S TAT E O F T H E A RT R E V I E W

Neuropathic pain: mechanisms and

their clinical implications
Steven P Cohen,1 2 Jianren Mao3

1
Departments of Anesthesiology
and Critical Care Medicine A B S T RAC T
and Physical Medicine and Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons
Rehabilitation, Johns Hopkins
School of Medicine, Baltimore, MD and along nociceptive and descending modulatory pathways in the central nervous system. The myriad
21029, USA neurotransmitters and other substances involved in the development and maintenance of neuropathic
2
Uniformed Services University of
the Health Sciences, Bethesda, pain also play a part in other neurobiological disorders. This might partly explain the high comorbidity
MD, USA rates for chronic pain, sleep disorders, and psychological conditions such as depression, and why drugs
3
Massachusetts General Hospital,
Harvard Medical School, Boston, that are effective for one condition may benefit others. Neuropathic pain can be distinguished from
MA, USA non-neuropathic pain by two factors. Firstly, in neuropathic pain there is no transduction (conversion
Correspondence to: S P Cohen
scohen40@jhmi.edu of a nociceptive stimulus into an electrical impulse). Secondly, the prognosis is worse: injury to major
Cite this as: BMJ 2014;348:f7656 nerves is more likely than injury to non-nervous tissue to result in chronic pain. In addition, neuropathic
doi: 10.1136/bmj.f7656 pain tends to be more refractory than non-neuropathic pain to conventional analgesics, such as non-
steroidal anti-inflammatory drugs and opioids. However, because of the considerable overlap between
neuropathic and nociceptive pain in terms of mechanisms and treatment modalities, it might be more
constructive to view these entities as different points on the same continuum. This review focuses on
the mechanisms of neuropathic pain, with special emphasis on clinical implications.

Introduction Rationale for mechanism based treatment

Pain is a survival mechanism that serves as a warning sign One reason for the high prevalence rate of chronic pain, and
of ongoing or impending tissue damage. According to an neuropathic pain in particular, is the absence of effective
Institute of Medicine report released in 2011, one in three treatments. Unlike opioids and non-steroidal anti-inflam-
Americans experiences chronic pain—more than the total matory drugs, which form the cornerstone of drug treatment
number affected by heart disease, cancer, and diabetes for nociceptive pain, the adjuvants used to treat neuropathic
combined.1 In Europe, the prevalence of chronic pain is pain tend to have only a modest effect and in a minority of
25-30%.2 About a fifth of people who report chronic pain patients. The main reason for this is the inability to target
are thought to have predominantly neuropathic pain.3 4 underlying mechanisms precisely; this is why syndromes
(such as fibromyalgia), which lack distinct pathophysiologi-
S U M M A RY P O I N T S cal mechanisms, tend to be associated with lower treatment
success rates than diseases.5
As more accurate instruments have been developed to
Generally, mechanism based treatments, which target
identify neuropathic pain, estimates of its prevalence
specific pain mechanisms, are superior to disease based or
and socioeconomic impact have increased
cause based treatments, which target less proximate causes.
The development of neuropathic pain requires a plethora
This may be one reason why so many drugs that are success-
of different mechanisms that extend from the periphery
ful in preclinical studies fail in clinical trials.6 As a general
to the central nervous system where they involve the
rule, painful conditions such as inflammatory arthritis, in
spinal cord, brain, and descending modulation systems
which the mechanisms have been clearly identified, have
Although conceptually appealing, the mechanism based
more effective treatments.7 But in clinical practice, eluci-
treatment of pain is challenging to implement
dating the pain mechanisms responsible for neuropathic
Many drugs shown to be effective in preclinical models of symptoms can be difficult. One method for identifying
neuropathic pain fail in clinical studies, mostly because
mechanisms and predicting treatment outcomes is the use
animal models tend to emphasize evoked, rather than
of intravenous infusion tests, such as intravenous ketamine
spontaneous, pain and do not account for the emotional
to predict response to dextromethorphan or other NMDA
aspects of pain
(N-methyl-D-aspartate) receptor antagonists. However,
In view of the large degree of overlap between
studies that have evaluated these treatments have been
neuropathic and nociceptive pain in terms of
methodologically flawed and usually have reported only
mechanisms and treatment response, many experts view
them as different points on a chronic pain continuum,
modest predictive value.8
rather than distinct entities In the past decade, several reviews have been written
on the mechanisms of neuropathic pain, most of which

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are directed at neuroscientists. Yet it is essential that clini-

