Clinical Review - Neuropathic pain

Contributed by Dr Karen Simpson, consultant in pain medicine, Leeds Teaching Hospitals NHS Trust.

Deformity to foot and ankle due to neuropathy

Section 1: Aetiology and epidemiology
The International Association for the Study of Pain has defined more than 600 pain syndromes. Patients with complex or persistent pain present with physical and behavioural symptoms.

Nociceptive pain is classically defined as tissue damage that releases local mediators that stimulate healthy A(delta) and C fibres to transmit pain signals to the spinal cord, via the spino-thalamic tract to the thalamus and higher centres.

However, in reality, noci-ceptive mechanisms are much more complex; many other pathways are involved in pain processing.

The nervous system is plastic; it responds to afferent stimulation with neuronal and gene changes in the periphery, spinal cord and brain.

Neuropathic pain is defined as 'pain arising as a direct consequence of a lesion or disease affecting the somatosensory system'.1 It is commonly seen in primary care and may be caused by a wide variety of disease processes (see box).

Neuropathic pain can be classified into four categories: focal/multifocal lesions in the peripheral nervous system (PNS), generalised peripheral neuropathies, CNS lesions and complex neuropathic disorders.2

In western Europe, chronic pain prevalence is one in five. Some 70 million adults experience persistent pain and a third of households are affected.

A European telephone survey of more than 46,000 householders showed that 11-30 per cent of people had significant chronic pain that led to effects on quality of life.3

A more detailed assessment was made of a UK subset (n=300), average age 49 years; 70 per cent had pain at least daily. Quality of life, mood and capacity to work were all adversely affected by pain.

Neuropathic pain occurs in about 6-8 per cent of the general population.4 It is associated with advancing age, female gender and lower socioeconomic groups. It is more common in certain conditions, for example diabetes (24 per cent), and after shingles (20 per cent).

However, the most common causes are radicular pain from spinal pathology or after trauma/surgery.

Several studies have shown that neuropathic pain has a greater deleterious effect on quality of life than nociceptive pain, leading to poorer physical and mental health.

Baron's classification of neuropathic pains2
  • PNS (focal and multifocal)
  • Trigeminal neuralgia
  • Postherpetic neuralgia
  • Diabetic mononeuropathy
  • Postamputation pain
  • Plexus avulsions
  • Nerve entrapments e.g. carpal tunnel syndrome
  • Postoperative nerve pains e.g. post-hernia repair
PNS (generalised)
  • Toxic e.g. alcohol, chemotherapy, heavy metal poisons
  • Metabolic e.g. diabetes, hypothyroid
  • Nutritional e.g. vitamin B deficiency
  • Infective e.g. HIV, Guillain-Barre syndrome
  • Malignant e.g. carcinonatous neuropathy
  • Infarction in brain or spinal cord
  • Multiple sclerosis
  • Spinal cord tumour or trauma
  • Disc prolapse
Complex neuropathic disorders
  • Complex regional pain syndromes (CRPS) I and II

Section 2: Diagnosis
Those we label as 'chronic pain patients' may be disadvantaged if this leads to healthcare professionals failing to assess pain causation.

Detailed assessment is an essential prerequisite of successful pain management. This involves recognising that neuropathic pain is not a single disorder but a constellation of symptoms and physical signs.

The classical presentation is painful symptoms arising from an area of altered sensation, which may be numb or hyperexcitable. There is often spontaneous pain or abnormal responses to non-painful and painful stimuli.

Allodynia is pain evoked by a stimulus that is not usually painful. There are three types of allodynia: mechanical (static and dynamic), thermal (warm and cold) and movement.

Hyperalgesia is a response of exaggerated severity following a noxious stimulus such as a pinprick. Hyperpathia is an increased reaction to a painful, often repetitive, stimulus.

There can also be spatial abnormalities, so for example a stimulus in one area causes pain in another. This could manifest as a noxious stimulus to a normal limb causing pain in the contra-lateral phantom limb.

There may also be autonomic dysfunction, for example skin temperature, sweating, hair and nail changes. Patients may have impaired sensation and muscle wasting/weakness.

Clinical assessment
The diagnosis of neuropathic pain is made by careful clinical history and examination.

This diagnosis may be supported by the use of validated tools to assess neuropathic pain, for example the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)5 or the painDETECT questionnaires.6

These tools have about 80 per cent accuracy but cannot replace good clinical assessment. Clinical assessment involves comparing the affected area to an unaffected adjacent or contra-lateral site.

