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INTRODUCTION
Pain
is usually the natural consequence of tissue injury
resulting in approximately forty million medical
appointments per year. In general, as the healing
process commences, the pain and tenderness
associated with the injury will resolve.
Unfortunately some individuals experience pain
without an obvious injury or suffer protracted pain
that persists for months or years after the initial
insult. This pain condition is usually neuropathic
in nature and accounts for a large number of
patients presenting to pain clinics with chronic,
non-malignant pain. Rather than the nervous system
functioning properly to sound an alarm regarding
tissue injury, in neuropathic pain the peripheral or
central nervous systems are malfunctioning and
become the cause of the pain.
TERMININOLOGY
Acute
pain and chronic pain differ in their etiology,
pathophysiology, diagnosis and treatment. Acute pain
is self-limiting and serves a protective biological
function by acting as a warning of on-going tissue
damage. It is a symptom of a disease process
experienced in or around the injured or diseased
tissue. Associated psychological symptoms are
minimal and are usually limited to mild anxiety.
Acute pain is nociceptive in nature, and occurs
secondary to chemical, mechanical and thermal
stimulation of A-delta and C-polymodal pain
receptors.
Chronic
pain, on the other hand, serves no protective
biological function. Rather than being the symptom
of a disease process, chronic pain is itself a
disease process. Chronic pain is unrelenting and not
self-limiting and as stated earlier, can persist for
years and even decades after the initial injury.
Chronic pain can be refractory to multiple treatment
modalities. If chronic pain is inadequately treated,
associated symptoms can include chronic anxiety,
fear, depression, sleeplessness and impairment of
social interaction. Chronic, non-malignant pain is
predominately neuropathic in nature and involves
damage either to the peripheral or central nervous
systems.
Nociceptive
and neuropathic pain are caused by different
neuro-physiological processes, and therefore tend to
respond to different treatment modalities.
Nociceptive pain is mediated by receptors on A-delta
and C-fibers which are located in skin, bone,
connective tissue, muscle and viscera. These
receptors serve a biologically useful role at
localizing noxious chemical, thermal and mechanical
stimuli. Nociceptive pain can be somatic or visceral
in nature. Somatic pain tends to be well localized,
constant pain that is described as sharp, aching,
throbbing, or gnawing. Visceral pain, on the other
hand, tends to be vague in distribution, paroxysmal
in nature and is usually described as deep, aching,
squeezing and colicky in nature. Examples of
nociceptive pain include: post-operative pain, pain
associated with trauma, and the chronic pain of
arthritis. Nociceptive pain usually responds to
opioids and non-steroidal anti-inflammatories
(NSAIDS).
Neuropathic
pain, in contrast to nociceptive pain, is described
as "burning", "electric",
"tingling", and "shooting" in
nature. It can be continuous or paroxysmal in
presentation. Whereas nociceptive pain is caused by
the stimulation of peripheral of A-delta and
C-polymodal pain receptors, by algogenic substances
(eg. histamine bradykinin, substance P, etc.)
neuropathic pain is produced by damage to, or
pathological changes in the peripheral or central
nervous systems.
Examples
of pathological changes include prolonged peripheral
or central neuronal sensitization, central
sensitization related damage to nervous system
inhibitory functions, and abnormal interactions
between the somatic and sympathetic nervous systems.
The hallmarks of neuropathic pain are chronic
allodynia and hyperalgesia. Allodynia is defined as
pain resulting from a stimulus that ordinarily does
not elicit a painful response (eg. light touch).
Hyperalgesia is defined as an increased sensitivity
to a normally painful stimuli. Primary hyperalgesia,
caused by sensitization of C-fibers, occurs
immediately within the area of the injury. Secondary
hyperalgesia, caused by sensitization of dorsal horn
neurons, occurs in the undamaged area surrounding
the injury.
Examples
of neuropathic pain include: monoradiculopathies,
trigeminal neuralgia, postherpetic neuralgia,
phantom limb pain, complex regional pain syndromes
and the various peripheral neuropathies. Neuropathic
pain tends to be only partially responsive to opioid
therapy.
