Peripheral neuropathy

Peripheral neuropathy may be classified according to the number and distribution of nerves affected (mononeuropathy, mononeuritis multiplex, or polyneuropathy), the type of nerve fiber predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (neuritis), compression (compression neuropathy), chemotherapy ([[chemother completion.{{Cite web|url=https://upoj.org/archive/volume-12-spring-1999/|title=Volume 12, Spring 1999 {{!}} University of Pennsylvania Orthopaedic Journal|language=en-US|access-date=2019-10-28}}

{{See also|Compression neuropathy|Ulnar neuropathy}}

Mononeuropathy is a type of neuropathy that only affects a single nerve.{{cite web |url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/five/000067367.htm |title=Dorlands Medical Dictionary:mononeuropathy }} Diagnostically, it is important to distinguish it from polyneuropathy because when a single nerve is affected, it is more likely to be due to localized trauma or infection.{{citation needed|date=July 2022}}

The most common cause of mononeuropathy is physical compression of the nerve, known as compression neuropathy. Carpal tunnel syndrome and axillary nerve palsy are examples. Direct injury to a nerve, interruption of its blood supply resulting in (ischemia), or inflammation also may cause mononeuropathy.{{citation needed|date=June 2022}}

{{Main|Polyneuropathy}}

"Polyneuropathy" is a pattern of nerve damage that is quite different from mononeuropathy, often more serious and affecting more areas of the body. The term "peripheral neuropathy" sometimes is used loosely to refer to polyneuropathy. In cases of polyneuropathy, many nerve cells in various 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 distal axonopathy, one common pattern is that the cell bodies of neurons remain intact, but the axons are affected in proportion to their length; the longest axons are the most affected. Diabetic neuropathy is the most common cause of this pattern. In demyelinating polyneuropathies, the myelin sheath around axons is damaged, which affects axons' ability to conduct electrical impulses. The third and least common pattern directly affects the cell bodies of neurons. This affects the sensory neurons (known as sensory neuronopathy or dorsal root ganglionopathy).{{cite journal |last1=Amato |first1=Anthony A. |last2=Ropper |first2=Allan H. |title=Sensory Ganglionopathy |journal=New England Journal of Medicine |date=22 October 2020 |volume=383 |issue=17 |pages=1657–1662 |doi=10.1056/NEJMra2023935|pmid=33085862 }}{{cite journal |last1=Gwathmey |first1=Kelly Graham |title=Sensory neuronopathies |journal=Muscle & Nerve |date=January 2016 |volume=53 |issue=1 |pages=8–19 |doi=10.1002/mus.24943|pmid=26467754 }}

The effect of this is to cause symptoms in more than one part of the body, often symmetrically on the left and right sides. As for any neuropathy, the chief symptoms include motor symptoms such as weakness or clumsiness of movement; and sensory symptoms such as unusual or unpleasant sensations such as tingling or burning; reduced ability to feel sensations such as texture or temperature, and impaired balance when standing or walking. In many polyneuropathies, these symptoms occur first and most severely in the feet. Autonomic symptoms also may occur, such as dizziness on standing up, erectile dysfunction, and difficulty controlling urination.{{citation needed|date=June 2022}}

Polyneuropathies usually are caused by processes that affect the body as a whole. Diabetes and impaired glucose tolerance are the most common causes. Hyperglycemia-induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy.{{cite journal | vauthors = Sugimoto K, Yasujima M, Yagihashi S | title = Role of advanced glycation end products in diabetic neuropathy | journal = Current Pharmaceutical Design | volume = 14 | issue = 10 | pages = 953–61 | year = 2008 | pmid = 18473845 | doi = 10.2174/138161208784139774 }} Other causes relate to the particular type of polyneuropathy, and there are many different causes of each type, including inflammatory diseases such as Lyme disease, 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. It is important to recognize that at one time it was thought that many of the cases of small fiber peripheral neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. However, in August 2015, the Mayo Clinic published a scientific study in the Journal of the Neurological Sciences showing "no significant increase in...symptoms...in the prediabetes group", and stated that "A search for alternate neuropathy causes is needed in patients with prediabetes."{{cite journal | vauthors = Kassardjian CD, Dyck PJ, Davies JL, Carter RE, Dyck PJ | title = Does prediabetes cause small fiber sensory polyneuropathy? Does it matter? | journal = Journal of the Neurological Sciences | volume = 355 | issue = 1–2 | pages = 196–8 | date = August 2015 | pmid = 26049659 | pmc = 4621009 | doi = 10.1016/j.jns.2015.05.026 }}

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.{{citation needed|date=June 2022}}

Mononeuritis multiplex, occasionally termed polyneuritis multiplex, is simultaneous or sequential involvement of individual noncontiguous nerve trunks,{{MedlinePlusEncyclopedia|000782|Multiple mononeuropathy}} either partially or completely, evolving over days to years and typically presenting with acute or subacute loss of sensory and motor function of individual nerves. The pattern of involvement is asymmetric. However, as the disease progresses, deficit(s) becomes more confluent and symmetrical, making it difficult to differentiate from polyneuropathy.{{cite web|last1=Ball|first1=Derick A. |title=Peripheral Neuropathy|url=http://www.neuravite.com/peripheral-neuropathy|publisher=NeuraVite|access-date=24 March 2016}} Therefore, attention to the pattern of early symptoms is important.

Mononeuritis multiplex is sometimes associated with a deep, aching pain that worsens at night and frequently in the lower back, hip, or leg. In people with diabetes mellitus, mononeuritis multiplex typically is encountered as acute, unilateral, and severe thigh pain followed by anterior muscle weakness and loss of knee reflex.{{medical citation needed|date=March 2016}}

Electrodiagnostic medicine studies will show multifocal sensory motor axonal neuropathy.{{citation needed|date=July 2022}}

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

{{columns-list|colwidth=30em|

• Diabetes mellitus
• Vasculitides: polyarteritis nodosa,{{cite journal | vauthors = Criado PR, Marques GF, Morita TC, de Carvalho JF | title = Epidemiological, clinical and laboratory profiles of cutaneous polyarteritis nodosa patients: Report of 22 cases and literature review | journal = Autoimmunity Reviews | volume = 15 | issue = 6 | pages = 558–63 | date = June 2016 | pmid = 26876385 | doi = 10.1016/j.autrev.2016.02.010 }}{{cite journal | vauthors = Samson M, Puéchal X, Devilliers H, Ribi C, Cohen P, Bienvenu B, Terrier B, Pagnoux C, Mouthon L, Guillevin L | title = Mononeuritis multiplex predicts the need for immunosuppressive or immunomodulatory drugs for EGPA, PAN and MPA patients without poor-prognosis factors | journal = Autoimmunity Reviews | volume = 13 | issue = 9 | pages = 945–53 | date = September 2014 | pmid = 25153486 | doi = 10.1016/j.autrev.2014.08.002 }} granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. This results in vasculitic neuropathy.
• Immune-mediated diseases, such as rheumatoid arthritis,{{cite journal | vauthors = Hellmann DB, Laing TJ, Petri M, Whiting-O'Keefe Q, Parry GJ | title = Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases | journal = Medicine | volume = 67 | issue = 3 | pages = 145–53 | date = May 1988 | pmid = 2835572 | doi = 10.1097/00005792-198805000-00001 | s2cid = 24059700 | doi-access = free }} systemic lupus erythematosus (SLE)
• Infections: leprosy, lyme disease, parvovirus B19,{{cite journal | vauthors = Lenglet T, Haroche J, Schnuriger A, Maisonobe T, Viala K, Michel Y, Chelbi F, Grabli D, Seror P, Garbarg-Chenon A, Amoura Z, Bouche P | title = Mononeuropathy multiplex associated with acute parvovirus B19 infection: characteristics, treatment and outcome | journal = Journal of Neurology | volume = 258 | issue = 7 | pages = 1321–6 | date = July 2011 | pmid = 21287183 | doi = 10.1007/s00415-011-5931-2 | s2cid = 8145505 }} HIV{{cite journal | vauthors = Kaku M, Simpson DM | title = HIV neuropathy | journal = Current Opinion in HIV and AIDS | volume = 9 | issue = 6 | pages = 521–6 | date = November 2014 | pmid = 25275705 | doi = 10.1097/COH.0000000000000103 | s2cid = 3023845 | doi-access = free }}
• Sarcoidosis{{cite journal | vauthors = Vargas DL, Stern BJ | title = Neurosarcoidosis: diagnosis and management | journal = Seminars in Respiratory and Critical Care Medicine | volume = 31 | issue = 4 | pages = 419–27 | date = August 2010 | pmid = 20665392 | doi = 10.1055/s-0030-1262210 | s2cid = 260321346 }}
• Cryoglobulinemia{{cite journal | vauthors = Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D | title = Cryoglobulinemia Vasculitis | journal = The American Journal of Medicine | volume = 128 | issue = 9 | pages = 950–5 | date = September 2015 | pmid = 25837517 | doi = 10.1016/j.amjmed.2015.02.017 | s2cid = 12560858 | url = https://hal.sorbonne-universite.fr/hal-01142000/file/Cacoub_Cryoglobulinemia.pdf | url-access = | url-status = | archive-url = | archive-date = }}
• Reactions to exposure to chemical agents, including trichloroethylene and dapsone{{medical citation needed|date=March 2016}}
• Rarely, following the sting of certain jellyfish, such as the sea nettle{{medical citation needed|date=March 2016}}

