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Neuropathic pain: diagnosis and treatment
  1. Francesca Magrinelli1,
  2. Giampietro Zanette2,
  3. Stefano Tamburin1
  1. 1Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Verona, Italy
  2. 2Section of Neurology, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
  1. Correspondence to Dr Stefano Tamburin, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Piazzale Scuro 10, Verona 37134, Italy; stefano.tamburin{at}univr.it, s_tamburin{at}yahoo.com

Abstract

Neuropathic pain (NP) develops as a consequence of a lesion or disease affecting the somatosensory pathways in the peripheral or central nervous system, and occurs in many neurological diseases (eg, peripheral neuropathy, radiculopathy, spinal cord injury, stroke and multiple sclerosis). It affects 6%–8% of the general population and its impact on quality of life, mood and sleep exceeds the burden of its causative pathology. A peculiar feature of NP is the coexistence of negative and positive symptoms and signs, reflecting loss-of-function and gain-of-function of the somatosensory system, respectively. NP has long been considered a difficult clinical issue because of the lack of a diagnostic gold standard and the unsatisfactory response to treatment. In recent years, a redefinition, diagnostic algorithm, and some guidelines on diagnosis and treatment of NP have been published. This review offers an updated overview on the definition, pathophysiology, clinical evaluation, diagnosis and treatment of NP and focuses on some of the most frequent NP conditions. We intend to help overcome uncertainties on NP and bridge the gap between evidence based medicine and the real clinical world.

  • Neuropathic pain
  • Diagnosis
  • Treatment
  • Assessment
  • Pathophysiology
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Introduction

Neuropathic pain (NP) affects 6%–8% of the general population and has a great impact on the patients’ quality of life and disability.1 ,2 While these epidemiological figures suggest that NP is endemic, with a prevalence similar to that of diabetes mellitus and asthma, NP is still considered difficult to diagnose and treat by the general practitioners and by pain and neurology specialists. The recent redefinition and diagnostic algorithm and the guidelines on diagnosis and treatment of NP may help overcome these uncertainties and bridge the gap between evidence based medicine and the real world (table 1).

Table 1

Pain terminology

The International Association for the Study of Pain (IASP) stipulated that NP is initiated or caused by a primary lesion or dysfunction in the nervous system.3 However, this classical definition lacked pathophysiological and anatomical specificity because it did not specify what fell under the umbrella term dysfunction, and included patients with pain secondary to motor disorders (eg, spasticity, dystonia). To overcome these limitations, the Neuropathic Pain Special Interest Group of the IASP (NeuPSIG) recently redefined NP as arising as a direct consequence of a lesion or disease affecting the somatosensory system.4 According to this new definition, some conditions (eg, fibromyalgia, complex regional pain syndrome type 1) which were traditionally defined as putative NP according to the classical IASP definition should not be considered as such (table 2).

Table 2

NP syndromes according to the IASP classical definition and the NeuPSIG revised one

We favour the NeuPSIG redefinition because it is more specific than the IASP one and offers a diagnostic grading system (see below), which is similar to those used for other neurological diseases (eg, Alzheimer's disease, Parkinson's disease, multiple sclerosis, motor neurone disease), but there is no consensus on which NP definition is better.5

NP syndromes can be divided into those that are peripheral or central, based on the anatomical location of the causative lesion or disease (box 1).

Box 1

NP syndromes according to the site of damage of the somatosensory system

  • Asymmetrical (focal and multifocal) lesions in the peripheral nervous system

  • Entrapment mononeuropathies (carpal tunnel syndrome, ulnar nerve entrapment at the elbow, meralgia paraesthetica due to injury to lateral femoral cutaneous nerve, peroneal nerve entrapment at the fibular head)

  • Post-traumatic and postsurgical mononeuropathies

  • Phantom limb pain

  • Cervical, thoracic and lumbosacral radiculopathies

  • Trigeminal neuralgia

  • Diabetic monoradiculopathies and mononeuropathies

  • Postherpetic neuralgia

  • Brachial and lumbosacral plexopathies (inflammatory, traumatic, brachial plexus avulsion, neoplastic, radiotherapy, diabetic lumbosacral radiculoplexus neuropathies)