DEFINITIONS
cians understand the mechanisms too, because such an
understanding can steer future research and guide clinical Allodynia: Painful response to a normally innocuous stimulus
practice. Central pain: A subset of neuropathic pain caused by a lesion or disease of the central
somatosensory nervous system
Central sensitization: Increased responsiveness of nociceptive neurons in the central nervous
Search methods
system to normal or subthreshold sensory input
In September 2013, we searched the databases on Medline
Deafferentation pain: Pathological pain condition associated with a partial or complete loss of
via PubMed and Ovid, Embase, and CINAHL Plus using the sensory input from a part of the body after lesions in somatosensory pathways, often as a result
keywords “neuropathic pain”, “sensitization”, “neuroplas- of reorganization in the central nervous system. Common examples include phantom limb pain
ticity”, “mechanisms”, “reorganization”, “sympathetically and brachial plexopathy
maintained”, “antinociceptive”, and “descending modu- Descending modulation: The process by which pathways that descend from the brain to
lation”, with no date restrictions. For individual sections, the spinal cord modify incoming somatosensory information so that the perception of and
keywords relating to specific topics and mechanisms were reactions to somatosensory stimuli are altered, resulting in increased or decreased pain
identified from the initial search (for example, “ion channel Ectopic discharge: Trains of ongoing electrical nerve impulses that occur spontaneously
expression”, “cytokine”, “glial cell”) and searched using the without stimulation or originate at sites other than the normal location (or both). This
same databases. Additional articles and prime references phenomenon typically occurs after nerve injury
were obtained by cross referencing all search terms with Ephaptic transmission: The phenomenon by which two independent nerves communicate with
“review article” and searching through reference lists. We each other through an artificial synapse, which often develops after injury to the insulating
considered animal studies, experimental and clinical trials, myelin sheath that normally prevents crosstalk between parallel nerves
Hyperalgesia: Increased pain response to a normally painful stimulus
and review articles published in English.
Neuropathic pain: Pain caused by a lesion or disease of the somatosensory nervous system
Neuroplasticity: Changes in neural pathways and synapses that result from bodily injury
Physiology and classification
or changes in behavior, the environment, or neural processes. This is consistent with the
The generation of pain in response to tissue injury involves
concept that the brain is a dynamic organ that constantly changes in response to internal
four basic elements: and outside events throughout life
•   Transduction: a function of nociceptors that converts Nociception: The neural responses of encoding and processing noxious stimuli
noxious stimulation to nociceptive signals Nociceptive pain: Pain that arises from the activation of peripheral nerve endings
•   Transmission: a process that sends nociceptive signals (nociceptors) that respond to noxious stimulation. Nociceptive pain arises from actual or
along nerve fibers from the site of injury to the central potential damage to non-neural tissue and can be categorized as visceral or somatic
nervous system (CNS) Noxious stimulus: A stimulus that damages or threatens to damage normal tissues
•   Transformation or plasticity: a mechanism that Peripheral sensitization: A lowering of the stimulus (pain) threshold for nociceptor
modulates nociceptive signals at synaptic sites and at activation and an increased frequency of nerve impulse firing in response to stimulation
the level of the CNS through ascending, descending, or (hyperexcitability). Peripheral sensitization is often found at the site of tissue damage or
regional facilitation and inhibition inflammation
•   Perception: a key component of the clinical pain Sympathetically maintained pain: Pain that is enhanced or maintained by a functional
experience that integrates cognitive and affective abnormality of the sympathetic nervous system, such as functional sympathetic afferent
(emotional) responses. coupling or increased expression of adrenergic receptors at the peripheral terminals of
nociceptive afferent fibers
In evolutionary terms the activation of high threshold
Windup: Progressive increase in the frequency and magnitude of firing of dorsal horn
mechanical nociceptors or other types of specialized nocic-
neurons produced by repetitive activation of C fibers above a critical threshold, leading to a
eptor served a protective role, acting as a warning system for
perceived increase in pain intensity
dangerous stimuli. But whereas inflammatory pain is adap-
tive, evolution has failed to account for our enhanced ability
to survive trauma, disease, or iatrogenic trauma intended
Table 1 | Classification of neuropathic and nociceptive pain
to prolong or enhance quality of life (such as surgery). In
Clinical Neuropathic pain Nociceptive pain
these contexts pain no longer serves a useful function but characteristic
becomes the disease itself. Cause Injury to the nervous system, often accompanied by Damage or potential damage to
Although it is easy to conceptualize pain as a homoge- maladaptive changes in the nervous system tissues
neous entity, this is overly simplistic. In reality there are Descriptors Lancinating, shooting, electric-like, stabbing pain Throbbing, aching, pressure-like
several different types, each with distinct neurobiological pain
Sensory deficits Common—for example, numbness, tingling, pricking Uncommon; if present they have
and pathophysiological mechanisms. The most common
a non-dermatomal or non-nerve
categorization divides pain into two main types: neuro- distribution
pathic and nociceptive pain (table 1). This distinction is Motor deficits Neurological weakness may be present if a motor nerve May have pain induced weakness
important because it not only reflects the cause of pain but is affected; dystonia or spasticity may be associated with
central nervous system lesions and sometimes peripheral
also informs treatment. lesions (such as complex regional pain syndrome)
Nociceptive pain can be classified as somatic (for exam- Hypersensitivity Pain often evoked by non-painful (allodynia) or painful Uncommon except for
ple, muscles, joints) or less often visceral (internal organs). (exaggerated response) stimuli hypersensitivity in the immediate
Because of the high concentration of nociceptors in somatic area of an acute injury
tissues, chronic somatic pain is typically well localized and Character Distal radiation common Distal radiation less common;
proximal radiation more common
often results from degenerative processes (such as arthri-
Paroxysms Exacerbations common and unpredictable Exacerbations less common and
tis). By contrast, internal organs are usually unresponsive often associated with activity
to classic painful stimuli, such as cutting and burning, but Autonomic Color changes, temperature changes, swelling, or sudomotor Uncommon
respond to ischemia (for example, angina), inflammation signs (sweating) activity occur in a third to half of patients

