|
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.
Terminology
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 ways.40,41
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. All rights reserved. Used
by permission. You may reach The Richeimer Pain Institute at www.helpforpain.com
Continue this article...
|
