Review Article Section

Neuropathic Pain
Pain in Neurological Disease Complex Regional Pain Syndrome (CRPS, formerly
Pain is a frequent symptom of neurological disease. known as Reflex Sympathetic Dystrophy, RSD).
Although there have been improvements in treatment,
pain often remains unresponsive to all treatment modal- Causes of NP
ities. A convenient classification of NP is anatomical, accord-
ing to the site of initiating nervous system pathology,
What is Neuropathic Pain? with an aetiological sub-classification (Tables 1 and 2). A
A limited understanding of underlying pathophysiology, mechanism-based classification is needed, but it is not yet
and recent changes in terminology have led to some con- possible to reliably link symptoms and signs to patho-
fusion. The International Association for the Study of physiology (see Table 4). The development of specific and John Scadding is
Pain (IASP) defines NP as "pains resulting from disease consultant neurologist at
selective treatments will depend on a mechanism-based the National Hospital for
or damage of the peripheral or central nervous systems, classification. For the majority of NP sufferers, the pain Neurology and
and from dysfunction of the nervous system". Originally, will persist lifelong. Co-morbidities (depression, Neurosurgery and
NP was used to describe only pain related to peripheral impaired quality of life, employment, domestic issues etc) Whittington Hospital,
London, and Honorary
neuropathies, and central pain (CP) to lesions of the cen- are very common. Senior Lecturer at the
tral nervous system associated with pain. Neurogenic Institute of Neurology. He
pain embraced all causes, both peripheral and central. Clinical Features of NP (Table 3) is also Associate Dean at
the Royal Society of
The addition of a category of "dysfunction" in the def- Patients often find it difficult to describe the quality of Medicine. As a registrar
inition of NP allows the inclusion of organic pain states NP; it is outside their previous experience of pain. he worked with PD Wall
which share the clinical features of NP, but which are not Sensory loss may be mild and overshadowed by allodynia and PK Thomas, and this
initiated by an identifiable lesion of any part of the ner- (all stimuli producing pain), hyperalgesia and hyper- kindled a clinical and
research interest in
vous system. However, this is a contentious issue; some pathia (delayed perception, summation and painful after- mechanisms and
argue that the "dysfunctional" category should be exclud- sensation). Rarely, (eg trigeminal neuralgia) there is no management of chronic
ed, on the grounds that there is no initiating neural demonstrable sensory loss. neuropathic pain.
injury. While it is true that including dysfunctional pain There may be signs of sympathetic dysfunction, and
causes difficulties in recognising the limits of NP, exclu- occasionally dystrophic changes. The onset of pain may
sion of this important type of pain ignores the clinical be delayed, the commonest example being central post-
reality of the existence of similar pain states, one pro- stroke pain (thalamic), which may start months or years
voked by neurological damage and the other by damage after the initiating stroke.
to non-neural tissues. Creation of a separately defined Pain is often of mixed nociceptive and neuropathic
category of dysfunctional pain is acceptable, as long as it types, for example, mechanical spinal pain with radicu-
is recognised that there may be pathophysiological mech- lopathy or myelopathy. It is not generally recognised that
anisms common to both NP and dysfunctional pain. The nociceptive spinal pain can radiate widely, mimicking a
debate continues, but from a practical point of view, the root distribution. It can be difficult to identify the domi-
current approach to treatment is broadly similar for NP nant pain type and treat appropriately. Such patients
and dysfunctional pain. require careful examination, imaging and neurophysio-
The most important of the dysfunctional pain states is logical investigation.

