reactions of the drugs that can be used in the treatment of neuropathic pain, the results of which are detailed in a practical guide for healthcare professionals to consider.1 By following the recommendations, it is hoped that there will be improvements in the identification and management of neuropathic pain in non-specialist settings.

Neuropathic pain

Neuropathic pain is defined as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.2 It is associated with ‘shooting’ or ‘burning’ pains, sensations similar to electric shocks, and abnormal responses to touch, heat, or cold. Neuropathic pain tends to be more unpleasant than nociceptive pain and can be associated with poorer general health, at levels similar to that of serious depression or ischemic heart disease.3 It is also usually resistant to standard analgesics.

Common causes of peripheral neuropathic pain encountered in primary care include lumbar radiculopathy, peripheral diabetic neuropathy, and post-herpetic neuralgia. Central neuropathic pain can be associated with, among other common conditions, stroke and multiple sclerosis.

Although pain types have traditionally been divided into nociceptive and neuropathic pains, there is increasing evidence that this split is not entirely clear. Many pains, such as back pain and post-surgical pain, are actually caused by a combination of these mechanisms, and most other pains probably lie somewhere on a spectrum between ‘pure’ nociceptive and ‘pure’ neuropathic pain.4

Although there are many different causes of neuropathic pain, a common feature is that they can generally be treated using the same drug classes. The NICE guideline, therefore, considers neuropathic pain as a single diagnostic entity, rather than dividing it into cause-specific sub-groups.1

Neuropathic pain

A review of the epidemiology of chronic pain found that there is no accurate estimate available for the population prevalence of neuropathic pain.5 This figure has been estimated at between 1% and 2%, and may increase to up to 8% for individuals who experience pain with some neuropathic features.6 This represents a large part of the primary care population, probably more than most GPs would have estimated, and the NICE guideline is therefore important, both in highlighting the importance of neuropathic pain, and the need for more evidence-based treatment.

There is evidence that neuropathic pain is often unsatisfactorily treated in primary care partly because:7,8

  • it tends to be under-recognised
  • there is a lack of high-quality independent evidence on the effectiveness of the treatments currently available
  • of the concerns about potential side-effects of the available drugs.

Generally the drugs used in the management of neuropathic pain differ to the first-line treatments for other types of pain. They include relatively new drugs (such as pregabalin), as well as some well-established treatments (such as amitriptyline), and a review of their effectiveness and costs is timely.

There is now an important consensus on how neuropathic pain can be assessed in primary care and this allows a platform from which this guideline can be implemented.9

Remit of the guideline

The NICE clinical guideline explicitly examines the drugs that should be used for adults in non-specialist NHS healthcare settings.1 It does not examine the role of non-pharmacological treatment, but does highlight the importance of this type of management in parallel with the use of drugs.

Antidepressants, anticonvulsants, and opioids were included in the literature search, as were topical treatments (capsaicin and lignocaine).1 The guideline only considered randomised controlled trials (RCTs) and effective treatment was judged in the event of a 30% or a 50% reported reduction in a pain scale score; improved quality of life was also taken into account. All RCTs that addressed treatment of neuropathic pain with these drug classes were rigorously assessed for their quality. Particular attention was given to drug treatment of painful diabetic neuropathy (PDN).1

The evidence review for the NICE guideline also included:1

  • assessment of adverse reactions:
    • treatment withdrawal because of side-effects
    • specific side-effects
  • critical appraisal and application of a current Health Technology Assessment report describing a detailed cost-effectiveness study of drugs used for neuropathic pain.

Most of the RCTs included in the evidence review were trials of drugs that have been developed relatively recently. There was a lack of good trial evidence relating to some of the drugs commonly used in primary care, such as carbamazepine and amitriptyline, and this is reflected in the guideline recommendations.1

Main recommendations

The main recommendations for pharmacological treatment of neuropathic pain in non-specialist settings are summarised in Box 1 and Figure 1. Alongside these recommendations, the guideline highlights the following needs:1

