Dr João Calinas Correia explains what neuropathic pain is, how and when it should be assessed, and how comorbid conditions affect prescribing choices
Read this article to learn more about:
- when to consider neuropathic pain
- how to screen for, assess, and diagnose neuropathic pain
- pharmacological treatments for neuropathic pain.
Neuropathic pain is currently defined by the International Association for the Study of Pain (IASP) as a neurological condition manifesting as ‘pain caused by a lesion or disease of the somatosensory nervous system’.1 However, this is a recent (2008–2010) modification of a previous IASP definition, which defined neuropathic pain as a clinical presentation, where the patient’s pain has been modified by sensitisation (i.e. by a neurological functional change, not necessarily a lesion or disease) and presents with some specific clinical characteristics.
The vast majority of epidemiological and pharmacological research has been performed under the functional understanding of neuropathic pain. Therefore, current guidance on the treatment of neuropathic pain is applicable to sensitisation in general, whether or not it arises from a definite lesion or disease of the somatosensory nervous system.
When to consider neuropathic pain
The classic ‘types’ of pain—nociceptive,1 neuropathic, visceral2—refer to aetiologies, to origins of the pain process, rather than to their clinical presentations. Through interconnecting phenomena (e.g. neurogenic inflammation, viscero-somatic convergence, sensitisation) one type of pain may trigger events typical of other pain types. Therefore, clinical presentations are very often of a mixed type, and the likelihood of a mixed presentation increases over time as these interconnected processes develop.3
Neuropathic pain in primary care is most relevant within the context of chronic pain; in a large national population-based study in France in 2004, 22% of people with chronic pain reported pain with neuropathic characteristics.4 Furthermore, some conditions will show a higher prevalence of sensitisation symptoms and signs, for example diabetes, cancer, HIV, low back pain (see Table 1, below).5
|Chronic condition||Study population||Prevalence of neuropathic pain|
|Low back pain||Germany||37%|
Chronic pain is a common problem not just in musculoskeletal conditions but also in many chronic diseases, for example chronic obstructive pulmonary disease6,7 and heart failure.8 Therefore, pain and adequacy of pain management should be considered in the context of all chronic disease reviews,9 and given the prevalence discussed above, neuropathic pain should be considered whenever there is chronic pain.
How to screen for neuropathic pain
Many tools are available to screen for neuropathic pain.10–12 The DN413 has been extensively used in epidemiological studies and is reported to have high specificity and sensitivity.10–12 The S-LANSS was developed in the UK,14 is well validated for its self-reported form,15 and has been widely used in the UK (see Box 1, below).
Whichever tool is used, a positive result will indicate the need for a clinical assessment to establish the clinical significance of the findings, and an agreed management plan.
Box 1: DN4 and S-LANSS screening tools for neuropathic pain
- The DN4 requires a minimum of four positive answers to diagnose neuropathic pain with a specificity of 90%, therefore a minimum of one positive reply to the seven possibilities in Q1/Q2 is required for the possibility of neuropathic pain to be considered (as Q3/Q4 can only generate a maximum of three positive replies). With one or more positive answers to Q1/Q2, the completion of Q3 and Q4 is indicated, requiring a clinical assessment.13
- The S-LANSS requires a minimum of 12 points on scoring seven binary questions for pain of a predominantly neuropathic origin to be diagnosed. It has the advantage of providing a diagnosis of ‘predominantly neuropathic pain’ without further tests.14
Assessment of sensation
- Both DN4 and S-LANSS rely on brushing to test for sensory gain (allodynia) within the area of pain. The DN4 requires assessment of pinprick and touch, scoring only for loss of sensation to these stimuli within the painful area; the S-LANSS only requires the assessment of touch and scores on altered sensation, either a gain (pain, unpleasantness) or loss of sensation (numbness).