  • Vasculitic multineuropathies

  • Symmetrical lesions of the peripheral nervous system (painful polyneuropathies)

  • Diabetic distal symmetrical and small fibre polyneuropathies

  • Metabolic (alcohol-related, secondary to vitamin deficiency) neuropathies

  • Malignancy-associated neuropathies

  • Immune-mediated polyneuropathies

  • Neuropathy secondary to chemotherapy

  • HIV/AIDS-related polyneuropathy

  • Hereditary sensory neuropathies, amyloid neuropathies

  • Neuropathy in Fabry's disease

  • Lesions in the central nervous system

  • Spinal cord lesions (injury, infarction, inflammatory, spondylotic)

  • Central poststroke pain

  • Multiple sclerosis-related NP

NP, neuropathic pain.

The pathophysiology of NP involves both the peripheral and the central nervous systems. The term peripheral sensitisation indicates changes in the excitability of the peripheral nerve and the dorsal root ganglion, and central sensitisation includes changes in the spinal cord neurones, the descending pain-controlling systems and abnormal brain plasticity (table 3).6

Table 3

Main pathophysiological mechanisms of NP

Clinical presentation

The clinical presentation of NP is similar despite different aetiologies. Common features include burning, cold and shock-like qualities of spontaneous pain, paraesthesia, numbness and pain evoked to various stimuli, but some patients find difficulties in describing their pain. Studies exploring whether any pain quality or combination of qualities helps to separate NP from other types of pain could not identify a specific pattern, as they found considerable overlap between definite/possible and unlikely NP.7 ,8 NP patients usually show both negative and positive symptoms and signs (figure 1): this combination strongly suggests NP. However, this is still not specific for NP because patients with nociceptive pain may also have negative signs.9 A pain distribution that suggests a lesion or disease to a specific peripheral or central nervous system site (ie, a plausible neuroanatomical distribution) would be more specific for NP.4 Asking the patient to draw the distribution of pain and related symptoms on a body diagram often helps (figure 2). The frequent extraterritorial spread of NP10 ,11 should be considered as it may make it difficult to define to what extent a pain distribution is neuroanatomically plausible or not.12

Figure 1

Clinical features of NP. NP syndromes are characterised by the coexistence of negative symptoms and signs, which are expression of loss-of-function of the somatosensory system, and positive symptoms and signs, which indicate gain-of-function of the somatosensory system. Figure lists symptoms and signs of NP syndromes and their underlying pathophysiology. NP, neuropathic pain.

Figure 2

Body diagram showing pain distribution in a representative patient. Example of a diabetic patient with long-lasting and complex NP scenario that was difficult to understand when collecting clinical history. Asking the patient to draw the distribution of pain indicates the presence of different types of NP, which turned out to depend upon the coexistence of three types of DM neuropathy (ie, distal symmetrical neuropathy, bilateral diabetic lumbosacral radiculoplexus neuropathy and thoracic radiculopathy; see section on Diabetic NP). DM, diabetes mellitus; NP, neuropathic pain; NRS, Numerical Rating Scale.

Clinical diagnosis

At present, no single diagnostic procedure allows a definite diagnosis of NP. There are some validated screening tools to enable a quick and easy identification of patients with NP (table 4).13–19 They include questions on pain qualities, itemising the most common verbal pain descriptors and a simplified examination of the patient. Their sensitivity and specificity are high, when explored by their developers in expert pain centres, but there is no information on their predictive value in non-expert settings (general practitioners, primary neurological centres), where they would represent important tools. Screening tools are for operational guidance to give more robust diagnostic evaluation and never replace clinical judgement and a global assessment of the patient.20 The use of screening tools should be governed by the specific clinical applications for which they have been validated (eg, peripheral and/or central NP, neuropathic low back pain).

Table 4

Screening tools for NP

The NeuPSIG revised definition comes with a diagnostic algorithm, defining five levels of certainty (unlikely, possible, probable, definite and unconfirmed NP; figure 3).4 The first two questions of the algorithm (Has the pain a neuroanatomically plausible distribution? Does the history suggest a relevant lesion or disease of the somatosensory system?) are addressed to the patient's history: if their answer is YES, the level of certainty goes to possible.

