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Peripheral Neuropathy: A Practical Approach to

Diagnosis and Symptom Management
James C. Watson, MD, and P. James B. Dyck, MD

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associated with peripheral neuropathy and appropriate dosing guidelines. Date of Release: 7/1/2015
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Peripheral neuropathy is one of the most prevalent neurologic conditions encountered by physicians of all spe-
cialties. Physicians are faced with 3 distinct challenges in caring for patients with peripheral neuropathy: (1) how to
efficiently and effectively screen (in less than 2 minutes) an asymptomatic patient for peripheral neuropathy when
they have a disorder in which peripheral neuropathy is highly prevalent (eg, diabetes mellitus), (2) how to
clinically stratify patients presenting with symptoms of neuropathy to determine who would benefit from specialty
consultation and what testing is appropriate for those who do not need consultation, and (3) how to treat the
symptoms of painful peripheral neuropathy. In this concise review, we address these 3 common clinical scenarios.
Easily defined clinical patterns of involvement are used to identify patients in need of neurologic consultation, the
yield of laboratory and other diagnostic testing is reviewed for the evaluation of length-dependent, sensorimotor
peripheral neuropathies (the most common form of neuropathy), and an algorithmic approach with dosing
recommendations is provided for the treatment of neuropathic pain associated with peripheral neuropathy.
ª 2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(7):940-951

n adults, chronic neurologic disease symp- neuropathy in the general population is 2.4%
toms are one of the most common reasons and increases with age to an estimated 8% in
From the Department of for physician visits (even if headache is those older than 55 years.4,5 Peripheral neu-
Neurology (J.C.W., P.J.B.D.)
and Department of
excluded),1,2 and evaluation of sensory distur- ropathy is more common in patients with dia-
Anesthesiology, Division of bance, including peripheral neuropathy, is one betes mellitus, human immunodeficiency virus
Pain Medicine (J.C.W.), Mayo of the 5 most common reasons for neurologic infection, and dysproteinemic disorders and in
Clinic, Rochester, MN.
consultation.3 The prevalence of peripheral those receiving chemotherapy. In patients with

940 Mayo Clin Proc. n July 2015;90(7):940-951 n n ª 2015 Mayo Foundation for Medical Education and Research

diabetes, for example, length-dependent senso- cohorts, combination testing of vibration plus
rimotor peripheral neuropathy is evident in 8% 10-g monofilament testing provides the best
at the time of diagnosis6,7 but increases in fre- balance of an efficient (less than 2-minute),
quency with disease duration to 30% to sensitive (90%), and specific (85%-89%)
66%,6-9 depending on whether the neuropathy screen for diabetic peripheral neuropathy and
is defined by clinical or electrophysiologic correlates with the development of diabetic
criteria. foot ulcers.15-17 Light touch with a cotton
The primary care physician is presented swab is often substituted for monofilament
with 3 distinct clinical challenges in caring for testing in clinical practice, although its effect
patients with peripheral neuropathy: (1) how on sensitivity and specificity is unknown.
to efficiently and effectively screen (in less than There is an age-related decline in vibration
2 minutes) an asymptomatic patient for periph- sensation, with almost one-quarter of those
eral neuropathy when they have a disorder in older than age 65 years and one-third of those
which peripheral neuropathy is highly prevalent older than 75 years having absent vibration
(eg, diabetes mellitus), (2) how to clinically strat- sensation on clinical examination.18 As such,
ify patients presenting with symptoms of neu- reduced or absent vibration sensation in isola-
ropathy to determine who would benefit from tion should not be overinterpreted in elderly
specialty consultation and what testing is appro- patients and should instead prompt further
priate for those who do not need consultation, history and consideration of other sensory mo-
and (3) how to treat the symptoms of painful dalities to determine its relevance.
peripheral neuropathy. Importantly, screening is meant to identify
whether an asymptomatic patient, at risk for pe-
SCREENING FOR PERIPHERAL ripheral neuropathy secondary to a systemic dis-
NEUROPATHY ease, is likely or unlikely to have a peripheral
The recognition of peripheral neuropathy in pa- neuropathy. Alone, it is insufficient to fully
tients with disorders in which it is highly prev- characterize the neuropathy or direct the neces-
alent may affect the management for that sity of further diagnostic tests or consultations.
disease. Annual screening for peripheral neu- Patients with a positive screening result (ie,
ropathy is recommended in diabetic pa- clinical signs of probable neuropathy) require
tients.10,11 Physicians must be able to screen further clinical history and examination and
these patients in an efficient manner during re- can be evaluated similarly to a patient who pre-
turn office visits that are often focused on other sents with clinical symptoms concerning for
components of the disease and its treatments. neuropathy.
Most recommendations for office screening for
neuropathy have utilized light touch perception EVALUATING PATIENTS PRESENTING
to a 10-g Semmes-Weinstein monofilament, WITH CLINICAL SIGNS OR SYMPTOMS
vibration testing with a 128-Hz tuning fork, SUGGESTING PERIPHERAL NEUROPATHY
superficial pain (pinprick) perception, or
testing of ankle deep tendon reflexes.12-16 Clin- Clinically Stratifying Patients With
ical history alone is an insufficient screen to Peripheral Neuropathy
recognize peripheral neuropathy.15 Although Sensory symptoms (eg, numbness, tingling),
most patients with objective evidence of dia- weakness, autonomic symptoms (eg, early
betic length-dependent peripheral neuropathy satiety, impotence, orthostatic hypotension,
are clinically asymptomatic, they remain at sweat abnormalities), or neuropathic (burning,
risk for injury to insensate feet.17 stabbing, electrical) pain may suggest the pres-
If single-modality screening is used, monofil- ence of a peripheral neuropathy. Once a neu-
ament light touch or vibration testing appears to ropathy is suspected (from patient history
be more sensitive and specific than superficial or screening examination in at-risk patients),
pain (pinprick) or ankle reflex testing.12,13,15 the clinical history and a detailed examination
Because peripheral neuropathies may affect (including strength, sensation, reflexes, and
different types of nerve fibers to different degrees, gait) allow the neuropathy to be categorized
single-modality testing may miss 25% to 50% by either clinical symptom distribution (length
of those with diabetic neuropathy.15 In diabetic dependent, length independent, or multifocal)

