British Journal of Anaesthesia 101 (1): 48–58 (2008)

doi:10.1093/bja/aen107 Advance Access publication May 28, 2008

Neuropathic pain: emerging treatments

A. Dray*†

AstraZeneca Research and Development, 7171 Frederick Banting Street, Montreal, Canada H4S 1Z9
*E-mail: [email protected]
Neuropathic pain remains one of the most challenging of all neurological diseases and presents
a large unmet need for improved therapies. Many mechanistic details are still lacking, but
greater knowledge of overlapping mechanisms and disease comorbidities has highlighted key
areas for intervention. These include peripheral and central hyperexcitability. Among the mole-

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cular drivers are ion channels (Nav1.7, Nav1.8, Nav1.3, Cav2.2, and alpha2-delta subunits)
whose expression is changed during neuropathic pain and their block shows therapeutic utility.
Block of a number of ligand-gated channels [transient receptor potential (TRP)V1, TRPM8, and
neuronal nicotinic receptors (NNRs)], important in neural sensitization, may also prove ben-
eficial. Other approaches, such as the modulation of peripheral excitability via CB1 receptors,
reduction of spinal excitability through block of glutamate receptors (metabotropic glutamate
receptor 5 and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate), block of activated
spinal neuroglial (CCR2 and P2X7), or increasing spinal inhibition by enhancing monoaminergic
activity, all offer exciting opportunities currently being validated in the clinic. Finally of note is
the emergence of biological approaches, for example, antibodies, siRNA, gene therapy, offering
powerful therapeutic additions with which to redress the neurological disease imbalances
causing neuropathic pain.
Br J Anaesth 2008; 101: 48– 58
Keywords: glia; ions, ion channels; neuroinflammation; pain, chronic; pathophysiology;
receptors, cannabinoid; receptors, glutamate; receptors, TRP

Of all the neurological diseases, neuropathic pain is one of limitations with respect to efficacy and side-
the most challenging with respect to understanding the effects (dizziness, sedation, and weight gain). Similarly,
relationships between symptoms and mechanisms, and antiarrhythmic drugs including mexiletine are claimed to
rationalizing approaches to treatment.12 It is not surprising provide pain relief in some 50% of patients but also suffer
therefore that effective and safe neuropathic pain treatment severe side-effect limitations (sedation tachycardia, hyper-
remains a large unmet therapeutic need. tension, and weight gain). In some cases, the antidepress-
Most (90%) neuropathic pain states have been con- ant drug amitriptyline, acting as an ion channel and
sidered to arise from peripheral [ peripheral nervous monoamine modulator, has been shown to provide pain
system (PNS), post diebetic neuralgia (PDN), post herpetic relief. Building on this, the serotonin – norepinephrine
neuralgia (PHN), post traumatic neuralgia (PTN), and reuptake inhibitor (SNRI) duloxetine has been approved to
iatrogenic injuries] rather than central nervous system treat chronic depression comorbidity and PDN pain,33 pro-
(CNS) injuries [stroke, multiple sclerosis (MS), and viding a differentiated therapeutic approach that may
Parkinson’s disease (PD)], although emerging functional harness endogenous monoaminergic pathways, addressing
magnetic resonance imaging data have been highlighting important aspects of pain/depression comorbidity.33 74 98
that some prevalent chronic pain states [low back pain Other current therapeutic initiatives are either following
(LBP), fibromyalgia; and there may be more] may also these innovative approaches, using clinically validated
present with secondary CNS neurodegeneration.6 59 drugs, or drug combinations, or are providing preclinical
Current chronic neuropathic treatments indicate general and clinical validation for progression of new concepts. For
insensitivity to non-steroidal anti-inflammatory drugs and the most part, these new therapeutic approaches are addres-
relative resistance to opioids, but can be treated by high sing improvements in either efficacy or safety relative to the
opioid doses53 at the expense of untoward side-effects. current clinical choices (summarized in Table 1).
Treatments of choice, or treatments that have received There are many emerging opportunities, arising from
regulatory approvals, include ion channel blocking drugs the growth of animal and human pathobiology of chronic
such as the anticonvulsants gabapentin (Neurontin) and
pregabalin (Lyrica).85 Overall some 10– 30% of pain †
Declaration of interest. A.D. works in Research and Development
patients are responsive to these drugs which suffer dose at AstraZeneca.

