Overview

This guideline covers managing neuropathic pain (nerve pain) with pharmacological treatments (drugs) in adults in non-specialist settings. It aims to improve quality of life for people with conditions such as neuralgia, shingles and diabetic neuropathy by reducing pain and promoting increased participation in all aspects of daily living. The guideline sets out how drug treatments for neuropathic pain differ from traditional pain management.

MHRA advice on valproate: In April 2018, we added warnings that valproate must not be used in pregnancy, and only used in girls and women when there is no alternative and a pregnancy prevention plan is in place. This is because of the risk of malformations and developmental abnormalities in the baby. See update information for details. The MHRA has published temporary advice on the valproate pregnancy prevention programme during the COVID-19 pandemic.

MHRA advice on pregabalin and gabapentin: In July 2019, we updated footnotes in this guideline to reflect a change in the law relating to pregabalin and gabapentin. As of 1 April 2019, because of a risk of abuse and dependence, pregabalin and gabapentin are controlled under the Misuse of Drugs Act 1971 as class C substances and scheduled under the Misuse of Drugs Regulations 2001 as schedule 3.

Introduction

Pain is an unpleasant sensory and emotional experience that can have a significant impact on a person’s quality of life, general health, psychological health, and social and economic wellbeing. The International Association for the Study of Pain (IASP 2011) defines neuropathic pain as ‘pain caused by a lesion or disease of the somatosensory nervous system’. Central neuropathic pain is defined as ‘pain caused by a lesion or disease of the central somatosensory nervous system’, and peripheral neuropathic pain is defined as ‘pain caused by a lesion or disease of the peripheral somatosensory nervous system’.

Neuropathic pain is very challenging to manage because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms (Beniczky et al. 2005). There is often uncertainty regarding the nature and exact location of a lesion or health condition associated with neuropathic pain, particularly in non-specialist settings. Examples of common conditions that have peripheral neuropathic pain as a symptom are painful diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-surgical chronic neuropathic pain, and neuropathic cancer pain (such as, chemotherapy-induced neuropathy, neuropathy secondary to tumour antigens, or caused by direct invasion or compression of neural structures). Examples of conditions that can cause central neuropathic pain include stroke, spinal cord injury and multiple sclerosis. Neuropathic pain can be intermittent or constant, and spontaneous or provoked. Typical descriptions of the pain include terms such as shooting, stabbing, like an electric shock, burning, tingling, tight, numb, prickling, itching and a sensation of pins and needles. People may also describe symptoms of allodynia (pain caused by a stimulus that does not normally provoke pain), hyperalgesia (an increased response to a stimulus that is normally painful), anaesthesia dolorosa (pain felt in an anaesthetic [numb] area or region), and sensory gain or loss (IASP 2011).

A review of the epidemiology of chronic pain found that there is still no accurate estimate available for the population prevalence of neuropathic pain (Smith et al. 2012). For example, the prevalence of neuropathic pain overall has been estimated to be between 6% and 8%, from postal surveys in France (Bouhassira 2008) and the UK (Torrance 2006). However, these estimates came from studies using different questionnaires. Other condition-specific studies have also mirrored the heterogeneous nature of neuropathic pain. For example, painful diabetic neuropathy is estimated to affect between 16% and 26% of people with diabetes (Jensen et al. 2006; Ziegler 2008). Prevalence estimates for post-herpetic neuralgia range from 8% to 19% of people with herpes zoster when defined as pain at 1 month after rash onset, and 8% when defined as pain at 3 months after rash onset (Schmader 2002).

The development of chronic pain after surgery is also fairly common, with estimates of prevalence ranging from 10% to 50% after many common operations (Shipton 2008). This pain is severe in between 2% and 10% of this subgroup of patients, and many of the clinical features closely resemble those of neuropathic pain (Jung et al. 2004; Mikkelsen et al. 2004; Kehlet et al. 2006). Furthermore, a study of 362,693 computerised records in primary care from the Netherlands estimated the annual incidence of neuropathic pain in the general population to be almost 1% (Dieleman et al. 2008). This considerable variability in estimates of the prevalence and incidence of neuropathic pain and similar conditions from general population studies is likely to be because of differences in the definitions of neuropathic pain, methods of assessment and patient selection (Smith and Torrance 2010, Smith et al. 2012).

A number of pharmacological treatments can be used to manage neuropathic pain outside of specialist pain management services. However, there is considerable variation in how treatment is initiated, the dosages used and the order in which drugs are introduced, whether therapeutic doses are achieved and whether there is correct sequencing of therapeutic classes. A further issue is that a number of commonly used treatments are unlicensed for treating neuropathic pain, which may limit their use. These factors may lead to inadequate pain control, with considerable morbidity.

Commonly used pharmacological treatments include antidepressants (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs] and serotonin–norepinephrine reuptake inhibitors [SNRIs]), antiepileptic (anticonvulsant) drugs, topical treatments and opioid analgesics. In addition to their potential benefits, all of these drug classes are associated with various adverse effects.

This short clinical guideline aims to improve the care of adults with neuropathic pain by making evidence-based recommendations on the pharmacological management of neuropathic pain outside of specialist pain management services. A further aim is to ensure that people who require specialist assessment and interventions are referred appropriately and in a timely fashion to a specialist pain management service and/or other condition-specific services.