Pathophysiology
Table 1 The pathophysiological properties that are responsible
Peripheral Causes of Neuropathic Pain for NP can be broadly categorised into five groups:
ectopic impulse generation in damaged primary afferent
Mononeuropathies and multiple mononeuropathies
Trauma: compression, transection, post-thoracotomy, painful fibres, fibre interactions, central sensitisation, disinhibi-
scars tion (failure or reduction of normal inhibitory mecha-
Diabetic mononeuropathy and amyotrophy
Neuralgic amyotrophy
Connective tissue disease
Malignant and radiation plexopathy Table 2
Trench foot
Borreliosis Central Causes of Neuropathic Pain
Polyneuropathies Spinal Root/Dorsal Root Ganglion
Metabolic/ Prolapsed disc Root avulsion
Nutritional: Diabetic Cuban neuropathy Arachnoiditis Surgical rhizotomy
Alcoholic Tanzanian neuropathy Post-herpetic neuralgia Tumour
Pellagra Burning feet syndrome Trigeminal neuralgia
Beri-beri Strachan's (Jamaican)
neuropathy Spinal Cord
Amyloid Trauma including compression
Syringomyelia and intrinsic tumours
Drugs/Toxic: Isoniazid Thallium Multiple sclerosis
Cisplatin Arsenic Vascular: infarction, haemorrhage, AVM
Vincristine Clioquinol Spinal dysraphism
Nitrofurantoin Vitamin B 12 deficiency
Disulfiram HIV
Syphylis
Infective: HIV Anterolateral cordotomy
Acute inflammatory polyneuropathy Brain Stem
(Guillain-Barre) / CIDP Lateral medullary syndrome Multiple sclerosis
Tumours Tuberculoma
Hereditary: Fabry's disease Syrinx
Dominantly inherited sensory neuropathy
/ HSAN Thalamus
Infarction Tumours
Malignant: Myeloma Haemorrhage Surgical lesions
Carcinomatous
Sub-cortical and Cortical
Idiopathic small fibre neuropathy Infarction Trauma
AVM Tumour

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Table 3 Table 4
Clinical Features of Neuropathic Pain
Pathophysiology of Neuropathic Pain
Abnormal pain quality: burning, stabbing, raw, gnawing,
sickening 1. Peripheral Nerve
Poorly localised, sometimes diffuse Ectopic impulse generation - EIG
Paroxysmal pains common (abnormal sodium channel expression)
Immediate or delayed onset after injury Increased by: Decreased by:
Pain intensity altered by emotion and fatigue mechanical stimulation local anaesthetic
Sensory impairment usually in an anatomical distribution noradrenaline / adrenaline alpha receptor
Associated allodynia, hyperalgesia and hyperpathia blockers
Vasomotor and sudomotor changes ischaemia axon transport blockers
Associated dystrophic change in a minority of patients warming-myelinated fibres corticosteroid
cooling-unmyelinated fibres carbamazepine
nisms), and plasticity (degenerative and regenerative phenytoin
changes associated with altered connectivity). Table 4 2. Dorsal root ganglion
EIG
summarises these properties. It is beyond the scope of
this short article to discuss pathophysiology in detail, but 3. Spinal Nerve Roots
some important points include: EIG
1. The mechanisms of NP are substantially different to 4. Central Nervous System
those of nociceptive pain. Central sensitisation
2. Novel impulse generators develop at various sites, Dorsal horn neuron "wind up": NMDA receptor
and these are not stimulus-dependent. mediated
Prostaglandin and nitric oxide synthesis in dorsal horn
3. In peripheral nerve, it has been shown that ectopic neurones
impulse generation (EIG) develops as a result of the
expression of abnormal sodium channels. This can be Disinhibition
Deafferentation of dorsal horn cells: bursting
modified by neurotrophic growth factors (a potential discharge
target for new treatments). Reduced spinal inhibitions: surround, segmental,
4. Abnormal chemical sensitivities develop in damaged descending brain stem
primary sensory neurons, notably to catecholamines. Reduced insular cortex inhibition in central pain
Whilst this can be readily demonstrated in experi- Plasticity
mental preparations, the clinical relevance remains Neurotransmitter excitotoxicity: cell death
uncertain. Post-synaptic receptor up-regulation
5. Degenerative and then regenerative changes in the Altered Connectivity
spinal cord may lead to aberrant connectivity, and Inappropriate regeneration (Growth Associated
possibly a permanently reorganised, irreversible state. Protein expression)
Reorganised state
6. Damage at one level in the nervous system may lead
to secondary pathophysiological changes at more ros- Rostral Effects
tral levels. This has important implications when tar- Altered physiology at rostral levels resulting from
geting treatments for NP. caudal lesions

