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Peripheral neuropathy
Classification and external resources
ICD-10 G64., G90.0
ICD-9 356
DiseasesDB 9850
MeSH D010523

Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system,[1] which may be caused either by diseases of the nerve or from the side-effects of systemic illness.

The four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy. The most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs. The form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, i.e., large fiber or small fiber peripheral neuropathy. Frequently the cause of a neuropathy cannot be identified and it is designated idiopathic.

Neuropathy may be associated with varying combinations of weakness, autonomic changes and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle may be seen. Sensory symptoms encompass loss of sensation and "positive" phenomena including pain. Symptoms depend on the type of nerves affected; motor, sensory, autonomic, and where the nerves are located in the body. One or more types of nerves may be affected. Common symptoms associated with damage to the motor nerve are muscle weakness, cramps, and spasms. Loss of balance and coordination may also occur. Damage to the sensory nerve can produce tingling, numbness, and pain. Pain associated with this nerve is described in various ways such as the following: sensation of wearing an invisible "glove" or "sock", burning, freezing, or electric-like, extreme sensitivity to touch. The autonomic nerve damage causes problems with involuntary functions leading to symptoms such as abnormal blood pressure and heart rate, reduced ability to perspire, constipation, bladder dysfunction (e.g., incontinence), and sexual dysfunction.[2]



The causes are broadly grouped as follows:

Many of the diseases of the peripheral nervous system may present similarly to muscle problems (myopathies), and so it is important to develop approaches for assessing sensory and motor disturbances in patients so that a physician may make an accurate diagnosis.

Types by pattern of nerve involvement


Mononeuropathy is a type of neuropathy that only affects a single nerve.[8] It is diagnostically useful to distinguish them from polyneuropathies, because the limitation in scope makes it more likely that the cause is a localized trauma or infection.

The commonest cause of mononeuropathy is by physical compression of the nerve, known as compression neuropathy. Carpal tunnel syndrome is one example of this. The "pins-and-needles" sensation of one's "foot falling asleep" (paresthesia) is caused by a compression mononeuropathy, albeit a temporary one which can be resolved merely by moving around and adjusting to a more appropriate position. Direct injury to a nerve, interruption of its blood supply (ischemia), or inflammation can also cause mononeuropathy.

Mononeuritis multiplex

Mononeuritis multiplex, or mononeuropathy multiplex, is the clinical result of damage to several different nerves, either serially or concurrently.

Mononeuritis multiplex typically presents with acute or subacute loss of sensory and motor function of individual peripheral nerves. The pattern of involvement is asymmetric.

Mononeuritis multiplex may also cause pain, which is characterized as deep, aching pain that is worse at night, is frequently in the lower back, hip, or leg. In people with diabetes mellitus, mononeuritis multiplex is typically encountered as acute, unilateral, severe thigh pain followed by anterior muscle weakness and loss of knee reflex.

Electrodiagnostic studies will show multifocal sensory motor axonal neuropathy.

It is caused by, or associated with, several medical conditions:


Polyneuropathy is a pattern of nerve damage which is quite different from mononeuropathy. The term "peripheral neuropathy" is sometimes used loosely to refer to polyneuropathy. In a polyneuropathy, many nerve cells in different parts of the body are affected, without regard to the nerve through which they pass. Not all nerve cells are affected in any particular case. In one common pattern (distal axonopathy), the cell bodies of neurons remain intact, but the axons are affected in proportion to their length. Diabetic neuropathy is the most common cause of this pattern. In demyelinating polyneuropathies, the myelin sheath around axons is damaged, which affects the ability of the axons to conduct electrical impulses. The third and least common pattern affects the cell bodies of neurones directly. This usually picks out either the motor neurones (known as motor neurone disease), or the sensory neurones (known as sensory neuronopathy or dorsal root ganglionopathy).

The effect of this is to cause symptoms in more than one part of the body, often on left and right sides symmetrically. As for any neuropathy, the chief symptoms include weakness or clumsiness of movement (motor); unusual or unpleasant sensations such as tingling or burning, reduction in the ability to feel texture, temperature etc., and impaired balance when standing or walking (sensory). In many polyneuropathies, these symptoms occur first and most severely in the feet. Autonomic symptoms may also occur, such as dizziness on standing up, erectile dysfunction and difficulty controlling urination.

