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Treatment of
Painful Peripheral Neuropathies
Thomas H Brannagan III, MD
Peripheral Neuropathy Center
Weill Medical College of Cornell University
INTRODUCTION
Peripheral neuropathy is a common problem and for some patients, pain is a
disabling component of the neuropathy. The first goal in evaluating patients
with painful peripheral neuropathies is to identify the cause, with the hope of
identifying treatment to reverse nerve damage. There are a large number of
disorders that may be associated with a painful peripheral neuropathy. (Table 1)
When neuropathic pain is present, it is appropriate to treat this concurrently,
during the evaluation, as well as during the treatment of the neuropathy, if
identified is in process. For some types of neuropathy, there are no available
treatments for the underlying disorder, and therapy for neuropathic pain, if
present may be the only treatment available.
Pain can be classified broadly as two types. Nociceptive pain is protective and
is a normal response to tissue injury, serving to warn of the presence of
injury. There is also sensitization of peripheral nociceptors and central
nervous system changes, which protect the damaged area by avoiding contact.
Neuropathic pain is a pathologic or maladaptive pain, which results from damage
to the nervous system, producing pain in the absence of stimulation of
nociceptors or inappropriate response to stimulation of nociceptors. Nociceptive
and neuropathic pain are not synonymous with acute and chronic pain. For
instance, rheumatoid arthritis is a chronic pain, which is nociceptive pain. A
herniated disc can cause acute sciatic pain, which is neuropathic.
Patients with neuropathic pain typically describe burning, lancinating,
stabbing, cramping, aching and sometimes vice-like pain. It can be paroxysmal or
constant. On examination hyperalgesia, allodynia or hyperpathia are sometimes
elicited.
The normal pathways involved in the transmission of pain begin with stimulation
of nociceptors including those that respond to chemical irritant stimuli such as
VR1, DRASIC, P2X3 and noxious heat stimuli such as VR1 and VRL1. Signals
resulting from intense mechanical and thermal stimulate A delta fiber
nociceptors and intense mechanical ,thermal and chemical stimuli stimulate
polymodal C nociceptors. Afferent fibers synapse in Rexed’s lamina I, II and V
in the spinal cord, which is the first level of modulation. Opiate receptors and
interneurons are present at the dorsal horn. There are are also descending
inputs from the hypothalamus, periaqueductal gray. Opiods, norepineprhine and
serotonin have modulatory effects on pain transmission.
MECHANISMS OF NEUROPATHIC PAIN
Why certain neuropathies cause pain is unknown, but there has been increasing
knowledge about the mechanism of pain. The gate theory of pain proposed that the
substantia gelatinosa acted as a gate allowing pain transmission to proceed and
that the inhibitory affect of the substantia gelatinosa is increased by large
diameter fibers. Central descending influence was also postulated. Though
specifics of this theory have been shown to be incorrect, the basic premise of
central modification of pain perception at the dorsal horn and other parts of
the central nervous system is still held. Dyck et al, noted that neuropathic
pain was related to the rate and kind of nerve fiber degeneration. It is not
related simply to the ratio of remaining large and small nerve fibers. Brown et
al noted that unmyelinated and small myelinated fibers were most prominently
involved and unmyelinated nerve fiber sprouting was evident in painful diabetic
neuropathy.
Animal models of pain have added to the understanding of neuropathic pain. There
are 4 commonly used animal models, which include the chronic constrictive injury
(CCI) model, the partial nerve transection, spinal nerve transection model and
the spared nerve model. The chronic constrictive injury model is produced by a
loosely constrictive ligature around the sciatic nerve. Almost all of A-β fibers
die, as do the majority of Aδ fibers. A large percentage of C fibers persist.
The partial nerve transection model involves tightly ligating and transecting
1/3 to ½ of of the rat sciatic nerve. The spinal nerve transection model
involves tight ligation and transection of the L5 and L6 nerve roots. This
affects 50% of the sural and saphenous nerve fibers. The spared nerve model
involves a lesion of 2 of the 3 terminal branches of the sciatic nerve (tibial
and peroneal) intact, leaving the sural nerve intact. There is partial
deafferentation but not differential involvement of nerve fibers, in these three
models.
Heat hyperalgesia, mechano-hyperalgesia, mechano-allodynia and cold-allodynia
may be observed and behavioral changes consistent with spontaneous pain such as
limping and guarding the hind paw are seen. Both peripheral and central
mechanisms have been observed in animal models.
After nerve injury there are spontaneous discharges of nerve fibers, neuromas
and dorsal root ganglion. This has been seen in traumatic nerve injury models ,
as well as models of peripheral neuropathy from diabetes and heavy metal
intoxication. Increased expression of sodium channels are seen in neuroma’s in
humans and animal models. The density of sodium channel expression correlates
with the degree of pain. Changes in sodium channel expression are seen and may
contribute to nerve excitability and spontaneous pain..