PATHOPHYSIOLOGY
The
mechanisms involved in neuropathic pain are complex
and involve both peripheral and central
pathophysiologic phenomenon. The underlying
dysfunction may involve deafferentation within the
peripheral nervous system (eg. neuropathy),
deafferentation within the central nervous system
(eg. post-thalamic stroke) or an imbalance between
the two (eg. phantom limb pain).
PERIPHERAL
MECHANISMS:
Following
a peripheral nerve injury (eg. crush, stretch, or
axotomy) sensitization occurs which is characterized
by spontaneous activity by the neuron, a lowered
threshold for activation and increased response to a
given stimulus. Should the injured nerve be a
nociceptor then increased nervous discharge will
equate to increased pain. Following nerve injury
C-fiber nociceptors can develop new adrenergic
receptors and sensitivity, which may help to explain
the mechanism of sympathetically maintained pain.
In
addition to sensitization following damaged
peripheral nerves, the formation of ectopic neuronal
pacemakers can occur at various sites along the
length of the nerve. Increased densities of abnormal
or dysfunctional sodium channels are thought to be
the cause of this ectopic activity.1,2,3 The sodium
channels in damaged nerves differ pharmacologically
and demonstrate different depolarization
characteristics.4 This may explain the rationale of
treatment with lidocaine, mexiletine, phenytoin,
carbamazepine, and tricyclic antidepressants each of
which blocks sodium channels. These ectopic
pacemakers can occur in the proximal stump (eg.
neuroma), in the cell bodies of the dorsal root
ganglion, and in focal areas of demylenation along
the axon. Neuromas are composed of abnormal
sprouting axons and have a significant degree of
sympathetic innervation.5 Neuromas have been
reported to accumulate sodium channels at their
distal ends which can modulate their sensitivity.
They can acquire adrenergic sensitivity, as
indicated by increased pain following injection of
norepinephrine into the neuroma. Neuromas can also
acquire sensitivity to catecholamines, prostanoids
and cytokines.6 Novel ion channels or receptors, not
found in normal nerves, appear to be expressed in
the regenerating terminal/axon.4
Further
animal investigations suggest that abnormal
electrical connections can occur between adjacent
demyelinated axons. These are referred to as
ephapses. "Ephaptic cross talk" may result
in the transfer of nerve impulses from one axon to
another. Cross talk between A and C fibers develops
in the dorsal root ganglion.7 Nerve growth trophic
factors may be important in the elaboration of these
changes.4 A similar event referred to as
"crossed afterdischarge" has also been
described whereby "the sprouts of primary
afferents with damaged axons can be made to
discharge at high frequencies by the discharge of
other afferents."8 It is also theorized that
injured nerves may contain ephapses between sensory
and sympathetic fibers, and such cross-connections
may play a role in the pathogenesis of
sympathetically mediated pain.
Neurogenic
inflammation is a useful model for understanding
pain and hyperalgesia.9 Neurogenic inflammation and
the cascade of events following neural injury have
been described.10 Inflammatory neuropeptides
(substance P) and prostaglandins (PGE2) may be
released from primary afferent nociceptors and
sympathetic postganglionic neurons respectively,9,11
activating nearby receptors and triggering a process
of spreading activation. These mechanisms may
explain the clinical response of some neuropathic
pain patients to topical nonsteroidal
anti-inflammatory drugs, lidocaine, and capsaicin.9
The
connective tissue sheath around peripheral nerves is
innervated by the nervi nervorum. Injury,
compression, and inflammation of the sheath may
cause pain.12 In cancer patients, pain associated
with tumor compression of neural structures is
clinically indistinguishable from non-malignant
neuropathic pain.9 This nervi nervorum related pain
may resolve following tumor resection or treatment
of tumor induced inflammation.9 Anti-inflammatory
medications (NSAIDs and corticosteroids) have been
shown to be effective in certain neuropathic pain
conditions. The mechanism of pain relief may be
decreased edema at the tumor or injury site.9
However these medications also have membranes
stabilizing effects and central analgesic effects.
