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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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