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Emerging Treatments for Chronic Pain
A critical consideration for utilising the therapeutic benefit of Na
V
treatments for neuropathic pain. Additional α
2
δ-ligands with improved
blockers is a clear separation between cardiovascular and sensory bioavailability and efficacy are in development.
neuronal effects without numbness, which requires subtype selectivity. A
potent and selective isoform-specific small-molecule (Na
V
1.8) blocker (A- Hyperpolarization-activated Cyclic
803467) that reduced inflammatory and neuropathic pain behaviors in Nucleotide-gated Channels
rats is in development, and represents a potentially exciting new Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which
treatment for allodynia and hyperalgesia in chronic pain patients.
10,11
generate spontaneous rhythmic activity in the cardiovascular and nervous
systems, play an important role in modulating neuronal excitability and
plasticity in chronic pain states.
25
Nerve injury results in increased HCN1
Chronic pain is different from acute expression in DRGs and spontaneous activity in the damaged nerve.
Studies using the selective antagonist ZD7288 decreased ectopic activity in
pain in that therapies that provide
DRGs and reversed spontaneous pain and allodynia induced by mild
transient pain relief do not resolve the thermal injury and nerve injury. Thus, drugs targeting HCN currents could
prove beneficial for chronic pain treatment.
26,27
underlying pathological processes
maintaining the pain. Transient Receptor Potential Channels
The first cloned nociceptor was identified as the transient receptor
potential (TRP) V1 channel.
28
Expressed at sensory nerve terminals, this
Other promising new treatments include lacosamide and ralfinamide. ligand-gated nociceptor can integrate various painful stimuli, e.g.
Antinociceptive efficacy for the anticonvulsant lacosamide was shown in capsaicin, low pH, and noxious heat, and may underlie neuronal
models of chronic inflammation and neuropathic pain, and has translated hypersensitivity due to modulation by inflammatory and nerve-damage-
into promising results in phase II and III clinical trials for painful diabetic associated mediators, e.g. prostaglandins, bradykinin, and nerve growth
neuropathy; the drug produced marked reductions in pain scores factor (NGF).
29
Paradoxically, antinociception is achieved with agonists via
compared with placebo and was generally well tolerated, and low receptor desensitization, e.g. topical high-dose capsaicin is effective in
drug–drug interactions were reported.
12,13
Unlike other anticonvulsants, neuropathic patients, and also with antagonists. In the latter case, the
the drug has a novel dual mode of action, whereby it enhances slow efficacy of antagonists relies on the promiscuous nature of the receptor
inactivation of voltage-gated sodium channels and interacts with since blocking heat rather than mechanical responses is unlikely to be
collapsin-response mediator protein-2.
14
This possibly sets the drug apart clinically important.
30,31
Caution is needed due to the potential for altered
from other sodium-channel-blocking drugs such as lamotrigne and body temperature.
topimarate, which have proved disappointing in treating painful diabetic
neuropathy.
15,16
Ralfinamide is proposed to inhibit Na
V
1.3, 1.7, and 1.8 An intriguing recent development utilizes TRPV1 to enable the delivery of
and Ca
V
2.2 currents in rat dorsal root ganglia (DRGs) to suppress evoked a lidocaine derivative to specifically block damage-sensing neurons
and spontaneous pain in chronic inflammatory and neuropathic pain without blocking all nerve cells, thus avoiding paralysis and numbness.
32
models, and positive phase II trials in neuropathic pain patients have been Here, activation of TRPV1 is used to induce opening of Na channels, thus
reported.
17
Understanding how alterations in Na
V
channels contribute to enabling better access for the lidocaine. This strategy would most likely
the pathogenesis of chronic pain conditions should enable selective be useful peri- and post-operatively for surgical pain, but similar therapies
blockers to be produced that have therapeutic efficacy at doses well could eventually be developed for chronic pain treatment.
below those that impair nerve conduction or cardiovascular function,
among other side effects.
Antinociceptive efficacy for the
Calcium Channels
anticonvulsant lacosamide was shown
Voltage-dependent calcium channels (VDCCs) are important for both
transmitter release from peripheral afferents and neuronal excitability. Ten
in models of chronic inflammation and
subtypes have been cloned, many of which are critical in pain regulation.
neuropathic pain, and has translated
The N-type (Ca
V
2.2) is of particular interest since its activity is enhanced
in chronic pain states.
18
Genetic deletion results in an attenuation of
into promising results in phase II
inflammatory and neuropathic pain behaviors, and the selective blocker
and III clinical trials for painful
ziconotide has proved successful in both animals and human studies.
19,20
diabetic neuropathy.
To date the most clinically successful modulators of Ca
2+
channel activity
are agents targeting the α
2
δ-1 and 2 subunit of high-voltage Ca
2+
Other TRP channels of interest include TRPV3, TRPV4, and TRPA1, which
channels, with antinociceptive efficacy seen in cancer/ chemotherapy, are upregulated in neuropathy and sensitized by inflammatory
HIV, and diabetic neuropathies and osteoarthritis.
21–24
Furthermore, a mediators.
33,34
TRPM8, the receptor for cooling found in sensory nerves,
marked upregulation of α
2
δ-subunits has been correlated with the onset transduces cold hypersensitivity following inflammation and nerve injury;
and development of allodynia and hyperalgesia and the effectiveness of paradoxically, this channel also produces profound analgesia in chronic
α
2
δ ligands. Gabapentin and its newer analog pregabalin are first-line pain states, including neuropathic pain.
35
FUTURE DIRECTIONS IN NEUROLOGY 17
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