1. Recommendations

The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.

Additional information

2. Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

2.1. Monotherapy versus combination therapy for treating neuropathic pain

What is the clinical effectiveness, cost effectiveness and tolerability of pharmacological monotherapy compared with combination therapy for treating neuropathic pain?

Why this is important

Combination therapy is commonly prescribed for neuropathic pain. It may also be a helpful option as a stepwise approach if initially used drugs are insufficient at reducing pain. Combination therapy may also result in better tolerability because smaller doses of individual drugs are often used when combined with other drugs. However, there is a lack of trial evidence comparing the clinical and cost effectiveness and tolerability of different drug combinations. Further research should be conducted as described in table 1 below.

Table 1

Monotherapy versus combination therapy for treating neuropathic pain.

2.2. Relationship between symptoms, cause of neuropathic pain and its treatment

Is response to pharmacological treatment predicted more reliably by underlying aetiology or by symptom characteristics?

Why this is important

There is little evidence about whether certain symptoms that present in healthcare settings, or whether different neuropathic pain conditions with different aetiologies, respond differently to different treatments. Current evidence is typically focused on particular conditions and is limited to particular drugs. Further research should be conducted as described in table 2 below.

Table 2

Relationship between symptoms, cause of neuropathic pain and its treatment.

2.3. Carbamazepine for treating trigeminal neuralgia

What is the clinical and cost effectiveness of carbamazepine as initial treatment for trigeminal neuralgia compared with other pharmacological treatments?

Why this is important

Carbamazepine has been the standard treatment for trigeminal neuralgia since the 1960s. Despite the lack of trial evidence, it is perceived by clinicians to be efficacious. Further research should be conducted as described in table 3 below.

Table 3

Carbamazepine for treating trigeminal neuralgia.

2.4. Factors affecting participation and quality of life

What are the key factors, including additional care and support, that influence participation and quality of life in people with neuropathic pain?

Why this is important

There is evidence suggesting that people with neuropathic pain experience poorer physical and mental health than people with other forms of pain, even when adjusted for pain intensity. The discrepancy between pain intensity and quality of life implies that other, unrecognisable factors are important for people with neuropathic pain and that these factors may influence their daily activities and participation. Further research should be conducted as described in table 4 below.

Table 4

Factors affecting participation and quality of life.

2.5. Impact of drug-related adverse effects on cost effectiveness and quality of life

What is the impact of drug-related adverse effects on health economics and quality of life in neuropathic pain?

Why this is important

Pharmacological agents for neuropathic pain are associated with various adverse effects. However, there is little evidence about how this affects cost of the quality of life of patients receiving treatment. Further research should be conducted as described in table 5 below.

Table 5

Impact of drug-related adverse effects on cost effectiveness and quality of life.

2.6. Potential for dependence associated with pharmacological drugs for neuropathic pain

Is there a potential for dependence associated with pharmacological agents for neuropathic pain?

Why this is important

There has been some suggestion that some pharmacological agents for neuropathic pain are associated with increased potential for misuse. However, there had not been enough high-quality evidence to adequately explore this issue. Further research should be conducted as described in table 6 below.

Table 6

Potential for dependence associated with pharmacological drugs for neuropathic pain.

Finding more information and committee details

You can see everything NICE says on this topic in the NICE Pathway on neuropathic pain.

To find NICE guidance on related topics, including guidance in development, see the NICE webpage on neuropathic and persistent pain.

For full details of the evidence and the guideline committee’s discussions, see the full guideline. You can also find information about how the guideline was developed, including details of the committee.

NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.

Update information

This guidance is an update of NICE guideline CG96 (published March 2010) and replaces it.

September 2020: As part of a surveillance review on neuropathic pain, the available evidence on treating sciatica was reviewed. As the NICE guideline on low back pain and sciatica already covered this topic area, it was agreed that the revised advice would be best placed in that guideline (see the section on pharmacological management of sciatica). Some research recommendations that included sciatica have also been amended in the full version of this guideline.

July 2019: Because of a risk of abuse and dependence, pregabalin and gabapentin are controlled under the Misuse of Drugs Act 1971 as class C substances and scheduled under the Misuse of Drugs Regulations 2001 as schedule 3 (as of 1 April 2019). Footnotes in this guideline have been updated to reflect this change.

April 2018: Cautions in the guideline have been added to link to the MHRA’s latest advice and resources on sodium valproate. Medicines containing valproate taken in pregnancy can cause malformations in 11% of babies and developmental disorders in 30–40% of children after birth. Valproate treatment must not be used in girls and women including in young girls below the age of puberty, unless alternative treatments are not suitable and unless the terms of the European Medicines Agency pregnancy prevention programme are met. This programme includes: assessment of patients for the potential of becoming pregnant; pregnancy tests; counselling patients about the risks of valproate treatment; explaining the need for effective contraception throughout treatment; regular (at least annual) reviews of treatment by a specialist, and completion of a risk acknowledgement form. In pregnancy, valproate is contraindicated and an alternative treatment should be decided on, with appropriate specialist consultation. See the MHRA toolkit to ensure female patients are better informed about the risks of taking valproate during pregnancy. Recommendations marked [2018] have had a note on sodium valproate added during the April 2018 update.

Your responsibility: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.