  • Non-pharmacological treatments should be considered in parallel to the recommended drug treatments, even though they are not addressed in this guideline. While many of these will not be directly available in primary care, GPs should consider the psychological impact (including depression) of neuropathic pain and the added benefit of treatment modalities such physiotherapy. Complementary therapies were not considered
  • Referral should be considered at any stage during this process. Due to the potential severity of neuropathic pain, the distress it causes, and difficulty with assessment and/or diagnosis, it will often be appropriate to refer patients at an early stage, and not to delay until the end of the treatment line. Referral may be directed to a pain clinic or to a neurologist
  • Prescribing should be in accordance with the British National Formulary,10 as well as the individual patient’s co-morbidities and risk factors
  • Doses should be titrated to the maximum effective tolerated dose, and reduction should be considered after a period of pain relief
  • Review of patients is important. This should be frequent at first—during the titration phase—and consider effectiveness, adverse reactions, and overall quality of life. Specific recommendations on the timing of review are not made, as this depends on individual patients and doctors. However, once treatment is established, it is still important to review patients periodically and to consider changes in their pain, treatment, and other relevant circumstances.

Further details on the recommendations can be found in the guideline, available at: www.nice.org.uk/CG96.

Neuropathic pain is a complex condition that is still the subject of much scientific and clinical research. With this in mind, the NICE guideline provides a manageable approach to this common and sometimes distressing condition. Treating neuropathic pain as a single diagnostic entity, rather than as a symptom of multiple other diagnoses, allows GPs a straightforward approach to its management. It is, of course, important to diagnose and address any curable or dangerous causes of pain, and to minimise associated co-morbidity. However, for most patients it will be their pain that has the greatest impact, and this guideline promotes a rapid and effective means of managing this.

Many GPs may already be treating neuropathic pain along similar lines to those recommended by NICE. Apart from confirming this good practice, perhaps the most useful outcome of the guideline will be to highlight the importance of managing neuropathic pain in primary care. Furthermore, those patients who are already achieving satisfactory pain relief from the use of drugs not consistent with the guideline recommendations should remain on these drugs;1 the NICE guideline should be used in conjunction with a practitioner’s clinical judgement and decision making should be tailored to the individual patient.

Pregabalin
Pregabalin, one of the newer available treatments, appears as a first-line treatment, alongside amitriptyline. Although pregabalin is more expensive to prescribe, the NICE review found it to be associated with:1

  • fewer adverse effects than its cheaper counterpart, gabapentin
  • fewer treatment withdrawals
  • greater overall cost effectiveness.

It is important that prescribers and policy makers view the wider picture of cost effectiveness rather than just price, when considering implementation of the guideline.

Opioids and topical treatment
Tramadol is the only opioid to be included in the prescribing recommendations. Strong opioids, such as morphine, may have a role in neuropathic pain; however NICE recommends that they must only be prescribed in partnership with a specialist as the evidence to support their use is inconclusive.1 Furthermore, considering that neuropathic pain is a long-term condition, the added risks of addiction and the debilitating side-effects associated with opioids mean that careful consideration needs to be given before choosing to prescribe these drugs.

Similarly, there was little evidence to support the use of topical treatments, such as lidocaine patches, as well as the potential for adverse effects and the high costs for the NHS. Therefore, topical treatments should only be used in collaboration with specialists, or as third-line treatment in patients unable to tolerate oral medication, and who are awaiting referral.1

Box 1: Main recommendations for prescribing for adults with neuropathic pain in the non-specialist setting*1

First-line treatment

  • Amitriptyline† OR pregabalin (duloxetine in patients with painful diabetic neuropathy, OR amitriptyline† if contraindicated)

Second-line treatment

  • If first-line treatment was amitriptyline†, switch to or combine with pregabalin
  • If first-line treatment was pregabalin, switch to or combine with amitriptyline† (or other tricyclic antidepressant)
  • For patients with painful diabetic neuropathy—if first-line treatment was:
    • duloxetine, switch to amitriptyline† or pregabalin, or combine with pregabalin
    • amitriptyline† switch to or combine with pregabalin

Third-line treatment

  • Consider referral to specialist pain service or condition-specific specialist. While waiting for referral, consider adding:
    • tramadol alone or in combination with second-line treatment in the interim
    • topical lidocaine† if the patient is unable to take medication
*Patients currently on effective treatment for neuropathic pain that falls outside of these recommendations should not have their treatment changed.
†Although amitriptyline and lidocaine are not licensed for use in neuropathic pain, their use as recommended here, is supported by the British National Formulary
Figure 1: Management of neuropathic pain 1
figure 1

Communication

There should be advance discussion between the GP and the patient about possible drug treatment side-effects and concerns as this is likely to minimise their negative effect, and to lead to the most efficient route through the treatment pathway. Ongoing doctor–patient communication is therefore important.