}}

Autonomic neuropathy is a form of polyneuropathy that 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 the spinal cord. They have connections with the spinal cord and ultimately the brain, however. 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.{{citation needed|date=June 2022}}

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 also may cause autonomic dysfunction, such as multiple system atrophy, and therefore, may cause similar symptoms to autonomic neuropathy.{{citation needed|date=June 2022}}

The signs and symptoms of autonomic neuropathy include the following:

• Urinary bladder conditions: bladder incontinence or urine retention
• Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhoea, constipation
• Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion
• Respiratory system: impairments in the signals associated with regulation of breathing and gas exchange (central sleep apnea, hypopnea, bradypnea).{{cite book | vauthors = Vinik AI, Erbas T | chapter = Diabetic autonomic neuropathy | volume = 117 | pages = 279–94 | year = 2013 | pmid = 24095132 | doi = 10.1016/b978-0-444-53491-0.00022-5 | isbn = 978-0-444-53491-0 | series = Handbook of Clinical Neurology | title = Autonomic Nervous System }}
• Skin: thermal regulation, dryness through sweat disturbances
• Other areas: hypoglycemia unawareness, genital impotence

Neuritis is a general term for inflammation of a nerve{{DorlandsDict|six/000071661|neuritis}} or the general inflammation of the peripheral nervous system. Symptoms depend on the nerves involved, but may include pain, paresthesia (pins-and-needles), paresis (weakness), hypoesthesia (numbness), anesthesia, paralysis, wasting, and disappearance of the reflexes.

Causes of neuritis include:

{{columns-list|colwidth=30em|

• Physical injury
• Infection
• Diphtheria
• Herpes zoster (shingles)
• Leprosy
• Lyme disease
• Chemical injury such as chemotherapy
• Radiation therapy

Types of neuritis include:

• Brachial neuritis
• Cranial neuritis such as Bell's palsy
• Optic neuritis
• Vestibular neuritis
• Wartenberg's migratory sensory neuropathy
• Underlying conditions including:
• Alcoholism
• Autoimmune disease, especially multiple sclerosis and Guillain–Barré syndrome
• Beriberi (vitamin B₁ deficiency)
• Cancer
• Celiac disease{{cite journal | vauthors = Chin RL, Latov N | title = Peripheral Neuropathy and Celiac Disease | journal = Current Treatment Options in Neurology | volume = 7 | issue = 1 | pages = 43–48 | date = January 2005 | pmid = 15610706 | doi = 10.1007/s11940-005-0005-3 | s2cid = 40765123 }}
• Non-celiac gluten sensitivity
• Diabetes mellitus (Diabetic neuropathy)
• Hypothyroidism
• Porphyria
• Vitamin B₁₂ deficiency{{cite journal |last1=Ghosh |first1=Shampa |last2=Sinha |first2=Jitendra Kumar |last3=Khandelwal |first3=Nitin |last4=Chakravarty |first4=Sumana |last5=Kumar |first5=Arvind |last6=Raghunath |first6=Manchala |title=Increased stress and altered expression of histone modifying enzymes in brain are associated with aberrant behaviour in vitamin B12 deficient female mice |journal=Nutritional Neuroscience |date=1 September 2020 |volume=23 |issue=9 |pages=714–723 |doi=10.1080/1028415X.2018.1548676 |pmid=30474509 |s2cid=53785219 }}
• Vitamin B₆ excess{{EMedicine|article|819426|Vitamin Toxicity}}

}}

Those with diseases or dysfunctions of their nerves may have problems with normal nerve functions. Symptoms vary depending on the types of nerve fiber involved.{{cite web| title = Peripheral Neuropathy Fact Sheet | publisher = National Institute of Neurological Disorders and Stroke | url = https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet | access-date = 30 May 2020}} {{citation needed|date=July 2016}} In terms of sensory function, symptoms commonly include loss of function ("negative") symptoms, including numbness, tremor, impairment of balance, and gait abnormality. Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins-and-needles. Motor symptoms include loss of function ("negative") symptoms of weakness, tiredness, muscle atrophy, and gait abnormalities; and gain of function ("positive") symptoms of cramps, and muscle twitch (fasciculations).

In the most common form, length-dependent peripheral neuropathy, pain, and parasthesia appear symmetrically and generally at the terminals of the longest nerve in the lower legs and feet. Sensory symptoms usually develop before motor symptoms such as weakness. Length-dependent peripheral neuropathy symptoms make a slow ascent of the lower limbs, while symptoms may never appear in the upper limbs; if they do, it will be around the time that leg symptoms reach the knee.{{cite journal | vauthors = Watson JC, Dyck PJ | title = Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management | journal = Mayo Clinic Proceedings | volume = 90 | issue = 7 | pages = 940–51 | date = July 2015 | pmid = 26141332 | doi = 10.1016/j.mayocp.2015.05.004 | doi-access = free }} When the nerves of the autonomic nervous system are affected, symptoms may include constipation, dry mouth, difficulty urinating, and dizziness when standing.

A user-friendly, disease-specific, quality-of-life scale can be used to monitor how someone feels with the burden of chronic, sensorimotor polyneuropathy. This scale, called the Chronic, Acquired Polyneuropathy - Patient-reported Index (CAP-PRI), contains only 15 items and is completed by the person affected by polyneuropathy. The total score and individual item scores can be followed over time, with item scoring used by the patient and care provider to estimate the clinical status of some of the more common life domains and symptoms impacted by polyneuropathy.{{cite journal |author1=Gwathmey KG |author2=Conaway MR |author3=Sadjadi R |display-authors=etal |title=Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument |journal=Muscle & Nerve |publisher=Muscle Nerve |date=2015-12-29|volume=54 |issue=1 |pages=9–17 |doi=10.1002/mus.24985 |pmid=26600438 |pmc=4950873 }}

The causes are grouped broadly as follows:

{{columns-list|colwidth=30em|

• Ribose-5-Phosphate Isomerase Deficiency
• Surgery: LASIK (corneal neuropathy — 20 to 55% of people).{{cite journal | vauthors = Levitt AE, Galor A, Weiss JS, Felix ER, Martin ER, Patin DJ, Sarantopoulos KD, Levitt RC | title = Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders | journal = Molecular Pain | volume = 11 | pages = s12990–015–0020 | date = April 2015 | pmid = 25896684 | pmc = 4411662 | doi = 10.1186/s12990-015-0020-7 | doi-access = free }}
• Genetic diseases: Friedreich's ataxia, Fabry disease,{{cite journal | vauthors = Gilron I, Baron R, Jensen T | title = Neuropathic pain: principles of diagnosis and treatment | journal = Mayo Clinic Proceedings | volume = 90 | issue = 4 | pages = 532–45 | date = April 2015 | pmid = 25841257 | doi = 10.1016/j.mayocp.2015.01.018 | doi-access = free }} Charcot-Marie-Tooth disease,{{cite journal | vauthors = Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ | title = 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 | journal = Neurology | volume = 49 | issue = 6 | pages = 1635–40 | date = December 1997 | pmid = 9409359 | doi = 10.1212/WNL.49.6.1635 | s2cid = 37715021 }} hereditary neuropathy with liability to pressure palsy
• Hyperglycemia-induced formation of advanced glycation end products (AGEs){{cite journal | vauthors = Hayreh SS, Servais GE, Virdi PS | title = Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy | journal = Ophthalmology | volume = 93 | issue = 1 | pages = 74–87 | date = January 1986 | pmid = 3951818 | doi = 10.1016/s0161-6420(86)33773-4 }}/{{cite journal | vauthors = Kawana T, Yamamoto H, Izumi H | title = A case of aspergillosis of the maxillary sinus | journal = The Journal of Nihon University School of Dentistry | volume = 29 | issue = 4 | pages = 298–302 | date = December 1987 | pmid = 3329218 | doi = 10.2334/josnusd1959.29.298 | doi-access = free }}
• Metabolic and endocrine diseases: diabetes mellitus, chronic kidney failure, porphyria, amyloidosis, liver failure, hypothyroidism{{cite book | last1=Wood-allum | first1=Clare A. | last2=Shaw | first2=Pamela J. | title=Neurologic Aspects of Systemic Disease Part II | chapter=Thyroid disease and the nervous system | series=Handbook of Clinical Neurology | publisher=Elsevier | volume=120 | year=2014 | issn=0072-9752 | pmid=24365348 | doi=10.1016/b978-0-7020-4087-0.00048-6 | pages=703–735| isbn=978-0-7020-4087-0 }}
• Idiopathic peripheral neuropathy refers to neuropathy with no known cause.{{cite journal |vauthors=Valdivia JM, Weinand M, Maloney CT, Blount AL, Dellon AL |title=Surgical treatment of superimposed, lower extremity, peripheral nerve entrapments with diabetic and idiopathic neuropathy |journal=Ann Plast Surg |volume=70 |issue=6 |pages=675–79 |date=June 2013 |pmid=23673565 |doi=10.1097/SAP.0b013e3182764fb0 |s2cid=10150616 |url=}}
• Toxic causes: drugs (vincristine, metronidazole, phenytoin, nitrofurantoin, isoniazid, ethyl alcohol, statins),{{medical citation needed|date=October 2018}} organic herbicides TCDD dioxin, organic metals, heavy metals, excess intake of vitamin B₆ (pyridoxine). Peripheral neuropathies also may result from long-term (more than 21 days) treatment with linezolid.{{medical citation needed|date=September 2013}}
• Adverse effects of fluoroquinolones: irreversible neuropathy is a serious adverse reaction of fluoroquinolone drugs{{cite journal | vauthors = Cohen JS | title = Peripheral neuropathy associated with fluoroquinolones | journal = The Annals of Pharmacotherapy | volume = 35| issue = 12 | pages = 1540–7 | date = Dec 2001 | pmid = 11793615 | doi = 10.1345/aph.1Z429 | s2cid = 12589772 }}
• Inflammatory diseases: Guillain–Barré syndrome, systemic lupus erythematosus, leprosy, Sjögren's syndrome, Babesiosis, Lyme disease, vasculitis, sarcoidosis.{{cite journal | vauthors = Heck AW, Phillips LH | title = Sarcoidosis and the nervous system | journal = Neurologic Clinics | volume = 7 | issue = 3 | pages = 641–54 | date = August 1989 | pmid = 2671639 | doi = 10.1016/S0733-8619(18)30805-3 }} Multiple sclerosis may also be causal.Note NO mention of MS
• Vitamin deficiency states: Vitamin B₁₂ (Methylcobalamin), vitamin A, vitamin E, vitamin B₁ (thiamin)
• Physical trauma: compression, automobile accident, sports injury, sports pinching, cutting, projectile injuries (for example, gunshot wound), strokes including prolonged occlusion of blood flow, electric discharge, including lightning strikes{{medical citation needed|date=October 2018}}
• Effect of chemotherapy – see Chemotherapy-induced peripheral neuropathy
• Exposure to Agent Orange{{Cite web |title=Service-Connected Disability Compensation For Exposure To Agent Orange |url=http://www.vva.org/Guides/AgentOrangeGuide.pdf |publisher=Vietnam Veterans of America |date=April 2015 |page=4 |access-date=20 August 2015}}
• Others: Carpal tunnel syndrome, electric shock, HIV,{{cite journal | vauthors = Gonzalez-Duarte A, Cikurel K, Simpson DM | title = Managing HIV peripheral neuropathy | journal = Current HIV/AIDS Reports | volume = 4 | issue = 3 | pages = 114–8 | date = August 2007 | pmid = 17883996 | doi = 10.1007/s11904-007-0017-6 | s2cid = 34689986 }} malignant disease, radiation, shingles, MGUS (Monoclonal gammopathy of undetermined significance).{{cite journal | vauthors = Nobile-Orazio E, Barbieri S, Baldini L, Marmiroli P, Carpo M, Premoselli S, Manfredini E, Scarlato G | title = Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies | journal = Acta Neurologica Scandinavica | volume = 85 | issue = 6 | pages = 383–90 | date = June 1992 | pmid = 1379409 | doi = 10.1111/j.1600-0404.1992.tb06033.x | s2cid = 30788715 }}

}}

Peripheral neuropathy may first be considered when an individual reports symptoms of numbness, tingling, and pain in feet. After ruling out a lesion in the central nervous system as a cause, a diagnosis may be made on the basis of symptoms, laboratory and additional testing, clinical history, and a detailed examination.

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

A physical examination will involve testing the deep ankle reflex as well as examining the feet for any ulceration. For large fiber neuropathy, an exam will usually show an abnormally decreased sensation to vibration, which is tested with a 128-Hz tuning fork, and diminished sensation of light touch when touched by a nylon monofilament.

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers. Testing for small-fiber peripheral neuropathies often relates to the autonomic nervous system function of small thinly- and unmyelinated fibers. These tests include a sweat test and a tilt table test. Diagnosis of small fiber involvement in peripheral neuropathy may also involve a skin biopsy in which a 3 mm-thick section of skin is removed from the calf by a punch biopsy, and is used to measure the skin intraepidermal nerve fiber density (IENFD), the density of nerves in the outer layer of the skin. Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.

In EMG testing, demyelinating neuropathy characteristically shows a reduction in conduction velocity and prolongation of distal and F-wave latencies, whereas axonal neuropathy shows a reduction in amplitude.{{cite journal |last1=Chung |first1=Tae |last2=Prasad |first2=Kalpana |last3=Lloyd |first3=Thomas E. |title=Peripheral Neuropathy – Clinical and Electrophysiological Considerations |journal=Neuroimaging Clinics of North America |date=February 2014 |volume=24 |issue=1 |pages=49–65 |doi=10.1016/j.nic.2013.03.023 |pmid=24210312 |pmc=4329247 }}

Laboratory tests include blood tests for vitamin B₁₂ levels, a complete blood count, measurement of thyroid stimulating hormone levels, a comprehensive metabolic panel screening for diabetes and pre-diabetes, and a serum immunofixation test, which tests for antibodies in the blood.{{cite journal | vauthors = Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab MY | title = Peripheral neuropathy: differential diagnosis and management | journal = American Family Physician | volume = 81 | issue = 7 | pages = 887–92 | date = April 2010 | pmid = 20353146 }}

The treatment of peripheral neuropathy varies based on its cause, and treating the underlying condition can help neuropathy treatment. When peripheral neuropathy results from diabetes mellitus or prediabetes, blood sugar management is key to treatment. In prediabetes, strict blood sugar control can significantly alter the course of neuropathy.{{cite journal | last1=Cioroiu |first1=Comana M. |last2=Brannagan |first2=Thomas H.| title=Peripheral Neuropathy | journal = Current Geriatrics Reports | volume = 3 | issue = 2 | year = 2014 | pages = 83–90 | doi = 10.1007/s13670-014-0079-4 |s2cid=195246984 }} In peripheral neuropathy that stems from immune-mediated diseases, the underlying condition is treated with intravenous immunoglobulin or steroids. When peripheral neuropathy results from vitamin deficiencies or other disorders, those are treated as well.