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(appendicitis), or occlusion of flow that results in capsular differences between individuals, the degree of pathology
distension (bowel obstruction). tends to correlate poorly with the intensity of pain for con-
Neuropathic pain is defined as pain resulting from injury ditions such as back pain.13 To illustrate, conditions such
to, or dysfunction of, the somatosensory system.9 In neuro- as fibromyalgia have high reported pain scores despite the
pathic pain, tissue damage directly affects the nervous sys- absence of overt disease.
tem, resulting in the generation of ectopic discharges that Secondary order neurons arising in the spinal cord trans-
bypass transduction.10 One subtype of neuropathic pain is mit nociceptive input to the thalamus through ascending
central pain (for example, as a result of spinal cord injury), pathways such as the spinothalamic tract, which functions
which manifests as a constellation of signs and symptoms as a relay station to higher cortical centers. These centers
that follows an insult to the CNS as a necessary, but not include:
always sufficient, inciting event. Although many forms of •   The anterior cingulate cortex, which is involved in
nociceptive pain, and some forms of neuropathic pain, may anxiety, anticipation of pain, attention to pain, and
confer evolutionary benefits, chronic neuropathic pain is motor responses
always maladaptive. •   The insular cortex, which may play a role in the sensory
Compared with previous studies, estimates of the preva- discriminative and affective aspects of pain that
lence of neuropathic pain have significantly increased over contribute to the negative emotional responses and
the past decade since the development of instruments behaviors associated with painful stimuli14
designed to identify such pain.11 Around 15-25% of people •   The prefrontal cortex, which is important for sensory
with chronic pain are currently thought to have neuropathic integration, decision making, memory retrieval, and
pain.3  4 However, the prevalence of neuropathic pain may attention processing in relation to pain15
belie its socioeconomic impact, because studies have found •    he primary and secondary somatosensory cortices that
T
that it is associated with a greater negative impact on qual- localize and interpret noxious stimuli16
ity of life than nociceptive pain.12 •   The nucleus accumbens, which is involved in placebo
analgesia17
Emotional versus physiological aspects •   The amygdala, hippocampus, and other parts of the
A common misconception is that pain is purely a physi- limbic system, which are involved in the formation and
ological phenomenon. In fact, “pain” represents a final storage of memories associated with emotional events,
integrative package, the components of which consist of affect, arousal, and attention to pain and learning. The
neurophysiological processes as well as contextual, psy- limbic system may also be partially responsible for the
chological, and sociocultural factors. This is one reason fear that accompanies pain.18
for the discrepancies between preclinical studies (which Because pain is multidimensional experience, it is not
measure increased tolerance to painful stimuli in animals surprising that psychosocial factors such as depression,
(anti-nociception)), clinical studies (which assess efficacy), somatization, poor coping skills, social stressors, and nega-
and clinical practice, which measures effectiveness (table 2). tive job satisfaction can predict the development of chronic
Partly because of these factors and the neurophysiological pain after an acute episode.19  20 In addition, the context in
which a painful stimulus occurs affects how we perceive it.
Table 2 | Comparison of pain in animal models and clinical pain This is why an injury that occurs during a football game may
Variable Animal models Clinical pain be less painful than a similar injury that occurs while walk-
Study methods Deficiencies in blinding, randomization, Greater attention to methodological quality ing to school, and why acute pain, which we anticipate will
and power calculation (low numbers) are in large scale clinical trials get better, is better tolerated than chronic pain.
common
Time course of Minutes to hours to days; largely coincides Weeks to months to years; usually outlasts
development with the time course of tissue damage the time course of tissue damage
Peripheral mechanisms
Hallmark Increased neuronal excitability, decreased Altered pain quality with or without Peripheral sensitization
nociceptive threshold, and expanded neurological deficits (such as numbness, Once injury occurs, inflammation and reparatory processes
receptive fields weakness) ensue, leading to a hyperexcitable state known as periph-
Pattern Correlations between tissue damage and Considerable individual variations in pain eral sensitization. In most patients, this state resolves as
cellular responses; near uniformity in experience; dynamic changes in pain
response patterns; sustainability of neuronal intensity, timing, location, modality, and healing occurs and inflammation subsides. However, when
responses not confirmed quality nociception persists because of repeated stimulation from
Presentation Mainly hyperalgesia and allodynia; rarely Usually spontaneous pain; often extends ongoing injury or disease (for example, in diabetes), the
contralateral behavioral changes beyond a single nerve or dermatome changes in primary afferent neurons may persist.
distribution; contralateral responses may be
present; behavioral responses common Several factors can contribute to peripheral sensitization.
Affective component Absent or unknown Powerful contributor to the pain experience; Inflammatory mediators such as calcitonin gene related
has a strong influence on treatment outcome peptide and substance P, which are released from nocic-
Intervention Behavioral changes can be prevented or Similar approaches (blocking key eptive terminals, increase vascular permeability, leading
reversed (or both) by blocking key cellular cellular elements) have had mostly
elements negative outcomes in clinical trials; long
to localized edema and the escape of the byproducts of
interval between positive results and injury, such as prostaglandins, bradykinin, growth factors,
implementation of intervention in practice and cytokines. These substances can sensitize as well as
Outcomes Considered over the course of days or Considered over the course of weeks or excite nociceptors, resulting in lowered firing thresholds
weeks; treatment response rates are higher months for clinical trials, and months or
than in clinical trials years in practice; success rates are lower and ectopic discharges. The fact that multiple substances
than in animal models, especially in clinical can sensitize nociceptors may partly explain why no drug is
practice universally effective and there is a ceiling effect for antago-

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Fig 1 | Diagram depicting expression of some of these channels increases de novo,