Complex Regional Pain Syndrome (CRPS) there is evidence of a noradrenergic sympathetic influ-
CRPS is the name now given to reflex sympathetic dys- ence on the development of pain, both with and without
trophy (RSD) and causalgia (Table 5). The term RSD nerve injury. Chronic inflammatory processes contribute
implied a pathogenic role for the sympathetic nervous in CRPS type 1; microangiopathic changes have been
system that is no longer tenable. found in limbs amputated from CRPS sufferers, and anti-
The current definition of CRPS is clinical, and the lim- inflammatory treatment may help early in the course of
its are not clearly drawn (Table 6). As with NP, a mecha- the disease. Secondary central sensitisation is an impor-
nism based definition is obviously needed, but is not yet tant component of the pain.
possible. Psychological factors have often been suggested in the
CRPS is divided into type 1, which includes conditions pathogenesis of CRPS. Patients with conversion disorder
caused by tissue injury other than peripheral nerve (the and factitious illnesses can present with symptoms close-
majority of cases), and type 2, in which the syndrome is ly resembling CRPS. The severe pain of CRPS, with loss
provoked by major nerve injury. The latter corresponds of function, produces anxiety and depression in many
to causalgia, though strictly speaking, causalgia merely patients, but there is no evidence that secondary psycho-
means burning pain, and thus denotes a symptom rather logical factors developing early after an injury predispose
than a disease. For the moment, however, the IASP to CRPS.
approved terminology makes CRPS type 2 and causalgia Prospective studies indicate an incidence of CRPS of
one and the same. about 1-2% after fractures (type 1 CRPS), and 1-5% after
The nosology of these conditions is a matter of ongo- peripheral nerve injury (CRPS type 2).
ing debate; the difficulties in finding agreed terms
emphasises the limited understanding of their patho- Diagnostic Limits of CRPS
physiology. There are no diagnostic tests for CRPS, which is a clini-
The causes of CRPS are listed in Table 7. cal diagnosis. One of the problems with the current
defining diagnostic criteria for CRPS is establishing the
Clinical Features and Pathophysiology of CRPS limits of the diagnosis. This is at present a matter of
The common clinical features of CRPS are shown in clinical judgement, and not surprisingly, opinions differ
Table 8. These may vary over time in an individual in relation to individual patients. Three-phase isotope
patient. Not all patients develop dystrophic changes. bone scans are frequently abnormal in CRPS, but a nor-
The pathogenesis of CRPS is probably heterogeneous; mal scan does not exclude the diagnosis.

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Table 5 Table 7

Complex Regional Pain Syndrome (CRPS) Causes of Complex Regional Pain Syndrome
Previously Described Syndromes
Peripheral Tissues
Reflex Sympathetic Dystrophy (RSD) Fractures and dislocations
Causalgia Soft tissue injury
Post-traumatic sympathetic dystrophy Fasciitis, tendonitis, ligament strain
Algodystrophy Arthritis
Sudeck's atrophy Deep vein thrombosis
Post-traumatic vasomotor syndrome Prolonged immobilisation of a limb
Shoulder-hand syndrome
Peripheral Nerve
Peripheral nerve trauma
Table 6 Post-ganglionic brachial plexus lesions

Definition of Complex Regional Pain Dosal Root

Syndrome (CRPS) Post-herpetic neuralgia
Spinal nerve root lesions
CRPS describes a variety of painful conditions that Brachial plexus avulsion
usually
Central Nervous System
● follow injury Myelopathies, particularly trauma
● occur regionally Head injury
● have a distal predominance of abnormal findings Cerebral infarction/haemorrhage
● exceed in both magnitude and duration the expected Cerebral tumour
course of the inciting event
● result in marked impairment of motor function Viscera
● are associated with oedema, abnormal skin blood Abdominal disease
flow, or sudomotor activity in the region of the pain at Myocardial infarction
some time during the course of the illness
Idiopathic
(International Association for the Study of Pain, 1999) No identifiable provoking cause