A range of medications that act on the central nervous system have been used to treat neuropathic pain. Commonly used medications include tricyclic antidepressants (such as nortriptyline,{{cite journal | vauthors = Derry S, Wiffen PJ, Aldington D, Moore RA | title = Nortriptyline for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD011209 | date = January 2015 | issue = 5 | pmid = 25569864 | pmc = 6485407 | doi = 10.1002/14651858.CD011209.pub2 }} amitriptyline.{{cite journal | vauthors = Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ | title = Amitriptyline for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 7 | pages = CD008242 | date = July 2015 | pmid = 26146793 | pmc = 6447238 | doi = 10.1002/14651858.CD008242.pub3 }} imapramine,{{cite journal | vauthors = Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ | title = Imipramine for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 5 | pages = CD010769 | date = May 2014 | pmid = 24838845 | pmc = 6485593 | doi = 10.1002/14651858.CD010769.pub2 }} and desipramine,) serotonin-norepinephrine reuptake inhibitor (SNRI) medications (duloxetine,{{cite journal | vauthors = Lunn MP, Hughes RA, Wiffen PJ | title = Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD007115 | date = January 2014 | volume = 2015 | pmid = 24385423 | doi = 10.1002/14651858.cd007115.pub3 | pmc = 10711341 }} venlafaxine,{{cite journal | vauthors = Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC | title = Venlafaxine for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD011091 | date = August 2015 | volume = 2017 | pmid = 26298465 | pmc = 6481532 | doi = 10.1002/14651858.CD011091.pub2 }} and milnacipran{{cite journal | vauthors = Derry S, Phillips T, Moore RA, Wiffen PJ | title = Milnacipran for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 7 | pages = CD011789 | date = July 2015 | volume = 2019 | pmid = 26148202 | pmc = 6485877 | doi = 10.1002/14651858.CD011789 }}) and antiepileptic medications (gabapentin,{{cite journal | vauthors = Wiffen PJ, Derry S, Bell RF, Rice AS, Tölle TR, Phillips T, Moore RA | title = Gabapentin for chronic neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 6 | pages = CD007938 | date = June 2017 | issue = 2 | pmid = 28597471 | pmc = 6452908 | doi = 10.1002/14651858.CD007938.pub4 }} pregabalin,{{cite journal | vauthors = Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA | title = Pregabalin for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007076 | date = January 2019 | issue = 1 | pmid = 30673120 | pmc = 6353204 | doi = 10.1002/14651858.CD007076.pub3 }} oxcarbazepine{{cite journal | vauthors = Zhou M, Chen N, He L, Yang M, Zhu C, Wu F | title = Oxcarbazepine for neuropathic pain | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD007963 | date = December 2017 | issue = 12 | pmid = 29199767 | pmc = 6486101 | doi = 10.1002/14651858.CD007963.pub3 }} zonisamide{{cite journal | vauthors = Moore RA, Wiffen PJ, Derry S, Lunn MP | title = Zonisamide for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD011241 | date = January 2015 | issue = 1 | pmid = 25879104 | pmc = 6485502 | doi = 10.1002/14651858.CD011241.pub2 }} levetiracetam,{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA, Lunn MP | editor1-first = Sheena | editor1-last = Derry | title = Levetiracetam for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 7 | pages = CD010943 | date = July 2014 | volume = 2014 | pmid = 25000215 | pmc = 6485608 | doi = 10.1002/14651858.cd010943.pub2 }} lamotrigine,{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA | title = Lamotrigine for chronic neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD006044 | date = December 2013 | volume = 2019 | pmid = 24297457 | pmc = 6485508 | doi = 10.1002/14651858.CD006044.pub4 | editor-last = Cochrane Pain, Palliative and Supportive Care Group }} topiramate,{{cite journal | vauthors = Wiffen PJ, Derry S, Lunn MP, Moore RA | editor1-first = Sheena | editor1-last = Derry | title = Topiramate for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD008314 | date = August 2013 | volume = 2013 | pmid = 23996081 | doi = 10.1002/14651858.CD008314.pub3 | pmc = 8406931 }} clonazepam,{{cite journal | vauthors = Corrigan R, Derry S, Wiffen PJ, Moore RA | title = Clonazepam for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD009486 | date = May 2012 | volume = 2019 | pmid = 22592742 | pmc = 6485609 | doi = 10.1002/14651858.cd009486.pub2 }} phenytoin,{{cite journal | vauthors = Birse F, Derry S, Moore RA | title = Phenytoin for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD009485 | date = May 2012 | volume = 2019 | pmid = 22592741 | pmc = 6481697 | doi = 10.1002/14651858.cd009485.pub2 }} lacosamide,{{cite journal | vauthors = Hearn L, Derry S, Moore RA | title = Lacosamide for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD009318 | date = February 2012 | volume = 2016 | pmid = 22336864 | doi = 10.1002/14651858.cd009318.pub2 | pmc = 8406928 }} sodium valproate{{cite journal | vauthors = Gill D, Derry S, Wiffen PJ, Moore RA | title = Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD009183 | date = October 2011 | volume = 2011 | pmid = 21975791 | pmc = 6540387 | doi = 10.1002/14651858.cd009183.pub2 }} and carbamazepine{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA, Kalso EA | title = Carbamazepine for chronic neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD005451 | date = April 2014 | volume = 2019 | pmid = 24719027 | pmc = 6491112 | doi = 10.1002/14651858.CD005451.pub3 | editor-last = Cochrane Pain, Palliative and Supportive Care Group }}). Opioid and opiate medications (such as buprenorphine,{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA, Stannard C, Aldington D, Cole P, Knaggs R | title = Buprenorphine for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD011603 | date = September 2015 | volume = 2019 | pmid = 26421677 | pmc = 6481375 | doi = 10.1002/14651858.CD011603.pub2 }} morphine, methadone,{{cite journal | vauthors = McNicol ED, Ferguson MC, Schumann R | title = Methadone for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD012499 | date = May 2017 | issue = 5 | pmid = 28514508 | pmc = 6353163 | doi = 10.1002/14651858.CD012499.pub2 | editor-last = Cochrane Pain, Palliative and Supportive Care Group }} fentanyl,{{cite journal | vauthors = Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA | title = Fentanyl for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 10 | pages = CD011605 | date = October 2016 | issue = 5 | pmid = 27727431 | pmc = 6457928 | doi = 10.1002/14651858.CD011605.pub2 }} hydromorphone,{{cite journal | vauthors = Stannard C, Gaskell H, Derry S, Aldington D, Cole P, Cooper TE, Knaggs R, Wiffen PJ, Moore RA | title = Hydromorphone for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD011604 | date = May 2016 | volume = 2016 | pmid = 27216018 | pmc = 6491092 | doi = 10.1002/14651858.CD011604.pub2 }} tramadol and oxycodone{{cite journal | vauthors = Gaskell H, Derry S, Stannard C, Moore RA | title = Oxycodone for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD010692 | date = July 2016 | issue = 7 | pmid = 27465317 | pmc = 6457997 | doi = 10.1002/14651858.CD010692.pub3 | editor-last = Cochrane Pain, Palliative and Supportive Care Group }}) are also often used to treat neuropathic pain.