Figure 3

Algorithm for the diagnosis of NP. The NeuPSIG algorithm for the diagnosis of NP is represented here.4 Similar to other neurological diseases, this algorithm defines five levels of certainty (unlikely, possible, probable, definite and unconfirmed NP). NeuPSIG, Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (IASP); NP, neuropathic pain.

When collecting clinical history, clinicians should assess the intensity of NP. Common tools to measure pain intensity are the Visual Analogue Scale, the Numerical Rating Scale, and the Verbal Rating Scale (figure 4). A modified visual analogue scale may include colours or pain intensity descriptors. All of these scales are valid and the choice between them may depend on personal preference or the patient's characteristics (eg, age, literacy). The Wong–Baker or Faces Pain Scale help to assess paediatric pain, but may be useful in some adult patients (ie, poor literacy, language disorders or dementia). Scales which measure the intensity of NP descriptors include PainDETECT (table 4)18 and the Neuropathic Pain Symptoms Inventory;21 these are mainly used as research tools, but may help in assessing the intensity of some NP features (eg, allodynia). NP patients should be asked about quality of life, disability, changes to social, family or work activities, sleep, mood, and anxiety. These features may be examined with the McGill Pain Questionnaire, the Brief Pain Inventory, the Pain Disability Index and the Short Form 36 Health Survey Questionnaire. These questionnaires are not specific for NP, but offer quantified measures and are self-administered.

Figure 4

Scales for measuring pain intensity. The scales that are commonly used to measure the intensity of pain in NP patients and the instructions for the patient are represented here. The visual analogue scale is a 100 mm horizontal line, and the pain intensity score is the distance in millimetres between the left end of the line and the mark. For the NRS, the pain intensity is the number indicated by the patient. For VRS (range=0–4) and FPS (range=0–5), the pain intensity corresponds to the term or face indicated by the patient. FPS, Faces Pain Scale; NP, neuropathic pain; NRS, Numerical Rating Scale; VAS, Visual Analogue Scale; VRS, Verbal Rating Scale.

The third question (Are there negative or positive signs confined to the innervation territory of the lesioned nervous structure?) is often answered during the bedside examination, which slightly differs from conventional neurological examination in that it focuses on the presence of negative and positive somatosensory signs. Examination should not be limited to the territory where pain is reported but extended to other ones, to test the topographical specificity of the findings and to rule out widespread pain conditions, such as fibromyalgia. Testing for negative and positive NP signs usually takes a few minutes and should include examination of tactile, thermal, and punctate hypaesthesia, hypopallaesthesia (decreased sensitivity to vibration), thermal and punctate hyperalgesia and mechanical allodynia (table 5; see online supplementary video). Bedside testing needs elementary training and gives quick and important information; its only limitation is that changes are explored qualitatively rather than quantitatively; however, quantified information is often unnecessary in the clinical setting.

Table 5

How to test negative and positive NP signs during bedside examination (see also online supplementary video)

Several instrumental techniques may help to answer the third question of the NeuPSIG algorithm when bedside testing is difficult (reduced cooperation or limited patient understanding, intellectual disability, linguistic difficulties, malingering) or gives uncertain or incomplete findings (medico-legal issues, somatisation). Instrumental tests may also help to answer the fourth question of the algorithm (Does a diagnostic test confirm lesion or disease explaining NP?), which cannot usually be addressed on physical examination alone (table 6).

Table 6

Instrumental tests for the diagnosis of NP

Instrumental diagnosis

Electrodiagnostic tests include electromyography and electroneurography, and the study of reflex responses (eg, trigeminal reflexes) and can help to document peripheral nervous system abnormalities. Since peripheral causes of NP are the most common, these tests are important for many patients. Electrodiagnostic tests may identify the presence and extent of sensory damage in asymmetrical and symmetrical peripheral nervous system lesions, but their use in NP goes beyond the diagnosis in that they may offer information on the pathological process (myelin or axonal damage, neuropraxia or axonotmesis/neurotmesis, presence and degree of denervation), the site of the lesion (root, plexus, nerve trunk), the extent of damage (sensory or sensorimotor, involvement of other peripheral nervous sites, even subclinical) and the prognosis (timing and degree of reinnervation).

Somatosensory evoked potentials may document a lesion in the central sensory pathways in patients with suspected central NP, and give information on the pathological process (demyelination, degenerative), the site of the lesion (spinal cord, brain) and the presence of subclinical involvement at other sites.