normally perceived pain, the expression of others diminishes, and some translocate
as well as allodynia and into different cellular compartments.24 The proliferation of
hyperalgesia after injury heterotopic sodium channels, such as Nav1.3, Nav1.7, and
Pain intensity
Injury Normal Pain
Nav1.8, may lower the stimulation threshold and provoke
ectopic discharge, resulting in spontaneous pain. In addi-
tion, the spread of sodium channels may trigger central
sensitization, leading to allodynia. Several adjuvant drugs,
such as carbamazepine, act through the blockade of sodium
channels. Yet, because none of these drugs is selective for
T1 T0
Stimulus intensity
channel subtypes involved in pain, all have low therapeutic
indices and many side effects.
Allodynia Certain types of calcium channels (N-type, T-type, and
Hyperalgesia
Non-injured pain response curve
L-type), and to a lesser extent potassium channels (hyper-
Amplified pain response curve polarization activated cyclic nucleotide gated channels),
T0 = Pre-injury pain threshold also play a role in neuropathic pain. After nerve injury,
T1 = Post-injury pain threshold
the expression of α2δ calcium channels increases in and
around the dorsal root ganglia, increasing excitability.25
BMJ 2014;348:f7656 These voltage gated calcium channels are the primary site
of action for gabapentinoids, a first-line treatment for neu-
nists that work at only one receptor (such as non-steroidal ropathic pain,26 which have been shown in preclinical stud-
anti-inflammatory drugs (NSAIDs)). ies to reduce hyperalgesia and spontaneous pain (table 3).27
Ectopic discharges can give rise to spontaneous pain
and may originate from the dorsal root ganglion, other Phenotypic switch
points along an injured nerve, or even uninjured adjacent Differentiated neurons have different properties from undif-
fibers.21 The process by which adjacent uninjured nerve fib- ferentiated ones, which enable them to perform specific
ers become excited as a result of non-synaptic “cross talk” functions (Aδ and C fibers transmit pain). After nerve injury,
is known as ephaptic transmission. Allodynia refers to pain hundreds of genes that affect nerve function are upregulated
produced by a normally non-painful stimulus, and it may or downregulated, and this can affect excitability, as well
result from decreased stimulation thresholds. Allodynia can as transduction and transmission properties. Because gene
be classified as mechanical (pain in response to light touch) expression affects cellular characteristics, this can result in
or thermal, and it can readily be detected on physical exam- a change in the phenotype of the nerve fiber, such that neu-
ination. An example is a patient with diabetic neuropathy romodulators usually expressed in C fibers (such as calci-
whose feet are sensitive to putting on socks. tonin gene related peptide, substance P) are now expressed
Hyperalgesia refers to exaggerated pain perception as in other fibers.28 This may theoretically result in stimuli that
a result of damaged peripheral pain fibers, and it can be are usually innocuous being perceived as painful.
categorized as primary or secondary. Primary hyperalge-
sia occurs in injured tissue as a result of sensitization of Sensory denervation and sprouting of collateral nerve
peripheral nociceptors (for example, tenderness after a fibers
cut), whereas secondary hyperalgesia is seen in adjacent After injury to a sensory nerve, atrophic changes (wallerian
undamaged tissue owing to sensitization within the CNS degeneration) cause a decrease in the size of the cell body
and can be assessed with a sharp object. In part, this may be and the axon diameter, and eventually neuronal death. This
caused by ephaptic transmission or the expansion of recep- leads to a decreased density of intraepidermal nociceptors.
tive fields of injured nerves (or both). A clinical example of Depending on the type of nerve injury, this may cause loss
hyperalgesia might be an amputee who is unable to use a of sensation or, paradoxically, hyperalgesia and increased
prosthesis because of tenderness overlying the stump. Both pain (deafferentation pain).29 Severing the link between a
allodynia and hyperalgesia are forms of evoked, or stimulus nerve and its end organ also deprives the nerve of nerve
dependent, pain. Although spontaneous neuropathic pain growth factor and other neurotrophins, which are essential
is often more common and distressing than evoked pain for growth and maintenance and serve as signaling mole-
in clinical practice, preclinical studies usually measure cules. One example of deafferentation pain is phantom limb
evoked pain (fig 1).22 It is still not clear whether animals pain after amputation. Although electrodiagnostic studies
that develop evoked pain incited by models of peripheral may be normal in people with a loss of small pain transmit-
nerve injury experience spontaneous pain. ting nerve fibers, a decreased density of C fibers can be seen
on skin biopsy. In response to local release of nerve growth
Expression of ion channels factor, collateral sprouting may follow neuronal loss.
One contributor to spontaneous firing of nerve fibers after
injury is the increased expression of sodium channels in Sympathetically maintained pain
dorsal root ganglia and around the terminal injury site Sympathetically maintained pain is pain that is enhanced
(neuroma) of injured axons.23 Since this discovery, further or maintained by an abnormality in the sympathetic
preclinical studies have shown that a variety of sodium nervous system. Functional coupling between the sym-
channels are involved in pain. After nerve injury, the pathetic nervous system and somatosensory nerves after

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Table 3 | Evidence for pharmacotherapy based on mechanisms of neuropathic pain

Mechanism Symptoms Target Treatment Evidence
Phosphorylation of TRPV-1 by protein Hyperalgesia, burning, and other TRPV-1 Capsaicin Strong evidence for peripheral
kinase C spontaneous pain neuropathic pain
Release of proinflammatory cytokines Spontaneous pain, hyperalgesia, Cytokines, such as TNF-α, IL-1β, Cytokine inhibitors (such as etanercept, Strong evidence for inflammatory
from immune cells inflammation IL-6, and other interleukins infliximab) arthritis; conflicting results in human
studies for neuropathic pain
Release of nerve growth factor and Hyperalgesia, burning and other Nerve growth factor and its Nerve growth factor inhibitors (such as Moderate clinical evidence for
other neurotrophins from mast cells spontaneous pain, inflammation receptors (trkA/p75) tanezumab) inflammatory pain (such as arthritis),
evidence for neuropathic pain in
preclinical studies
Release of substance P in the dorsal Hyperalgesia NK1 receptor NK1 receptor antagonists (such as Evidence in preclinical but not clinical
horn aprepitant) studies
Proliferation of and redistribution of Spontaneous pain, Tinel’s sign Tetrodotoxin sensitive and Membrane stabilizers (such as Moderate to strong evidence for
sodium channels resistant sodium channels carbamazepine, lamotrigine) and anti- peripheral neuropathic pain
arrhythmics (such as systemic lidocaine,
mexiletine)
Increased expression of cannabinoid Hyperalgesia CB1 and CB2 Natural and synthetic cannabinoids (such as Strong preclinical and clinical evidence
receptors in the peripheral and central cannabis, dronabinol) for a modest effect for central and
nervous systems, and in glial cells peripheral neuropathic pain, and
inflammatory pain
Activation of spinal NMDA receptors Hyperalgesia, opioid tolerance NMDA receptor NMDA receptor antagonists (such as Strong evidence in preclinical and
ketamine, dextromethorphan, memantine) clinical trials for peripheral and central
neuropathic pain; conflicting results for
reduction of opioid tolerance
Increased expression of voltage Spontaneous pain, hyperalgesia N-type, L-type, and T-type calcium Calcium channel antagonists (such as Strong evidence for peripheral and
gated calcium channels at dorsal root channels gabapentin, pregabalin, ziconotide) central neuropathic pain
ganglia and presynaptic terminals
Increased release of CGRP from Hyperalgesia, spontaneous CGRP inhibitors CGRP receptor antagonists (such as Evidence in preclinical studies; in
primary afferents pain, inflammation olcegepant and telcagepant) clinical studies, strong evidence only for
migraine
Increased expression and sensitivity Spontaneous pain, pain Sympathetic ganglia, sympathetic Phentolamine, clonidine, sympathetic Weak evidence for short term effect for
of α adrenoceptors, sympathetic exacerbated by cold and stress nervous system blocks peripheral neuropathic pain
sprouting
Reduced descending inhibition/ Hyperalgesia, spontaneous Opioid receptors, CB2 receptor, µ opioid agonists, GABA agonists, Strong evidence for opioids and
facilitated transmission pain, anxiety serotonin and norepinephrine antidepressants and serotonin/ antidepressants. Weak, negative or
reuptake, adenosine norepinephrine reuptake inhibitors, conflicting evidence for other drug
adenosine reuptake inhibitors classes in neuropathic pain
Diminished spinal inhibition Hyperalgesia, spontaneous GABA and glycine receptors GABA A and GABA B antagonists (such as Negative or weak positive (baclofen)
pain, anxiety benzodiazepines, baclofen) evidence in clinical studies
Glial cell activation Hyperalgesia, opioid tolerance Phosphodiesterase enzyme Phosphodiesterase inhibitors (such as Evidence in preclinical, but not clinical
pentoxifylline, propentofylline, ibudilast) studies for neuropathic pain
Activation of p38 mitogen activated Hyperalgesia, opioid tolerance P38 mitogen activated protein Microglial inhibitors, such as dilmapimod, Evidence in preclinical studies, but
protein kinase/microglial activation kinase losmapimod mostly negative evidence in clinical trials
CB=cannabinoid; CGRP=calcitonin gene related peptide; GABA=γ-aminobutyric acid; IL=interleukin; NK=neurokinin; NMDA=N-methyl-D-aspartate; TNF-α=tumor necrosis factor α; trkA=tropomyosin related kinase
A; TRPV-1=transient receptor potential cation channel subfamily V member 1 or vanilloid receptor subtype 1.

