9/28/2020 Management of diabetic neuropathy - UpToDate

Author: Eva L Feldman, MD, PhD

Section Editors: Jeremy M Shefner, MD, PhD, David M Nathan, MD
Deputy Editor: Richard P Goddeau, Jr, DO, FAHA

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2020. | This topic last updated: Jun 26, 2020.

INTRODUCTION

Distal symmetric polyneuropathy (DSPN), often considered synonymous with the term "diabetic
neuropathy," is the most common neurologic complication of diabetes and a major cause of
morbidity. Diabetic neuropathy leads to gradual loss of integrity of the longest nerve fibers, with
symptoms beginning distally and symmetrically in the toes and feet. In addition to neurologic
disability related to sensory loss and risk of foot ulcers and amputations, approximately 15 to 20
percent of patients have painful symptoms that can further limit function and decrease quality of life.

Patients with diabetic neuropathy should be treated with a systematic, stepwise approach that
includes glycemic control and control of the metabolic syndrome, education and counseling on foot
care and safety measures, and symptomatic treatment of pain, when present.

Management of DSPN is reviewed here. The evaluation, diagnosis, and management of other forms
of neuropathy in patients with diabetes, including autonomic neuropathy, are reviewed in detail
separately. (See "Epidemiology and classification of diabetic neuropathy" and "Screening for
diabetic polyneuropathy" and "Diabetic autonomic neuropathy".)

PREVENTIVE CARE

Established, symptomatic diabetic neuropathy is generally not reversible, and management aims to
slow further progression and prevent complications, including diabetic foot ulcers, arthropathy, and
falls.

Glycemic control — The role and importance of glucose control for slowing the progression of
neuropathy and other microvascular complications of diabetes vary by type of diabetes.

In patients with type 1 diabetes, high-quality evidence supports the recommendation to aim for
stable and optimal glycemic control in the management of patients with diabetic neuropathy [1].
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Long-term follow-up of the landmark Diabetes Control and Complications Trial (DCCT)
demonstrated that more intensive glucose control ameliorated the onset of neuropathy as well as
progression of surrogate electrophysiologic markers of neuropathy (figure 1) [2,3]. In a meta-
analysis of DCCT and one additional trial in a total of 1228 patients with type 1 diabetes, enhanced
glucose control lowered the annualized risk of neuropathy (absolute risk difference -1.8 percent,
95% CI -2.6 to -1.1), the incidence of clinical neuropathy after five years (8 versus 17 percent;
relative risk [RR] 0.46, 95% CI 0.33-0.63), and the progression of surrogate measures of
neuropathy, including nerve conduction velocity and vibration perception thresholds [4]. (See
"Glycemic control and vascular complications in type 1 diabetes mellitus".)

In patients with type 2 diabetes, glucose control has a more modest effect on the course of
neuropathy. A meta-analysis of four trials in 6669 patients with type 2 diabetes found a
nonsignificant trend toward a small reduction in the annualized risk of neuropathy with enhanced
glucose control (-0.58 percent, 95% CI -1.4 to 0.01) [4]. The lack of a larger independent effect of
glucose control may reflect a difference in the pathophysiology of neuropathy in type 2 diabetes,
which may relate to components of the metabolic syndrome collectively [5]. As in all patients with
type 2 diabetes, treatment should focus on multiple patient-centered targets to normalize lipids,
blood pressure, weight, and glucose, along with lifestyle modifications to achieve a healthy diet and
regular exercise [1]. (See "Overview of general medical care in nonpregnant adults with diabetes
mellitus", section on 'Multifactorial risk factor reduction'.)

Available data suggest that surgical treatment of type 2 diabetes (ie, bariatric surgery) has the
potential to reduce neuropathy incidence, along with other microvascular complications [6,7]. In a
retrospective case-control study of over 15,000 obese adults with type 2 diabetes, bariatric surgery
was associated with a lower rate of neuropathy at five years (7 versus 21 percent) [7]. Rates of
retinopathy and nephropathy were also lower in the surgical patients. The outcomes of bariatric
surgery are reviewed in more detail separately. (See "Outcomes of bariatric surgery".)