Mayo Clin Proc. n July 2015;90(7):940-951 n 941

or by which clinical modality is affected (motor, motor manifestations are usually more evident
sensory, autonomic, or some combination). than in length-dependent neuropathies. Reflexes
The most common pattern of clinical can be useful in these cases because they are glob-
involvement is that of a length-dependent pe- ally reduced or absent. Rare patients present with
ripheral neuropathy. This form of neuropathy is multifocal clinical symptoms (eg, a wrist drop,
symmetric, and symptoms begin in the longest followed by a foot drop). As multifocal processes
nerves at their terminals (ie, distal foot). Negative progress, further neurologic deficits accrue, and
(lack of feeling) or positive (prickling, tingling, the process may begin to look more diffuse. Care-
burning) sensory symptoms usually precede ful history and examination are necessary to
motor weakness. The symptoms ascend insidi- recognize these multifocal neuropathies.
ously up the leg, with hand symptoms often Polyradiculoneuropathies and multifocal
becoming evident around the time leg symptoms neuropathies have a distinct differential diagnosis
approach the knee. Upper limb involvement may from that for length-dependent neuropathies.
never occur. Development of symptoms in the Etiologies include sarcoidosis, amyloidosis,
hands and feet at the same time is atypical for a and neoplastic, paraneoplastic, vasculitic, in-
diabetic length-dependent neuropathy and may fectious, and inflammatory immune-mediated
indicate coexisting carpal tunnel syndrome or causes (such as chronic inflammatory demye-
an alternative cause of neuropathy (eg, a toxic eti- linating polyradiculoneuropathy), all of which
ology). Proprioception is spared relative to other have distinct treatment algorithms. Patients
sensory modalities in mild to moderate length- with a polyradiculoneuropathy or a multifocal
dependent neuropathies and only becomes neuropathy therefore warrant specialty
affected as the neuropathy severity progresses. consultation.
Patients with notable early proprioceptive def- Patients with pure motor or autonomic
icits (gait ataxia, imbalance with eyes closed) signs and symptoms are uncommon and
require further evaluation for posterior column would benefit from neurologic consultation.
disease (eg, vitamin B12 deficiency) or for sen- Those with isolated sensory symptoms that
sory cell body dysfunction (a sensory ganglion- are mild and length dependent can be evalu-
opathy as seen in Sjögren syndrome or a ated similarly to those with length-dependent
paraneoplastic disorder). In length-dependent sensorimotor peripheral neuropathies, where-
neuropathies, as the sensory signs and symp- as patients with severe or diffuse sensory
toms progress, weakness and reflex abnormal- neuropathies causing gait ataxia and proprio-
ities develop distally. ceptive dysfunction would benefit from spe-
The majority of peripheral neuropathies are cialty consultation.
length dependent, sensory predominant, and Regardless of clinical pattern of involvement,
clinically mild to moderate in severity without patients with acute or subacute onset of symp-
major functional limitations. These neuropathies toms or progressive or functionally limiting neu-
can often be effectively evaluated and managed ropathies should be considered for neurologic
without specialty consultation. consultation (Table 1). Similarly, clinicians
Sensory and/or motor symptoms in a should refer any patient when there is clinical
more diffuse, length-independent pattern (ie, uncertainty.
involving both proximal and distal limbs) sug-
gest a polyradiculoneuropathy. Although these Evaluation of Length-Dependent Peripheral
neuropathies may still be sensory predominant, Neuropathies
The combination of history (including family
history), examination, ancillary testing, and
TABLE 1. Neuropathies in Which Specialty Consultation Would Be Beneficial serologic evaluation yields the etiology of a
d Acute, subacute in onset length-dependent peripheral neuropathy in
d Rapidly progressive Regardless of clinical pattern or affected modality 74% to 82% of cases.19 Importantly, although
d Severe, functionally limiting the etiology of 20% to 25% of these neuropa-
d Length independent (polyradiculoneuropathy) thies remains uncertain, the natural history of
d Multifocal these idiopathic neuropathies is that they
d Motor predominant
progress slowly and are unlikely to cause
d Associated with severe dysautonomia
severe physical disability.19
n n
942 Mayo Clin Proc. July 2015;90(7):940-951