Assessment of sensitisation
The clinical assessment of neuropathic pain rests on the finding of sensory functional loss and/or functional gain in the same area as the pain. The full sensory assessment16 was distilled by the creators of the DN4 and S-LANSS into tests that were the most reliable for making a diagnosis of neuropathic pain. The tests found to be most useful are touch, pinprick, brushing, and noticing the loss (numbness) or gain (allodynia) of sensation, in comparison with non-affected areas.
The comparison is traditionally made with the contralateral area (e.g. right loin compared with left loin). However, it does happen that sensitisation changes may alter sensation in the contralateral area.17
It is therefore advisable to compare a painful area with both the contralateral equivalent and with areas above/below or medial/lateral to the area of pain.
Grading of neuropathic pain
The distinction between sensitisation and neuropathic pain is somewhat blurred in clinical practice. To overcome this difficulty, a grading system was introduced by the IASP Special Interest Group on Neuropathic Pain (NeuPSIG).18
This grading system allows for three distinct levels with clinical significance (see Box 2, below):
- possible neuropathic pain—from history and symptoms alone:
- creates the indication for further assessment, in order to achieve a diagnosis and a proposed management plan.
- probable neuropathic pain—sensory disturbances characteristic of sensitisation are present:
- at this stage the presence of sensitisation can be affirmed, and this carries an indication for treatment, both pharmacological and non-pharmacological. NB The presence of sensitisation does not establish the diagnosis of neuropathic pain because non-neuropathic sensitisation is common (e.g. in fibromyalgia, low back pain, irritable bowel syndrome [IBS]).3
- definite neuropathic pain—clinical or laboratorial diagnosis of suitable aetiology:
- the diagnosis of a suitable neurological condition may be clinical (e.g. trigeminal neuralgia, postherpetic neuralgia, iatrogenic/pharmacological/ toxic neuropathy); or it may be laboratorial (e.g. diabetes mellitus supporting a clinical diagnosis of diabetic neuropathy); or it may require referral for specialised investigations (e.g. multiple sclerosis, motor neurone disease). The specific diagnosis is important to the extent that it may offer specific treatment strategies.
Box 2: Grading system for neuropathic pain18
Criteria to be evaluated for each patient
1. Pain with a distinct neuro-anatomically plausible distribution*
2. A history suggestive of a relevant lesion or disease affecting the peripheral or central somatosensory system†
3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test‡
4. Demonstration of the relevant lesion or disease by at least one confirmatory test§
Grading of certainty for the presence of neuropathic pain:
- definite neuropathic pain: all (1 to 4);
- probable neuropathic pain: 1 and 2, plus either 3 or 4;
- possible neuropathic pain: 1 and 2, without confirmatory evidence from 3 or 4
* A region corresponding to a peripheral innervation territory or to the topographic representation of a body part in the CNS.
† The suspected lesion or disease is reported to be associated with pain, including a temporal relationship typical for the condition.
‡ As part of the neurologic examination, these tests confirm the presence of negative or positive neurologic signs concordant with the distribution of pain. Clinical sensory examination may be supplemented by laboratory and objective tests to uncover subclinical abnormalities.
§ As part of the neurologic examination, these tests confirm the diagnosis of the suspected lesion or disease. These confirmatory tests depend on which lesion or disease is causing neuropathic pain.
Treede R, Jensen T, Campbell J et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurol 2008; 70 (18): 1630–1635. Reproduced with permission.
Drug treatment for neuropathic pain in primary care
There are three important guidelines on managing neuropathic pain:
- NICE Clinical Guideline (CG) 173—Neuropathic pain in adults: pharmacological management in nonspecialist settings (2013)19
- European Federation of Neurological Societies (EFNS)—EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision (2010)20
- IASP NeuPSIG—Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis (2015)21
It is important to note that NICE CG173 is the only guideline that focuses on the primary care setting; for an interactive summary of this guidance, see NICE Neuropathic pain overview pathway. The EFNS and IASP guidelines have a considerable overlap of authorship, although the latter involves a number of American authors absent from the European group.