Light stroking of the skin may show allodynia. Numbness or an exaggerated response to pinprick is important. Inability to differentiate warm and cold suggest alteration in thermal thresholds.

Painful symptoms and altered sensations such as these are very suggestive of neuropathic pain mechanisms.

It is often the case that there will be a mixed presentation and it is uncommon to have pain that is purely nociceptive or purely neuropathic. However, pain with a neuropathic component requires different management and so it is essential to seek and identify neuropathic pain qualities.

Section 3: Non-pharmacological treatment
About a third of patients with chronic neuropathic pain do not receive any treatment.7

Treatment often needs to be both pharmacological and non-pharmacological. These are not mutually exclusive strategies and should be explored when deciding the most appropriate management plan.

It is also vital to consider the patient's capabilities and carefully manage their expectations to ensure maximum concordance with treatments.

Non-invasive therapies include exercise, heat and cold therapy, ultrasound, transcutaneous electrical nerve stimulation (TENS), orthotics and acupuncture.

However, the evidence for some of these strategies needs to be carefully considered before they can be included in common clinical practice.

In patients with neuropathic pain, some physical treatments can be difficult to administer because of areas of absent sensation or allodynia. Some techniques, such as TENS and acupuncture, rely on reasonable function within the nervous system that may be lacking in patients with neuropathic pain.

Invasive therapies can help some patients. These range from a variety of nerve blocks or radio-frequency lesioning to neuromodulation such as spinal cord stimulation, intrathecal drug delivery or deep brain stimulation.

More ablative procedures may be needed for refractory pain, for example microvascular decompression for trigeminal neuralgia, cordotomy for cancer pain, chemical sympathectomy for vascular pain and dorsal root entry zone lesions for plexus pain.

These therapies are usually offered by specialists in pain management or neurosurgery.

Psychological therapies
It is important to maintain emotional as well as physical function, so psychological therapies are often helpful. Treatments are multimodal and incorporate a range of behavioural and cognitive interventions. Many treatment programmes are delivered in a group setting.

In addition to specific interventions such as pacing and shaping of behavioural change, central features include an attempt to engage patients in a collaborative partnership and the provision of education about chronic pain.

Section 4: Pharmacological treatment
In primary care an important part of treatment for neuropathic pain is pharmacological.

Anticonvulsants (gabapentin or pregabalin) and tricyclic antidepressants are first-line therapy in neuropathic pain. Tertiary amines (amitriptyline, imipramine) are often less well tolerated than secondary amines (nortriptyline).

SNRIs (duloxetine, venlafaxine) can be used as firstor second-line choices; they may be less effective but they have better tolerability.

Topical 5% lignocaine patches can be used for localised areas of pain, especially if there is allodynia. Capsaicin cream, which acts via depletion of the neurotransmitter substance P, may help peripheral nerve pains and postherpetic neuralgia. However it needs diligent, regular and prolonged use.

Strong opioids are effective in neuropathic pain and may be required. These are usually second or third line. They should be used according to the British Pain Society guidelines on prescribing.8

Combination therapy
It is usual to start with monotherapy, but there may be a need to move to combinations of drugs quite quickly if pain proves difficult to control.

Effective pain relief with a single drug is achieved in less than 50 per cent of patients with neuropathic pain.9

It is safest to start with a low dosage, up-titrate slowly and assess the patient frequently.

It is necessary to provide a two to eight week trial of each drug. There needs to be at least two weeks at the maximum tolerable dosage before assessing efficacy.

The patient must be made aware that if pain is long-standing in nature it is unlikely to be completely relieved, titration may be slow and that the goal is pain management rather than cure.

Drug side-effects mean that it may not be possible to reach the therapeutic window in all cases. This often requires several appointments and careful drug trials to ensure maximum efficacy with the minimum acceptable side-effects.


1. Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-5.

2. Baron R. Mechanisms of disease: neuropathic pain - a clinical perspective. Nat Clin Pract Neurol 2006; 2: 95-106.

3. Breivik H, Collett B, Ventafridda V et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006; 10(4): 287-333.

4. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. J Pain 2006; 7: 281-9.

5. Bennett M. The LANSS pain scale. Pain 2001: 92: 147-57.

6. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006; 22: 1911-20.

7. Finnerup NB, Otto M, McQuay HJ et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005; 118: 289-305.

8. Recommendations for the appropriate use of opioids in persistent non-cancer pain (2005); British Pain Society;

9. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of non-malignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 2005; 293: 3043-52.

10. Freynhagen R, Bennett MI. Diagnosis and management of neuropathic pain. BMJ 2009; 339: 391-95.


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