Serologic Evaluation. The American Academy considered.8 In up to 10% of diabetic patients,

of Neurology has published a practice parameter neurologic deficits can be attributed to an alterna-
for the evaluation of clinically mild to moderate, tive cause.8 Inherited neuropathy is one of the
symmetric, sensory-predominant length-depen- common alternative causes. Although diabetes
dent peripheral neuropathies.19 The highest- is the likely cause in diabetic patients presenting
yield testing includes screens for diabetes melli- with a length-dependent peripheral neuropathy,
tus, vitamin B12 with methylmalonic acid, and a limited screening laboratory evaluation (eg,
serum protein immunofixation electrophoresis serum protein immunofixation electrophoresis,
(SPIEP).19 A practical evaluation for chronic, vitamin B12 with methylmalonic acid, thyroid
length-dependent peripheral neuropathy is pre- studies) for other treatable metabolic disorders
sented in Table 2. Clinical practice reviews have is reasonable before attributing the neuropathy
revealed poor adherence to screening recom- to diabetes.
mendations.20 In a review of 1031 cases of pe- Diabetes can cause other patterns of neu-
ripheral neuropathy, more than 400 patterns of ropathy including mononeuropathies, thoracic
diagnostic testing were identified.20 In an analysis radiculopathy, a length-independent polyradi-
of patients without known diabetes mellitus to culoneuropathy, and diabetic lumbosacral rad-
explain their neuropathy, low-cost, high-yield iculoplexus neuropathy (also known as diabetic
studies were underutilized (fasting glucose, amyotrophy), so called because of its pathologic
<20%; hemoglobin A1c, 17%; vitamin B12, 41%; predilection toward the lumbosacral segments
monoclonal protein, 19%).20 (although thoracic or cervical involvement is
possible) at the root (“radiculo”), plexus, and
Diabetic Neuropathy. Diabetes mellitus is the peripheral nerve (“neuropathy”) levels. Diabetic
most common cause of peripheral neuropathy radiculoplexus neuropathy is a unique subacute
in Western societies, with a prevalence of up to neuropathy that affects 1% of patients with
30% to 66%6-9 of diabetic patients, depending diabetes.8 It begins with severe pain, often
on whether the neuropathy is defined by clinical involving the proximal aspect of the thigh
or electrophysiologic criteria. Despite the objec- and mimicking a radiculopathy. Weakness
tive evidence of neuropathy, only 10% to 15% of follows and may remain localized or progress
patients with diabetic neuropathy are neurologi- multifocally within the limb or to other
cally symptomatic (from motor, sensory, or limbs. Weight loss often precedes the onset
autonomic dysfunction),8 whereas 11% to 26% of symptoms.27
are limited by associated neuropathic pain.21-23
Although many patients with objective evidence Impaired Glucose Tolerance. There has been
of diabetic neuropathy are asymptomatic, they increasing interest in the role of impaired
remain at risk for injury to insensate feet.17 All glucose tolerance (IGT) as a potential expla-
patients presenting with signs or symptoms of nation for many of the cases of otherwise
peripheral neuropathy should be screened for
diabetes mellitus with fasting glucose and/or he-
TABLE 2. Recommended Evaluation of Chronic, Length-Dependent Peripheral
moglobin A1c measurements.19 The risk of dia- Neuropathy
betic neuropathy, and other late microvascular d Complete blood cell count
complications of diabetes mellitus, can be d Renal function
reduced with tight glycemic control.17,24-26 d Liver function tests
Diabetic neuropathy can take many forms. A d Erythrocyte sedimentation rate (extractable nuclear antigen if dry eyes/mouth and
chronic, length-dependent, sensorimotor periph- sensory neuropathy are present)
eral neuropathy is the most common form. It is a d Fasting glucosea (11%) or hemoglobin A1ca (26%)
late complication of poorly controlled diabetes. It d Thyroid stimulating hormone
usually occurs with other late microvascular d Monoclonal proteina (serum protein immunofixation electrophoresis) (10%)
complications of diabetes mellitus, namely reti- d Vitamin B12 (2%) (with methylmalonic acid 9%)a
nopathy and nephropathy. This association is d Infectious (if risk factors or endemic region): Lyme disease, human immunodefi-
ciency virus
so strong that if there is no clinical evidence of
d Family history of peripheral neuropathy, pes cavus, hammertoesa
retinopathy or nephropathy in a patient with sus-
pected diabetic distal symmetric neuropathy, a
Indicates highest-yield serologic tests with percentage of cases identified.
alternative nondiabetic etiologies should be