Electrodiagnostic tests and somatosensory evoked potentials explore large myelinated nerve fibres and lemniscal pathways, which do not convey nociceptive afferents, but these tests are important in the diagnosis of NP because they are available in many neurological centres. They have diagnostic value, because most diseases causing NP do not result in damage or lesion limited to the nociceptive system, but extend to the whole peripheral nerve or involve non-nociceptive pathways.

In patients with selective damage to either small nerve fibres (eg, diabetic small fibre neuropathy) or central nociceptive pathways (eg, Wallenberg's syndrome), electrodiagnostic tests and somatosensory evoked potentials may be normal; instrumental tests, which selectively explore the nociceptive system, may be necessary to reach a definite diagnosis of NP. They include quantitative sensory testing, laser evoked potentials, skin biopsy, autonomic tests, microneurography and functional neuroimaging; these tests are usually available only in tertiary or specialised centres.22 ,23

Quantitative sensory testing is non-invasive and measures a patient's response to thermal and mechanical stimuli of standardised intensity. It gives quantified information on detection and pain thresholds and may document abnormalities in nociceptive and non-nociceptive pathways. The limitations of quantitative sensory testing include the absence of a gold standard protocol, the need for patient's cooperation and the inability to demonstrate the anatomical level of damage to the nervous system. Quantitative sensory testing is of limited value in cases of malingering or when there is a suspected psychogenic component of pain.

Laser evoked potentials explore brain responses to laser stimuli, which cause a rapid increase in temperature in the epidermis and activate small nerve fibres. Laser evoked potentials may offer robust information on damage to small nerve (Aδ) fibres and nociceptive pathways, but they are invasive, expensive and cannot specify the anatomical level of somatosensory damage. Laser evoked potentials to C fibre stimulation and contact heat evoked potentials are less reliable and not routinely used.

Radiological tests, including conventional radiography, CT and MRI scans, are widely available and may confirm the lesion or disease, and so explain the NP. Nerve ultrasonography—performed only in specialised centres—may complement information obtained through electrodiagnostic testing.

The rationale of skin biopsy is that nociceptive (Aδ and C) nerve fibres free endings penetrate into the epidermis and may be seen with specific antibodies and quantified. The morphology and the density of intraepidermal nerve fibres correlate well with small nerve fibre dysfunction.24 Limitations of skin biopsy include its invasivity, cost, and the need strictly to follow standardised processing of specimen and nerve fibre counting.

Techniques to explore autonomic function include sympathetic skin response, measurement of sudomotor function and studying laser Doppler flow. These may help in patients with NP because nociceptive and autonomic systems share small peripheral nerve fibres. While such autonomic tests are less invasive and widely available their diagnostic role in NP needs further clarification.

Microneurography allows single fibre recording from peripheral nerve. This technique is time-consuming, invasive and needs detailed training of the examiner and cooperation from the patient. Microneurography has only a very limited or no clinical role and should be reserved for research purposes.

Functional neuroimaging includes positron-emission tomography and functional MRI techniques, which explore brain responses to spontaneous or evoked pain (ie, the pain matrix). Despite its role as a research tool, functional neuroimaging currently has no routine clinical use for NP.

There is a good correlation among quantitative sensory testing, laser evoked potentials and intraepidermal nerve fibre density;24 choosing the test to perform on an individual patient depends on the availability, specific clinical problem and personal preference.

Treatment

Various classes of drugs have proven effectiveness in NP in randomised clinical trials; they include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors antidepressants, antiepilepsy drugs active on sodium channels (carbamazepine, lamotrigine) and calcium channels (α2-δ ligands), opioids, topical lidocaine and capsaicin, and cannabinoids. Some recent meta-analysis and guidelines indicate which drugs should be first, second and third line treatment for NP.25–29 Despite this, the treatment of NP is still challenging in the real-life setting. Patients with NP usually require more drugs and report less pain relief than those with nociceptive pain.30 ,31 Common practical reasons for these unsatisfactory outcomes include the prescription of drugs without proven efficacy on NP or use of drugs effective on NP but at insufficient dosage,30 and side effects, which frequently cause drugs to be stopped. There are other methodological reasons for the gap between guidelines/meta-analysis and real life. The randomised controlled trials enrolled patients mostly with diabetic NP and postherpetic neuralgia, and it is unclear whether their conclusions can be extrapolated to other NP conditions. More recent trials have had more robust designs and explored measures of quality of life, sleep, anxiety and depression in addition to NP intensity (which was the only outcome in older studies). As a result, the evidence for older drugs (eg, tricyclic antidepressants) may be less robust and less complete than for newer ones. There are very few head-to-head randomised controlled trials; comparisons between drugs are based on their respective number needed-to-treat and number needed-to-harm, which may be influenced by different patient populations and differences between placebo effects between trials.