Risk factor modification — Lifestyle interventions are endorsed as an essential practice to prevent
onset and progression of neuropathy, particularly in individuals with prediabetes and type 2 diabetes
[1,8]. Goals include achieving a normal body weight and attaining individualized glycemic, blood
pressure, and lipid goals along with 150 minutes of moderate-to-vigorous aerobic activity and two to
three sessions of resistance training weekly [9]. (See "Nutritional considerations in type 1 diabetes
mellitus" and "Nutritional considerations in type 2 diabetes mellitus" and "Effects of exercise in
adults with diabetes mellitus".)

Vascular risk factor treatment is also endorsed to slow or prevent the progression of diabetic
neuropathy, including improved control of blood pressure, lipids, avoidance of cigarette smoking,

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and avoidance of excess alcohol consumption [1]. (See "Overview of general medical care in
nonpregnant adults with diabetes mellitus".)

Foot care — Peripheral neuropathy is one of the most important risk factors for ulcers and
amputations in patients with diabetes. Foot care in patients with neuropathy is essential to help
lower risk of complications.

On a daily basis, patients should inspect their feet for the presence of dry or cracking skin, fissures,
plantar callus formation, and signs of early infection between the toes and around the toenails.
Regular clinical foot examinations to detect peripheral neuropathy are also an essential component
of preventive care in all patients with diabetes. (See "Evaluation of the diabetic foot" and
"Management of diabetic foot ulcers".)

Safety and falls — Patients with diabetic neuropathy are at increased risk for gait instability and
falls due to progressive loss of proprioception, foot pain, orthostatic hypotension due to autonomic
dysfunction, age-related functional impairments, and medication side effects [1]. Although not well
studied in this specific patient population, multifaceted interventions including home-based exercise,
physical and occupational therapy, and home safety evaluation have been shown to reduce fall risk
in older adults and should be considered for patients with gait and balance abnormalities on
neurologic examination (algorithm 1). (See "Falls: Prevention in community-dwelling older persons",
section on 'Preventing falls'.)

Additional safety precautions in patients with diabetic neuropathy may include handlebars in the
bathroom and shower, use of nightlights to improve visibility, and testing water temperature with an
elbow or uninvolved body part before entering a bath or shower to avoid scalding injury.

B12 deficiency — Metformin reduces intestinal absorption of B12, and the prevalence of borderline
or low B12 levels in metformin-treated patients approaches 20 percent at five years [10]. Patients on
metformin with worsening neuropathy symptoms should be screened for B12 deficiency, particularly
if examination findings are atypical or suddenly worsening. (See "Metformin in the treatment of
adults with type 2 diabetes mellitus", section on 'Vitamin B12 deficiency'.)

PAIN MANAGEMENT

Approximately 15 to 20 percent of patients with diabetic neuropathy have pain in the feet, often
described as burning or stabbing, as a symptom of small myelinated fiber involvement (table 1)
[11,12]. While pain may be self-limited and spontaneously resolve within a year of onset in up to half
of patients [13], others have persistent symptoms and disability related to pain. Symptomatic

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therapies for neuropathic pain are an important component of care in such patients. Pain
medications are not useful for nonpainful symptoms of neuropathy, such as numbness.

Initial pharmacotherapy

Choice of agent — First-line pharmacotherapy options for painful diabetic neuropathy include
several antidepressants (eg, duloxetine, venlafaxine, amitriptyline and other tricyclic drugs) and the
gabapentinoid antiepileptic drugs (pregabalin, gabapentin) [14,15]. Capsaicin can also be used but
is generally poorly tolerated.

The available evidence suggests that all are better than placebo in patients with diabetic neuropathy
and that comparative efficacy is similar, although few high-quality comparative trials have been
done [16-19]. Side effects, dosing frequency, cost, and regulatory approval status may vary. In the
United States, three of these medications are approved by the US Food and Drug Administration
(FDA) for the indication of diabetic neuropathy (duloxetine, pregabalin, and the capsaicin patch
[8%]).