These spontaneous discharges by themselves can cause pain, but they also have
additional affects. C fiber afferents trigger cell death of neurons in the
dorsal horn, where inhibitory interneurons are concentrated, possibly through an
excitotoxic mechanism. This may result in increased pain transmission.. C fiber
afferents release glutamate and synapse on 2nd order neurons and have excitatory
affects. Glutamate synapses at AMPA receptors which depolarizes the membrane.
This depolarization releases the inhibition of the NMDA receptor by the
magnesium ions and there is an influx of calcium. Second order neurons are
gradually depolarized and responses are amplified and this changes the response
of neurons to subsequent input.
Two processes that are distinct occur at the dorsal horn which are designated
“windup” and “central sensitization.” Windup up results from repetitive C fiber
firing at low frequencies that result in a progressive buildup of the amplitude
of the response of the dorsal horn neuron, only during the repetitive train.
Central sensitization is an abnormal sensitivity with a spread of
hypersensitivity to uninjured sites and pain resulting from stimulation of low
threshold A mechanoreceptors. Central sensitization follows a brief high
frequency input and the increased response to subsequent inputs is prolonged.
Both can be blocked by NMDA receptor antagonists. Central sensitization can
result from windup. This is a result of the calcium influx through the NMDA
receptor following depolarization of the dorsal horn membrane. The intracellular
calcium activated a number of kinases of which protein kinase C (PKC) is likely
important. PKC enhances the NMDA receptor , which results in subsequent
glutamate binding of the NMDA receptor generating an inward current. Though
windup can result in central sensitization it is not necessary for central
sensitization to occur.
Similar observations had previously been noted by Denny-Brown who described an
enlarged and hypersensitive dermatomal region in primates when severing the
surrounding nerve roots distal to the dorsal root ganglion compared with
severing proximal to the DRG. This suggested plasticity of the dorsal horn
neurons secondary to input from the DRG.
Nerve injury also results in sprouting of myelinated fibers into lamina II of
the dorsal horn, which under normal circumstances receives only C fiber input.
This may result in allodynia.
There is a genetic influence on the experience of neuropathic pain though it is
poorly delineated. There are variations on the expression of pain behaviors seen
in different strains of animals. A recent study noted that 56% of patients with
painful diabetic neuropathy had a relative with painful diabetic neuropathy
suggesting a genetic component.
The relative importance of these various mechanisms is not clearly known,
however there is potentially multiple sites for intervention in treating painful
neuropathies.
Medications
Tricyclic anti-depressants have been beneficial in controlled studies of
neuropathic pain. They block the reuptake of norepinephrine and serotonin and
are thought to modulate descending inhibitory pathways. There benefit with
neuropathic pain is independent of their effect on depression. Patients who are
not depressed can respond and lower doses than are used to treat depression are
effective to treat neuropathic pain. Tricyclic anti-depressants can block
voltage dependent sodium channels and this may contribute to their efficacy to
treat neuropathic pain. They are typically started at a dose of 10-25 mg at
night and titrated as tolerated up to a dose of 150 mg if necessary. Side
effects include dry mouth, cardiac arrhythmias, urinary retention and sexual
dysfunction. Venlafaxine has fewer side effects and has also been reported to
benefit neuropathy pain.
The selective serotinin reuptake inhibitors (SSRI) have been less effective for
treatment of neuropathic pain. Fluoxetine was not effective in clinical trials.
Paroxetine and Citalopram been reported to be effective.
Anticonvulsants have also been studied in neuropathic pain. Both phenytoin (Dilantin)
and carbamezapine (Tegretol) have been beneficial in trials of diabetic
neuropathy. They act as sodium channel blockers. Both medications have frequent
side effects that are well known.
Gapapentin (Neurontin), binding site alpha delta Ca channel. It is though to act
at a spinal site of action. Controlled studies in diabetic neuropathy,
post-herpetic neuralgia and other neuropathic pain states. Starting doses are
usually100mg tid or 300mg qhs. Unless the drug is not tolerated or a dose of 600
mg tid has been tried it should not be considered a treatment failure. Often
higher doses provide more benefit. Side effects include drowsiness, fogginess,
leg edema. Gabapentin is cleared by the kidneys and there are not significant
drug interactions. The dosing should be adjusted in renal insufficiency and
failure.