Therefore it is extremely difficult to distinguish
primary tumor-associated inflammation and
involvement of the nervi nervorum from other
mechanisms of neuropathic pain.9
CENTRAL
MECHANISMS:
Following
a peripheral nerve injury, anatomical and
neuro-chemical changes can occur within the central
nervous system (CNS) that can persist long after the
injury has healed.13 This "CNS plasticity"
may play an important role in the evolution of
chronic, neuropathic pain. As is the case in the
periphery, sensitization of neurons can occur within
the dorsal horn following peripheral tissue damage
and this is characterized by an increased
spontaneous activity of the dorsal horn neurons, a
decreased threshold and an increased responsivity to
afferent input, and cell death in the spinal dorsal
horn.14,15,16,17 In the non-injured state, A beta
fibers (large myelinated afferents) penetrate the
dorsal horn, travel ventrally, and terminate in
lamina III and deeper. C fibers (small unmyelinated
afferents) penetrate directly and generally
terminate no deeper than lamina II. However, after
peripheral nerve injury there is a prominent
sprouting of large afferents dorsally from lamina
III into laminae I and II.20 After peripheral nerve
injury, these large afferents gain access to spinal
regions involved in transmitting high intensity,
noxious signals, instead of merely encoding low
threshold information.18
Significant
alterations have been shown in the dorsal horn
ipsilateral to the injury. The mechanisms are likely
related to the barrage of afferent impulses or the
factors transported from the lesion site.4,9,21
Studies have revealed that peripheral nerve injury
may lead to increased mRNA for specific
neurotransmitters (e.g. substance P), differential
temporal expression of mRNA and receptors,22
decreased levels of opiod binding sites,23,24,25
appearance of immediate early gene products (e.g.
c-fos),26,27 of which the significance is that
peripheral nerve injury is causing changes in the
cell's synthesis of products, and alterations in the
relative levels of neuropeptides/neuromodulators
(e.g. increased galanin and VIP and reductions in sP
and CGRP)4 .
Several
forms of thermal or tactile hyperalgesia may involve
the intercellular and intracellular messengers
nitric oxide and arachidonic acid and
metabolites.28,29,30 Cyclooxygenase inhibition
appears to suppress tactile allodynia.4 Blockade of
activation of protein kinase C has been shown to
prevent behavioral neuropathic manifestations.31,32
Protein kinase C removes the voltage gating of the
NMDA receptor, allowing activation of the receptor
by glutamate.4 Protein kinase C may also modulate
sodium channels.33
The
injured axon may release factors which may be
transported in a retrograde or orthograde fashion to
initiate changes important to the development of a
pain state.4,34 Thermal hyperalgesia has been
prevented in the Bennett model of nerve injury by
blocking axonal transport bidirectionally with
colchicine.2,35 It has been shown also that
colchicine blocks orthograde transport of
tachykinins which may explain its ability to induce
prolonged reductions in sciatic neurogenic
extravasation at concentrations that spare C-fiber
nociceptor function.34
Repetitive
noxious stimulation of unmyelinated C-fibers can
result in prolonged discharge of dorsal horn cells.
This phenomenon which is termed "wind-up",
is a progressive increase in the number of action
potentials elicited per stimulus that occurs in
dorsal horn neurons.36 Repetitive episodes of
"wind-up" may precipitate long-term
potentiation (LTP), which involves a long lasting
increase in the efficacy of synaptic transmission.
Where "wind-up" is thought to last only
minutes, LTP by definition, lasts at least one hour
and maybe even months. Both "wind-up" and
LTP are believed to be part of the sensitization
process involved in many chronic pain states.
Animal
studies suggest that expansion of receptive fields
may also occur following tissue injury. Therefore,
any peripheral stimulation would activate a greater
number of dorsal horn cells because of an increased
overlap of their receptive fields.
Evidence
suggests that excessive nociceptive input to the
dorsal horn can have excitotoxic consequences
resulting in the death of inhibitory interneurons.
This inhibition may contribute to spinal
hyper-excitability.
