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 Ab 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:
Treatment of Painful Peripheral Neuropathies