Mayo Clin Proc. n July 2015;90(7):940-951 n 943

idiopathic, chronic, sensory-predominant, mL [to convert to pmol/L, multiply by 0.7378]),

length-dependent peripheral neuropathies. 5% to 10% will have elevated serum methyl-
Impaired glucose tolerance has been noted to malonic acid concentrations indicating cellular
be more prevalent in those with idiopathic B12 deficiency.19 Adding methylmalonic acid
neuropathy than in controls.28-30 It has been (with or without homocysteine) to a screen of
suggested that 25% to 50% of idiopathic neu- serum B12 level improves the yield of identifying
ropathies (especially painful small-fiber neu- cellular B12 deficiency as a cause of neuropathy
ropathies) may be explained by IGT.19 The from 2% to 8%.34,35
glucose tolerance test is more sensitive in
identifying IGT than fasting glucose or hemo- Dysproteinemias. Up to 10% of peripheral
globin A1c measurements, and many have neuropathies are associated with dysproteine-
advocated its use as a standard laboratory mias (a 6-fold increase over the general popula-
screen in unexplained length-dependent neu- tion), with the majority being a monoclonal
ropathies.19,30 These associations, however, gammopathy of undetermined significance
have not proven cause and effect, and other (MGUS).36 Evaluation by SPIEP is more sensitive
studies have not found this association.31 in identifying a monoclonal protein than serum
A recent large, controlled trial has addressed protein electrophoresis (SPEP); SPEP misses
this question.32 Patients with new-onset diabetes 17% of all monoclonal proteins identified with
mellitus or IGT and healthy controls had clini- immunofixation and 30% of all IgM monoclonal
cally blinded assessments (history, examination, gammopathies.37 The most common monoclonal
nerve conduction studies, quantitative sensory protein associated with peripheral neuropathy is
testing) for evidence of large- or small-fiber IgM. For the evaluation of patients presenting
peripheral neuropathy, as well as nephropathy with peripheral neuropathy, SPIEP is recom-
and retinopathy. Although as expected, patients mended over SPEP.19
with new-onset type 2 diabetes had a higher The finding of a monoclonal protein neces-
prevalence of peripheral neuropathy, retinop- sitates further evaluation, and possible hemato-
athy, and nephropathy than healthy controls or logic evaluation, to exclude disorders such as
patients with IGT, there was no difference in amyloidosis, multiple myeloma, osteosclerotic
the prevalence of clinically or electrophysiologi- myeloma (POEMS [polyneuropathy, organome-
cally defined peripheral neuropathy, retinopathy, galy, endocrinopathy, monoclonal protein, skin
or nephropathy between the IGT cohort and the abnormalities] syndrome), lymphoma, Walden-
healthy control cohort. This study strongly chal- ström macroglobulinemia, or cryoglobulinemia.
lenges the assertion that IGT causes peripheral Most MGUS neuropathies occur in the
neuropathy or is a frequent cause of idiopathic setting of IgM, IgG, or IgA paraproteinemias
neuropathies. If a patient being evaluated for a (IgM being the most common) and usually
peripheral neuropathy has evidence of IGT, an cause axonal, length-dependent sensorimotor
alternative etiology should be considered (by neuropathies (although polyradiculoneuropa-
defining clinical pattern of involvement, labora- thies can also occur). Most IgM paraproteine-
tory and electrophysiologic testing, and family mias are associated with an MGUS; however,
history). If this same patient subsequently has some are associated with a distinct demyelin-
progression to diabetes, the patient is at risk for ating (distinguishing it from MGUS-associated
the diabetes worsening the neuropathy. axonal neuropathies) clinical syndrome with se-
vere symmetric distal sensory-predominant def-
Vitamin B12 Deficiency. In the nervous system, icits (distal acquired demyelinating symmetric
vitamin B12 is integral in the initial development neuropathy).38,39 Two-thirds of patients with
of and maintenance of myelin.33 Vitamin B12 distal acquired demyelinating symmetric neu-
deficiency can cause classic subacute combined ropathy have serum antimyelin-associated
degeneration or an isolated peripheral neuropa- glycoprotein antibodies.38 This syndrome is
thy without central nervous system involve- important because it may respond to immuno-
ment.34 In patients presenting with a length- modulatory treatments.40
dependent peripheral neuropathy, the serum The peripheral neuropathy associated with
B12 level should be measured. Among patients POEMS syndrome is typically a uniform mixed
with low-normal serum B12 levels (200-500 pg/ demyelinating and axonal length-independent
n n
944 Mayo Clin Proc. July 2015;90(7):940-951