The
allodynia and hyperalgesia associated with
neuropathic pain may be best explained by: 1) the
development of spontaneous activity of afferent
input 2) the sprouting of large primary efferents
(eg. A-beta fibers from lamina 3 into lamina 1 and
2), 3) sprouting of sympathetic efferents into
neuromas and dorsal root and ganglion cells, 4)
elimination of intrinsic modulatory systems and 5)
up regulation of receptors in the dorsal horn which
mediate excitatory processes.
Recent
animal studies have shown that dynamic and static
hyperalgesia are probably mediated by different
mechanisms,37 tactile allodynia and hyperalgesia are
likely mediated by different mechanisms38,39 and
repetitive thermal and mechanical stimuli are likely
processed in different ways40,41 .
On
a cellular level, the central nervous system plastic
changes appear to be associated with enhanced
neurotransmission via the NMDA receptor. Under the
appropriate conditions, appropriate C-fiber
stimulation can activate dorsal horn inter-neurons,
causing them to release excitatory amino acids (eg.
aspartate and glutamate), which will excite wide
dynamic range (WDR) neurons via the NMDA receptor.
Hanai found that the C fiber response to stimulation
of the superficial peroneal nerve consisted of three
components: early, middle, and late.42 The
separation into three components was found to be
caused by asynchronous volleys in three different
classes of C fibers in the superficial peroneal
nerve.42 The phenomenon of wind up was observed to
occur always in the late component, frequently in
the middle component and to a far lesser extent in
the early component.42 The NMDA antagonist, MK801
significantly suppressed the middle and late
components of the C fiber response, although the
effect on the early component was insignificant.42
NMDA receptor activation triggers a cascade of
events leading to sensitization of dorsal horn wide
dynamic range neurons then ensues. There is a
significant increase in intracellular calcium and
activation of protein kinases and phophorylating
enzymes. NMDA receptor stimulation will also
increase the production of spinal phospholipase and
induce the production of nitric oxide synthetase.
The prostaglandins and nitric oxide which are
subsequently produced and released into the
extracellular milieu can facilitate further release
of excitatory amino acids and neuropeptides from
primary afferent pain fibers. The NMDA receptor
antagonists ketamine and dextromethorphan can block
this cascade of events which contribute to
sensitization.
MANAGEMENT
OF NEUROPATHIC PAIN
Early
recognition and aggressive management of neuropathic
pain is critical to successful outcome. Oftentimes,
multiple treatment modalities are provided by an
interdisciplinary management team. Numerous
treatment modalities are available and include
systemic medication, physical modalities (eg.
physical rehabilitation), psychological modalities
(eg. behavior modification, relaxation training),
invasive procedures (eg. trigger-point injections,
epidural steroids, sympathetic blocks), spinal cord
stimulators, intrathecal morphine pump systems and
various surgical techniques (eg. dorsal root entry
zone lesions, cordotomy and sympathectomy). It
should be noted that caution is warranted regarding
the use of neuroablative techniques. Such approaches
may produce deaffrentation and exacerbate the
underlying neuropathic mechanisms. The focus of this
review will be on pharmacological interventions.
As
previously mentioned, most neuropathic pain responds
poorly to NSAIDS and opioid analgesics. The mainstay
of treatment are predominantly the tricyclic
antidepressants (TCA's), the anticonvulsants and the
systemic local anesthetics. Other pharmacological
agents that have proven efficacious include the
corticosteroids, topical therapy with substance P
depletors, autonomic drugs and NMDA receptor
antagonists.
The
TCA's have been successfully used for the treatment
of neuropathic pain for some 25 years. The mechanism
of action for the alleviation of neuropathic pain is
thought to be due to the inhibition of re-uptake of
serotonin and norepinephrine within the dorsal
horn,49 however, other possible mechanisms of action
include alpha-adrenergic blockade, sodium channel
effects and NMDA receptor antagonism.
Amitriptyline
is the prototypical tertiary amine. Other tertiary
amines include imipramine, doxepine, clomipramine
and trimipramine. Unlike the dosing regimen utilized
for the treatment of depression doses of TCA's for
treatment of neuropathic pain are considerably less.