# The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: [email protected]
 Neuropathic pain

Table 1 Emerging targets and treatments

Drug Company Mechanism Phase Indications

Prialt (ziconotide) Elan/Eisai N-type Ca-channel blocker, Launched Severe chronic pain
intrathecal
Lacosamide (Vimpat, Schwarz Nav block Ph3 Positive in PDN. Evaluation in fibromyalgia
Harkoseride) Pharma and OA ongoing
Ralfinamide Alipamide NW1029 Newron Nav blocker MAO-inhibitor Ph2 Evaluation in several NP conditions
Topamax topiramate J&J Glut antag/GABA agonist/Na Ph3 (PDN) Launch for epilepsy and migraine. Effective in
blocker PDN
ADX10059, ADX48621 Addex mGluR5 inhibitor Ph2 Efficacy in acute migraine. Ph2 planned for NP
AZD 2066 AstraZeneca mGluR5 inhibitor Ph1 Ongoing
XP13512 GSK/Xenoport Pro-gabapentin Ph 2 Recruiting Ph2
Tezampanel NGX426 TorreyPines AMPA/kinate antagonist Ph2 Ongoing
TC6499 GSK/ Neuronal nicotinic receptor Ph1 Recruiting Ph1
Targacept agonist

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Retigabine Valeant Potassium channel KCNQ2/3 Ph3 Efficacy in epilepsy, PHN
opener
NGD8243 (MRK2295) Merck/ TRPV1 antag Ph2 Postop dental pain
Neurogen
GRC-6211 Lilly/ TRPV1 antag Ph2 Ongoing for NP and OA
Glenmark
AMG 986 Amgen TRPV1 antag Ph1 In progress
AZD1386 AstraZeneca TRPV1 antag Ph1 In progress
Transacin (Transdolor, NeurogesX TRPV1 agonist (capsaicin) Ph3 (PHN, HIV) and Pain reduction in HIV and PHN
NGX-4010) (topical) Ph2 (PDN)
Sativex, GW-1000, Buccal spray GW Pharma Cannabinoid-receptor agonist Ph3, Ph2 in PDN Approved for cancer and MS pain. Effective in
NP with allodynia
IP 751, CT-3, ajulemic acid Indevus CB1 receptor-agonist/CoX-2/IL-1 Ph2 Reduces spinal and nerve injury pain
block
KDS2000 (topical) Kadmus Cannabinoid Ph 2 Progress in PHN and PDN
Pharma
AZD 1940 AstraZeneca Cannabinoid-receptor agonist Ph1 Progress
TRO-19622 (oral) Trophos Unknown Ph2a Recruiting PDN patients
RN624 PF-4383119 Pfizer/Rinat Anti-NGF mAb Ph2 (OA) Recruiting for PHN, LBP, bone pain, cystitis
AMG403 Amgen Anti-NGF mAb Ph2 starting
SB-509 Sangamo Plasmid DNA to up-regulate Ph2 (PDN) Disease modifying for diabetes
VEG-F

pain, for targeting key molecular events that underlie pain symptoms and key cellular and molecular mechanisms.
mechanisms and cellular processes. In this review, I will This provides powerful strategies to direct rational drug
select some of the most promising targets and provide an therapy rather than follow clinical serendipity. The major
assessment of the most advanced concepts that are in their cellular mechanisms include ectopic or spontaneous nerve
early phases of clinical development. activity and peripheral and central hyperexcitability, phe-
notypic changes in pain conducting pathways, secondary
Pain mechanisms and targets neurodegeneration, and morphological reorganization.12 127
To date, most drug discovery approaches for neuropathic It is also recognized that episodic inflammation, and
pain have been based on symptom management, directed chronic inflammatory conditions, cause nerve injury,
at the most commonly described clinical symptoms encouraging a broader appreciation of the heterogeneity of
namely spontaneous pain, mechanical and cold allodynia, chronic pain aetiology.30 103 Here there are emerging data
hyperalgesia, and hyperpathia. Little attention has been that implicate host defence mechanisms and powerful neu-
devoted to understanding or addressing the treatment of roimmune modulation involving peripheral and central
severe dysesthesias such as numbness, tingling, or prick- immune cell activation in the initiation and maintenance
ling that also appear as cardinal features of the neuropathic of neuropathic pain.94 103 109 123
pain spectrum. Multiple symptoms (and mechanisms) may Mechanistic and molecular-based understanding of
be present at the same time in neuropathic pain with fea- chronic neuropathic pain has relied heavily on animal studies
tures that change over time.12 Indeed, it seems likely that using few and approximated disease or mechanism-related
there is an aetiological and progressive relationship models that emphasize key symptomatic characteristics (e.g.
between the initiation and maintenance of chronic neuro- mechanical allodynia). Often these models involve peri-
pathic pain providing clinical challenges and treatment pheral nerve lesions, for example, sciatic nerve ligation,
opportunities. partial sciatic nerve transection, transaction of sciatic
With the growth of evidence-based and translational branches (spared nerve model), or ligation of L4 or L5
medicine, we are understanding the relationship between spinal nerves.12 There are relatively fewer studies from other