Selection of a specific agent should therefore be individualized based on comorbidities (table 2),
drug interactions, side effect profiles, and cost. In practice, comorbidities and concurrent
medications often favor one class or another (ie, an antidepressant or a gabapentinoid) in an
individual patient, and then the narrower choice within a class is influenced by the patient's age,
preferences with regard to dosing frequency, side effects, and cost/formulary considerations.

● When comorbidities favor an antidepressant – Among the first-line options, a serotonin-

norepinephrine reuptake inhibitor (SNRI; duloxetine or venlafaxine) is a common choice for
patients of any age who are not already taking an antidepressant, as these two drugs are
generally well tolerated and taken once daily. Some clinicians prefer duloxetine over
venlafaxine based on FDA approval status, but most consider them interchangeable when
confronted with cost/formulary differences. For younger patients without a cardiac history, a
tricyclic antidepressant (TCA) is considered an equally reasonable alternative to an SNRI and
may be preferred in a patient with difficulty sleeping, for example, as the drowsy side effects of
the TCAs may alleviate insomnia.

● When comorbidities favor a gabapentinoid – When a gabapentinoid is favored based on a

relevant comorbidity (eg, restless legs syndrome), the choice between pregabalin and
gabapentin is also individualized. The two drugs are similar in their side effect profiles and
requirement for renal dosing; differences include FDA approval status for diabetic neuropathy,
dosing frequency, and sometimes cost.

Administration and efficacy

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Duloxetine — Duloxetine, an SNRI, is a first-line treatment option for neuropathic pain in

patients with diabetic neuropathy [1,20]. It also has efficacy for the treatment of depression, anxiety,
and fibromyalgia. The pain modulatory effect is thought to be mediated primarily by synaptic
norepinephrine and effects on central perception of pain [21].

The recommended starting dose of duloxetine in patients with diabetic neuropathy is 20 to 30 mg

daily [1]. The dose can be gradually titrated upwards based on response and tolerability to a
maximum of 60 to 120 mg daily. Pain improvement may be seen as early as the first week of
treatment [22-24].

Patients are encouraged to take the drug on a full stomach to reduce risk of nausea. Duloxetine
should not be taken with other serotonin or norepinephrine uptake inhibitors (including tricyclic
drugs) but can be combined with pregabalin or gabapentin.

Common side effects of duloxetine include nausea, somnolence, dizziness, decreased appetite,
constipation, diaphoresis, and sexual dysfunction. Duloxetine and other SNRIs can exacerbate
restless legs syndrome, which is common in patients with peripheral neuropathy and can further
disrupt sleep. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb
movement disorder in adults" and "Serotonin-norepinephrine reuptake inhibitors (SNRIs):
Pharmacology, administration, and side effects", section on 'Duloxetine'.)

A 2014 systematic review identified eight randomized trials of duloxetine for painful diabetic
neuropathy in a total of 2728 patients [25]. For duloxetine 60 mg daily, a 50 percent or greater
reduction in pain at 12 weeks was more likely with duloxetine than placebo (45 versus 26 percent;
relative risk [RR] 1.73, 95% CI 1.44-2.08). In trials that included an 11-point Likert score scale to
measure pain, duloxetine reduced the mean pain score by approximately 1 point more than placebo
by 12 weeks. Across trials for multiple painful conditions, drug discontinuation due to adverse
effects was twice as likely for duloxetine compared with placebo (RR 1.96, 95% CI 1.6-2.37). The
120 mg daily dose was similarly effective but not as well tolerated as 60 mg daily.

Venlafaxine — Venlafaxine is an SNRI with a similar spectrum of clinical activity as

duloxetine. Although not as well studied as duloxetine in patients with diabetic neuropathy, the
available data suggest that venlafaxine is a reasonable alternative to duloxetine for this purpose [1].

The recommended starting dose of venlafaxine in patients with diabetic neuropathy is 37.5 mg daily,
titrated gradually upwards to a usual effective dose range of 75 to 225 mg daily [1]. In the largest
randomized trial, pain scores declined gradually from week 1 to week 6, reaching a maximum
reduction at week 6 [26].