As is revealed in many of the Cochrane systematic reviews listed below, studies of these medications for the treatment of neuropathic pain are often methodologically flawed and the evidence is potentially subject to major bias. In general, the evidence does not support the usage of antiepileptic and antidepressant medications for the treatment of neuropathic pain. Better-designed clinical trials and further review from non-biased third parties are necessary to gauge just how useful for patients these medications truly are. Reviews of these systematic reviews are also necessary to assess their failings.

It is also often the case that the aforementioned medications are prescribed for neuropathic pain conditions for which they had not been explicitly tested for which controlled research is severely lacking; or even for which evidence suggests that these medications are not effective.{{cite journal | vauthors = Mafi JN, McCarthy EP, Davis RB, Landon BE | title = Worsening trends in the management and treatment of back pain | journal = JAMA Internal Medicine | volume = 173 | issue = 17 | pages = 1573–81 | date = September 2013 | pmid = 23896698 | pmc = 4381435 | doi = 10.1001/jamainternmed.2013.8992 }}{{cite journal | vauthors = Pinto RZ, Maher CG, Ferreira ML, Ferreira PH, Hancock M, Oliveira VC, McLachlan AJ, Koes B | title = Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis | journal = BMJ | volume = 344 | pages = e497 | date = February 2012 | pmid = 22331277 | pmc = 3278391 | doi = 10.1136/bmj.e497 }}{{cite journal | vauthors = Pinto RZ, Verwoerd AJ, Koes BW | title = Which pain medications are effective for sciatica (radicular leg pain)? | journal = BMJ | volume = 359 | pages = j4248 | date = October 2017 | pmid = 29025735 | doi = 10.1136/bmj.j4248 | s2cid = 11229746 }} The NHS for example explicitly states that amitriptyline and gabapentin can be used for treating the pain of sciatica.{{Cite web|url=https://www.nhs.uk/live-well/healthy-body/which-painkiller-to-use/|title=Which painkiller?|date=2018-04-26|website=nhs.uk|language=en|access-date=2019-05-20}} This is despite both the lack of high-quality evidence that demonstrates the efficacy of these medications for that symptom, and also the prominence of generally moderate to high-quality evidence that reveals that antiepileptics in specific, including gabapentin, demonstrate no efficacy in treating it.{{cite journal | vauthors = Enke O, New HA, New CH, Mathieson S, McLachlan AJ, Latimer J, Maher CG, Lin CC | title = Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis | journal = CMAJ | volume = 190 | issue = 26 | pages = E786–E793 | date = July 2018 | pmid = 29970367 | pmc = 6028270 | doi = 10.1503/cmaj.171333 }}

In general, according to Cochrane's systematic reviews, antidepressants have shown to either be ineffective for the treatment of neuropathic pain or the evidence available is inconclusive.{{cite journal|vauthors=Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T|editor1-first=Leslie|editor1-last=Hearn|date=September 2014|title=Desipramine for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=2014 |issue=9|pages=CD011003|doi=10.1002/14651858.CD011003.pub2|pmid=25246131|pmc=6804291}}{{cite journal|vauthors=Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC|date=August 2015|title=Venlafaxine for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=2017|issue=8|pages=CD011091|doi=10.1002/14651858.CD011091.pub2|pmc=6481532|pmid=26298465}}{{cite journal|vauthors=Derry S, Phillips T, Moore RA, Wiffen PJ|date=July 2015|title=Milnacipran for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=2019 |issue=7|pages=CD011789|doi=10.1002/14651858.CD011789|pmc=6485877|pmid=26148202}} Evidence also tends to be tainted by bias or issues with the methodology.{{cite journal|vauthors=Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ|date=July 2015|editor-last=Cochrane Pain, Palliative and Supportive Care Group|title=Amitriptyline for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=2015 |issue=7|pages=CD008242|doi=10.1002/14651858.CD008242.pub3|pmc=6447238|pmid=26146793}}{{cite journal|vauthors=Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ|date=May 2014|title=Imipramine for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=2019 |issue=5|pages=CD010769|doi=10.1002/14651858.CD010769.pub2|pmc=6485593|pmid=24838845}}

Cochrane systematically reviewed the evidence for the antidepressants nortriptyline, desipramine, venlafaxine, and milnacipran and in all these cases found scant evidence to support their use for the treatment of neuropathic pain. All reviews were done between 2014 and 2015.

A 2015 Cochrane systematic review of amitriptyline found no evidence supporting amitriptyline that did not possess inherent bias. The authors believe amitriptyline may have an effect in some patients but that the effect is overestimated. A 2014 Cochrane systematic review of imipramine notes that the evidence suggesting benefit were "methodologically flawed and potentially subject to major bias."

A 2017 Cochrane systematic review assessed the benefit of antidepressant medications for several types of chronic non-cancer pains (including neuropathic pain) in children and adolescents and the authors found the evidence inconclusive.{{cite journal | vauthors = Cooper TE, Heathcote LC, Clinch J, Gold JI, Howard R, Lord SM, Schechter N, Wood C, Wiffen PJ | title = Antidepressants for chronic non-cancer pain in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 8 | pages = CD012535 | date = August 2017 | issue = 8 | pmid = 28779487 | pmc = 6424378 | doi = 10.1002/14651858.CD012535.pub2 }}

A 2017 Cochrane systematic review found that daily dosages between 1800–3600 mg of gabapentin could provide good pain relief for pain associated with diabetic neuropathy only. This relief occurred for roughly 30–40% of treated patients, while placebo had a 10–20% response. Three of the seven authors of the review had conflicts of interest declared. In a 2019 Cochrane review of pregabalin the authors conclude that there is some evidence of efficacy in the treatment of pain deriving from post-herpetic neuralgia, diabetic neuropathy, and post-traumatic neuropathic pain only. They also warned that many patients treated will have no benefit. Two of the five authors declared receiving payments from pharmaceutical companies.

A 2017 Cochrane systematic review found that oxcarbazepine had little evidence to support its use for treating diabetic neuropathy, radicular pain, and other neuropathies. The authors also call for better studies. In a 2015 Cochrane systematic review the authors found a lack of evidence showing any effectiveness of zonisamide for treating pain deriving from any peripheral neuropathy. A 2014 Cochrane review found that studies of levetiracetam showed no indication of its effectiveness at treating pain from any neuropathy. The authors also found that the evidence was possibly biased and that some patients experienced adverse events.{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA, Lunn MP | editor1-first = Sheena | editor1-last = Derry | title = Levetiracetam for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 7 | pages = CD010943 | date = July 2014 | volume = 2014 | pmid = 25000215 | pmc = 6485608 | doi = 10.1002/14651858.CD010943.pub2 }}

A 2013 Cochrane systematic review concluded that there was high-quality evidence to suggest that lamotrigine is not effective for treating neuropathic pain, even at high dosages 200–400 mg.{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA | title = Lamotrigine for chronic neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD006044 | date = December 2013 | volume = 2019 | pmid = 24297457 | pmc = 6485508 | doi = 10.1002/14651858.CD006044.pub4 }} A 2013 Cochrane systematic review of topiramate found that the included data had a strong likelihood of major bias; despite this, it found no effectiveness for the drug in treating the pain associated with diabetic neuropathy. It had not been tested for any other type of neuropathy. Cochrane reviews from 2012 of clonazepam and phenytoin uncovered no evidence of sufficient quality to support their use in chronic neuropathic pain."{{cite journal | vauthors = Corrigan R, Derry S, Wiffen PJ, Moore RA | title = Clonazepam for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD009486 | date = May 2012 | volume = 2019 | pmid = 22592742 | pmc = 6485609 | doi = 10.1002/14651858.CD009486.pub2 }}{{cite journal | vauthors = Birse F, Derry S, Moore RA | title = Phenytoin for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD009485 | date = May 2012 | volume = 2019 | pmid = 22592741 | pmc = 6481697 | doi = 10.1002/14651858.CD009485.pub2 }}