There is a good agreement between guidelines that tricyclic antidepressants, α2-δ ligands, serotonin-norepinephrine reuptake inhibitors, carbamazepine (for trigeminal neuralgia) and topical lidocaine (for localised peripheral NP) are the first line drugs, and tramadol and opioids are second line drugs (figure 5; table 7). Concerns about side effects, long-term safety, opioids hyperalgesia and addiction have made opioids second line treatment, except in cancer NP, acute or breakthrough (ie, with transitory worsening) NP, or when rapid pain relief is needed while titrating other drugs.

Table 7

First and second line drugs for NP

Figure 5

Algorithm for the treatment of NP. AEDs, antiepilepsy drugs; BTX, botulinum toxin; CBZ, carbamazepine; CLZ, clonazepam; COPD, chronic obstructive pulmonary disease; CPSP, central poststroke pain; DXM, dextromethorphan; GBP, gabapentin; IVIG, intravenous immunoglobulin; LTG, lamotrigine; MAOIs, monoamine oxidase inhibitors; NP, neuropathic pain; PGB, pregabalin; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TN, trigeminal neuralgia.

When first and second line treatments are ineffective or not tolerated, there are other possibilities. They include selective serotonin reuptake inhibitors, other antidepressants (bupropion, citalopram, paroxetine), antiepileptic medications (carbamazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, valproate), high-concentration capsaicin patches, cannabinoids (for central NP, especially multiple sclerosis), mexiletine, memantine, dextromethorphan, clonazepam, botulinum toxin type A and intravenous immunoglobulin.32

Few randomised controlled trials have examined combination therapy in NP, but they converged on there being a more marked pain reduction and fewer side effects when using two drugs together (α2-δ ligands+opioids; α2-δ ligands+tricyclic antidepressants) than each drug alone.33 The combination of NP drugs may also target different NP mechanisms in the same patient.

Mixed pain (ie, a combination of NP and nociceptive pain) is present in many conditions, including neuropathic low back pain, nerve/root compression and cancer pain. Evidence based medicine does not offer any information for these patients, but combining NP drugs and analgesics for nociceptive pain seems reasonable.

Invasive treatments (neurostimulation, intrathecal infusion of opioids, local anaesthetics, baclofen and ziconotide) are commonly used for patients whose NP is refractory to other therapies. There is only a weak quality of evidence base for these invasive approaches,34 largely from open case series without a control group. Spinal cord stimulation is a reasonable choice in refractory neuropathic low back pain, and motor cortex stimulation may be the last resort in refractory central poststroke pain.

Despite the availability of several drugs, no more than 30%–50% of NP patients achieve a satisfactory response. Randomised controlled trials recruit patients according to the NP aetiology, and this fails to capture the complex relationship among causes, pathophysiology and clinical manifestations of NP.35 Furthermore, most trials do not assess pain quality, although some drugs might be effective in subgroups of patients with specific clinical phenotypes or with some NP features. For these reasons, the definition of sensory profiles through symptoms (NP questionnaires) and signs (bedside assessment and quantitative sensory testing) may better stratify patients in randomised controlled trials and personalise treatment of NP. This perspective is tempting but its clinical utility has not yet been demonstrated.

Patients with NP often receive non-pharmacological treatments, including physical exercise, physical therapies (eg, transcutaneous electrical nerve stimulation, graded motor imagery), cognitive behavioural therapy or supportive psychotherapy. There is only limited evidence supporting these treatments, but they play a role in the comprehensive and multidisciplinary management of a complex clinical problem.