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Common side effects of venlafaxine include nausea, somnolence, dizziness, dyspepsia, insomnia,
diaphoresis, and sexual dysfunction. Increased blood pressure and heart rate occur more often with
venlafaxine than placebo. Like duloxetine, venlafaxine can exacerbate restless legs syndrome and
should not be taken with other serotonin or norepinephrine uptake inhibitors (including tricyclic
drugs). (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement
disorder in adults" and "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology,
administration, and side effects", section on 'Venlafaxine'.)

A 2015 systematic review identified six randomized trials of venlafaxine versus placebo or an active
comparator for neuropathic pain in a total of 460 patients, most having painful diabetic neuropathy
[27]. All the included trials showed some benefit for venlafaxine, but all had limitations that could
cause an overestimation of effect size. In the largest trial, extended-release (ER) venlafaxine was
evaluated in 244 patients with painful diabetic neuropathy [26]. For venlafaxine ER at higher doses
(150 to 225 mg daily), a 50 percent or greater reduction in pain at 12 weeks was more likely with
venlafaxine than placebo (56 versus 34 percent). The effects of the 75 mg daily dose were smaller
and not statistically significant.

Tricyclic drugs — Several TCA drugs (amitriptyline, desipramine, nortriptyline) are effective
for neuropathic pain in patients with diabetic neuropathy and can be used cautiously for this
purpose, with attention to their higher risk of serious side effects [1]. Tricyclics are thought to impact
the central perception of pain via effects on synaptic monoamines. Patients should be screened for
heart disease before use. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and
side effects", section on 'Baseline testing and monitoring for safety'.)

The starting dose of amitriptyline or nortriptyline is 10 to 25 mg/day with a gradual titration up to 100
mg/day if painful symptoms persist. Desipramine is begun at 25 mg/day, and the dose can gradually
be increased to a maximum of 200 mg/day over a few weeks. Both amitriptyline and desipramine
should be given at bedtime because of their sedating properties. The therapeutic effect of tricyclic
drugs for pain usually occurs sooner (within six weeks) and at lower doses than is typical when
these drugs are given for the treatment of depression.

Common side effects of TCAs include dry mouth and somnolence. Urinary retention may occur,
especially in men with enlarged prostates. We frequently substitute nortriptyline for amitriptyline if
anticholinergic side effects are a problem, and some experts use nortriptyline as first line because it
has fewer anticholinergic side effects than amitriptyline. Importantly, TCAs are contraindicated in
patients with cardiac disease (either conduction system or ischemic). Similar to the SNRIs, they
should not be given in combination with other serotonergic drugs.

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Supporting data for tricyclic drugs include results of several randomized controlled trials in patients
with painful diabetic neuropathy [17,28-31]. In part because these are older drugs, the number and
size of the trials are generally small, and amitriptyline is the most studied agent. Examples of
comparative trials illustrating the effects and tolerability of tricyclics in the diabetes population
include the following:

● In two randomized, blinded crossover trials in 84 patients with painful diabetic neuropathy,
amitriptyline and desipramine were equally effective and superior to fluoxetine or placebo [29].
The benefit of the tricyclic drugs was noted within two weeks and continued to increase at six
weeks. Desipramine had somewhat fewer side effects than amitriptyline, particularly dry mouth.
The average effective dose, titrated over six weeks to achieve control of symptoms, was 111
mg/day for desipramine and 105 mg/day for amitriptyline. There was no correlation between
relief of pain, dose, or plasma drug concentrations, suggesting that the clinical response and
tolerability of side effects are the best guides to dose titration.

● A randomized, blinded crossover trial in 58 patients with painful diabetic neuropathy that
compared amitriptyline (10 to 50 mg daily) and duloxetine (20 to 60 mg daily) given at bedtime
found an improvement in pain with both medications compared with pretreatment baseline [17].
A good outcome, defined as a median pain score reduction of >50 percent, was reported at a
similar rate for amitriptyline and duloxetine (55 versus 59 percent). Dry mouth was more
frequent with amitriptyline compared with duloxetine (55 versus 24 percent), while constipation
was nonsignificantly more frequent with duloxetine (37 versus 17 percent).

Pregabalin — Pregabalin is an effective first-line alternative to the antidepressant

medications reviewed above in patients with painful diabetic neuropathy [1]. It is an alpha-2-delta
ligand antiepileptic drug that is structurally related to gabapentin. The pain modulatory effect is
thought to relate to presynaptic inhibition of the release of excitatory neurotransmitters including
glutamate, substance P, and calcitonin gene-related peptide (CGRP) [32,33].