A 2012 Cochrane systematic review of lacosamide found it very likely that the drug is ineffective for treating neuropathic pain. The authors caution against positive interpretations of the evidence.{{cite journal | vauthors = Hearn L, Derry S, Moore RA | title = Lacosamide for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD009318 | date = February 2012 | volume = 2016 | pmid = 22336864 | doi = 10.1002/14651858.CD009318.pub2 | pmc = 8406928 }} For sodium valproate the authors of a 2011 Cochrane review found that "three studies no more than hint that sodium valproate may reduce pain in diabetic neuropathy". They discuss how there is a probable overestimate of the effect due to the inherent problems with the data and conclude that the evidence does not support its usage.{{cite journal | vauthors = Gill D, Derry S, Wiffen PJ, Moore RA | title = Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD009183 | date = October 2011 | volume = 2011 | pmid = 21975791 | doi = 10.1002/14651858.CD009183.pub2 | pmc = 6540387 }} In a 2014 systematic review of carbamazepine the authors believe the drug benefits some people. No trials were considered greater than level III evidence; none lasted longer than 4 weeks and had poor reporting quality.{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA, Kalso EA | title = Carbamazepine for chronic neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD005451 | date = April 2014 | volume = 2019 | pmid = 24719027 | pmc = 6491112 | doi = 10.1002/14651858.cd005451.pub3 }}

A 2017 Cochrane systematic review aiming to assess the benefit of antiepileptic medications for several types of chronic non-cancer pains (including neuropathic pain) in children and adolescents found the evidence inconclusive. Two of the ten authors of this study declared receiving payments from pharmaceutical companies.{{cite journal | vauthors = Cooper TE, Wiffen PJ, Heathcote LC, Clinch J, Howard R, Krane E, Lord SM, Sethna N, Schechter N, Wood C | title = Antiepileptic drugs for chronic non-cancer pain in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 8 | pages = CD012536 | date = August 2017 | issue = 8 | pmid = 28779491 | pmc = 6424379 | doi = 10.1002/14651858.CD012536.pub2 }}

A Cochrane review of buprenorphine, fentanyl, hydromorphone, and morphine, all dated between 2015 and 2017, and all for the treatment of neuropathic pain, found that there was insufficient evidence to comment on their efficacy. Conflicts of interest were declared by the authors in this review.{{cite journal | vauthors = Cooper TE, Chen J, Wiffen PJ, Derry S, Carr DB, Aldington D, Cole P, Moore RA | title = Morphine for chronic neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD011669 | date = May 2017 | issue = 5 | pmid = 28530786 | pmc = 6481499 | doi = 10.1002/14651858.CD011669.pub2 }} A 2017 Cochrane review of methadone found very low-quality evidence, three studies of limited quality, of its efficacy and safety. They could not formulate any conclusions about its relative efficacy and safety compared to a placebo.

For tramadol, Cochrane found that there was only modest information about the benefits of its usage for neuropathic pain. Studies were small, had potential risks of bias and apparent benefits increased with risk of bias. Overall the evidence was of low or very low quality and the authors state that it "does not provide a reliable indication of the likely effect".{{cite journal | vauthors = Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA | title = Tramadol for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD003726 | date = June 2017 | issue = 6 | pmid = 28616956 | pmc = 6481580 | doi = 10.1002/14651858.CD003726.pub4 }} For oxycodone the authors found very low-quality evidence showing its usefulness in treating diabetic neuropathy and postherpetic neuralgia only. One of the four authors declared receiving payments from pharmaceutical companies.

More generally, a large-scale 2013 review found opioids to be more effective for intermediate-term use than short-term use, but couldn't properly assess effectiveness for chronic use because of insufficient data. Most recent guidelines on the pharmacotherapy of neuropathic pain however are in agreement with the results of this review and recommend the use of opioids.{{cite journal | vauthors = McNicol ED, Midbari A, Eisenberg E | title = Opioids for neuropathic pain | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD006146 | date = August 2013 | volume = 2019 | pmid = 23986501 | pmc = 6353125 | doi = 10.1002/14651858.CD006146.pub2 }} A 2017 Cochrane review examining mainly propoxyphene therapy as a treatment for many non-cancer pain syndromes (including neuropathic pain) concluded, "There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents."{{cite journal | vauthors = Cooper TE, Fisher E, Gray AL, Krane E, Sethna N, van Tilburg MA, Zernikow B, Wiffen PJ | title = Opioids for chronic non-cancer pain in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 7 | pages = CD012538 | date = July 2017 | issue = 7 | pmid = 28745394 | pmc = 6477875 | doi = 10.1002/14651858.CD012538.pub2 }}

A 2016 Cochrane review of paracetamol for the treatment of neuropathic pain concluded that its benefit alone or in combination with codeine or dihydrocodeine is unknown.{{cite journal | vauthors = Wiffen PJ, Knaggs R, Derry S, Cole P, Phillips T, Moore RA | title = Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD012227 | date = December 2016 | issue = 5 | pmid = 28027389 | pmc = 6463878 | doi = 10.1002/14651858.CD012227.pub2 }}

Few studies have examined whether nonsteroidal anti-inflammatory drugs are effective in treating peripheral neuropathy.{{cite journal | vauthors = Moore RA, Chi CC, Wiffen PJ, Derry S, Rice AS | title = Oral nonsteroidal anti-inflammatory drugs for neuropathic pain | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD010902 | date = October 2015 | pmid = 26436601 | pmc = 6481590 | doi = 10.1002/14651858.CD010902.pub2 }}

There is some evidence that symptomatic relief from the pain of peripheral neuropathy may be obtained by the application of topical capsaicin. Capsaicin is the factor that causes heat in chili peppers. However, the evidence suggesting that capsaicin applied to the skin reduces pain for peripheral neuropathy is of moderate to low quality and should be interpreted carefully before this treatment is used.{{cite journal | vauthors = Derry S, Rice AS, Cole P, Tan T, Moore RA | title = Topical capsaicin (high concentration) for chronic neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007393 | date = January 2017 | issue = 7 | pmid = 28085183 | pmc = 6464756 | doi = 10.1002/14651858.CD007393.pub4 }}

Evidence supports the use of cannabinoids for some forms of neuropathic pain.{{cite journal | vauthors = Hill KP | title = Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review | journal = JAMA | volume = 313 | issue = 24 | pages = 2474–83 | date = June 2015 | pmid = 26103031 | doi = 10.1001/jama.2015.6199 | quote = Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence }} A 2018 Cochrane review of cannabis-based medicines for the treatment of chronic neuropathic pain included 16 studies. All of these studies included THC as a pharmacological component of the test group. The authors rated the quality of evidence as very low to moderate. The primary outcome was quoted as, "Cannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo" but "the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality". The authors also conclude, "The potential benefits of cannabis-based medicine... might be outweighed by their potential harms."{{cite journal | vauthors = Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W | title = Cannabis-based medicines for chronic neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 3 | pages = CD012182 | date = March 2018 | issue = 7 | pmid = 29513392 | pmc = 6494210 | doi = 10.1002/14651858.CD012182.pub2 }}

A 2014 Cochrane review of topical lidocaine for the treatment of various peripheral neuropathies found its usage supported by a few low-quality studies. The authors state that no high-quality randomised control trials demonstrate its efficacy or safety profile.{{cite journal | vauthors = Derry S, Wiffen PJ, Moore RA, Quinlan J | editor1-first = Sheena | editor1-last = Derry | title = Topical lidocaine for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 7 | pages = CD010958 | date = July 2014 | volume = 2014 | pmid = 25058164 | pmc = 6540846 | doi = 10.1002/14651858.CD010958.pub2 }}