49
 Dray

disease-related models, for example, diabetic neuropathy or (A-803467) has been described51 with a profile of activity
cytotoxic injury, to provide a balanced view about the ubi- in a variety of chronic pain models but surprisingly was
quity of key mechanisms. Nevertheless these studies, sup- ineffective in models of acute pain, suggesting that this
ported by emerging human genetic and empirical clinical channel makes little contribution to nociception in the
observations, have highlighted a number of emerging thera- physiological range.
peutic opportunities that reduce hyperexcitability in pain Nav1.3 is also overexpressed in large Ab fibres from
pathways, through block of abnormally active ion channels chronic pain patients and in the spinal cord of pain
(voltage and ligand gated), direct inhibition of excitability models.20 43 This channel may also be an important sub-
(via GPCRs), or restoring normal neural phenotype and strate for oscillations in peripheral and central neurone
metabolism (e.g. neurotrophins). excitability, which is considered to be important for neuro-
pathic pain.
Among the major safety challenges in exploiting Na
channel biology for neuropathic pain treatment is channel

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Reduction of abnormal excitability
subtype selectivity comparing heart (e.g. Nav1.5) and CNS
channels (e.g. Nav1.2). Some of these pitfalls are avoided by
Ion channel (voltage and ligand gated) blockers localized treatment of hyperexcitability with local anaesthetic
Hyperexcitability in small and large peripheral sensory formulations such as lidoderm. Emerging oral treatments
nerves acts as an important driving mechanism for neuro- include new sodium channel blockers such as lacosamide
pathic pain and can account for the initiation and mainten- (also called Vimpat or harkoseride, Schwarz Pharma) and
ance of central hyperexcitability.127 Thus, block of local ralfinamide (NW-1029, Alipamide, Newron Pharma) with
excitability using the local anaesthetic, lidocaine, reverses activity at both TTX-sensitive and TTX-resistant channels.
primary and secondary allodynia in neuropathic pain41 at These drugs have been shown to be anti-hyperalgesic in
concentrations that do not affect normal nerve conduction. models of inflammatory and neuropathic pain.8 45 118 In
This is due to the well-known activity-dependent increase addition, lacosamide is claimed to modulate collapsin
in voltage-gated ion (sodium and calcium) channel affinity response mediator protein 2 which may influence axon
for local anaesthetics. Though peripheral excitability may growth and neuronal plasticity.
be regulated by many mechanisms, selective depression of Clinical benefits of lacosamide have been reported to
small and large fibre excitability appears to be a valuable include significant reductions in pain measures compared
path towards new therapies.72 with placebo, achieved in some (but not all) phase 3 trials
Changes in the expression and activity of several and accompanied by improvements in other efficacy
voltage-gated sodium, potassium, and calcium channels measures including somnolence and quality of life (QOL)
have been highlighted after nerve injury. Voltage-gated measures. Although reportedly well tolerated in the phase
sodium channels are characterized by their primary struc- 3 trials, lacosamide was associated with high rates of
ture and sensitivity to tetrodotoxin (TTX). A variety of adverse events and dropouts in trials in diabetic neuro-
TTX-sensitive (Nav1.3 and Nav1.7) and TTX-insensitive pathic pain.
(Nav 1.8 and Nav1.9) channels are involved in regulating Ralfinamide is another important therapeutic develop-
sensory neural excitability.32 71 Changes in the expression, ment blocking Na-ion channels and inhibiting the enzyme
trafficking, and redistribution of Navs, after inflammation monoamine oxidase. This compound has shown a robust
or nerve injury, are considered to account for unstable activity in a number of preclinical pain models. Clinical
oscillations of membrane potential, abnormal firing, and reports also suggest good tolerability overall with positive
the generation of ectopic activity in afferent nerves.3 27 Ph2 outcome in a mixed population of neuropathic pain
Mutations of Nav1.7 have been identified as the cause of patients.13
burning pain in erythromelalgia,125 whereas loss, or func- Voltage-gated calcium channels are subdivided into two
tion mutations in these channels, leads to complete abla- major categories: low-voltage-activated calcium channels
tion of pain perception in humans, without any other (T-type channels) and high voltage activated. High-voltage-
notable pathology. Similar ablation of pain sensation has activated channels are further subdivided, based on pharma-
been observed in mice with Nav1.7-deficient sensory cology and biophysical characteristics, into L-, N-, R-, P-,
neurones.79 and Q-types. Several have been shown to be prominently
Nav1.8 is uniquely expressed in small sensory neurones involved in pain regulation.128 With respect to calcium chan-
and may be down-regulated in small injured axons but nels, N-type channels are unique to neurones and critical for
up-regulated in adjacent uninjured C fibres and in human pain neurotransmission. Thus, deletion of the N-channel
peripheral neuropathies.20 39 Nav1.8 appears important for gene reduced inflammatory and neuropathic pain96 whereas
the generation of spontaneous activity in damaged sensory intraspinal block with the snail conopeptide Ziconotide
axons,95 and knockdown of Nav1.8 in models of neuro- (Prialt, Elan/Eisai),76 or channel block with the orally avail-
pathic pain produces a marked reduction in abnormal pain able small molecule NMED-160 (Merck/Neuromed),105 has
responsiveness.40 Recently, an Nav1.8 selective compound shown efficacy across a range of chronic pain conditions