polyradiculoneuropathy in the setting of an IgG be related to medication toxicity include the

or IgA paraproteinemia with a l light chain.41 use of a known neurotoxic medication (eg,
POEMS syndrome is associated with osteoscler- chemotherapeutic agents), temporal onset of
otic myeloma and increased levels of serum symptoms with initiation or dosage adjustment
vascular endothelial growth factor. of an implicated medication, worsening symp-
Electrophysiologic characterization of the toms with higher dosages, onset of symptoms
neuropathy and neurologic consultation should in the hands and feet concomitantly, and symp-
be considered in patients with non-MGUS para- tom stabilization or resolution following discon-
proteinemias, IgM paraproteinemias, and/or tinuation of the offending agent.46 Of note,
functionally limiting neuropathies. although most toxic neuropathies show at least
stabilization soon after the toxic agent is dis-
Other Laboratory Tests. Although patients continued, some medications (particularly
presenting with a thyroid disorder often have platinum-based chemotherapeutic agents) may
neuromuscular complaints, hypothyroidism is remain active for several weeks or months after
an uncommon cause of a length-dependent pe- discontinuation, and stabilization or improve-
ripheral neuropathy. Because hypothyroidism is ment may not be evident immediately.47
a prevalent treatable disorder, however, patients Excessive, long-term alcohol use can cause
presenting with peripheral neuropathy are peripheral neuropathy, usually in the context of
commonly tested for this disease.35 other systemic complications including nutri-
In geographic regions where Lyme disease tional deficiencies, particularly thiamine defi-
is prevalent or in patient populations with risk ciency. Long-term alcohol use may also have a
factors for human immunodeficiency virus direct neurotoxic effect.46
infection, routine screening may be appro- A comprehensive list of potentially neuro-
priate as part of the evaluation of peripheral toxic medications or supplements is beyond
neuropathy. the scope of this article but has been addressed
Celiac disease was found to be responsible by others.46,48
for 2.5% of peripheral neuropathy cases present-
ing to a tertiary referral center.42 Usually, these Hereditary Neuropathies. Inherited neurop-
patients have sensory-predominant neuropa- athies are the most common inherited neuro-
thies and associated gastrointestinal symptoms, muscular condition worldwide and likely
although neurologic signs and symptoms may represent the most commonly overlooked eti-
precede gastrointestinal symptoms and some ology of peripheral neuropathy.49-51 In fact,
recommend screening all patients.42 Antietissue they may be the most common cause of pe-
transglutaminase antibodies are the most sensi- ripheral neuropathy (although this has not
tive serologic screen, but their specificity is been firmly established). Charcot-Marie-Tooth
limited in association with neurologic disease, disease, also referred to as hereditary motor
and confirmation with small-bowel biopsy and sensory neuropathy, is the most common
should be obtained before attributing neuropa- form of hereditary neuropathy and can be
thy to celiac disease.42,43 categorized into axonal and demyelinating
Copper deficiency can mimic vitamin B12 forms. In Western countries, these neuropathies
deficiency clinically (with a myelopathy and are most commonly autosomal and X-linked
sensory-predominant neuropathy) and should dominant.52
be considered when patients have a history of Clinically, a hereditary neuropathy is sug-
bariatric surgery or multiple nutritional defi- gested by an insidious onset of symptoms
ciencies or if high zinc exposure (nutritional with a slow progressive course over years,
supplement or in some denture pastes) is distal-predominant motor greater than sensory
suspected.44,45 complaints, lack of positive sensory symptoms
Vitamin E deficiency may be considered in (dysesthesias, burning), associated structural
patients at risk for fat malabsorption. foot and ankle deformity (pes cavus, hammer-
toes, and inverted champagne bottle legs with
Toxic Neuropathies. Many neuropathies are very thin ankles), and a family history of neurop-
the result of toxic effects of prescribed medica- athy. It is common that family members are un-
tions. Contextual cues that a neuropathy may aware of a family history even when one is

Mayo Clin Proc. n July 2015;90(7):940-951 n 945

TABLE 3. Neuropathic Pain Treatment Tiersa

Maximum Common and notable Comorbid
Agent Dosing dosage Precautions adverse effects conditions treated Comments
Tier 1
Gabapentinb 300 mg at bedtime, increase every 4-7 3600 mg/ d Renal insufficiency (dosage adjust); Sedation, dizziness, confusion, Seizure disorder, sleep 100-mg increments available for slower
d by 300-mg increments initially to 3 (split TID) risk of seizure if abruptly stopped edema, tremor disturbance, chronic titration; no notable drug interactions
times daily, then to goal of 1800 migraine, hot flashes
mg/d as necessary to 3600 mg/d
Pregabalinb 75 mg twice daily; after 4-7 d, increase 600 mg/d Renal insufficiency (dosage adjust); Sedation, dizziness, confusion, Seizure disorder, sleep Can split 3 times daily but better compliance
Mayo Clin Proc.