The typical dosing schedule for amitriptyline may be
simply 10 mg orally at bedtime with a gradual
escalation every three days, in 10 mg increments, to
a maximum to 30 to 50 mg orally at bedtime.
Furthermore, the onset analgesia usually occurs over
several days versus the two weeks that are required
for the onset of the antidepressant effects of the
drugs.
The
side effect profile of the TCA's include sedation
and anticholinergic effects. Since these side
effects are more prominent with the tertiary amines
prudence would dictate the use of a secondary amine
such as nortriptyline or desipramine, particularly
in the elderly population who are more sensitive to
the side effects.
The
recently introduced selective serotonin reuptake
inhibitors (SSRI's) have not proven to be as
effective against neuropathic pain as anticipated.
Fluoxetine (Prozac) only appears to relieve pain in
patients with co-morbid depression. Paroxetine
(Paxil) has found some utility in the treatment of
chronic, daily headaches. In general, the SSRI's are
partially effective in the treatment of diabetic
neuropathy, but not to the extent of the TCA's.
Venlafaxine (Effexor) may have some analgesic
effects since, like the TCA's, it inhibits the
reuptake of both serotonin and norepinephrine. Its
side effect profile is similar to the other SSRI's
and can include agitation, insomnia, or somnolence,
gastrointestinal distress and inhibition of sexual
functioning. Anticholinergic side effects are less
bothersome than with the TCA's.
The
anti-convulsant medications can be particularly
effective treatment for neuropathic pain that is
described as burning and lancinating in nature.
Commonly used medications in this category include
phenytoin, carbamazepine, valproic acid, clonazepam,
and gabapentin.
Carbamazepine
has proven to be particularly effective against
glossopharyngeal neuralgia, post herpetic neuralgia,
trigeminal neuralgia, and diabetic neuropathies.
Should carbamazepine prove ineffective, it can be
replaced with phenytoin. Unlike the other
anticonvulsants, valproic acid has found some
success in treating migraine headaches. The
combination of an anticonvulsant with a TCA can be
synergistic.
The
mechanism of action of the anticonvulsant
medications is thought to involve membrane
stabilization. Evidence also suggests that some of
the agents, such as carbamazepine and phenytoin can
depress both segmental and descending excitatory
pathways in the CNS and at the same time facilitate
inhibitory mechanisms. For example, carbamazepine
has been shown to inhibit the electrical C and A
fiber evoked neuronal responses of spinal nerve
ligated rats.50 Valproic acid, on the other hand,
has been reported to increase gamma-amino butyric
acid (GABA) levels in the substantia nigra and
corpus striatum. Gabapentin, which we will be
discussing subsequently, reportedly increases
extracellular GABA levels throughout the brain,
including the thalamus and causes the release of
GABA from glial cells. However it is unlikely that
Gabapentin increases GABAergic tone because neither
GABAa nor GABAb antagonists reverse the analgesic
effects of Gabapentin.48
Because
of the significant risks of the blood dyscrasias and
liver dysfunction, baseline and periodic monitoring
of blood chemistries and liver function tests are
highly recommended when prescribing phenytoin,
carbamazepine, or valproic acid.
Although
clonazepam, a benzodiazepine, is usually used for
the treatment of petite mal and myoclonic seizures,
it has been successfully utilized to treat the
lancinating and pain associated with phantom limb
pain.51 Its mechanism of action may be associated
with its reputed ability to enhance the inhibitory
action of GABA within the CNS, and also possibly
secondary to increased serotonin levels.