50
 Neuropathic pain

indicating the validity of this approach. Unfortunately, devel- degeneration due to prolonged cation influx into the nerve,
opment challenges have halted the Ph2 delivery of osmotic damage, and metabolic collapse.111 In this regard,
NMED-160 whereas the technical limitations of intraspinal topical formulation of high-dose capsaicin (e.g. Transacin
delivery of Prialt restricts the wide-spread usage of this from NeurogesX) has been shown to be efficacious in a
approved agent. number of neuropathic pain conditions including Ph3
Another highly validated approach targets the alpha2 studies in PHN patients.9
delta-1 calcium channel subunit, the substrate for the On the other hand, antagonists aim to selectively inhibit
anticonvulsant gabapentin and pregabalin, commonly peripheral nerve fibre activity by block of TRPV1 signal
used for neuropathic pain therapy. This subunit is import- transduction. Supporting these approaches, competitive (AM
ant for channel assembly and its overexpression in small G9810 and AMG628)38 121 and non-competitive TRPV1
dorsal root ganglia (DRGs) and spinal neurones has been antagonists (DD161515)37 block chemical and thermal pain
associated with allodynia in a number of specific pain sensitivity, supporting the emergence of a novel therapy.
models.56 67 The exact mechanism of action of gabapen- Indeed, recent clinical studies in volunteers have shown that

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tin is unknown, although block of N-channel regulated- oral SB705498 (GSK) attenuated capsaicin and UVC-induced
release of CNS neurotransmitters has been considered to pain and hyperalgesia,16 without notable side-effects. These
be critical. More recent evidence suggests that gabapentin studies herald the way for a number of Ph2 trials for compet-
is transported into cells via an L-neutral amino acid trans- ing antagonists (e.g. GRC 6211 Lilly/Glenmark; NDG6243
porter and acts to displace an endogenous ligand that Merck/Neurogen; AZD1386, AstraZeneca). However, others
regulates the trafficking of alpha2 delta-1 subunit to the have noted the occurrence of hyperthermia with this class of
neural membrane.47 On the clinical side, emerging thera- antagonists both in animal and in human volunteer studies.38
peutic differentiation in terms of bioavailability is Other TRP channels (TRPV3, TRPV4, TRPA1, and
claimed for the gabapentin prodrug XP 13512 (Xenoport/ TRPM8) that also act as temperature transducers have been
GSK) which is currently in Ph2 development. suggested to be involved in pain particularly when sensitized
Low-voltage-activated T-channels also appear important by a pathophysiological environment. TRPA1 is co-localized
for pain transmission and as targets for pain therapy. Thus, with TRPV1, is activated by capsaicin, and like TRPM8, can
they are expressed in superficial laminae of the spinal cord also be sensitized by inflammatory mediators and nerve
and in dorsal root ganglion neurones128 and play a promi- injury to produce cold-induced burning pain.7 83 87 A TRPA1
nent role in regulating spinal excitability after repetitive selective antagonist HC030031 has been claimed to reduce
C-fibre stimulation.49 Moreover, nerve injury-induced pain signalling in animal models.73 TRPV3 is also found in
hyperresponsiveness was reported to be blocked by the keratinocytes and sensory neurones28 and appears to be
T-channel blocker ethosuximide70 which also attenuated up-regulated in diabetic neuropathy. So far there are few
mechanical allodynia in animal models of vincristine and available chemical tools to help characterize the functions of
paclitaxel-induced neuropathic pain.35 these receptors, although TRPV3 ligands (Pfizer/Hydra)
In addition to the voltage-gated ion channels described appear to be in early development.
above, a number of ligand-gated ion channels are also Neuronal nicotinic receptors (NNRs) are part of a
being proposed as targets for neuropathic pain (NP) complex family of ligand-gated ion channels. These com-
therapy. For example, the mammalian transient receptor prise five subunit proteins that form a cation permeable
potential (TRP) channels represents a large receptor ion channel. Models of chronic injury suggest that there is
family, subdivided into six subfamilies (for review see significant overexpression of key subunits including the
Richardson and colleagues),92 but attention has been alpha7 NNR and alpha4 and alpha5 subunits. This has
focused mainly on TRPV1, TRPV3, and TRPM8. Many supported the therapeutic potential of NNRs in pain
TRP channels are localized to sensory neurones and control.24 119 Thus, nicotinic receptor agonists (epibatidine,
nearby keratinocytes, acting as temperature and mechan- ABT-594, Abbott) selective for these subunits, particularly
ical transduction proteins. TRPV1 has been investigated in compared with alpha4 beta2 have demonstrated antinoci-
detail. This is a non-selective cation channel, gated by ception in several models of pain including neuropathic
capsaicin, noxious heat (.458C), acidic pH (,5.3), and is pain.75 Several sites of action have been proposed includ-
regulated by a variety of inflammatory mediators (e.g. bra- ing supraspinal sites via descending monoaminergic and
dykinin and PGE2) and neuroregulators [anandamide and muscarinic pathways, and actions on peripheral sensory
nerve growth factor (NGF)]. It is emerging as an important neurones. Earlier clinical evaluation of ABT-594 revealed
molecular focal point that is thought to play an important inadequate tolerability, but more recent compounds such
role in neural sensitization caused by mediators of inflam- as TC 6499 (GSK/Targacept) and ABT-894 (Abbott
mation and nerve injury.91 117 Pharma) are progressing in clinical phases 1 and 2,
Current analgesia strategies are aimed at developing respectively, towards a diabetic neuropathy pain
either TRPV1 agonist or antagonist drugs to attenuate excit- indication.
ability in sensory fibres. TRPV1 agonists induce receptor The excitatory transmitter glutamate plays an important
desensitization or a reversible sensory nerve terminal role in the initiation and maintenance of neuropathic pain.