Implementation

The NICE guideline provides a straightforward, unified approach to the pharmacological management of neuropathic pain, which should be easy to implement in primary care. For these recommendations to be successfully implemented, excellent communication between primary care physicians and specialists, which should include clear care plans, is imperative.

Future research

Research recommendations form an important part of NICE guidelines. In the case of neuropathic pain, it became clear that there are still many unanswered questions about treatment. The Guideline Development Group recommended a number of areas for further research including: the use of carbamazepine, the use of combinations of drugs, the effect of neuropathic pain and its treatment on overall quality of life, and whether certain neuropathic pain conditions respond differently to different drugs.1

Conclusion

The NICE guideline is a welcome addition to the portfolio of treatment guidance currently available to GPs. Neuropathic pain is a common and distressing condition, and primary care now has a clear and pragmatic approach to its effective management, in collaboration with our specialist colleagues, while the results of further research are awaited. For more information, visit: www.nice.org.uk/guidance/CG/Wave19/7

NICE implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 96 on neuropathic pain. They are now available to download from the NICE website: www.nice.org.uk

Costing statement

Implementation of the NICE clinical guideline on the pharmacological management of neuropathic pain in non-specialist settings may have resource implications, but quantifying the cost of implementation with an acceptable degree of certainty is not possible for the reasons outlined in this statement.

Slide set

The slides are aimed at supporting organisations to raise awareness of the guideline and resulting implementation issues at a local level, and can be edited to cater for local audiences. This information does not supersede or replace the guidance itself.

Audit support

Audit support has been developed to support the implementation of the NICE guideline on the pharmacological management of neuropathic pain in non-specialist settings. The aim is to help NHS organisations with a baseline assessment and to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. The audit support is based on the key recommendations of the guidance and includes criteria and data collection tools.

Baseline assessment tool

This form can be used to conduct a baseline assessment of a trust's current activity in relation to the NICE guideline on the pharmacological management of neuropathic pain in adults in non-specialist settings. Current activity can be included along with actions needed to meet the recommendations and the trust lead.

  • The NICE guideline includes a simple algorithm that can form part of a local care pathway
  • It can help GPs prescribe appropriate first-line treatments and may avoid some pain clinic referrals
  • Local formularies may need to be modified to be compliant with this guideline (especially with reference to pregabalin)
  • Some of the drugs recommended will cost more in the short term, but offer cost efficiencies in the longer term
  • PBC groups should look to reduce inappropriate prescribing of opioids through adoption of this guideline to help offset the cost of pregabalin
  • Costs:a,b
  • pain management for outpatients = £160 (new), £84 (follow up)
  • pregabalin costs (at 50 mg tds) £96.60 per month
  • duloxetine costs (at 60–120 mg daily) £27.72–£55.44 per month
  • amitriptyline costs (10 mg = £1.08 per month; 50 mg = £1.21 per month)

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  1. National Institute for Health and Care Excellence. Neuropathic pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. Clinical Guideline 96. London: NICE, 2010. Available at: www.nice.org.uk/guidance/CG96
  2. Loeser J, Treede R. The Kyoto protocol of IASP basic pain terminology. Pain 2008; 137 (3): 473–477.
  3. Smith B, Torrance N, Bennett M, Lee A. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin J Pain 2007; 23 (2): 143–149.
  4. Bennett M, Smith B, Torrance N, Lee A. Can pain be more or less neuropathic? Comparison of symptom assessment tools with ratings of clinician certainty. Pain 2006; 122 (3): 289–294.
  5. Smith B, Torrance N. Neuropathic pain. In Croft P, editor: Chronic pain epidemiology: from Aetiology to Public Health. Oxford University Press (in press).
  6. Torrance N, Smith B, Bennett M, Lee A. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7 (4): 281–289.
  7. Hall G, Carroll D, Parry D, McQuay H. Epidemiology and treatment of neuropathic pain: The UK primary care perspective. Pain 2006; 122 (1): 156–162.
  8. Torrance N, Smith B, Watson M, Bennett M. Medication and treatment use in primary care patients with chronic pain of predominantly neuropathic origin. Fam Pract 2007; 24 (5): 481–485.
  9. Haanpää M, Backonja M, Bennett M et al. Assessment of neuropathic pain in primary care. Am J Med 2009; 122 (Suppl 10): S13–S31.
  10. Joint Formulary Committee. British National Formulary—BNF 59. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 2010.G