Regarding the pharmacological approach, there is considerable agreement between the guidelines though they differ in specific recommendations, approaches, and conclusions. The guidelines broadly agree on the use of the following treatments:
- amitriptyline, gabapentin, pregabalin, duloxetine
- carbamazepine for trigeminal neuralgia.
At the time of publication (April 2017), several of the drugs mentioned in this article did not have a UK marketing authorisation for the indications discussed. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices 22 for further information.
Practitioners should also be aware that off-label use of generic pregabalin for specific indications may infringe the patent of the branded product, which has a licensed indication for treatment of peripheral and central neuropathic pain; see summaries of product characteristics of pregabalin products for details, and NICE CG173.19
NICE guidance for primary care
NICE CG173 is very restrictive on the use of opiates and other anti-epileptics in primary care:19
- tramadol: consider only if acute (short-term) rescue therapy is needed (refer for specialist management if longer-term treatment is needed)
- do not use: cannabis sativa extract, capsaicin patch, lacosamide, lamotrigine, levetiracetam, morphine, oxcarbazepine, oxycodone,23 topiramate, tramadol (long-term use), venlafaxine without specialist advice.
The EFNS evidence, published in 2010, offers a less restrictive although more nuanced picture:20
- for (diabetic) painful polyneuropathy (PPN) the following treatments are recommended:
- tricyclic antidepressants (TCA), gabapentin, pregabalin, and serotonin and noradrenaline reuptake inhibitors (SNRI) (duloxetine, venlafaxine) as first-line treatment in PPN
- tramadol recommended second line except for patients with exacerbations of pain or those with predominant co-existing non-neuropathic pain
- third-line therapy includes strong opioids
- for post-herpetic neuralgia:
- TCA, gabapentin, or pregabalin recommended as first-line treatment
- topical lidocaine may be first line in selected cases
- strong opioids and capsaicin are recommended as second choice
- there continues to be a lack of evidence for SNRIs
- for trigeminal neuralgia, oxcarbazepine or carbamazepine are both listed as first line.
Irrespective of the authorship overlap with the EFNS guidance, the 2015 IASP guidance21 demonstrates the heightened concerns about long-term opioid use. Although the effectiveness of opioids is well established and second only to tricyclic agents (TCAs number needed to treat [NNT] = 3.6; strong opioids NNT = 4.3; SNRIs NNT = 6.4; gabapentin NNT = 7.2; pregabalin NNT = 7.7), opioids are only recommended as third line,21 a noticeable downgrade from EFNS 2010.20 The IASP 2015 recommendation is very much in agreement with NICE on its firstline recommendations (except for the inclusion of venlafaxine as an alternative to duloxetine).
When to refer
See Box 3 (below) for NICE’s recommendations on when to refer patients to a specialist pain or condition-specific service.19
Box 3: When to refer19
Consider referring the person to a specialist pain service and/or a condition-specific service at any stage, including at initial presentation and at the regular clinical reviews (see recommendation 1.1.6), if:
- they have severe pain or
- their pain significantly limits their lifestyle, daily activities (including sleep disturbance) and participation* or
- their underlying health condition has deteriorated.
* The World Health Organization ICF (International Classification of Functioning, Disability and Health) (2001) defines participation as ’A person’s involvement in a life situation.’ It includes the following domains: learning and applying knowledge, general tasks and demands, mobility, self-care, domestic life, interpersonal interactions and relationships, major life areas, community, and social and civil life.
National Institute for Health and Care Excellence. Neuropathic pain in adults: pharmacological management in non-specialist settings. Clinical Guideline 173. NICE, 2013 (updated 2017). Available from: www.nice.org.uk/cg173
NICE has not checked the use of its content in this article to confirm that it accurately reflects the NICE publication from which it is taken.