Gabapentin
(Neurontin), 1-(aminomethyl) cyclohexane-acetic
acid, is an anti-epileptic drug which was introduced
in 1993 and was originally approved for the
treatment of partial seizures with or without
secondary generalization. Recently, however, reports
have documented its efficacy in the treatment of
various neuropathic pain states such as complex
regional pain syndrome, deafferentation neuropathy
of the face, postherpetic neuralgia, sciatic type
pain, and HIV-related neuropathy.52 The effective
dose range is 30-300 mg/kg (systemic) and >37.5
mg/kg (IT).48 Gabapentin is reportedly completely
ineffective in altering threshold responses to acute
nociceptive stimuli at doses up to 300 mg/kg.53-56
Presently the mechanism of action as either an
anticonvulsant or an analgesic is unknown. The
antinociceptive effects are likely to be due to
actions within the spinal cord, because 1000 times
the IT dose is required to produce equianalgesic
effects when given intraperitoneally .53,57
Gabapentin binds to the alpha 2 delta calcium
channel subunit .48 However, the relationship
between binding at this site and the analgesic
properties of gabapentin have not been determined.
The NMDA receptor complex may be a potential spinal
locus for neuropathic pain relief , but it has not
been conclusively found that this is the major site
of action.48 Gabapentin has a relatively benign side
effect profile and is well tolerated if dosing
proceeds in a gradually escalating manner. It has
few if any drug interactions and is primarily
renally excreted. Although expensive, it does not
require the routine monitoring of blood chemistries
and liver functions tests like carbamazepine and
phenytoin. To date, little evidence suggests the
efficacy of felbamate or lamotrogine in the
treatment of neuropathic pain. Further investigation
is necessary.
The
systemic local anesthetics which are commercially
available include lidocaine, tocainide, and
mexiletine. The assumed mechanism of action to
effect analgesia is the acute blocking of sodium
channels. Phenytoin, carbamazepine and tricyclic
antidepressants also act as sodium channel blockers.
Following the use of the TCA's and anticonvulsants,
local anesthetics tend to be third line drugs.
Lidocaine has proven effective for noncancer
patients58 but not for those with cancer.59 In
cancer patients tumor involvement of nervi nervorum
with "nociceptive neuropathic pain" (as
discussed earlier) may represent a different
mechanism with variable response to therapy.9 The
predictive value of lidocaine in determining the
expected benefits of drugs such as mexilitene
remains important in allowing us to move more
efficiently through therapeutic trials. 9 Recent
studies have suggested that the duration and pattern
of spontaneous discharge is dependent on the level
and kinetics of Na+ slow channel inactivation.60
Slow inactivation of voltage-gated ion channels
could be major factors in the induction and
treatment of neuropathic pain.60 QX-314, a
positively charged lidocaine derivative which is
frequently assumed to be membrane impermeant, has
recently been shown to acutely block Na+ channels at
nerve injury sites in rats.61 We avoid the use of
tocainide because of unacceptable side effects which
include blood dyscrasis and pulmonary fibrosis.
Dosing of mexiletine is begun at 150 mg po qd and is
slowly escalated by 150 mg q 72 hours to a maximum
of 10 mg/kg/day as tolerated.62 The only absolute
contraindication to the use of mexiletine is
pre-existing second or third degree AV block or
known allergy to the medication.
Autonomic
drugs which are proven beneficial in the treatment
of neuropathic pain include the alpha-2 agonists
(eg. Clonidine) and alpha-1 antagonists (eg.
prazosin, terazosin). The role of the _ 2 adrenergic
system in neuropathic pain has been studied using
various pharmacologic interventions and animal
models.63 In animal studies, alpha 2 adrenergic
agonists produce analgesia by actions in the
periphery, supraspinal CNS, and in the spinal
cord.64 Spaulding et al studies in mice suggested a
primary spinal site of action.65 Clonidine is
believed to produce analgesia at the spinal level in
part through stimulation of cholinergic interneurons
in the spinal cord. This cholinergic mediation of
analgesia, as reflected by CSF acetylcholine
concentration is activated by intrathecal, but not
IV, injection of clonidine .66 However, clonidine
has been shown to produce analgesia to experimental
pain stumuli after systemic67 and epidural68
injection. Yet, clinical studies of systemic
clonidine for analgesia have yielded conflicting
results.64 Alpha 2 adrenergic agonists produce
sedation and reduced blood pressure in addition to
analgesia small doses (ie 50 mg) clonidine may
reduce blood pressure more after an intrathecal than
IV injection.64 Clonidine has also been shown to
potentiate the neuropathic pain relieving action of
NMDA antagonist MK-801 while preventing its
neurotoxic and hyperactivity side effects.69
Clonidine is available in several different dosage
forms and can be administered orally,
transdermally70 or spinally. Conversely, systemic
Dexmedetomidine, another alpha 2 adrenergic agonist,
has been shown neither to prevent nor attenuate
neuropathic pain behavior in rats.63 Dexmedetomidine
has affinity to all three alpha 2- adrenergic
subtypes.71 The role of the different subtypes of
alpha 2 adrenoreceptors is unclear.