Treatment of Neuropathic Pain Electrical Spinal Cord and Deep Brain

NP due to a compressive lesion may be completely Stimulation
relieved by surgery, particularly if there has been little Spinal cord (dorsal column) stimulation (SCS) may be
damage. helpful in patients with pain due to major limb injury,
However, there may be severe continuing NP with rel- CRPS affecting a limb, plexopathies, thoracic or post-her-
atively minor damage (eg root compression). For the petic neuralgia, and occasionally, thoracic myelopathies.
majority of patients with NP, the realistic goal of treat- The commonest indication is lumbar disease with spinal
ment, undertaken in a multidisciplinary pain clinic, is pain, persistent root pain and arachnoiditis (the majority
partial analgesia, and an improvement in functional sta- of whom have had at least one operation). The mode of
tus. action is thought to be activation of dorsal horn and pos-
The modalities of treatment used for NP are listed in sibly thalamic gating mechanisms.
Table 9. SCS can provide lasting useful analgesia in a minority
of patients with NP, but in many, the duration of analge-
Local and Regional Treatments sia is only weeks or months, due either to technical fac-
In some circumstances, local measures may be sufficient, tors, or changing physiology.
but many patients will also require systemic drugs. The principal indication for deep brain stimulation,
In the presence of severe allodynia, treatment may not targeting a number of sites in the thalamus, is severe cen-
be tolerated in the affected area, but applied in adjacent tral post-stroke pain. As with SCS, the analgesic effect
areas, these measures may be helpful. may be short-lived.
Topical local anaesthetic applications are often partial-
ly effective in allodynia. Topical capsaicin, which initially Systemic Drugs
stimulates, then desensitises afferent C fibres, is helpful in The quality of trials of systemic drugs for NP has
a minority of patients; many find the initial burning pain undoubtedly improved in recent years, and several sys-
intolerable. tematic surveys help to guide treatment. The number
A successful local anaesthetic block, for example to a needed to treat (NNT) statistic, defined as the number of
painful scar, may be repeated, combined with corticos- patients needed to treat to produce one patient with 50%
teroid which can increase the duration of pain relief, pos- pain relief, is commonly used in these meta-analyses.
sibly by reducing EIG (see Table 4). However, this statistic masks variability in trial design
Since Leriche reported that causalgia could be dramat- and methodology, pain measures (including quality of
ically relieved by surgical sympathectomy, temporary life measures), and duration of treatment. Table 10 lists
blocking or permanent interruption of the noradrenergic systemic, local and spinally administered drugs found to
sympathetic efferent supply has become an accepted have an analgesic effect in NP, with NNTs where it is pos-
treatment for causalgia and other post-traumatic neural- sible to calculate these. Excluding trigeminal neuralgia,
gias, for CRPS, and for some CP. the two leading treatments for NP are amitriptyline /
Temporary partial analgesia lasting hours or days is nortriptyline, and gabapentin. Amitriptyline has multiple
commonly observed, and a small number of patients sites of action; one possible mechanism in NP may be a
seem to benefit from repeated blocks over long periods. facilitation of the descending serotoninergic analgesic
However, controlled trials have not shown significant pathway from the brain stem to the dorsal horn.
benefit from any type of sympathetic blockade. Gabapentin has an action on voltage dependent calcium
channels in spinal cord interneurones.