Polyneuropathies are usually caused by processes that affect the body as a whole. Diabetes (or impaired glucose tolerance) is the most common cause. Other causes relate to the particular type of polyneuropathy, and there are many different causes of each type, including inflammatory diseases, vitamin deficiencies, blood disorders, and toxins (including alcohol and certain prescribed drugs). Most types of polyneuropathy progress fairly slowly, over months or years, but rapidly progressive polyneuropathy also occurs. Sometimes this has an identifiable cause; when it does not it is often referred to as Guillain–Barré syndrome. It is important to recognize that glucose levels in the blood can spike to nerve-damaging levels after eating even though fasting blood sugar levels and average blood glucose levels can still remain below normal levels (currently typically considered below 100 for FBP, Fasting Blood Plasma, and 6.0 for HGBA1c, hemoglobin A1C the test commonly used to measure average blood glucose levels over an extended period). Studies have shown that many of the cases of peripheral small fiber neuropathy with typical symptoms of tingling, pain and loss of sensation in the feet and hands are due to glucose intolerance prior to a diagnosis of diabetes or pre-diabetes. Such damage is often reversible, particularly in the early stages, with diet, exercise and weight loss. 17

The treatment of polyneuropathies is aimed firstly at eliminating or controlling the cause, secondly at maintaining muscle strength and physical function, and thirdly at controlling symptoms such as neuropathic pain.

Other classifications

Peripheral neuropathy may also be classified according to the type of nerve cell affected (motor, sensory, autonomic), or the process affecting the nerves (e.g. inflammation in neuritis).

Autonomic neuropathy

Autonomic neuropathy is a form of polyneuropathy which affects the non-voluntary, non-sensory nervous system (i.e. the autonomic nervous system) affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen and pelvis outside spinal cord, however they have connections with the spinal cord and ultimately the brain. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most but not all cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy.

Autonomic neuropathy is one cause of malfunction of the autonomic nervous system, but not the only one; some conditions affecting the brain or spinal cord can also cause autonomic dysfunction, such as multiple system atrophy, and therefore cause similar symptoms to autonomic neuropathy.

The signs and symptoms of autonomic neuropathy include the following:


Neuritis is a general term for inflammation of a nerve[9] or the general inflammation of the peripheral nervous system. Symptoms depend on the nerves involved, but may include pain, paresthesia, paresis, hypoesthesia (numbness), anesthesia, paralysis, wasting, and disappearance of the reflexes. Causes include:

  • Underlying conditions causing localized neuritis (affecting a single nerve):

Types of neuritis include:

Signs and symptoms

Those with diseases or dysfunctions of their peripheral nerves can present with problems in any of the normal peripheral nerve functions.

In terms of sensory function, there are commonly loss of function (negative) symptoms, which include numbness, tremor, and gait imbalance.

Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins and needles. Pain can become intense enough to require use of opioid (narcotic) drugs (i.e., morphine, oxycodone).

Skin can become so hypersensitive that patients are prohibited from having anything touch certain parts of their body, especially the feet. People with this degree of sensitivity cannot have a bedsheet touch their feet or wear socks or shoes, and eventually become housebound.

Motor symptoms include loss of function (negative) symptoms of weakness, tiredness, heaviness, and gait abnormalities; and gain of function (positive) symptoms of cramps, tremor, and fasciculations.

There is also pain in the muscles (myalgia), cramps, etc., and there may also be autonomic dysfunction.

During physical examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, though those with a pathology (problem) of the peripheral nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies like Guillain–Barré syndrome); or may show focal sensory disturbance or weakness, such as in mononeuropathies. Ankle jerk reflex is classically absent in peripheral neuropathy.


Many treatment strategies for peripheral neuropathy are symptomatic. Some current research in animal models has shown that neurotrophin-3 can oppose the demyelination present in some peripheral neuropathies.[10]

A range of drugs that act on the central nervous system such as drugs originally intended as antidepressants and antiepileptic drugs have been found to be useful in managing neuropathic pain. Commonly used treatments include using a Tricyclic antidepressant (such as amitriptyline) and antiepileptic therapies such as gabapentin or sodium valproate. These have the advantage that besides being effective in many cases they are relatively low cost.