A typical starting dose of pregabalin for diabetic neuropathy is 75 to 150 mg per day. The
immediate-release formulation is given in two or three divided doses, and a once-daily extended-
release preparation is also available (165 mg of extended-release is equivalent to 150 mg of
immediate-release). Most trials have used a starting dose of 150 mg per day [34]. The dose can be
titrated in increments of 75 mg per day every three to seven days. A total daily dose of 300 mg is
the maximum dose approved by the FDA for diabetes-associated neuropathic pain, although some
patients may require 450 mg per day. The FDA has approved doses of pregabalin of up to 600 mg
per day for other indications. Higher doses are generally less well tolerated and may have limited
additional efficacy.

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Common adverse effects include dizziness, somnolence, peripheral edema, and weight gain. The
incidence of clinically meaningful weight gain (defined as a ≥7 percent weight increase from
baseline to endpoint) was approximately 2 to 4 percent in trials of pregabalin in patients with
diabetic neuropathy, without effects on glucose control [34].

A 2019 systematic review identified eight randomized trials of pregabalin for painful diabetic
neuropathy in a total of 2320 patients [35]. For pregabalin 300 mg per day, a 50 percent or greater
reduction in pain was more likely with pregabalin than placebo (31 versus 24 percent; RR 1.3, 95%
CI 1.2-1.5). A higher dose (600 mg per day) was studied in two trials and was also more effective
than placebo (41 versus 28 percent). There were no differences in the rate of discontinuation for
adverse effects at any dose level compared with placebo. In a separate meta-analysis, the median
time to a sustained 1-point improvement on an 11-point pain score for pregabalin (at 150, 300, and
600 mg) and placebo was 13, 5, 4, and 60 days, respectively [34].

Gabapentin — Gabapentin has a similar spectrum of clinical activity and side effects as
pregabalin and is a reasonable, sometimes lower-cost alternative to pregabalin when an
antiepileptic drug is favored for first-line therapy [1].

Typical starting doses for gabapentin are 100 to 300 mg one to three times daily; the drug can be
titrated slowly up to a usual effective dose of 900 to 3600 mg daily in three divided doses [1]. The
major side effects of gabapentin are somnolence, dizziness, and ataxia.

In a systematic review that identified six trials in a total of 1277 patients with painful diabetic
neuropathy, the proportion of patients achieving at least a 50 percent pain intensity reduction was
higher with gabapentin (dosed at ≥1200 mg daily) compared with placebo (38 versus 21 percent;
RR 1.9, 95% CI 1.5-2.3) [36]. Individual trials were small but showed consistent effects.

Inadequate response to initial therapy — None of the first-line choices are universally effective or
tolerated, even with appropriate titration. The time to peak response varies across medications, but
in general, a two- to three-month trial is typically required to titrate to effect and gauge response to
initial therapy.

For patients who do not improve on the first medication with appropriate titration, we suggest either
adding a second first-line drug from a different medication class or switching to an alternative
medication among the first-line options discussed above [1]. A common combination strategy is
pregabalin with duloxetine, although other combinations are reasonable as well depending on
individual patient factors.

Results from small trials suggest that the treatment of neuropathic pain with combinations of drugs
from different medication classes is modestly more effective than monotherapy. For example, a

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single-center randomized trial of 47 patients (most with diabetic neuropathy) found that the
combination of nortriptyline with gabapentin was more effective than either agent alone for reducing
the mean intensity of daily pain during week 4 of treatment at the maximum tolerated daily dose
(mean, nortriptyline 50 mg and gabapentin 2180 mg in combination) [37].

For patients who do not tolerate any of these medications or who prefer nonpharmacologic
therapies, we discuss capsaicin cream, lidocaine patch, alpha-lipoic acid (ALA), and transcutaneous
electrical nerve stimulation (TENS). (See 'Nonpharmacologic or topical therapies' below and
'Possibly effective' below.)