51
 Dray

Glutamate acts through a variety of receptors which have provided validation of this target in several clinical
include the N-methyl-D-aspartate receptors (NMDA), the pain conditions including migraine and fibromyalgia50
alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate whereas additional studies, for example, AZD2066
(AMPA)/kinate receptors, ionotropic glutamate receptors (AstraZeneca), are currently in progress, Ph1 and 2.
(iGluRs), and GPCR coupled, metabotropic glutamate Metabotropic Group II receptors (mGluR2 and 3) also
receptors (mGluRs) that are coupled with ligand-gated ion modulate pain transmission. The mGluR2 is located in
channels. Injections of glutamate or metabolically stable sensory neurones and presynaptic nerve terminals, whereas
receptor-selective agonists, such as NMDA, AMPA, and mGluR3 is found all over the brain. MgGluR3 can be
kainate, cause a pro-nociceptive response, whereas the selectively increased in spinal dorsal horn neurones
administration of iGluR and mGluR antagonists attenuates after peripheral injury.10 MgGluR2 and 3 receptor acti-
pain.80 112 Encouragingly, tezampanel (NGX426: Torrey- vation appears necessary to reduce nerve terminal excit-
Pines), an AMPA kinate antagonist formulated for i.v. ability and to modulate pain transmission since treatment
administration because of poor bioavailability, has shown with the agonist L-acetyl carnitine reduced inflammatory

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positive outcome in several clinical trials99 100 but with hyperalgesia and mechanical allodynia and increased the
dose-limiting side-effects including blurred vision and expression of mGluR2 and 3. The effects of L-acetyl carni-
sedation. The development of an oral prodrug is in pro- tine were attenuated by LY379268, an mGluR2 and 3
gress with the promise of improved bioavailability. antagonist.15
NMDA antagonists also show robust attenuation of pain
in animal models but induce a number of side-effects
(sedation, confusion, and motor incoordination) and thus
Enhancing inhibition
appear to have insufficient therapeutic margin.84 In an
attempt to avoid these side-effects, specific blockers of
NMDA receptor subtypes (NR1 and NR2) are being devel- Cannabinoids and monoamine pathways
oped directed at the strychnine-insensitive glycineB modu- Other emerging approaches to attenuate hyperexcitability
latory site. This site modulates the NMDA channel during in pain circuitry are to enhance cellular inhibitory mechan-
sustained receptor stimulation, which is considered to isms. These include targeting cannabinoid receptors or
occur during chronic pain. Selective NR1-glycine enhancing central monoaminergic inhibitory control.
(NR1-Gly) site antagonists have been claimed to reduce There are two major cannabinoid receptors, CB1 and
pain with reduced side-effects.23 88 However, clinical CB2, associated with pain modulation. CB1 receptors are
experience has not confirmed this. GV196771 (GSK) did widely distributed in the CNS and peripheral sensory neur-
not show efficacy against clinical pain, possibly due to ones, whereas CB2 receptors have been found in peripheral
inadequate penetration into the CNS.120 tissues including tissues of the immune system and kerati-
An alternative approach has targeted another NMDA nocytes with limited expression in sensory and CNS cells.37
receptor subtype, the NR2B receptor,40 which has a Several fatty acids (e.g. anandamide, 2-arachidonylglycerol,
specific distribution in sensory pathways. Block of this and palmitoylethanolamide) have been identified as endogen-
receptor has also been claimed to produce antinociception ous ligands for these receptors whereas specific antagonists
(ifenprodil, traxoprodil, CP-101606) with reduced side- such as SR141716A, SR147778 for CB1 and SR144428 for
effects.113 To date, traxoprodil has advanced into phase 1 CB2 have been used to characterize receptor function and
safety and efficacy studies for acute ischaemic stroke, and support the validation of CBs in models of chronic pain.36
there is little information about possible development in On the basis of current evidence, the efficacy of canna-
pain. On the other hand, other NR2B programmes includ- binoids towards pain modulation is mediated mainly
ing RGH 896 (Gideon Richter) and EV101 (Evotec) are through CB1 receptors located in both the peripheral and
continuing in phase 2 and are evaluated for cognition and CNS. Several clinical studies have shown that cannabi-
neuropathic pain.40 noids, such as delta(9)-tetrahydrocannabinol (THC) or
Metabotropic glutamate receptors, particularly mGluRs Sativex (THC plus cannabidiol: GW Pharma), reduce neu-
1 and 5, have been reported to play a key role in sustaining ropathic pain,81 but these compounds also produce adverse
heightened central excitability in chronic pain with effects such as euphoria, dizziness, and sedation at thera-
minimal involvement in acute nociception. Thus, spinal peutic concentrations.11 However, selective targeting of
administration of selective agonists such as dihydroxy- the peripheral cannabinoid CB1 receptors appears to
phenyl-glycine produced allodynia, whereas mGluR5 has reduce CNS side-effects while maintaining significant pain
been shown to be significantly over-expressed in some relief. Indeed, studies in which the central CB1 receptor
chronic pain models.48 Peripheral mGluR5 receptors have was deleted suggest significant analgesic efficacy can be
also been claimed to modulate pain. In keeping with this, retained through peripheral CB1 activation.2 Furthermore,
several mGluR5 antagonists (MPEP and SIB 1747) have localized or topical administration of non-selective ago-
shown robust efficacy in neuropathic pain models.29 130 In nists such as HU210 or KDS2000 (Kadmus Pharma) or
addition, several compounds (ADX10059 and ADX4861) the oral administration of a CB1 agonist with limited CNS