A great deal of research has been done between 2005 and 2010 which indicates that synthetic cannabinoids and inhaled cannabis are effective treatments fo a range of neuropathic disorders. [11] Research has demonstrated that the synthetic oral cannabinoid Nabilone is an effective adjunct treatment option for neuropathic conditions, especially for people who are resistant, tolerant, or allergic to common medications.[12] Orally, opiate derivatives were found to be more effective than cannabis for most people.[13] Smoked cannabis has been found to provide relief from HIV-associated sensory neuropathy. [14] Smoked cannabis was also found to relieve neuropathy associated with CRPS type I, spinal chord injury, peripheral neuropathy, and nerve injury. [15]

Pregabalin (INN) (pronounced /prɨˈgæbəlɨn/) is an anticonvulsant drug used for neuropathic pain. It has also been found effective for generalized anxiety disorder. It was designed as a more potent successor to gabapentin but is significantly more expensive, especially now the patent on gabapentin has expired and gabapentin is available as a generic drug. Pregabalin is marketed by Pfizer under the trade name Lyrica.

As noted above in the section on Polyneuropathies and their causes, symmetric small fiber neuropathy, commonly called peripheral neuropathy, can often be reversed, particularly in the early stages before a diagnosis of diabetes or pre-diabetes with diet, exercise and weight loss. It is also suggested that, because alcohol is a neurotoxin, even individuals with neuropathies from causes other than alcoholism may benefit from limiting or eliminating their alcohol intake.

TENS (Transcutaneous Electrical Nerve Stimulation) can be an effective in some cases as a non-pharmacological treatment and is free from adverse effects. It is believed to work via stimulating large afferent fibers, which in turn leads to an inhibition of small pain afferent fibers.[16]


  1. ^ "Peripheral Neuropathy Fact Sheet: National Institute of Neurological Disorders and Stroke (NINDS)". Retrieved 2008-11-30. 
  2. ^
  3. ^ Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ (1997). "Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies". Neurology 49 (6): 1635–40. PMID 9409359. 
  4. ^ Kiziltan ME, Akalin MA, Sahin R, Uluduz D (2007). "Peripheral neuropathy in patients with diabetes mellitus presenting as Bell's palsy". Neuroscience Letters 427: 138. doi:10.1016/j.neulet.2007.09.029. PMID 17933462. 
  5. ^ Cohen JS (December 2001). "Peripheral Neuropathy Associated with Fluoroquinolones" (PDF). Ann Pharmacother 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615. 
  6. ^ Gonzalez-Duarte A, Cikurel K, Simpson DM (2007). "Managing HIV peripheral neuropathy". Current HIV/AIDS reports 4 (3): 114–8. doi:10.1007/s11904-007-0017-6. PMID 17883996. 
  7. ^ Wilkes G (2007). "Peripheral neuropathy related to chemotherapy". Seminars in oncology nursing 23 (3): 162–73. doi:10.1016/j.soncn.2007.05.001. PMID 17693343. 
  8. ^ "Dorlands Medical Dictionary:mononeuropathy". 
  9. ^ neuritis at Dorland's Medical Dictionary
  10. ^ Liu N, Varma S, Tsao D, Shooter EM, Tolwani RJ (2007). "Depleting endogenous neurotrophin-3 enhances myelin formation in the Trembler-J mouse, a model of a peripheral neuropathy". J. Neurosci. Res. 85 (13): 2863–9. doi:10.1002/jnr.21388. PMID 17628499. 
  11. ^
  12. ^ Skrabek RQ, Galimova L, Ethans K, Perry D (2008). "Nabilone for the treatment of pain in fibromyalgia". J. Pain 9 (2): 164-73. 
  13. ^ Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D (2008). "Comparison of analgesic effects and patient toleration of nabilone and dihydrocodeine for chronic neuropathic pain: randomized, crossover, double blind study". BMJ 336 (7637): 119-201. 
  14. ^ Abrams DI, Jay CA, Shade SB, Vizozo H, Reda H, Press S, Kelly ME, Rowbotham Mc, Petersen KL (2007). "Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trail". J. Neurology 68 (7): 515-21. 
  15. ^ Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, Fishman S (2008). "A randomized, placebo-controlled, crossover trail of cannabis cigarettes in neuropathic pain". J. Pain 9 (6): 506-21. 
  16. ^ Ro, LS.; Chang, KH. (Sep 2005). "Neuropathic pain: mechanisms and treatments." (PDF). Chang Gung Med J 28 (9): 597-605. PMID 16323550. 

17. Latov, Norman; 'Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won't Stop; American Academy of Neurology Press Demos Medical Publishing; N.Y., N.Y.; 2007

External links

Classification and external resources
ICD-10 G56. - G63.,
G90.0, G99.0
ICD-9 337.0-337.1,
356-357, 377
eMedicine topic list

Neuropathy is a medical term referring to disorders of the nerves of the peripheral nervous system (specifically excluding encephalopathy and myelopathy, which pertain to the central nervous system.)[1] It is usually considered equivalent to peripheral neuropathy, which is defined as deranged function and structure of peripheral motor, sensory, and autonomic neurons, involving either the entire neuron or selected levels.[2] According to some sources, a disorder of the cranial nerves can be considered a neuropathy.[3]

Neuropathy should not be confused with neuropathology, which deals with the pathology (i.e. the study of disease and disease processes) of nervous tissue.