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Opioids are considerably less effective in NP than in later. The same applies to surgical lesions of peripheral
nociceptive pain, but the previous dogma that opioids are nerve, root or spinal cord, advocated for the relief of
without effect in NP has been modified in view of new chronic pain. Thalamotomy, with lesions at various sites,
evidence from controlled trials. In patients with severe often produces short duration analgesia. Thus, therapeu-
intractable NP, a trial of opioid therapy (controlled tic lesioning for NP are now considered obsolete by most
release morphine or fentanyl patches) is justified when authorities.
other treatments have failed.
Reports of relief of post-herpetic neuralgia with Psychological Treatment
intrathecal methyl prednisolone require confirmation. Patients with intractable NP are frequently depressed,
and may benefit from antidepressant drugs. Behavioural
Surgery for NP measures, and pain management programmes are helpful
NP results from damage to the nervous system, and that for many patients, both as adjunctive treatment and as
includes surgical trauma, even carefully placed lesions the sole treatment, when all other physical measures have
designed to relieve pain. Anterolateral cordotomy leads to failed.
contralateral analgesia, and this produces short-term
analgesia. But when performed for pain of non-malig- References
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Churchill Livingstone, Edinburgh.
the distribution of the lesioned tract, months or years Neuropathic Pain: Pathophysiology and Treatment. Eds Hansson
PT, Fields HL, Hill RG, Marchettini P. Progress in Pain Research
and Management. Volume 21. IASP Press. Seattle. 2001
Sindrup SH, Jensen TS. 1999. Efficacy of pharmacological treat-
Table 8 ments of neuropathic pain: an update and effect related to mecha-
nism of drug action. Pain. 83 389-400.
Clinical Features of Complex Regional Pain Kingery WS. 1997. A critical review of controlled clinical trials for
Syndrome peripheral neuropathic pain and complex regional pain syndromes.
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Perez RSGM, Kwakkel G, Zuurmond WWA, de Lange JJ. 2001.
Inflammatory: pain Treatment of reflex sympathetic dystrophy (CRPS type 1): a
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Casey KL. Ed. 1991. Pain and Central Nervous System Disease. The
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Dystrophic: skin muscle Edinburgh.
nails bone
Sympathetic: hyperhidrosis Table 10
changed hair and nail growth Drug Treatment of Neuropathic Pain: Controlled Trials
vasomotor abnormalities
Drug/Route Condition Efficacy
Systemic:
Table 9 Tricyclic antidepressants PHN + NNT=2.3
DPN + NNT=3.0
Treatment Modalities for Neuropathic Pain NP +
HIVN -
Topical: local anaesthetic SSRI: paroxetine DPN + NNT=6.7
capsaicin citalopram CPSP -
Carbamazepine TN + NNT=2.6
Local: transcutaneous electrical stimulation (TENS) DPN +
acupuncture CPSP -
thermal (heat, cold) Phenytoin DPN +
vibration Gabapentin PHN + NNT=3.7
massage DPN + NNT=3.2
Mexiletine DPN +/- less than 50%
Blocks: somatic of nerve, plexus, root analgesia
sympathetic of ganglia, or regional Baclofen TN +
guanethidine Fentanyl NP +
Oxycodone PHN +
Central spinal cord stimulation (SCS) Dextromethorphan DPN +
stimulation: deep brain stimulation (DBS) CPSP -
Phentolamine NP +/-

Spinal drugs: epidural or intrathecal (local Topical lignocaine PHN +

anaesthetics, opioids) Topical capsaicin PHN, DPN +
Topical non-steroidal anti-inflammatories PHN +
Systemic drugs: see Table 10 Epidural clonidine NP/CRPS +
Intrathecal methyl prednisolone PHN +
Surgery: decompression Regional guanethidine CRPS -
Intranasal calcitonin CRPS +/-
Psychological: behavioural measures, pain
management programmes Abbreviations: PHN = post-herpetic neuralgia. DPN = painful diabetic neuropathy. NP = neuropathic
pain. HIVN = painful HIV neuropathy. CPSP = central post-stroke pain. TN = trigeminal neuralgia.
Rehabilitation CRPS = complex regional pain syndrome. NNT = number needed to treat.

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