A 2015 (updated in 2022) Cochrane review of topical clonidine for the treatment of diabetic neuropathy included two studies of 8 and 12 weeks in length; both of which compared topical clonidine to placebo and both of which were funded by the same drug manufacturer. The review found that topical clonidine may provide some benefit versus placebo. However, the authors state that the included trials are potentially subject to significant bias and that the evidence is of low to moderate quality.{{Cite journal |last1=Serednicki |first1=Wojciech T. |last2=Wrzosek |first2=Anna |last3=Woron |first3=Jaroslaw |last4=Garlicki |first4=Jaroslaw |last5=Dobrogowski |first5=Jan |last6=Jakowicka-Wordliczek |first6=Joanna |last7=Wordliczek |first7=Jerzy |last8=Zajaczkowska |first8=Renata |date=2022-05-19 |title=Topical clonidine for neuropathic pain in adults |journal=The Cochrane Database of Systematic Reviews |volume=2022 |issue=5 |pages=CD010967 |doi=10.1002/14651858.CD010967.pub3 |issn=1469-493X |pmc=9119025 |pmid=35587172}}

A 2007 Cochrane review of aldose reductase inhibitors for the treatment of pain deriving from diabetic polyneuropathy found it no better than a placebo.{{cite journal | vauthors = Chalk C, Benstead TJ, Moore F | title = Aldose reductase inhibitors for the treatment of diabetic polyneuropathy | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD004572 | date = October 2007 | volume = 2010 | pmid = 17943821 | doi = 10.1002/14651858.CD004572.pub2 | pmc = 8406996 }}

Transcutaneous electrical nerve stimulation (TENS) therapy is often used to treat various types of neuropathy. A 2010 review of three trials, for the treatment of diabetic neuropathy explicitly, involving a total of 78 patients found some improvement in pain scores after 4 and 6 but not 12 weeks of treatment and an overall improvement in neuropathic symptoms at 12 weeks.{{cite journal | vauthors = Jin DM, Xu Y, Geng DF, Yan TB | title = Effect of transcutaneous electrical nerve stimulation on symptomatic diabetic peripheral neuropathy: a meta-analysis of randomized controlled trials | journal = Diabetes Research and Clinical Practice | volume = 89 | issue = 1 | pages = 10–5 | date = July 2010 | pmid = 20510476 | doi = 10.1016/j.diabres.2010.03.021 }} Another 2010 review of four trials, for the treatment of diabetic neuropathy, found significant improvement in pain and overall symptoms, with 38% of patients in one trial becoming asymptomatic. The treatment remains effective even after prolonged use, but symptoms return to baseline within a month of cessation of treatment.{{cite journal | vauthors = Pieber K, Herceg M, Paternostro-Sluga T | title = Electrotherapy for the treatment of painful diabetic peripheral neuropathy: a review | journal = Journal of Rehabilitation Medicine | volume = 42 | issue = 4 | pages = 289–95 | date = April 2010 | pmid = 20461329 | doi = 10.2340/16501977-0554 | doi-access = free }}

These older reviews can be balanced with a more recent 2017 review of TENS for neuropathic pain by Cochrane which concluded that "This review is unable to state the effect of TENS versus sham TENS for pain relief due to the very low quality of the included evidence... The very low quality of evidence means we have very limited confidence in the effect estimate reported." A very low quality of evidence means, 'multiple sources of potential bias' with a 'small number and size of studies'.{{cite journal | vauthors = Gibson W, Wand BM, O'Connell NE | title = Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD011976 | date = September 2017 | issue = 3 | pmid = 28905362 | pmc = 6426434 | doi = 10.1002/14651858.CD011976.pub2 }}

{{Main article|Nerve decompression}}

Peripheral neuropathy due to nerve compression is treatable with a nerve decompression.{{cite journal |vauthors=Kay J, de Sa D, Morrison L, Fejtek E, Simunovic N, Martin HD, Ayeni OR |date=December 2017 |title=Surgical Management of Deep Gluteal Syndrome Causing Sciatic Nerve Entrapment: A Systematic Review |url= |journal=Arthroscopy |volume=33 |issue=12 |pages=2263–2278.e1 |doi=10.1016/j.arthro.2017.06.041 |pmid=28866346}}{{cite journal |vauthors=ElHawary H, Barone N, Baradaran A, Janis JE |date=February 2022 |title=Efficacy and Safety of Migraine Surgery: A Systematic Review and Meta-analysis of Outcomes and Complication Rates |url= |journal=Ann Surg |volume=275 |issue=2 |pages=e315–e323 |doi=10.1097/SLA.0000000000005057 |pmid=35007230}}{{cite journal |vauthors=Giulioni C, Pirola GM, Maggi M, Pitoni L, Fuligni D, Beltrami M, Palantrani V, De Stefano V, Maurizi V, Castellani D, Galosi AB |date=March 2024 |title=Pudendal Nerve Neurolysis in Patients Afflicted With Pudendal Nerve Entrapment: A Systematic Review of Surgical Techniques and Their Efficacy |url= |journal=Int Neurourol J |volume=28 |issue=1 |pages=11–21 |doi=10.5213/inj.2448010.005 |pmc=10990758 |pmid=38569616}}{{cite journal |vauthors=Lu VM, Burks SS, Heath RN, Wolde T, Spinner RJ, Levi AD |date=January 2021 |title=Meralgia paresthetica treated by injection, decompression, and neurectomy: a systematic review and meta-analysis of pain and operative outcomes |url= |journal=J Neurosurg |volume=135 |issue=3 |pages=912–922 |doi=10.3171/2020.7.JNS202191 |pmid=33450741}} When a nerve is subject to localized pressure or stretching, the vascular supply is interrupted leading to a cascade of physiological changes that causes nerve injury.{{cite journal |vauthors=Lundborg G, Dahlin LB |date=May 1996 |title=Anatomy, function, and pathophysiology of peripheral nerves and nerve compression |url= |journal=Hand Clin |volume=12 |issue=2 |pages=185–93 |doi= |pmid=8724572}} In a nerve decompression, a surgeon explores the entrapment site and removes tissue around the nerve to relieve pressure. Common sites of entrapment are spaces of anatomic narrowing such as osteofibrous tunnels (e.g. carpal tunnel in carpal tunnel syndrome).{{cite journal |vauthors=Schmid AB, Fundaun J, Tampin B |date=2020 |title=Entrapment neuropathies: a contemporary approach to pathophysiology, clinical assessment, and management |url= |journal=Pain Rep |volume=5 |issue=4 |pages=e829 |doi=10.1097/PR9.0000000000000829 |pmc=7382548 |pmid=32766466}} In many cases the potential for nerve recovery (full or partial) after decompression is excellent, as chronic nerve compression is associated with low-grade nerve injury (Sunderland classification I-III) rather than high-grade nerve injury (Sunderland classification IV-V).{{cite journal |vauthors=Mackinnon SE |date=May 2002 |title=Pathophysiology of nerve compression |url= |journal=Hand Clin |volume=18 |issue=2 |pages=231–41 |doi=10.1016/s0749-0712(01)00012-9 |pmid=12371026}} Nerve decompressions for properly selected patients are associated with a significant reduction in pain, in some cases the complete elimination of pain.{{cite journal |vauthors=Louie D, Earp B, Blazar P |date=September 2012 |title=Long-term outcomes of carpal tunnel release: a critical review of the literature |url= |journal=Hand (N Y) |volume=7 |issue=3 |pages=242–6 |doi=10.1007/s11552-012-9429-x |pmc=3418353 |pmid=23997725}}

In people with diabetic peripheral neuropathy, two reviews make a case for nerve decompression surgery as an effective means of pain relief and support claims for protection from foot ulceration.{{cite journal |vauthors=Nickerson DS |title=Nerve decompression and neuropathy complications in diabetes: Are attitudes discordant with evidence? |journal=Diabet Foot Ankle |volume=8 |issue=1 |pages=1367209 |date=2017 |pmid=28959382 |pmc=5613909 |doi=10.1080/2000625X.2017.1367209 |url=}}{{cite journal |vauthors=Tu Y, Lineaweaver WC, Chen Z, Hu J, Mullins F, Zhang F |title=Surgical Decompression in the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review and Meta-analysis |journal=J Reconstr Microsurg |volume=33 |issue=3 |pages=151–57 |date=March 2017 |pmid=27894152 |doi=10.1055/s-0036-1594300 |s2cid=22825614 |url=}} There is less evidence for efficacy of surgery for non-diabetic peripheral neuropathy of the legs and feet. One uncontrolled study that did before/after comparisons with a minimum of one-year follow-up reported improvements in pain relief, impaired balance, and numbness. "There was no difference in outcomes between patients with diabetic versus idiopathic neuropathy in response to nerve decompression." There are no placebo-controlled trials for idiopathic peripheral neuropathy in the published scientific literature.