nerve injury has been noted since the American civil war. and spatial summation (increased neuronal responses to
Although the concept of sympathetically maintained pain is repeated noxious stimulation in a time and region depend-
most commonly linked to complex regional pain syndrome, ent manner).32 Other components include expanded recep-
the same principles apply to other pain conditions, such as tive fields of nociceptors and second order neurons,33 and
postherpetic neuralgia.8 The interaction between the ana- increased neuronal excitability of ascending nociceptive
tomically distinct autonomic and somatosensory systems is pathways that send pain signals to supraspinal regions.34
complex but probably includes the expression of α adreno- These neuroplastic changes take place along nociceptive
ceptors on primary afferent sensory fibers, sympathetic pathways in the spinal cord and in multiple brain regions.35
sprouting into dorsal root ganglia, and impaired oxygena- In the neural circuit, nociceptive signals generated by
tion and nutrition in response to sympathetically mediated nerve damage are modulated by supraspinal descending
vasoconstriction.30 Clinically, sympathetically maintained inhibition or facilitation that converges onto dorsal horn
pain may manifest as temperature or color changes (or neurons (or both).36 At the cellular level, transmission of
both) in an affected extremity, swelling or atrophy, and pain nociceptive signals within the central nervous system
worsened by cold weather or stress, which enhances sym- is regulated by cellular and intracellular elements that
pathetic outflow. Among the various diagnostic tests used include37  38:
to detect sympathetically maintained pain, clinical studies •   Ion (Na+, Ca++, K+) channels
have found that sympathetic blocks are more sensitive but •   Ionotropic and metabotropic receptors such as
less specific than intravenous infusion of phentolamine.31 glutamatergic, GABA (γ-aminobutyric acid)ergic,
serotoninergic, adrenergic, neurokinin, and vanilloid
Spinal mechanisms receptors
An important spinal component of neuropathic pain •   Inflammatory cytokines released from activated glial
mechanisms is synaptic plasticity in the form of temporal cells

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Fig 3 | Diagram showing the various mechanisms involved in neuropathic pain at different sites in the nociceptive pathway. AMPA=α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid; ASIC=acid sensing ion channel; B1/B2=bradykinin receptor 1/2; BDNF=brain derived neurotrophic factor; CCL=chemokine (C-C motif)
ligand; CC-R2=CC-chemokine receptor; DAMPs=danger associated molecular patterns; EPR=prostaglandin E2 sensitive receptor; GABA: γ-aminobutyric acid;
Glu=glutamate; H1R=histamine receptor; 5-HT=5-hydroxytryptamine; IL=interleukin; KCC=potassium-chloride cotransporter; m-Glu=metabatropic glutamate;
NGF=nerve growth factor; NK=neurokinin; NMDA=N-methyl-D-aspartate; PAMPs: pathogen associated molecular patterns; PG=prostaglandin; P2X=purinergic
receptor channel; -R=receptor; SP=substance P; TLR=toll-like receptor; TNF=tumor necrosis factor; Trk=tyrosine kinase; TTxR=tetrodotoxin resistant sodium
channel; TTxS=tetrodotoxin sensitive sodium channel; VR=vanilloid receptor (transient receptor potential cation channel subfamily V member 1 TRPV-1)

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•   Nerve growth factors and neuroma formation.49‑51 In animal models, adminis-