52
 Neuropathic pain

availability such as CT3 (ajulemic acid, CT3: indevus segmental input. Also of importance is that glia secrete a
Pharma), produced analgesia both in pain models31 92 and number of mediators (nitric oxide, neurotrophins, IL1b,
in a clinical test at a dose which caused minimal CNS TNF-a, and free radicals), some of these are associated
side-effects.54 Another oral, peripherally selective cannabi- with synaptogenesis but also with the plasticity that causes
noid agonist (AZD 1940 AstraZeneca) is currently under- changes in spinal and afferent neuronal excitability includ-
going clinical validation. ing secondary neurodegeneration and the loss of inhibitory
Interestingly, CB2 selective agonists (e.g. HU-308, inter-neurones.78
HU-210, CP55940, AM1241, and GW405833) have also The release of inflammatory mediators is regulated via
been shown to modulate chronic pain.60 68 116 It is unclear glial receptors for ATP, kinins, prostanoids, NMDA, and a
how the analgesic effects of CB2 agonists are produced variety of chemokine receptors, which may also modulate
since few CB2 receptors are found in the CNS or on spinal excitability.124 126 A number of compounds claimed
sensory neurones.106 However, de novo expression of CB2 to stabilize and reduce glial activity have been shown to
receptors occurs in central glial cells after peripheral nerve attenuate evoked pain in models of neuropathic pain.