According to a review, strict gluten-free diet is an effective treatment when neuropathy is caused by gluten sensitivity, with or without the presence of digestive symptoms or intestinal injury.

A 2015 review on the treatment of neuropathic pain with psychological therapy concluded that "There is insufficient evidence of the efficacy and safety of psychological interventions for chronic neuropathic pain. The two available studies show no benefit of treatment over either waiting list or placebo control groups."{{cite journal | vauthors = Eccleston C, Hearn L, Williams AC | title = Psychological therapies for the management of chronic neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD011259 | date = October 2015 | volume = 2015 | pmid = 26513427 | pmc = 6485637 | doi = 10.1002/14651858.CD011259.pub2 }}

A 2019 Cochrane review of the treatment of herbal medicinal products for people with neuropathic pain for at least three months concluded that "There was insufficient evidence to determine whether nutmeg or St John's wort has any meaningful efficacy in neuropathic pain conditions. The quality of the current evidence raises serious uncertainties about the estimates of effect observed, therefore, we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect."{{cite journal | vauthors = Boyd A, Bleakley C, Hurley DA, Gill C, Hannon-Fletcher M, Bell P, McDonough S | title = Herbal medicinal products or preparations for neuropathic pain | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD010528 | date = April 2019 | issue = 5 | pmid = 30938843 | pmc = 6445324 | doi = 10.1002/14651858.CD010528.pub4 }}

A 2017 Cochrane review on the usage of acupuncture as a treatment for neuropathic pain concludes, "Due to the limited data available, there is insufficient evidence to support or refute the use of acupuncture for neuropathic pain in general, or for any specific neuropathic pain condition when compared with sham acupuncture or other active therapies." Also, "Most studies included a small sample size (fewer than 50 participants per treatment arm) and all studies were at high risk of bias for blinding of participants and personnel." Also, the authors state, "we did not identify any study comparing acupuncture with treatment as usual."{{cite journal | vauthors = Ju ZY, Wang K, Cui HS, Yao Y, Liu SM, Zhou J, Chen TY, Xia J | title = Acupuncture for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD012057 | date = December 2017 | issue = 7 | pmid = 29197180 | pmc = 6486266 | doi = 10.1002/14651858.CD012057.pub2 }}

Alpha lipoic acid (ALA) with benfotiamine is a proposed pathogenic treatment for painful diabetic neuropathy only.{{Cite web|url=http://www.currentdiabetesreviews.com/articles/170231/review-of-diabetic-polyneuropathy-pathogenesis-diagnosis-and-management-according-to-the-consensus-of-egyptian-experts|title = Review of Diabetic Polyneuropathy: Pathogenesis, Diagnosis A}} The results of two systematic reviews state that oral ALA produced no clinically significant benefit, intravenous ALA administered over three weeks may improve symptoms and that long-term treatment has not been investigated.{{Cite journal|last1=Bartkoski|first1=Scott|last2=Day|first2=Margaret|date=2016-05-01|title=Alpha-Lipoic Acid for Treatment of Diabetic Peripheral Neuropathy|journal=American Family Physician|volume=93|issue=9|pages=786|issn=1532-0650|pmid=27175957}}

A 2008 literature review concluded that "based on principles of evidence-based medicine and evaluations of methodology, there is only a 'possible' association of celiac disease and peripheral neuropathy due to lower levels of evidence and conflicting evidence. There is not yet convincing evidence of causality."{{cite journal | vauthors = Grossman G | title = Neurological complications of coeliac disease: what is the evidence? | journal = Practical Neurology | volume = 8 | issue = 2 | pages = 77–89 | date = April 2008 | pmid = 18344378 | doi = 10.1136/jnnp.2007.139717 | s2cid = 28327166 }}

A 2019 review concluded that "gluten neuropathy is a slowly progressive condition. About 25% of the patients will have evidence of enteropathy on biopsy (CD [celiac disease]) but the presence or absence of an enteropathy does not influence the positive effect of a strict gluten-free diet."{{cite journal | vauthors = Zis P, Hadjivassiliou M | title = Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease | journal = Current Treatment Options in Neurology | volume = 21 | issue = 3 | pages = 10 | date = February 2019 | pmid = 30806821 | doi = 10.1007/s11940-019-0552-7 | s2cid = 73466457 | type = Review | doi-access = free }}

Stem-cell therapy is also being examined as a possible means to repair peripheral nerve damage but efficacy has not yet been demonstrated.{{cite journal | vauthors = Sayad Fathi S, Zaminy A | title = Stem cell therapy for nerve injury | journal = World Journal of Stem Cells | volume = 9 | issue = 9 | pages = 144–151 | date = September 2017 | pmid = 29026460 | pmc = 5620423 | doi = 10.4252/wjsc.v9.i9.144 | doi-access = free }}{{cite journal | vauthors = Xu W, Cox CS, Li Y | title = Induced pluripotent stem cells for peripheral nerve regeneration | journal = Journal of Stem Cells | volume = 6 | issue = 1 | pages = 39–49 | pmid = 22997844 | year = 2011 }}{{cite journal | vauthors = Zhou JY, Zhang Z, Qian GS | title = Mesenchymal stem cells to treat diabetic neuropathy: a long and strenuous way from bench to the clinic | journal = Cell Death Discovery | volume = 2 | pages = 16055 | pmid = 27551543 | pmc = 4979500 | doi = 10.1038/cddiscovery.2016.55 | year = 2016 }}

• Giant axonal neuropathy
• Scrambler therapy
• Sensory neuronopathy

{{reflist|30em}}

{{refbegin}}

• {{cite book |last=Latov |first=Norman | title = Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won't Stop | publisher = American Academy of Neurology Press Demos Medical | location = New York | year = 2007 | isbn =978-1-932603-59-0 }}
• {{cite journal | title = Practice advisory for the prevention of perioperative peripheral neuropathies: a report by the American Society of Anesthesiologists Task Force on Prevention of Perioperative Peripheral Neuropathies | journal = Anesthesiology | volume = 92 | issue = 4 | pages = 1168–82 | date = April 2000 | pmid = 10754638 | doi = 10.1097/00000542-200004000-00036 }}

{{refend}}

• [https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy Peripheral Neuropathy] from the US NIH
• [http://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/basics/definition/con-20019948?reDate=05042015 Peripheral Neuropathy] at the Mayo Clinic

{{Medical resources

| DiseasesDB = 9850

| ICD10 = {{ICD10|G|64||g|60}}, {{ICD10|G|90|0|g|90}}

| ICD9 = {{ICD9|356.0}}, {{ICD9|356.8}}

| ICDO =

| OMIM =

| MedlinePlus = 000593

| eMedicineSubj =

| eMedicineTopic =

| MeshID = D010523

}}

{{PNS diseases of the nervous system}}

{{Autonomic diseases}}

{{Neuropathic pain and fibromyalgia pharmacotherapies}}

{{Authority control}}

{{DEFAULTSORT:Peripheral Neuropathy}}

Category:Myelin disorders

Category:Peripheral nervous system disorders