•   Intracellular regulators such as protein kinases (for tration of cytokine inhibitors before nerve injury reduces
example, protein kinase C) and transcriptional factors neuropathology and pain-related behaviors.52  53 However,
(such as nuclear factor-κB). in controlled clinical trials, most of which were performed
in patients with radiculopathy, the use of systemic and
Spinal glutamatergic regulation neuraxial cytokine inhibitors has been largely disappoint-
Peripheral nerve injury increases neuronal excitability in ing.54  55
the spinal cord by activating excitatory glutamate recep- Glial cells comprise about 70% of the central nervous
tors.39 Nerve injury also induces downregulation of spinal system and play an important role in maintenance and
glutamate transporters responsible for maintaining synap- homeostasis. Microglia are activated within 24 hours of
tic glutamate homeostasis. Increased regional glutamate nerve injury, and astrocytes follow shortly thereafter, with
availability secondary to loss of glutamate transporters can activation persisting for up to 12 weeks. Glial cells undergo
result in persistent and enhanced activation of both iono- structural and functional transformation after injury, with
tropic (for example, NMDA and AMPA (α-amino-3-hydroxy- astrocytes releasing a host of different pronociceptive fac-
5-methyl-4-isoxazolepropionic acid)) and metabotropic tors, such as prostaglandins, excitatory amino acids, and
glutamate receptors (such as metabotropic glutamate recep- cytokines.56
tor 2), leading to lower activation thresholds and increased Microglial cells comprise less than 20% of spinal glial
neuronal excitability and neurotoxicity.40  41 cells under normal conditions but proliferate rapidly at the
The term “windup” refers to the progressive increase dorsal root ganglia and spinal cord after nerve injury.56  57
in the frequency and magnitude of firing of dorsal horn On activation, microglial cells stimulate the complement
neurons produced by repetitive activation of C fibers, a component of the immune system and release cytokines,
phenomenon that requires glutamatergic NMDA receptor chemokines, and cytotoxic substances such as nitric oxide
activity. Spinal glutamatergic activity can in turn initiate and free radicals.56  58  59 This proinflammatory milieu
intracellular signaling cascades, including activation of begins at synaptic sites in the brain stem and the site of
protein kinase C, that result in long-lasting neuroplastic nerve injury but spreads to more distant sites. The ensu-
changes in the spinal cord.42 Similar to the role of central ing release of cytokines from astrocytes and microglia
glutamatergic mechanisms in the pathogenesis of other induces an array of cellular responses such as upregula-
neurological disorders such as epilepsy and Alzheimer’s tion of glucocorticoid and glutamate receptors, leading to
disease, glutamate receptors are integral to the develop- spinal excitation and neuroplastic changes.60 IL-1β also
ment of central sensitization, and blockade of both NMDA enhances conditioned “fear memory” (conditioned fear
and non-NMDA receptors has been shown to attenuate related memories associated with behavioral responses)
neuropathic pain in animal models.43 Because of its pri- through glucocorticoids,61 suggesting that proinflamma-
mary role in neuroplasticity and excitotoxicity, the NMDA tory cytokines may participate in the affective experience of
receptor has been implicated in such diverse areas as pain. Drugs that modulate microglia, such as minocycline,
memory, opioid tolerance, and opioid induced hyperalge- pentoxifylline, and propentofylline, have shown some effi-
sia—the phenomenon whereby opioid use paradoxically cacy in preclinical models of neuropathic pain but have not
increases pain sensitivity.44 In clinical practice, the use of proved effective in a clinical context (table 3; fig 2).62
NMDA receptor antagonists to prevent opioid tolerance and
hyperalgesia has been disappointing.45 The long-term use of Supraspinal mechanisms
these drugs to treat chronic neuropathic pain has also had Nociceptive signals can also be altered at supraspinal lev-
mixed results, and their use may be limited by side effects, els. The brains of patients with chronic pain are different
particularly psychomimetic ones, which seem to increase from those without pain, with variations in metabolism and
in proportion to potency. The use of ketamine infusions as regional concentrations of neurotransmitters occurring in
a treatment for refractory neuropathic pain has generated areas such as the thalamus and cingulate cortex. These dif-
intense interest, although studies are limited by methodo- ferences vary according to the type of pain experienced (for
logical flaws and lack of long term follow-up (table 3).46 example, acute pain or allodynia).63 In patients with neu-
The rationale behind these infusions is that high doses may ropathic pain, cortical reorganization occurs after injury,
“reset” the nervous system back to its pre-injury state, in and the extent of the changes seems to correlate with the
essence reversing central sensitization. degree of pain. For example, in upper extremity amputees
with phantom limb pain, because of the close proximity
Glial activation and proinflammatory cytokines of their somatotopic representations, the area of the brain
The role of glial activation and cytokines in neuropathic responsible for moving the lips transgresses into the hand
pain has been extensively studied. Proinflammatory movement area of the motor cortex; this phenomenon does
cytokines including interleukin 1β (IL-1β), IL-6, and not occur in amputees without phantom limb pain.64 The
tumor necrosis factor α (TNF-α) are produced peripherally observation that these changes occur after injury suggests
and centrally in response to nerve injury.47 These proin- that disinhibition may not only be a consequence of nerve
flammatory cytokines play a crucial role in inflammatory injury, but may render patients susceptible to chronic
responses after nerve injury through intracellular mediators pain.65
such as protein kinase C and 3′,5′-cAMP.48 Proinflamma- Preclinical studies demonstrating changes in gene
tory cytokines also play an important role in sensitization expression after nerve injury have provided insight into
of the CNS and may contribute to allodynia, hyperalgesia, how changes in signal transduction and neuroprotection/

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trials provide evidence for a small effect size for ketamine