The four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy. The most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs.

A radiculopathy involves spinal nerve roots, but if peripheral nerves are also involved the term radiculoneuropathy is used.

The form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, i.e. large fiber or small fiber peripheral neuropathy. Frequently the cause of a neuropathy cannot be identified and it is designated idiopathic.

Neuropathy may be associated with varying combinations of weakness, autonomic changes and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle may be seen. Sensory symptoms encompass loss of sensation and "positive" phenomena including pain (for a more detailed discussion, see peripheral neuropathy).


Symptoms depend on the type of nerves affected; motor, sensory, autonomic, and where the nerves are located in the body. One or more types of nerves may be affected.

Common symptoms associated with damage to the motor nerve are muscle weakness, cramps, and spasms. Loss of balance and coordination may also occur. Damage to the sensory nerve can produce tingling, numbness, and pain. Pain associated with this nerve is described in various ways such as the following: sensation of wearing an invisible "glove" or "sock", burning, freezing, or electric-like, extreme sensitivity to touch.

The autonomic nerve damage results in affects in involuntary functions. Symptoms from this type of damage include abnormal blood pressure and heart rate, reduced ability to perspire, constipation, bladder dysfunction (e.g., incontinence), and sexual dysfunction.[4]

Neuropathic pain

According to the most widely accepted definition, neuropathic pain is "initiated or caused by a primary lesion or dysfunction in the nervous system."[5] Neuropathic pain cannot be explained by a single disease process or a single specific location of damage.

Neuropathic pain may be associated with abnormal sensations called dysesthesias which occur spontaneously and allodynias that occur in response to external stimuli. Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities of neuropathic pain includes burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain is more commonly described as aching.

As much as 7% to 8% of the of the population is affected and in 5% it may be severe.[6][7] Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.

Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia, a disorder of chronic widespread pain, is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain.[8]

Aside from diabetes (see Diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders.[9][10]

Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy[11] [12] , radiation injury or surgery.

Mechanisms of neuropathic pain

The starting point for neuropathic pain is a lesion or dysfunction within the somatosensory system. Current knowledge regarding the mechanisms of neuropathic pain is incomplete and is biased by a focus on animal models of peripheral nerve injury.

Peripheral Mechanisms

Under normal circumstances, pain sensations are carried by unmyelinated and thinly myelinated nerve fibers, designated C-fibers and A-delta fibers respectively. After a peripheral nerve lesion, a neuroma may develop at the stump. The neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and elevated sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization".

Central Mechanisms

The dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop an increased background activity, enlarged receptive field and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization has been proposed as an important mechanism of persistent neuropathic pain.

Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e loss of afferent inhibition. Nociceptive pain can be described as the one that can occur in our everyday life as an aftermath of a simple insult or injury. The mechanism for such type of pain can be generated by transduction, which converts the stimulus into electrical activity in specialized nociceptive primary afferent nerves. [13] Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”

Non-neural glial cells may play a role in central sensitization. Peripheral nerve injury induces glial to releasing glial proinflammatory cytokines and glutamate which, in turn influence neurons. [14]

Mechanisms at light-microscopic and submicroscopic levels

The phenomenon described above are dependent on changes at light-microscopic and submicroscopic levels. Aberrant regeneration, altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play. [15]

Treatments for neuropathic pain

Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.[16]

In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy.[17][18] These have combined evidence from randomized controlled trials with expert opinion.

Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.

It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.

Favored treatments are certain antidepressants e.g. tricyclics and selective serotonin-norepinephrine re-uptake inhibitors (SNRI's), anticonvulsants, especially pregabalin (Lyrica) and gabapentin (Neurontin), and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive receptors, or desensitize C fibers such that they transmit fewer signals.

Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.


The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the brain. Antidepressants will relieve neuropathic pain in non-depressed persons.

In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.[19][20][21][22][23][24][25][26] Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Compounds such as duloxetine, venlafaxine, and milnacipran that block both serotonin reuptake and norepinephrine reuptake do improve neuropathic pain.

Tricyclic antidepressants may also work on sodium channels in peripheral nerves.