Subtype-selective alpha 2-adrenergic agonists are
needed for further studies.
Several
other pharmacological treatments which have proven
beneficial in the treatment of neuropathic pain
include the corticosteroids, and capsaicin cream.
Corticosteroids are believed to provide long-term
pain relief because of their ability to inhibit the
production of phospholipase-A-2 and through membrane
stabilizing effects, hence their utility for
epidural steroid injections.1 Topical capsaicin
cream (Zostrix, 0.025% and 0.075%) is a substance P
depletor, and has on occasion provided relief for
both acute herpetic neuralgia (shingles) and
post-herpetic neuralgia. Capsaicin is known for its
selectivity for and effect on C-fiber nociceptors
and heat receptors.72 Studies have shown its ability
to trigger membrane depolarization and to open non
selective cation channels,73 which may be either
reversible or lytic. Capsaicin is theorized to cause
a neurotoxic cellular degeneration of primary
afferent nociceptors.74 Basically, exposure to
capsaicin results in activation, desensitization,
and under certain conditions, the destruction of
lightly myelinated or unmyelinated primary afferent
fibers.75 A recent preliminary study proposes a
clinical role for topical capsaicin at doses of
5%-10% in patients with intractable pain.72 A recent
animal study suggests that an orally bioavailable
capsaicin analogue, civamide
(cis-8-methyl-N-vanillyl-6-nonenamide) possessed
analgesic activity with respect to several noxious
stimuli, including nerve injury-induced tactile
allodynia.39 Compliance may be a problem with this
medication, since it needs to be applied 4-5 times a
day for several weeks before any significant benefit
is appreciated and it has intense initial burning
effects.76 A recent study demonstrated that if
famciclovior (Famvir) is administered within 72
hours of the onset of the vesicles of shingles then
damage to peripheral nerves can be minimized and
therefore, the subsequent pain of post-herpetic
neuralgia attenuated.77 The dose of famciclovior is
500 mg orally, three times a day for seven days.77
If
a chronic neuropathic pain condition is already well
established, treatment is more difficult.
Sensitization (eg. "wind-up") is presumed
to have already occurred, so the ideal medication
would include an NMDA receptor antagonist. Two
agents are currently available. Ketamine is an
injectable anesthetic that non-competitively
antagonizes NMDA receptors.78 Although it has proven
beneficial in the treatment of neuropathic pain,
side effects tend to be unacceptable.79 NMDA
receptor antagonists are known to induce
psychomimetic reactions in adult humans and induce
behavioral disturbances such as learning and memory
impairments, sensorimotor disturbances,
stereotypical behavior and hyperactivity and
pathomorphological changes in neurons of the
posterior cingulate/retrosplenial (PC/RS) cortex of
the adult rat.69 Recent animal studies have reported
that preemptive intrathecal ketamine delayed
mechanical hyperalgesia but did not prevent it.41
Also, a case report suggests that epidural
administration of a "very low dose" of
Ketamine is sufficient to block activated NMDA
receptors and is an effective choice for the
management of neuropathic pain without undesirable
side effects.80 We occasionally will prescribe
dextromethorphan, a readily available
over-the-counter antitussive, to supplement the
medication regimen of some of our patients with
neuropathic pain. Like Ketamine, it is a
non-competitive antagonist at the NMDA receptor.