Nonpharmacologic or topical therapies — For patients who do not tolerate first-line medications
for neuropathic pain, topical and nonpharmacologic therapies with some evidence of benefit in
diabetic neuropathy include the following:

● Capsaicin – Capsaicin cream (0.075 percent applied topically four times daily) can be used on
its own or added to first-line medications for patients with a partial response or intolerance of
higher doses. It is also available in gel, liquid, and lotion formulations for topical application.
Local burning and skin irritation can occur, but this becomes less of a problem with continued
use. Nevertheless, many patients are unable to tolerate the local burning pain, which is
exacerbated by contact with warm water and hot weather [20].

The high-concentration capsaicin (8%) patch is FDA approved to treat painful diabetic
neuropathy at the feet. Up to four patches are used for a period of 30 minutes once daily.
However, patients may report localized erythema, pain, or post-application sensory loss with
use. Patches must be handled carefully and the application site should be pretreated with a
local anesthetic such as topical lidocaine.

Capsaicin is a naturally occurring component of many hot peppers and causes analgesia
through local depletion of substance P. In randomized trials in patients with painful diabetic
neuropathy, capsaicin has been associated with modest but statistically significant
improvement in pain compared with placebo [20,38-41].

● Lidocaine patches – Limited evidence suggests that application of lidocaine patches (5

percent) can improve pain in patients with painful diabetic neuropathy [42]. Patches may
remain in place for no more than 12 hours in any 24-hour period.

● Electrical nerve stimulation – Although data are limited, a 2010 statement from the American
Academy of Neurology (AAN) assessing the use of TENS for pain in neurologic disorders
concluded that TENS is probably effective for reducing pain from diabetic neuropathy [43],
based upon the following evidence:

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• One trial assigned 31 patients with chronic painful diabetic neuropathy to either TENS or
sham treatment to the legs for 30 minutes daily for four weeks [44]. Symptomatic
improvement (of at least one grade on a unique 0 to 5 scale) occurred in 15 of 18 patients
(83 percent) with TENS treatment, compared with 5 of 13 patients (38 percent) who
received sham treatment (odds ratio 6, 95% CI 1.1-33.4) [44].

• Another trial evaluated 19 patients with mild to moderate symptomatic diabetic

polyneuropathy [45]. Compared with sham treatment, active treatment with TENS led to a
statistically significant reduction in total symptom score at 6 and 12 weeks. In addition,
TENS therapy was associated with a statistically significant but modest improvement in
pain on the visual analog scale at six weeks.

● Acupuncture – Pilot studies indicate that acupuncture may be an effective nonpharmacologic

option for painful neuropathy when delivered individually [46-48] or in a group setting [49]. A
meta-analysis of 25 randomized trials in China concluded that acupuncture improves global
symptoms of painful diabetic neuropathy compared with B vitamins (RR 1.3 to 1.6) or no
treatment (RR 1.6), with no adverse events reported [50].

Other therapies

Possibly effective

● Alpha-lipoic acid (ALA) – For patients who are refractory to or intolerant of first-line
pharmacotherapies and interested in a nutritional supplement approach, we suggest a trial of
oral ALA (600 mg daily). ALA is an antioxidant with the potential to diminish oxidative stress,
improve the underlying pathophysiology of neuropathy, and reduce pain. (See "Pathogenesis of
diabetic polyneuropathy".)

Several prospective, placebo-controlled trials have examined ALA (either intravenous or oral) in
patients with painful diabetic neuropathy [51-54]. In an initial trial, daily intravenous ALA for
three weeks was associated with reduced pain, paresthesia, and numbness compared with
placebo infusions [52]. In a second trial, oral ALA (600, 1200, or 1800 mg daily) versus placebo
was studied in 181 patients with diabetes and symptomatic distal symmetric polyneuropathy
(DSPN) [54]. All three doses of oral ALA treatment were associated with a reduction in the
neuropathy total symptom score (a summation of stabbing pain, burning pain, paresthesia, and
asleep numbness) compared with placebo. The benefit of ALA did not differ by dose. A ≥50
percent reduction in neuropathic symptoms was observed in 50 to 62 percent of patients
treated with ALA versus 26 percent with placebo. Doses higher than 600 mg daily were limited
by increasing adverse events (nausea, vomiting, and vertigo) without increasing efficacy.