Management of comorbidity in neuropathic pain
The diagnosis of neuropathic pain rests on the demonstration of sensory sensitisation. This is a central process, and has repercussions over a wide spectrum of physiological processes. In patients with sensitisation, the likelihood of several disorders is increased, e.g. IBS, fibromyalgia, chronic headache, mood disorders, sleep disturbance.3,19 Targeting the comorbidities is an important consideration in choosing a first-line agent. While tricyclics may aggravate a constipation-predominant IBS, other agents may be more appropriate. An SNRI may be useful in fibromyalgia,24 possibly due to its action on the diffuse inhibitory noxious control system.25
The patient with chronic pain typically presents a complex picture and considering the broader picture will guide the choice of treatment.
Useful information for patients and professionals
Further information for patients and professionals about chronic pain as well as neuropathic pain in particular can be found on the Patient website26 and on the University College London Hospitals website.27
Barriers to good patient care
Barriers to care for people with neuropathic pain stem, in the author’s experience, from a lack of good quality information from local leadership and from the need for more patient-centred decision-making about medication.
Professionals regard the issue of neuropathic pain as complicated and its treatment frustrating, due to delayed and less than perfect outcomes.
Neuropathic pain is a common and disabling condition with a significant prevalence in primary care. However, it will only be diagnosed, and therefore treated, if practitioners consider it as a possibility when patients present with pain; moreover, a patient with chronic disease should always be assessed for neuropathic pain.
Neuropathic pain is diagnosed through the presence of symptoms and signs of sensitisation (pain characteristics, sensory gain and loss). There are efficient tools available to screen for neuropathic pain and there is also a grading system to guide subsequent management. Diagnosing sensitisation is a clinically relevant action, because sensitisation is linked to an increased risk of several burdensome and disabling comorbidities. The pharmacological approach to the management of neuropathic pain is well described in authoritative recommendations, but it will be helpful to consider the comorbidities, as well as patient preferences, when deciding on the most appropriate treatments.
- Neuropathic pain is currently defined as pain caused by a lesion or disease of the somatosensory nervous system:
- current guidance on treatment, however, is applicable to sensitisation in general, whether or not it arises from a definite lesion or disease of the somatosensory nervous system
- Clinical presentations are often of a mixed type:
- the likelihood of a mixed presentation increases over time
- In primary care, neuropathic pain is most relevant in the context of chronic pain
- Some conditions show a higher prevalence of sensitisation symptoms and signs, e.g. diabetes, cancer, HIV, low back pain
- Chronic pain occurs in many chronic diseases, e.g. COPD, heart failure:
- pain and pain management should be considered at all chronic disease reviews and neuropathic pain should be considered where there is chronic pain
- The DN4 and S-LANSS screening tools for neuropathic pain have been widely used and validated
- Assessment and grading of neuropathic pain can be performed
- NICE CG173 is the only guideline that focuses on the management of neuropathic pain in non-specialist settings:
- other guidelines make broadly similar recommendations although they may differ in specific recommendations, approaches, and conclusions
- The likelihood of burdensome disorders increases in patients with sensitisation:
- patient comorbidities and preferences will help to guide choice of treatment.
COPD=chronic obstructive pulmonary disease; CG=clinical guideline
GP commissioning messages
written by Dr David Jenner, GP, Cullompton, Devon
- Neuropathic pain:
- is common and is often a feature of chronic pain syndromes
- can often be managed in primary care so local formularies should include information from NICE CG173 and identify suitable pharmacological agents and their licensed indications
- Commissioners should:
- identify and publish local care pathways for the management of neuropathic pain and indicate when referral for specialist assistance is indicated:
- these pathways could include the screening tools for neuropathic pain so an accurate diagnosis is made before treatment and referral
- ensure that specialist pain management services are commissioned and available to patients requiring specialist support
- consider providing a ‘real-time’ advice and guidance service to support practitioners in prescribing treatments for neuropathic pain.
- International Association for the Study of Pain website. IASP Taxonomy. Updated 2012. www.iasp-pain.org/Taxonomy (accessed 16 March 2017).
- Schwartz E, Gebhart G. Visceral pain. Curr Topics Behav Neurosci 2014; 20: 171–197.