The delivery of care for NP may vary between countries, but it is usually performed in an outpatient setting. General practitioners play an important role in first line treatment, given the high prevalence of NP, while consultations with specialised neurology or pain centres are limited to refractory cases. Specialised centres should include medical and paramedical specialties to offer a multidisciplinary approach.

Specific NP clinical pictures

We will briefly review some NP syndromes, which are frequent and present specific diagnostic and/or treatment problems.

Diabetic NP

Peripheral neuropathy affects 30%–50% of patients with diabetes mellitus and includes different syndromes, divided into the frequent symmetric polyneuropathies (distal sensorimotor, autonomic, small fibre polyneuropathy) and the less common focal/multifocal neuropathies (cranial neuropathy, thoracic/lumbar radiculopathy, lumbosacral radiculoplexus neuropathy). About half of diabetic patients with neuropathy (ie, 10%–20% of diabetic patients) have NP, which is usually chronic.36 Acute painful neuropathy is a separate condition precipitated by strict glycaemic control. Diabetic NP correlates with age, body mass index, waist circumference, physical activity, diabetic duration, nephropathy, peripheral arterial disease and severity of the neuropathy.

The diagnosis of NP in diabetes mellitus should conform to the NeuPSIG diagnostic algorithm (figure 3)4 and is easily made from the patient's history and bedside testing. Some validated questionnaires or checklists can score NP symptoms and signs. Electrodiagnostic tests may help in special cases (eg, for research purposes, atypical or asymmetrical presentations).

The treatment of diabetic NP follows the treatment algorithm (figure 5). Better glycaemic control, improving other metabolic markers and reducing cardiovascular risk factors are recommended but their effect on NP is still unclear. Intravenous α-lipoic acid may reduce NP, but there is insufficient evidence on the efficacy of the oral preparation. Tricyclic antidepressants, α2-δ ligands and serotonin-norepinephrine reuptake inhibitors are the first line drugs, while tramadol and opioids are second line treatments.

Postherpetic neuralgia

Postherpetic neuralgia is defined as severe pain in the area of distribution of a herpes zoster eruption, persisting more than 30 days after the onset of rash or after cutaneous healing. In all, 10%–15% of patients with zoster develop postherpetic neuralgia, the risk factors including age >50 years, immunodeficiency and prodromal sensory symptoms. The pain is usually described as continuous deep aching, burning, stabbing and shooting; allodynia is frequent. The condition is self-limiting, resolving within 2 months in half of the patients, but may persist longer—up to years—with considerable impact on functional status and health-related quality of life. Although randomised controlled trials give contradictory results on the effectiveness of antiviral agents in preventing postherpetic neuralgia, we consider that patients at high risk should receive these drugs during the acute phase of a zoster eruption. Postherpetic neuralgia is usually difficult to treat and first line treatments include antidepressants (tricyclics, serotonin-norepinephrine reuptake inhibitors), α2-δ ligands (gabapentin, pregabalin), opioids or their combination. Topical application of capsaicin or lidocaine patches may bring temporary relief. High-concentration capsaicin patches or invasive treatments may help in refractory cases.

Trigeminal neuralgia

Trigeminal neuralgia and persistent idiopathic facial pain are the commonest causes of facial pain (figure 6).

Figure 6

Trigeminal neuralgia and persistent idiopathic facial pain. Clinical and treatment differences between the two most frequent causes of facial pain are presented here. NSAIDs, non-steroidal anti-inflammatory drugs; TCAs, tricyclic antidepressants.

Trigeminal neuralgia is a chronic NP condition, affecting one or more branches of the trigeminal nerve. It is characterised by unilateral, sudden, shock-like and brief (fractions of a second to minutes) painful attacks, which follow the distribution of trigeminal nerve branches, and with no other sensorimotor or autonomic signs and symptoms. Simple activities (washing the face or teeth, eating, talking) and the stimulation of trigger zones may unleash attacks. Trigeminal neuralgia presents spontaneous remissions, even without treatment. Bilateral symptoms suggest multiple sclerosis or other secondary causes. MRI and neurophysiological investigations may exclude secondary trigeminal neuralgia (eg, lesions of the posterior fossa, multiple sclerosis). Carbamazepine and oxcarbazepine are first choices for trigeminal neuralgia and reduce symptoms in nearly 70% of cases. α2-δ Ligands and baclofen are second line drugs. Invasive treatments (eg, microvascular decompression, Gasserian ganglion radiofrequency) may help refractory trigeminal neuralgia.