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lesions.129 It is therapeutically significant that CB2 ago- These include propentofylline,89 110 minocycline,124 and
nists have not shown CB1-like side-effects. acetyl L-carnitine. Interestingly, ibudilast (Avigen 411), a
An alternative approach to utilize the endogenous can- drug used clinically for respiratory disorders, has recently
nabinoid systems is via inhibition of fatty acid amide been shown to be efficacious in neuropathic pain62
hydrolysis (FAAH), the major degradation pathway for through reduction of neuroglial activation. Although ibudi-
endogenous cannabinoids.22 Data supporting this show last is known as a PDE4 inhibitor, this does not readily
that mice lacking this enzyme,21 or treatment with FAAH explain its actions at neuroglia and for the most part the
inhibitors, such as URB597 and OL135, significantly ele- actions of the aforementioned drugs that attenuate glial
vated brain anandamide and increased pain threshold in activity are not well understood.
pain models.64 Moreover analgesic synergy has been Glial regulation may also be achieved through receptor
reported to occur between opioid and cannabinoid modulation. In this respect, a number of purinergic26 recep-
systems17 suggesting that in a clinical pain setting, greater tors have been highlighted. For example, P2X7 and P2X4
therapeutic benefit may be achieved by combinations of receptors are expressed in microglia and satellite cells and
these mechanisms. are up-regulated after peripheral nerve injuries.14 115
The successful treatment of neuropathic pain with amitrip- Deletion of the P2X7 receptor-gene produced a complete
tyline and duloxetine has stimulated further interest in absence of mechanical and thermal pain in mice14 whereas
exploring mechanisms and drugs (e.g. venlafaxine and bicifi- the selective P2X4 antagonist TNP-ATP attenuated mech-
dine) that enhance monoamine pathways in the CNS. Since anical allodynia.115
the effects of these SNRI drugs in chronic neuropathic pain Other major inflammatory products such as chemokines
appear to be independent of antidepressant activity, an attrac- and their receptors have important roles in neuropathic
tive hypothesis is that they reinforce descending inhibitory pain. The major chemokines and their respective receptors
pain circuitry. Other types of monoamine inhibitors, for are MCP1/CCR2, MDC/CCR4, RANTES/CCR5, fractalk-
example, SNRI (fluoxetine and paroxetine), selective ine/CX3CR1, and SDF-1alpha/CXCR4. Specific chemo-
serotonin reuptake inhibitor (SSRI) (mirtazapine), or kines, for example, TNF-alpha, IL-8, and patterns of
norepinephrine reuptake inhibitor (NRI) (reboxetine), require chemokine release58 65 have been strongly associated with a
further evaluation.74 However, it has been concluded that number of neuropathic pain conditions.63 102 With respect to
antidepressants represent useful tools in neuropathic pain chemokine receptors, CCR2, CXCR4, CCR4, and CX3CR1
treatment and must still be considered as first line treatments. have been shown to be expressed in glial and sensory neur-
Without head-to-head comparisons between antidepressants ones, and preliminary data have shown that block of
and other analgesics, it is not possible to provide real CX3CR1 by a receptor-neutralizing antibody induces power-
evidence-based treatment algorithms for neuropathic pain.107 ful anti-allodynic effects. In addition, CCR2 has emerged as
As mentioned earlier, there is emerging evidence for an important target being powerfully expressed is spinal glia
neuroimmune modulation in the aetiology of neuropathic and DRGs after peripheral nerve injuries and activated by its
pain. In particular, neuroglial cells (microglia, astrocytes, ligand MCP-1 to activate microglia and increase sensory
DRG satellite cells, and Schwann cells) have been high- fibre excitability.1 In support of this, deletion of the CCR2
lighted as key cellular elements in these processes. gene blocks glial cell recruitment and attenuates neuropathic
Importantly, both trafficking of peripheral leucocytes into pain.1 Although these preclinical data seem compelling, it
the CNS and activation of resident glial cells contribute in should be noted that CCR2 antagonists have been in devel-
the aetiology of neuropathic pain. Glial cell activity is opment (INCB3284, Pfizer/Incyte and MK-0812 Merck) for
important in pain amplification as many of these cell types treatment or rheumatoid arthritis but have not proved to be
regulate neuronal activity but also make close-junctional clinically efficacious.
connections with each other, providing a means of spread- Although many cytokines appear to have a detrimental
ing excitability changes beyond the boundaries of spinal role in initiation and maintenance of neuropathic pain,

53
 Dray

some cytokines appear to be beneficial. Thus, a gene activate a number of other kinase-pathways, for example,
therapy approach, using viral and non-viral vectors p38 kinase leading to altered gene transcription and the
(AV-333), has been used to increase spinal IL10 pro- increased synthesis of sensory neuropeptides (substance
duction. This experimental treatment reversed the mechan- P and CGRP), ion channels (TRPV1, Nav1.8, and
ical allodynia evoked in a model of neuropathic pain.77 ASIC3),34 52 69 membrane receptors such as bradykinin
These are instructive observations as they suggest that care and P2X3,90 and structural molecules including neurofila-
must be given to maintaining a positive therapeutic ment and channel anchoring proteins such as the annexin
balance when modulating the neuroimmune products that light chain p11.
regulate chronic pain. Increased expression and release of NGF have been
demonstrated, for example, in UV and surgical injury42
and human disease conditions including arthritis, cystitis,
Restoring the neural phenotype prostatitis, and headache.5 44 101 Localized administration
of exogenous NGF induces thermal and mechanical hyper-