However in humans, doses may be so high that
unacceptable side effects occur. MK801, an
antagonist for the N-methyl-D-aspartate receptor for
glutamate, has been shown to reverse mechanical
hyperalgesia in streptozotocin/diabetic rats81 and
conversely to have no effect on tactile allodynia in
nerve-injured rats.82 Amantadine, an antiviral and
anti Parkinsonian agent, was shown to act as a
non-competitive NMDA antagonist.83 Unlike other NMDA
antagonists amantadine is clinically available for
chronic use in humans and its level of toxicity is
low. Case reports84 and a preliminary double blind,
controlled trial85 show that acute administration of
amantadine significantly reduces surgical
neuropathic pain in cancer patients. Investigational
NMDA receptor antagonists are currently undergoing
clinical trials.
Activation
of NMDA receptors leads to calcium entry into the
cell and initiates a series of central
sensitization. This sensitization may be blocked not
only with NMDA receptor antagonists, but also with
calcium channel blockers that prevent Ca2+ entry
into cells. A double blind study revealed that
epidural verapamil and bupivacaine reduced the
amount of self administered post op analgesic versus
epidural bupivacaine alone. The authors suggest that
epidural verapamil may prevent central sensitization
by surgical trauma.86
Clinical
experience with the use of opioids for chronic
non-malignant pain which is neuropathic in character
suggests that there may be a sub-population of
chronic pain patients who may clearly benefit from
maintenance with opioid analgesics.87 Many studies
have shown that neuropathic pain is only slightly
responsive or not responsive at all to opioid
treatments.88 Yet others have shown that neuropathic
pain responds to high doses of opioids.89-91
Portenoy has stated that opioid responsiveness is
partly a matter of dosage and that satisfactory
outcomes can be obtained following dose escalation
to an endpoint determined by either adequate
analgesia or intolerable side effects. Benedetti et
al suggest that postop neuropathic pair responds to
opioid, opioid responsiveness of neuropathic pain is
partly a matter of dosage and higher doses of
opioids that are necessary to relieve neuropathic
pain may be not a characteristic of neuropathic pain
per se but a general feature related to the
individual.88 A randomized double-blind
active-placebo-controlled crossover trial suggested
that fentanyl may relieve non-cancer neurapathic
pain by its intrinsic analgesic effect.92 The
indiscriminate prescribing of chronic opioids,
seductive hypnotics and muscle relaxants, however,
is without justification, especially if patients are
not experiencing decreased pain and increased
function.
Agents
that may soon be available for the treatment of
neuropathic pain include: 1)
butyl-para-aminobensoate (Butamben®), an ester
local anesthetic, 2) bupivacaine microspheres,and 3)
SNX-III, a selective calcium channel blocker.
Nicotinic acetylcholine receptor agonists such as
ABT-594, which may also prove efficacious, are in
preliminary research stages. Animal studies have
revealed the following as potential therapies in
neuropathic pain 1) electroconvulsive treatment93 2)
intrathecal injection of chromaffin cells94-96 3)
inrathecal injection of Nitric oxide synthase
inhibitor L-N--G-nitro arginine methyl ester
(L-NAME)97 4) intrathecal neostigmine.98 A
clinically available agent which is currently being
investigated for the treatment of neuropathic pain
is levodopa.99
CONCLUSION:
Clearly,
numerous pharmacological agents are available for
the treatment of neuropathic pain. The definitive
drug therapy has however remained elusive.
Oftentimes triple drug therapy with tricyclic
antidepressants, anti-convulsants and a systemic
local anesthetic is necessary. Occasionally, there
is the patient who requires chronic opioid therapy
in conjunction with the above medications. When
patients fail systemic treatments implantable
systems, such as a spinal cord stimulator, or
intrathecal morphine pumps are available. Recently,
the spinal cord stimulator has been shown to
attenuate the augmented dorsal horn release of
excitatory amino acids via a GABAergic mechanism in
rats.100 Rarely, surgical intervention is required.
Copyright
© 2000, Steven Richeimer, MD.
You may reach The Richeimer Pain Institute at www.helpforpain.com
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