Persistent idiopathic facial pain persists throughout the whole day, or most of it. It usually starts in a small area of the face (eg, the nasolabial fold), and then can spread to the jaw or larger areas of the face and neck, irrespective of nerve branches distribution. The pain is deep and poorly localised, and there are no sensorimotor signs or symptoms. Dental procedures often precede its onset. Secondary causes of facial pain should be ruled out. Radiological and neurophysiological investigations are normal. Persistent idiopathic facial pain often responds to non-steroidal anti-inflammatory drugs (especially indometacin) and tricyclic antidepressants.

Low back pain

Low back pain has a lifetime prevalence of 70% and an important burden, especially when chronic. There is often an NP component, giving mixed pain, in 25%–30% of patients.37 Various spinal osteoarticular structures are responsible for nociceptive low back pain. Frequent causes of neuropathic low back pain include herniated disc with root compression, lumbar or foraminal stenosis, and scar tissue from previous spinal surgery.

Separating nociceptive from neuropathic low back pain is difficult. Radicular NP radiates to the lower limb according to the involved root (crural pain: L4, sciatic pain: L5, S1), but nociceptive low back pain may have pseudoradicular distribution because of referred pain phenomena.

History taking, including a pain diagram and bedside examination, is important in patients with low back pain. Red flags (weight loss, fever, pain at rest and during the night, no relief after 6–8 weeks of treatment, distal numbness and weakness, saddle anaesthesia, loss of bowel and bladder control) suggest a potentially serious cause and should always be sought. Yellow flags (poor compliance with exercise, poor work history, catastrophising, depression, feeling useless) are associated with poor prognosis.37 Standardised Evaluation of Pain is a screening tool with high sensitivity and specificity for separating neuropathic from nociceptive low back pain.19 The straight leg raising (Lasègue's sign), the cross–straight leg raising and the femoral nerve stretch tests are highly sensitive (88%–90%) but poorly specific (26%–29%) for root compression. Motor and sensory negative signs and reduced reflexes suggest neuropathic low back pain.

Spinal MRI and CT scan are often inconclusive in patients with low back pain, with poor correlation between radiological and clinical features, but should be performed in the presence of red flags. Electrodiagnostic tests and somatosensory evoked potentials are usually negative in patients with low back pain who have a normal neurological examination and no red flags.

Treatment of neuropathic low back pain should adhere to the NP treatment algorithm (figure 5). Nociceptive or mixed low back pain should be treated with non-steroidal anti-inflammatory drugs and analgesics.

Pain in patients with stroke

Pain is a frequent complaint in chronic stroke, involving up to half of the patients. The reasons for pain after stroke include pre-existing pain conditions (30%–40%), shoulder pain (30%–40%), painful spasticity (7%–10%), headache (5%–10%) and central poststroke pain (6%–8%).38 Among these, only central poststroke pain represents true NP, and should be diagnosed if developing after a stroke in a body region affected by the associated sensory abnormalities.4 There are proposed diagnostic criteria for central poststroke pain;38 applying them is straightforward for some patients, particularly after strokes involving the lateral medulla, the ventroposterior thalamus and the insula. However, diagnosing central poststroke pain may be a hard row to hoe in many stroke patients. The reasons for this difficulty include cognitive or language problems (making it difficult to demonstrate sensory signs), the presence of sensory deficits not related to NP (not all stroke patients with sensory deficits have central poststroke pain) and the coexistence of other types of pain.

Pain descriptors and thermal allodynia may help but are insufficient to make the diagnosis of central poststroke pain; other causes of pain (ie, nociceptive pain and peripheral NP) should be excluded (figure 7). Brain CT and MRI scans may show the stroke location. Quantitative sensory testing and laser evoked potentials may to help document the sensory deficits, but are not routine.

Figure 7

Diagnostic algorithm for pain in stroke patients. CPSP, central poststroke pain; GBP, gabapentin; LTG, lamotrigine; MCS, motor cortex stimulation; PGB, pregabalin; rTMS, repetitive transcranial magnetic stimulation; SNRIs, serotonin-norepinephrine reuptake inhibitors; TCAs, tricyclic antidepressants.