Pregabalin (Lyrica) and gabapentin (Neurontin) work by blocking specific calcium channels on neurons. The actions of the anticonvulsants carbamazepine (Tegretol) and oxcarbazepine (Trileptal), especially effective on trigeminal neuralgia, are principally on sodium channels.

Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in that subgroup on antiretroviral therapy.[27]


Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.

Several opioids, particularly methadone have NMDA antagonist activity in addition to their µ-opioid agonist properties.

Methadone and ketobemidone possess NMDA antagonsism. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist.[28]

There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of NMDA antagonism. It is reasonable to base the choice of opioid on other factors.[29]

Topical agents

In some forms of neuropathy, especially post-herpes neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.

Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. [30] Nevertheless, benefits appear to be modest. [31]


Marijuana and its active ingredients are called cannabinoids. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult.[32] Similar considerations apply to opioids.

A recent study showed smoked marijuana is beneficial in treating symptoms of HIV-associated peripheral neuropathy.[33] Nabilone is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine.[34]

The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use.[35] A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.[36]

Sativex, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain.[37]

Long-term studies are needed to assess the probability of weight gain[38], unwanted psychological influences and other adverse effects.

Botulinum Toxin Type A (Botox, BTX-A)

Botulinum Toxin Type A (BTX-A) is best know by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration. [39]

The utility of BTX-A in other painful conditions remains to be established.[40]

NMDA antagonism

The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance.Dextromethorphan is an NMDA antagonist at high doses.Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance.[41] Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by unacceptable side effects.

Reducing sympathetic nervous stimulation

In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.

Lesioning operations on the sympathetic branch of the autonomic nervous system are sometimes carried out.

Dietary supplements

There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.[42]

A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.[43] While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia),[44] the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".[43] There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.[45]

Benfotiamine is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.[46][47]

Other modalities

In addition to pharmacological treatment several other modalities are commonly recommended.[48] While lacking adequate double blind trials, these have shown to reduce pain and improve patient quality of life for chronic neuropathic pain: chiropractic, yoga, massage, meditation, cognitive therapy,[49] and prescribed exercise. Some pain management specialists will try acupuncture, with variable results.

Transcutaneous electrical nerve stimulation (TENS) may be worth considering in chronic neurogenic pain. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.

Infrared photo therapy has been used to treat neuropathic symptoms.[50] However, recent work has cast doubt on the value of this approach.[51]


Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.[52]

Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.

Spinal cord stimulators and implanted spinal pumps

Spinal cord stimulators, use electrodes placed adjacent to, but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage. Lack of pain relief sometimes prompts device removal.[53]

Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide[54] are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted.

There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. [55] These results must be viewed skeptically since placebo effects cannot be evaluated.

Motor cortex stimulation

Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.[56][57]

Deep Brain Stimulation

The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%).[58] There is a significant complication rate which increase over time.[59]

See also


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  2. ^ Dyck PJ (1982). "Current concepts in neurology. The causes, classification, and treatment of peripheral neuropathy". N. Engl. J. Med. 307 (5): 283–6. PMID 6283352. 
  3. ^ "eMedicine/Stedman Medical Dictionary Lookup!". Retrieved on 2008-11-30. 
  4. ^
  5. ^ Bogduk, Nikolai; Merskey, Harold (1994). Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms (2nd edition ed.). Seattle: IASP Press. pp. 212. ISBN 0931092051. 
  6. ^ Torrance N, Smith BH, Bennett MI, Lee AJ (April 2006). "The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey". J Pain 7 (4): 281–9. doi:10.1016/j.jpain.2005.11.008. PMID 16618472. 
  7. ^ Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C (June 2008). "Prevalence of chronic pain with neuropathic characteristics in the general population". Pain 136 (3): 380–7. doi:10.1016/j.pain.2007.08.013. PMID 17888574. 
  8. ^ Dworkin RH, Fields HL (2005). "Fibromyalgia from the perspective of neuropathic pain". J Rheumatol Suppl 75: 1–5. PMID 16078355. 
  9. ^ Portenoy RK (1989). "Painful polyneuropathy". Neurol Clin 7 (2): 265–88. PMID 2566901. 
  10. ^ Vaillancourt PD, Langevin HM (1999). "Painful peripheral neuropathies". Med. Clin. North Am. 83 (3): 627–42, vi. doi:10.1016/S0025-7125(05)70127-9. PMID 10386118. 
  11. ^ [1] Chemotherapy-induced Peripheral Neuropathy Fact Sheet, Retrieved on 29-Dec-2008
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