by same dosage to goal of 300 mg/d (split BID) risk of seizure if abruptly stopped; edema, tremor, euphoria disturbance, with 2 times daily dosing with similar
as necessary to 600 mg/d psychiatric disease or addiction (Schedule V controlled fibromyalgia, central efficacy; 25- and 50-mg dosing available
history (euphoria risk) substance) pain related to spinal for slower titration; no notable drug
cord injury, anxiety interactions

Amitriptyline, 10-25 mg at bedtime, increase every 150 mg/d Risk of serotonin syndrome; caution Sedation, dry mouth, Depression, Goal dosing for pain usually inadequate for
July 2015;90(7):940-951

nortriptylineb 4-7 d to goal of 100 mg at if cardiac disease or dysrhythmia orthostatic hypotension, fibromyalgia, chronic mood effect; higher dosages (w100
bedtime history confusion, weight gain, migraine, sleep mg/d) often necessary for neuropathic
urinary retention, disturbance, irritable pain; secondary amine TCAs
constipation, blurred vision bowel syndrome (nortriptyline, desipramine) have lower
adverse effect profile than tertiary amine
TCAs (amitriptyline)
Duloxetineb 20-30 mg once daily, then increase 120 mg/d Risk of serotonin syndrome; increased Sedation, fatigue, nausea, Depression, anxiety, Dosing for neuropathic pain is adequate for
fibromyalgia, chronic

weekly by same dosage to goal of (split BID) bleeding risk (care with hyperhidrosis, dizziness, treatment of depression/anxiety

60 mg/d anticoagulants), withdrawal syndromes modest hypertension musculoskeletal pain,

with abrupt discontinuation, caution urinary incontinence


with hepatic failure

a-Lipoic acid 600 mg once daily 600 mg/d Caution if tendency toward Nausea, rash, hypothyroidism None Generally well tolerated
Acetyl-L- 1000 mg 3 times per day 3000 mg/d None Nausea, bloating, agitation None Generally well-tolerated
carnitine (split TID)
Lidocaine Apply patch for 12 h 3 patches per Avoid over broken skin Localized skin irritation; no None May cut patch to shape
(5%) patch application notable systemic toxicity

Continued on next page
Mayo Clin Proc. n July 2015;90(7):940-951

TABLE 3. Continued
Maximum Common and notable Comorbid
Agent Dosing dosage Precautions adverse effects conditions treated Comments
Tier 1, continued
Capsaicin (8%) Should be placed by medical staff trained 4 patches per Avoid face or placing over broken skin Localized skin irritation; no None Postprocedural skin irritation common;
patch in its usage using nonlatex gloves; application notable systemic toxicity prescription oral analgesics frequently
pretreat area with 4% topical lidocaine required for 7-10 d after application;
for 60 min, confirm anesthesia, apply single application may provide pain relief
patch(es) to affected area (may cut to for up to 3 mo
shape) for 60 min, wipe clean with
provided soap
Tier 2


Venlafaxineb 37.5 mg once (extended release) or 225 mg/d Risk of serotonin syndrome; Sedation, nausea, dizziness, Depression, anxiety, Similar mechanism of action to duloxetine;
twice (immediate release) daily; withdrawal syndrome with abrupt headache, insomnia, panic attacks, social consider trial if duloxetine not covered by
increase by 75 mg/d weekly to initial discontinuation; caution with cardiac nervousness, abnormal phobia, hot flashes insurance; higher dosages (150-225
goal of 150 mg/d disease or poorly controlled ejaculation, modest mg/d) required for neuropathic pain;
hypertension hypertension (dosage >150 increasing blockage of norepinephrine
mg/d) reuptake at higher dosages causes
increased risk of hypertension
Tramadol 50 mg twice daily; increase every 400 mg/d Caution if history of addiction, Nausea, constipation, sedation, Is a nonspecific analgesic Blocks reuptake of serotonin and
4-7 d to maximum of 100 mg per analgesic misuse or diversion, severe dizziness, flushing, seizures that will cover norepinephrine (like antidepressants) in
dose 4 times per day psychiatric comorbidities, seizure (dosages >400 mg/d) multiple pain types addition to being m-opioid receptor
disorder, taking other serotonergic agonist; risk of serotonin syndrome when
agents, hepatic or renal dysfunction used with other serotonergic agents
Tier 3
Tapentadol 50 mg every 4-6 h prn; increase every 600 mg/d
Caution if history of addiction, Nausea, sedation, constipation, Is a nonspecific analgesic FDA approved for painful diabetic
4-7 d to maximum of 100 mg analgesic misuse or diversion, severe dizziness, pruritus, that will cover peripheral neuropathy; blocks reuptake of
every 4 h prn psychiatric comorbidities, seizure headache, hypotension, multiple pain types serotonin and norepinephrine (like
disorder, taking other serotonergic respiratory depression, antidepressants) in addition to being
agents, hepatic dysfunction seizure m-opioid receptor agonist; risk of
serotonin syndrome when used with
other serotonergic agents
Opioids 15 mg oral immediate release morphine No maximum Caution if history of addiction, Nausea, sedation, constipation, Is a nonspecific analgesic Neuropathic pain studies used long-acting
(or another opioid of equianalgesic dosage analgesic misuse or diversion, dizziness, pruritus, that will cover agents that should not be used in opioid-
dose such as 10 mg oxycodone) 3-4 severe psychiatric comorbidities headache, respiratory multiple pain types naive patients; begin with short-acting
times per day, transition to long-acting depression agents
agents if regular use of short-acting
BID ¼ twice daily; FDA ¼ US Food and Drug Administration; prn ¼ as needed; TID ¼ 3 times daily; TCA ¼ tricyclic antidepressant.
All antidepressants and anticonvulsants carry an FDA warning that they may paradoxically cause worsening mood or emerging suicidality in a very small percentage of patients. Patients should be aware of both physical and
emotional adverse effects of medications.