K EY R E S E A R C H Q U E S T I O N S in neuropathic pain, although the high doses given make it
Is it possible to devise a valid animal model that accounts for the “affective-motivational” difficult to identify the precise mechanism responsible for
(emotional) aspect of pain as well as the “sensory-discriminative” (physio-anatomical) analgesia.8  46 There is some evidence to support the use of
aspect? the GABA-B agonist baclofen for trigeminal neuralgia, but
Are there any measures that can be taken before (pre-emptive analgesia) or during the early most of the evidence in favor of benzodiazepines as anal-
phase after nerve injury that can prevent the transition to chronic neuropathic pain? gesics is anecdotal (table 3).79  80
Is neuropathic pain represented differently in the brain than other chronic pain conditions? Descending inhibition plays an important role in deter-
mining how people experience pain. Recently, it has been
Can we develop better animal models to reflect spontaneous pain, rather than those that
emphasize stimulus dependent pain (for example, allodynia), which may be less relevant in shown that descending modulation can be both inhibitory
clinical practice? and facilitatory, with conflicting signals often arising from
the same regions.81 The balance between inhibition and
Although the concept of mechanism based pain treatment is intellectually enticing, can this
amplification is dynamic and influenced by context, behav-
be routinely incorporated into clinical practice?
ior, emotions, expectations, timing, and pathology. After
injury, there is an initial spike mediated by changes in the
apoptosis contribute to neuropathic pain.66  67 Changes that activation and gene expression of NMDA and AMPA excita-
occur in supraspinal regions may explain the strong associ- tory glutaminergic receptors, and a subsequent decrease
ation between neuropathic pain and mood disorders. Inves- in the excitability of neurons in the rostral ventromedial
tigators recently found that altered corticotropin releasing medulla, which lead to facilitation and inhibition, respec-
factor signaling in the limbic system, an area involved in tively.82 The evolutionary advantage of these changes is that
emotions, may play a role in the development of neuro- the initial stimulus is reinforced to ensure that it is given
pathic pain.68 Patients with chronic pain have also been priority, but once this occurs the brain seeks to mitigate the
shown to have reduced gray matter compared with control consequences.
patients, and this can be partially reversed by treatment.69 Expectations and context also play a role in descending
modulation. In one randomized study,83 20 healthy sub-
Disinhibition jects were subjected to painful electrical stimulation of the
Spinal cord level sural nerve after immersion of an arm in cold water. Half the
Once a nociceptive stimulus is transmitted to higher cor- subjects were told that the immersion would decrease the
tical centers, a series of events occurs that results in the pain, whereas the other half were told that it would exac-
activation of inhibitory neurons that attenuate pain. At the erbate the pain. Normally, exposure to a spatially distinct
spinal cord level, there is increased release of GABA and noxious stimulus should decrease the response to pain, a
glycine from primary afferent terminals, and enhanced concept known as “descending (or diffuse) noxious inhibi-
activity in inhibitory GABAergic and glycinergic dorsal horn tory control.” The study found that the analgesia expec-
interneurons. These spinal interneurons synapse with cen- tancy group experienced a 77% decrease in pain intensity
tral terminals of primary afferent neurons, thereby reduc- during immersion compared with no significant reduction
ing their activity, and also regulate activity in ascending in pain in the group that anticipated hyperalgesia. Moreo-
secondary order neurons. Spinal inhibitory systems may ver, corresponding changes in activity levels were noted in
exert a greater effect on the development of mechanical cortical areas involved in descending inhibition and pla-
hyperalgesia than on thermal hyperalgesia.70  71 cebo analgesia.84 These findings agree with other studies
After nerve injury, a loss of inhibitory currents occurs as a that have found that a host of psychosocial factors such as
result of dysfunctional GABA production and release mech- emotions, expectations, and attention affect our intrinsic
anisms; impaired intracellular homeostasis from reduced ability to inhibit pain.84  85 This may explain why positive
activity of K+Cl− cotransporter or increased activity of Na+K− expectations tend to result in better treatment outcomes
Cl− cotransporter (or both), leading to increased Cl− levels; and a higher placebo response rate, and why we are less
and apoptosis of spinal inhibitory interneurons.72  73 Loss likely to perceive pain when an injury occurs while we are
of inhibitory control has been shown to provoke tactile preoccupied (for example, during a sports game rather than
allodynia and hyperalgesia,74 and to facilitate structural at bedtime).86
changes that increase transmission from Aβ fibers that nor-
mally transmit non-painful stimuli to nociceptive specific Supraspinal level
secondary order neurons in the dorsal horn.75 Descending pathways that modulate transmission of noci-
After nerve injury, dorsal root ganglia exhibit decreased ceptive signals originate in the periaqueductal gray, locus
expression of µ opioid receptors and secondary spinal coeruleus, anterior cingulate gyrus, amygdala, and hypo-
neurons become less responsive to opioids.76 By contrast, thalamus, and are relayed through brainstem nuclei in the
inflammation may result in an increase in the number and periaqueductal gray and medulla to the spinal cord. The
affinity of opioid receptors, thereby enhancing the efficacy inhibitory transmitters involved in these pathways include
of opioids.77 This may explain why patients with chronic norepinephrine (noradrenaline), 5-hydroxytryptamine,
neuropathic pain require higher doses of opioids than those dopamine, and endogenous opioids. After nerve injury,
with acute and chronic nociceptive pain.78 In preclinical several processes take place that mitigate the normal pain
studies, the administration of NMDA receptor antagonists, attenuating pathways. These include a diminution in tonic
protein kinase Cγ inhibitors, and GABA-A agonists has been noradrenergic inhibition and a shift from a predominantly
shown to reverse allodynia and hyperalgesia.75  79 Clinical inhibitory role to a facilitative function for descending

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serotonergic modulation.87 The manifold roles of these and the functional and practical classification. Consider-
neurotransmitters to affect pain, mood, and sleep may ing the large overlap between neuropathic and nociceptive
partially explain the high comorbidity rates between pain, pain, similar to the classification of other neurological dis-
depression, anxiety, and sleep disturbances.88 Monoamine orders (such as tension-type and migraine headaches) that
reuptake inhibitors such as tricyclic antidepressants are not share pathophysiological mechanisms and overlap in their
only effective for neuropathic pain and depression but also response to treatment,99 the different types of chronic pain
alleviate anxiety and improve sleep (fig 3).89 might best be viewed as points on the same continuum.