Lamotrigine (Lamictal) is a sodium channel blocker, which also inhibits
glutamate release. It has reduced cold allodynia in the CCI model. Lamotrigine
is effective in controlled studies in diabetic, HIV associated painful
neuropathy, post-herpetic neuralgia, and trigeminal neuralgia.. I’ve found
lamotrigine to cause less drowsiness or dizziness than most other medications
used for neuropathic pain and though these symptoms have been seen during
epilepsy trials, they were not seen more commonly than placebo in 2 recent
trials of neuropathy pain. Rash is a side effect and a Stevens Johnson syndrome
may occur. This is less frequent when the medication is titrated slowly. The
rash is less common with a slow titration. The following titration schedule has
been used for neuropathic pain: 25mg qd for 2 weeks, 25 mg bid for the next 2
weeks, 50 mg bid for the next 2 weeks, 100mg bid for 2 weeks. If the patient is
also taking valproate which inhibits the metabolism of lamotrigine, a dose of 25
mg qod is recommended as an initial dose.
Oxcarbazepine (Trileptal) is similar in structure to carbamezapine, but lacks
the 10,11 epoxide, which is thought to be responsible for better tolerability.
Autoinduction does not occur and rash and drug interactions are less frequent
than with carbamezapine. Hyponatremia does occur.
Double blind placebo controlled studies of mexilitine have been negative,
however subgroups with stabbing and burning pain had benefit. Another study
noted benefit in night time pain with the 675 mg dose, but not the lower doses
of 450 mg or 225 mg.
Topiramate (Topamax) showed benefit in animal models and preliminary studies and
anecdotal reports of diabetic neuropathy and neuropathic pain. Though the
results have not been published Johnson & Johnson announced that the results of
clinical trials in diabetic neuropathy pain were not positive (Reuter
9/18/2001).
Dextromorthorphan is a low affinity NMDA antigonist. It has been beneficial in
animal studies and painful neuropathies. Side effects are frequent and it is
poorly tolerated. Dextromethorphan in combination with other medications as well
as more selective NMDA receptor antagonists that may have less side effects are
being pursued.
Clonidine an alpha-2 agonist, as a transdermal patch was successfully used in a
subset of patients with painful diabetic neuropathy using an enrolled enrichment
design. Tizanidine, also an alpha-2 agonist, reduces thermal hyperalgesia in the
CCI rat model and has been successful in open label studies in neuropathic pain.
Tramodol (Ultram) has been effective in studies of painful diabetic neuropathy.
Side effects include nausea, headache, constipation, somnolence and seizures.
Lidoderm is beneficial for post-herpetic neuralgia. The dose of 1-3 patches for
12 hours, with 12 hours off the patch. It has been beneficial in other forms of
neuropathic pain.
Based on small preliminary and anecdotal series, as well as animal data, other
medications including zonisamide and levetiracetam may be beneficial.
HIV painful neuropathy is a particularly difficult syndrome to treat. Controlled
studies of amitriptyline, mexilitine, and acupuncture have been negative.
Gabapentin has been reported to be successful, though requiring higher doses.
Phenytoin and carbamezapine as P450 inducers should be avoided as they can
induce the metabolism of the protease inhibitors and make them ineffective.
Lamotrigine has been successful in blinded placebo controlled studies. Two
consecutive studies however provided conflicting data with the first suggesting
that there was no benefit above placebo in patients taking neurotoxic
dideoxynucleotide anti-retrovirals compared with those patient not taking
neurotoxic antiretrovirals and the second study showed the opposite. Since
several different mechanisms are involved in neuropathic pain, treatment
directed against the mechanism of pain would be desirable and has been proposed.
Unequivocally identifying mechanisms at work to date has been difficult in
patients. For instance the symptom of allodynia may occur from peripheral
sensitization or central sensitization. It is a commonly held belief that
tricyclic anti-depressants are more effective against burning pain and anti-convulsants
are more effective against paroxysmal stabbing pain. In clinical trials however
this has not been demonstrated.. Selective affects in animal models have been
demonstrated. For example dextrorphan reduces heat hyperalgesia, but has no
effect on mechanical allodynia in the CCI model. How this correlates to
treatment of people with neuropathic pain is still evolving. In the future
cocktails targeting different mechanisms at work in patients with peripheral
neuropathies may be possible.
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Table 1 Painful
peripheral neuropathies
Diabetes mellitus
HIV
Amyloidosis
Fabry’s disease
Celiac disease
Hereditary sensory neuropathy
Ideopathic
Toxic neuropathies
Dideoxynucleotide antiretrovirals
Antineoplastic agents (vincristine, taxol)
Isoniazid
Alcohol
Pyridoxine (B6)
Autoimmune
Anti-sulfatide antibody neuropathies
Neuropathy associated with monoclonal gammopathy
Sjogren’s disease
Lupus
Vasculitic neuropathy
Table 2 Potential
mechanisms of neuropathic pain
Sodium channel accumulation, redistribution, altered expression
Central sensitization
Peripheral sensitization
Α-receptor expression
Sympathetic sprouting
Increased transmission
Reduced inhibition
For original paper
see:
www.neuropathy.org/site/DocServer/Pain-ThomasBMD.doc?docID=1069
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