present. All patients with an idiopathic neurop- delta). As such, normal findings on EMG do
athy should be encouraged to discuss this not exclude a small-fiber peripheral neuropa-
further with their family. If a family member ac- thy (which clinically presents with prominent
companies the patient, a screening examination pain, sensory loss, and dysautonomia).
may suggest the diagnosis.
Algorithms have been developed to direct Test of Small Nerve Fiber Function. A num-
sequential genetic testing in suspected cases ber of tests can evaluate possible small-fiber
of hereditary neuropathy based on the inheri- peripheral neuropathies (autonomic reflex
tance pattern and whether the neuropathy is screen, testing of sweat function, quantitative
axonal or demyelinating.19,52 Indiscriminate, sensory testing, and epidermal skin biopsy for
nondirected serologic screens for hereditary nerve fiber density); however, some are not
neuropathies are expensive, have low yield, widely available. Like peripheral pain pathways,
and often do not alter management, especially the autonomic nervous system is under the
if there are no clinical features or family history control of small thinly myelinated and unmy-
to suggest a hereditary neuropathy. elinated fibers. As such, tests of sweat (sudo-
motor) function, heart rate variability to
Other Diagnostic Tests respiration and Valsalva maneuver, blood pres-
Nerve Conduction Studies and Electromyo- sure, and heart rate response to tilt (orthostatic
graphy. In patients presenting with neurologic hypotension) can objectively identify small
signs or symptoms suggestive of a peripheral neu- nerve fiber dysfunction. These autonomic tests
ropathy, electromyography (EMG) and nerve are most useful in neuropathies with notable
conduction studies (NCSs) are useful to confirm autonomic impairment. In the evaluation of
the suspected diagnosis, exclude mimickers (S1 small-fiber neuropathies without clinical dys-
radiculopathies in a patient with foot symptoms autonomia, tests of sweat function are more
or carpal tunnel syndrome in a patient with useful. All of these autonomic and sweat tests
hand paresthesias), localize the process (length can be substantially influenced by medications,
dependent, length independent, multifocal), adversely affecting specificity.
confirm the modalities affected (sensory, motor), Skin biopsy is a validated technique for
define whether the neuropathy is secondary to determining intraepidermal nerve fiber density
axonal loss, demyelination, or both, and define (somatic unmyelinated C-fiber nerve termi-
the severity of the neuropathy. In cases of mild, nals) and has increasing availability. It has a
nonefunctionally limiting length-dependent sensitivity of 90% in diagnosing a small-fiber
neuropathies in which there is little clinical un- neuropathy, with specificity of 95% to 97%.19
certainty, EMG may not be necessary. Electro- Quantitative sensory testing refers to
myography/NCSs are central to the evaluation of controlled applications of large- and small-
cases with diagnostic uncertainty, length- fiber sensations to the skin to determine the
independent or multifocal processes, function- threshold for detection. In small-fiber neurop-
ally limiting neuropathies, or any neuropathy athies, the response to thermal (hot and cold)
severe enough to require neurologic consultation. stimuli is most pertinent, and the heat-pain
Because the electrophysiologic pattern and path- threshold has very good sensitivity for a
ophysiology are so central to the evaluation of small-fiber neuropathy. Patient cooperation is
atypical neuropathies, specialists will likely prefer necessary for an accurate measurement,
to perform their own EMGs in patients with although testing paradigms can help identify
length-independent, multifocal, or severe neu- inconsistencies suggesting malingering or
ropathies. Electromyography can still be useful inattentiveness.
directly to the nonspecialist for confirming the
suspected diagnosis and excluding common Nerve Biopsy. A nerve biopsy may be useful to
mimickers such as mononeuropathies or assess for possible inflammatory-mediated neu-
radiculopathies. ropathies (vasculitis, sarcoidosis, chronic inflam-
Electromyography/NCSs assess the func- matory demyelinating polyradiculoneuropathy),
tion and integrity of large, myelinated A some infectious neuropathies (leprosy), or infil-
beta nerve fibers. They do not assess small trative neuropathies (carcinoma, lymphoma,
nerve fibers (C fiber and small myelinated A amyloidosis, polyglucosan bodies). These
n n
948 Mayo Clin Proc. July 2015;90(7):940-951