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As mentioned earlier, a variety of phenotypic changes have
algesia in animals and in humans4 108 which is considered
been identified in cellular elements of the pain pathways
to be due in part to mast cell degranulation and by directly
contributing to neuropathic pain and associated dysesthe-
increasing sensory neuronal excitability.
sias. These changes drive alterations in expression of recep-
Few NGF antagonists have been reported, but ALE0540
tor and ion channel proteins, alterations in cellular
and PD90780 which inhibit NGF binding to trkA and
neurochemistry and patterns of released transmitters, and
p75, respectively, have shown efficacy in chronic pain
synaptic reorganization that impacts on normal sensory
models.18 86 In addition, the therapeutic utility of targeting
function. These changes can be regarded as critical
NGF has also received clinical confirmation since huma-
elements of the disease processes that maintain the chronic
nized anti-NGF monoclonal antibodies (mAb) RN624
pain state. Phenotypic changes are understood to occur
(Pfizer/Rinat) and AMG403 (Amgen) have been reported to
through altered dynamic interactions between intracellular
be efficacious in reducing pain and improved mobility in
and extracellular regulators, the latter often being contribu-
osteoarthritis.61 Anti-NGF mAb therapy thus appears as an
ted by supporting cells such as keratinocytes, Schwann
attractive therapeutic approach with further validation
cells, and neuroglia or by migrating cells such as macro-
being pursued in other indications including PHN and low
phages and leucocytes that release neurotrophins.
back pain.
Modulation of neurotrophin regulation is seen as an attrac-
BDNF is another important neurotrophin released from
tive therapeutic possibility to address both chronic pain
neuroglial and sensory cells and whose expression can be
symptoms and disease progression and is being pursued by
regulated by NGF after painful nerve injury.97 In the spinal
developing both small molecule and biological approaches.
dorsal horn, BDNF increases spinal excitability by direct
neural excitation, activation of a signalling cascade via the
Neurotrophins and their receptors phosphorylation of NMDA receptors, and via altered regu-
Neurotrophins represent an important family of regulatory lation of the neural chloride-ion transporter that contributes
proteins essential for sensory nerve development, survival, to pain hypersensitivity.19 In addition, spinally administered
and the determination of neurochemical phenotype critical BDNF causes thermal and mechanical allodynia whereas
for the regulation of excitability.42 131 Several neuro- anti-BDNF neutralization or trkB IgG administration
trophins have been identified including nerve growth reduces nerve injury hypersensitivity in animal models.25 55
factor (NGF), brain-derived neurotrophic factor (BDNF), Finally, GDNF represents an extensive family of ligands
and neurotrophin 3 (NT3), NT 4/5. Each neurotrophin and membrane receptor complexes that have an important
binds with high affinity to a receptor tyrosine kinase (trk): role in regulating peripheral and central neural phenotypes.
NGF to trkA, BDNF and NT4/5 to trkB, and NT3 to trkC. GDNF-related ligands include neurturin and artemin,
NT3 also binds with trkA and trkB. Mature neurotrophins which act via the complex RET tyrosine kinase receptor
also bind to a structurally distinct receptor p75 which and co-receptors GFRalpha1, alpha2, alpha3, and alpha4.
affects neuronal development through downstream signal- GDNF has been shown to have neuroprotective and
ling. Neurotrophins arise from proneurotrophin precursors restorative properties in a number of neurodegenerative
after extracellular cleavage by metalloproteinases and and neuropathic pain states.97 Specifically, GDNF and
plasmin. It is notable that proneurotrophins may signal more recently artemin treatment have been shown to
through the p75 receptor in a manner that opposes the restore peripheral sensory neurone function,122 including
effects of neurotrophins, for example, to produce apoptosis peptide and ion channel expression patterns, after periph-
rather than cell survival.66 eral nerve injury accompanied by an attenuation of pain
NGF is one of the most studied neurotrophins. It is a behaviours.97 Unfortunately, clinical observations using
key regulator of sensory neurone excitability and an GDNF have shown unacceptable side-effects such as
important mediator of injury-induced nociceptive and weight loss and allodynia which has discouraged thera-
neuropathic pain.46 93 114 NGF acts via trkA and p75 to peutic development.82

54
 Neuropathic pain

Finally, it is worth mentioning another biological 6 Baliki MN, Gehe PY, Apkarain AV, Chialvo DR. Beyond feeling:
approach to neuropathic pain that involves gene therapy. chronic pain hurts the brain, disrupting the default mode
Thus, SB-509 (Sangamo Bioscience), a plasmid that network dynamics. J Neurosci 2008; 28: 1398 – 403
7 Bandell M, Story GM, Hwang SW, et al. Noxious cold ion
expresses an engineered gene transcription factor (a novel channel TRPA1 is activated by pungent compounds and bradyki-
DNA-binding zinc finger protein), binds the endogenous nin. Neuron 2004; 41: 849– 53
VEGF-A promotor gene to improve microvascular 8 Beyreuther B, Callizot N, Stohr T. Antinociceptive efficacy of
regrowth and thereby promote peripheral nerve regener- lacosamide in a rat model for painful diabetic neuropathy. Eur J
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currently in phase 2 for clinical validation. vanilloid receptor 1 agonist-based therapies. Expert Opin Investig
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10 Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of
Summary metabotropic glutamate receptor 3 messenger RNA in the rat

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Neuropathic pain therapy remains an enormously challen- spinal cord during ultraviolet irradiation induced peripheral
inflammation. Neuroscience 1998; 82: 591 –602
ging area of unmet medical need, despite the increases in
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PD90780 [7-(benzoylamino)-4,9-dihydro-4methyl-8-oxo-pyrazolo-
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