- Woolf C. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152 (3 Suppl): S2–S15.
- Bouhassira D, Lantéri-Minet M, Attal N et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008; 136 (3): 380–387.
- International Association for the Study of Pain. Epidemiology of neuropathic pain: how common is neuropathic pain, and what is its impact? IASP, 2014. Available at: iasp.files.cms-plus.com/AM/Images/GYAP/Epidemiology%20of%20Neuropathic%20Pain.pdf
- Roberts M, Mapel D, Hartry A et al. Impact of comorbid conditions in chronic obstructive pulmonary disease. American Thoracic Society 2013 International Conference abstract A5703, presented 22 May 2013. Am J Respir Crit Care Med 2013: 187: A5703.
- Mapel D, Roberts M, Von Worley A. PRS21—impact of chronic pain on health care costs in chronic obstructive pulmonary disease as compared to other chronic diseases. Value Health 2013; 16 (7): A369–A370.
- Evangelista L, Sackett E, Dracup K. Pain and heart failure: unrecognized and untreated. Eur J Cardiovasc Nurs 2009; 8 (3): 169–173.
- NICE. Multimorbidity: clinical assessment and management. NICE Guideline 56. NICE, 2016. Available at: www.nice.org.uk/ng56
- Jones R, Backonja M. Review of neuropathic pain screening and assessment tools. Curr Pain Headache Rep 2013: 17 (9); 363.
- Mathieson S, Maher C, Terwee C et al. Neuropathic pain screening questionnaires have limited measurement properties—a systematic review. J Clin Epidemiol 2015: 68 (8); 957–966.
- Cruccu G, Sommer C, Anand P et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol 2010; 17 (8): 1010–1018.
- Bouhassira D, Attal N, Alchaar H et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005; 114: 29–36.
- Bennett, M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001; 92 (1-2): 147–157.
- Bennett M, Smith B, Torrance N, Potter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain 2005; 6 (3): 149–158. Available at: www.specialistpainphysio.com/wp-content/uploads/2010/07/S-LANNS.pdf
- Rolke R, Baron R, Maier C et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006; 123 (3): 231–243.
- Shenker N, Haigh R, Mapp P et al. Contralateral hyperalgesia and allodynia following intradermal capsaicin injection in man. Rheumatology 2008; 47 (1): 417–1421.
- Treede R, Jensen T, Campbell J et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurol 2008; 70 (18): 1630–1635.
- NICE. Neuropathic pain in adults: pharmacological management in non-specialist settings. NICE Clinical Guideline 173. NICE, 2103 (updated 2017). Available at: www.nice.org.uk/cg173
- Attal N, Cruccu G, Baron R et al. EFNS guidelines on pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: 1113–1123.
- Finnerup N, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and metaanalysis. Lancet Neurol 2015; 14 (2): 162–173.
- General Medical Council. Good practice in prescribing and managing medicines and devices. Prescribing guidance: Prescribing unlicensed medicines. London: GMC, 2013. Available at: www.gmc-uk.org/guidance/ethical_guidance/14327.asp (accessed 27 March 2017).
- NICE Centre for Clinical Practice. Neuropathic pain—pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings. Clinical guideline 173 (full guideline). Available at: www.nice.org.uk/guidance/cg173/evidence
- Lunn M, Hughes R, Wiffen P. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014; (1): CD007115. DOI: 10.1002/14651858. CD007115.pub3.
- Staud R, Robinson M, Vierck C, Price D. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003; 101 (1–2): 167–174.
- Patient website. Health information. Neuropathic pain. patient.info/health/neuropathic-pain (accessed 5 April 2017).
- University College London Hospitals website. Pain Management Centre at National Hospital for Neurology and Neurosurgery. Self-help resources for pain management. www.uclh.nhs.uk/OurServices/ServiceA-Z/Neuro/PMC/Pages/Selfhelppain.aspx (accessed 5 April 2017).