Neuropathic versus nociceptive pain: different entities or Emerging treatments

part of the same continuum? It is anticipated that translational pain research will play an
It is generally acknowledged that neuropathic and non- important role in understanding pain mechanisms, formu-
neuropathic pain are distinct entities, but some experts lating treatment and research paradigms, and developing
dispute this assertion, considering it part of our natural new analgesics in the next decade. To facilitate this, several
tendency to categorize things. There are two main factors emerging developments must unfold.
that distinguish neuropathic pain from nociceptive pain: Firstly, new animal models should account for the influ-
•   Nociceptive pain requires transduction to convert a ence of clinical comorbidities such as depression on nocicep-
non-electrical signal (for example, mechanical) to tive behaviors.100 This will be challenging, because animal
an electrochemical one, whereas neuropathic pain models for emotional outcomes tend to be less studied than
involves direct nerve stimulation those for physiological parameters.
•   Different prognosis: most people with nociceptive Secondly, behavioral assessment tools should be capable
pain (for example, after surgery) recover, but injury of measuring the various dimensions of pain experiences,
to a major nerve (for example, plexopathy or limb such as the use of conditional place preference or aversion
amputation) often results in persistent pain.90 (forms of pavlovian conditioning used to measure the moti-
Even the requirement for “nerve injury” in neuropathic vational effects of positive and negative experiences) and
pain is contentious. After a nociceptive stimulus, we feel behavioral coding in preclinical studies.101  102 For exam-
pain because microscopic nerve fibers are embedded in ple, because the relief of pain is a reward in itself, analgesic
the injured tissue. The difference between neuropathic and agents that are not rewarding in the absence of pain should
non-neuropathic pain might therefore be considered one of become rewarding only in the presence of pain.
scope (large v small nerve injury), although many forms of Thirdly, the association between brain reorganization seen
neuropathic pain, such as small fiber neuropathy, also do on advanced imaging and the chronicity of pain should be
not involve discrete nerve injury. further explored, with emphasis on how changes on imaging
Neuroscientists use distinct models for non-neuropathic relate to pain behaviors and response to treatment.103
(for example, Carrageenan) and neuropathic pain, and even Lastly, the identification of biomarkers and the genotyping
different models (>40) of neuropathic pain to reflect myriad or phenotyping of pain characteristics may provide tools that
causes (for example, chronic constriction injury, spared enable us to understand better the heterogeneity of clinical
nerve injury models).91 Yet, the same neurotransmitters, pain and formulate individualized treatment regimens.104  105
neuropeptides, cytokines, and enzymes are implicated in These research advances, together with the development
both types of pain, with a large degree of overlap. NMDA of newer drugs tailored to individual patients and specific
receptor antagonists are often considered to be effective pain mechanisms, will probably improve the treatment of
for neuropathic pain only, being intricately involved in neuropathic pain in the coming years.
the process of central sensitization, but preclinical and
clinical studies have shown that they alleviate nociceptive Conclusions
pain too.46  92  93 Similarly, the voltage gated calcium channel Injury to the peripheral or central nervous system results
subunit α-2δ-1 is upregulated in injured dorsal root gan- in maladaptive changes in neurons along the nociceptive
glion neurons but not in inflammatory pain.25 However, pathway that can cause neuropathic pain. Unlike acute
drugs that block these channels, such as gabapentin, are pain, chronic neuropathic pain confers no individual or
effective in both preclinical models of nociceptive pain94 evolutionary advantage and is often considered to be a
and in preventing chronic postsurgical pain when given disease in itself. The myriad mechanisms involved in neu-
pre-emptively.95 Conversely, drugs widely acknowledged ropathic pain overlap considerably with non-neuropathic
to be effective only for nociceptive pain may also alleviate pain and other neurological conditions. Although treatment
neuropathic pain. NSAIDs are so widely viewed as being based on the mechanism(s) of pain is widely accepted to be
ineffective for neuropathic pain that no major guidelines theoretically better than treatment based on the cause of
even mention them in their algorithm.26 But preclinical and pain, or empirical treatment, this paradigm can be difficult
clinical studies have demonstrated efficacy for NSAIDs in to implement in clinical practice. The multitude of different
neuropathic pain states,96  97 and they are commonly pre- mechanisms, and the affective-motivational component of
scribed for neuropathic pain (tables 2 and 3).98 chronic pain that distinguishes “human pain” from nocic-
It is important to note that ascending spinal path- eption tested in preclinical pain models, make neuropathic
ways, supraspinal regions that process these signals, and pain notoriously refractory to treatment. This in turn has
descending modulation pathways are essentially the same resulted in chronic pain being considered not only a medi-
for neuropathic and non-neuropathic pain. This creates cal problem but also a socioeconomic concern that requires
a difference between the taxonomic classification of pain urgent attention.

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Thanks to Srinivasa Raja and Tony Yaksh for their help. 26 Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS
guidelines on the pharmacological treatment of neuropathic pain: 2010
Contributors: SPC conceived, designed, partly wrote, and reviewed the
revision. Eur J Neurol 2010;17:1113-e88.
article and tables, and helped with the figures. JM wrote part of the article 27 Field MJ, McCleary S, Hughes J, Singh L. Gabapentin and pregabalin,
and tables and critically reviewed the article. but not morphine and amitriptyline, block both static and dynamic
Funding: Funded in part by the Centers for Rehabilitation Sciences components of mechanical allodynia induced by streptozocin in the rat.
Research, Uniformed Services University of the Health Sciences, Bethesda, Pain 1999;80:391-8.
MD, USA. 28 Ueda H. Molecular mechanisms of neuropathic pain-phenotypic switch
and initiation mechanisms. Pharmacol Ther 2006;109:57-77.
Competing interests: We have read and understood the BMJ Group policy 29 Schüning J, Scherens A, Haussleiter IS, Schwenkreis P, Krumova EK, Richter
on declaration of interests and declare the following interests: None. H, et al. Sensory changes and loss of intraepidermal nerve fibers in painful
The opinions or assertions contained herein are the private views of the unilateral nerve injury. Clin J Pain 2009;25:683-90.
authors and must not be construed as official or as reflecting the views of 30 Nickel FT, Seifert F, Lanz S, Maihofner C. Mechanisms of neuropathic pain.
the US Department of the Army or the Department of Defense. Eur J Neuropsychopharmacol 2012;22:81-91.
31 Wehnert Y, Muller B, Larsen B, Kohn D: Sympathetically maintained pain
Provenance and peer review: Commissioned; externally peer reviewed. (SMP): phentolamine test vs sympathetic nerve blockade. Comparison of
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