neuropathies are frequently severe, progres- Patients with neuropathic pain can be chal-
sive, and not otherwise explained by serologic lenging to treat and have annual health care
and other ancillary testing. Neurologic expenditures three times higher than those
consultation should be obtained before nerve without pain.54 As with any chronic pain state,
biopsy. The sural nerve is most commonly comorbid depression, anxiety, and sleep distur-
biopsied, although the nerve selected for bances are common, occurring in up to one-
biopsy should be clinically involved. Impor- half of those with painful neuropathy.55
tantly, a sural nerve biopsy is not indicated Several consensus algorithms for the treat-
just because a neuropathy is idiopathic and ment of chronic neuropathic pain have been pro-
unexplained by serologic and ancillary posed and compared.56-60 Only one has focused
testing. explicitly on painful diabetic peripheral neuropa-
thy.61 However, because most randomized
SYMPTOMATIC MANAGEMENT OF controlled trials for neuropathic pain have been
PERIPHERAL NEUROPATHY performed for painful diabetic neuropathy or
The primary goal in the evaluation of neuropa- postherpetic neuralgia, this guideline mirrors
thy is to identify the etiology and if possible treat the other algorithms (Table 3). First-line agents
the underlying cause. However, even when the include anticonvulsants that block the a2-d ligand
neuropathy has a treatable etiology (such as dia- of the presynaptic calcium channel (gabapentin
betes mellitus, vitamin B12 deficiency, or toxic or pregabalin) and thereby decrease nociceptive
exposure), treatment serves primarily to prevent transmission, tricyclic antidepressants (secondary
further progression of the neuropathic symp- amines such as nortriptyline and desipramine
toms. Symptoms present at the start of treat- have a lower adverse effect profile than tertiary
ment or when a toxic agent is removed may amines such as amitriptyline), or selective
improve and occasionally resolve. However, serotonin-norepinephrine reuptake inhibitors
more commonly patients are left with lingering (duloxetine). The choice of first-line agents is
symptoms from the pretreatment neurogenic based on patient comorbidities. For example, pa-
injury. In these cases and in those in which tients with comorbid depression may benefit
the neuropathy is idiopathic or untreatable, from duloxetine, which can be used to treat
management is symptomatic. both the depression and the neuropathic pain
Because most patients with a length- with similar dosing, whereas the effective dosage
dependent peripheral neuropathy have sensory- of tricyclic antidepressants for neuropathic pain
predominant symptoms, patients should be is usually insufficient for therapeutic treatment
counseled on the importance of foot care and of depression or anxiety. Similarly, tricyclic anti-
properly fitted footwear. Patients should monitor depressants, duloxetine, or pregabalin may be a
their feet for early signs of ulceration or injury good first-line agent in patients with comorbid
that sensory loss may mask. fibromyalgia, whereas patients with comorbid
One of the most limiting symptoms from pe- chronic migraine may benefit from gabapentin
ripheral neuropathy is neuropathic pain. Among or a tricyclic antidepressant. Comorbidities may
diabetic patients with neuropathy, 11% to 26% also relatively contraindicate a particular agent.
have neuropathic pain.21-23 Common neuro- For example, tricyclic antidepressants should
pathic pain descriptors (burning, pins and nee- be avoided or used with caution in patients
dles, electrical, or shooting pain), whether with preexisting orthostatic hypotension, cardiac
used alone or in standardized surveys meant to dysrhythmia, or urinary hesitancy. Patients with
identify neuropathic pain, are limited in regard small areas of localized pain may be able to be
to sensitivity and specificity.53 In one diabetic treated with topical agents (Table 3).
cohort of patients with lower limb pain, the Effective dosages for neuropathic pain have
pain was attributable to diabetic neuropathy in been defined (Table 3), but failed medication tri-
only one-third of cases.21 Allodynia (pain from als are commonly caused by inadequate dosing. If
a nonpainful stimulus such as the light touch a patient has a partial response to a first-line agent,
of clothing) or hyperalgesia (excessive painful a second first-line agent with a distinct mecha-
response to a normally painful stimulus such nism of action should be added to the first agent.
as pinprick) are highly specific for neuropathic Combination therapy utilizing neuropathic pain
pain but are uncommon. medications with different mechanisms of action

Mayo Clin Proc. n July 2015;90(7):940-951 n 949

has been repeatedly found to be more efficacious Control and Prevention website.
than single-agent treatment.62 If a first-line agent ahcd/NAMCS_2010_factsheet_neurology.pdf. Accessed May
13, 2015.
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IGT = impaired glucose tolerance; MGUS = monoclonal
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