The treatment of central poststroke pain is disappointing (figure 7). The few randomised controlled trials on small populations of patients have given positive results for oral tricyclic antidepressants (amitriptyline 75 mg), pregabalin (300–600 mg), lamotrigine (200 mg), and intravenous lidocaine and propofol.38 Lamotrigine titration may take up to 3 months to avoid severe cutaneous reactions. Serotonin-norepinephrine reuptake inhibitors, opioids and psychotherapy help in other types of NP and could be considered in central poststroke pain.38 Case series report positive results for repetitive transcranial magnetic stimulation of the motor cortex, motor cortex stimulation and deep brain stimulation of the thalamus and the periacqueductal grey matter.

Pain in multiple sclerosis

Pain affects 57%–65% of multiple sclerosis patients and includes NP (ongoing extremity pain, 12%–28% of patients; Lhermitte's phenomenon, 15%; trigeminal neuralgia, 2%–5%, often bilateral), musculoskeletal pain (pain related to spasticity, <50%; painful tonic spasms, 6%–11%; back pain, 10%–16%), headache (21%–34%) and painful optic neuritis (8%).39 ,40 Extremity pain is continuous and burning, affects legs and feet bilaterally and usually worsens at night and during physical activity. Lhermitte's phenomenon is an electric shock sensation involving the neck, back and occasionally the limbs after neck flexion. Painful tonic spasms are stereotyped and short-lasting (<2 min), but may occur several times a day and be triggered by movement, sensory stimuli or emotions.

MRI may show the location of demyelinating lesions responsible for NP. Quantitative sensory testing and laser evoked potentials may document sensory deficits, but are not largely diffused.

There is debate over the treatment of multiple sclerosis-related pain.39 Carbamazepine and oxcarbazepine are the first line drugs for trigeminal neuralgia. Tricyclic antidepressants, α2-δ ligands and lamotrigine might help because they are useful in other types of central NP. It would also be reasonable to use drugs effective on peripheral NP (serotonin-norepinephrine reuptake inhibitors, tramadol, opioids). Despite some positive randomised controlled trials, cannabinoids have important side effects (psychosis, risk of addiction) and are not routinely recommended for NP or spasticity in multiple sclerosis. Botulinum toxin, intrathecal baclofen and, to a lesser extent, four oral drugs (baclofen, dantrolene, diazepam, tizanidine) may reduce spasticity and improve function, but their effect on pain has not been specifically studied.

Key messages

  • Neuropathic pain (NP) arises as a direct consequence of a lesion or disease of the somatosensory system; it affects 6%–8% of the general population and is caused by a range of conditions, including peripheral neuropathy, radiculopathy, spinal cord injury, stroke and multiple sclerosis.

  • A common feature of NP syndromes is the coexistence of negative and positive symptoms and signs, which reflect, respectively, loss-of-function and gain-of-function of the somatosensory system.

  • As with other neurological diseases, there is a grading system to define different degrees of diagnostic certainty for NP.

  • Although the diagnosis of NP has long been considered difficult, validated screening tools and a thorough bedside examination remain important to identify NP and to guide further investigations.

  • In randomised clinical trials, the best medications for NP achieve satisfactory pain relief in only 30%–50% of patients; side effects are a common reason for withdrawal of drugs.

References

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Supplementary materials

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Footnotes

  • Contributors FM designed the article, collected and interpreted the data, drafted the manuscript and revised it. GZ and ST designed the article, collected and interpreted the data, and revised the manuscript for important intellectual content. All authors approved the final version of the article. FM and ST take full responsibility for the content of this review.

  • Competing interests FM received travel grants from Grifols and Astellas for participation in scientific conferences and meetings. GZ received travel grants from Grifols and Pfizer for participation in scientific conferences and meetings. ST received travel grants from Grifols, Astellas and Pfizer for participation in scientific conferences and meetings. The Institution of ST received money from Pfizer for educational activities on neuropathic pain. The institution of ST received EFIC Grünenthal Grant 2010.

  • Patient consent Obtained.

  • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Lionel Ginsberg, London, UK.

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