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Confidence in the findings is limited by the short duration of this trial. There are no long-term
studies that assess the effect of ALA on progression of neuropathy.

● Valproic acid – Valproate (500 to 1200 mg daily) was effective for reducing pain in diabetic
neuropathy in two small placebo-controlled trials from a single center [55,56]. Larger
confirmatory studies have not been performed, and the gabapentinoids are generally safer and
require less monitoring. Valproate should not be used in patients with liver disease. It has well-
recognized teratogenic effects and should be avoided in women with childbearing potential.

● Carbamazepine – Carbamazepine has a potential role in patients who have failed standard
options based on its efficacy in the treatment of trigeminal neuralgia as well as historical reports
in patients with diabetic neuropathy [57,58]. Contemporary data are lacking, however.

Probably not effective — A systematic review that analyzed data from three randomized trials
concluded that topiramate is not effective for painful diabetic polyneuropathy [59]. Treatments
regarded as probably not effective by an AAN guideline were oxcarbazepine, lamotrigine,
lacosamide, clonidine, pentoxifylline, mexiletine, magnetic field treatment, low-intensity laser
therapy, and Reiki therapy [20].

Not recommended — We avoid the use of opioids for the treatment of painful diabetic
neuropathy because of the lack of evidence regarding long-term effectiveness, and because of the
potential for tolerance, addiction, and overdose. We acknowledge that tapentadol has an FDA
indication for diabetic neuropathy, and that the 2017 American Diabetes Association (ADA)
guidelines state that tramadol or tapentadol may be used as the "last-line" therapy prior to referral to
a pain clinic [1]. However, a more recent systematic review on generalized treatment of pain
suggests that the use of chronic opioid therapy has limited benefit and carries clear medical risk
[60].

This newer statement is supported by an earlier 2009 systematic review of opioids for chronic
noncancer pain, which found a paucity of evidence regarding long-term effectiveness and risks of
such treatment, including the potential for opioid abuse, addiction, and overdose [61]. Similarly, a
2013 systematic review noted that the available randomized controlled trials of opioids for
neuropathic pain did not clearly address the issues of abuse and addiction [62]. In a cohort study of
over 9900 patients prescribed long-term opioid therapy for nonmalignant pain, the use of higher-
dose regimens was associated with an increased risk of opioid overdose [63]. Because of these
issues, we do not use opioids for treatment of painful diabetic neuropathy. A referral to a pain clinic
is suggested for patients whose pain is unresponsive to conventional therapies.

SOCIETY GUIDELINE LINKS

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Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Neuropathy" and "Society guideline
links: Neuropathic pain".)

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e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Nerve damage caused by diabetes (The Basics)" and
"Patient education: Neuropathic pain (The Basics)")

● Beyond the Basics topics (see "Patient education: Diabetic neuropathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Established, symptomatic diabetic neuropathy is generally not reversible, and management

aims to slow further progression and prevent complications, including diabetic foot ulcers,
arthropathy, and falls. (See 'Preventive care' above.)

● Approximately 15 to 20 percent of patients with diabetic neuropathy have pain in the feet, often
described as burning or stabbing, as a symptom of small myelinated fiber involvement. While
pain may be self-limited and spontaneously resolve within a year of onset in up to half of
patients, others have persistent symptoms and disability related to pain. Symptomatic therapies
for neuropathic pain are an important component of care in such patients. (See 'Pain
management' above.)

● Effective pharmacotherapy options for patients with painful diabetic neuropathy include
serotonin-norepinephrine reuptake inhibitors (SNRIs; duloxetine, venlafaxine), tricyclic
antidepressants (TCAs; amitriptyline, desipramine, nortriptyline), and gabapentinoid
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antiepileptic drugs (pregabalin, gabapentin). All have been shown to be more effective than
placebo in randomized trials, and limited comparative data suggest that efficacy is similar
across agents.

• Selection of a specific agent should be individualized. In practice, comorbidities and

concurrent medications often favor one class or another (ie, an antidepressant or a
gabapentinoid anticonvulsant) (table 2). The narrower choice within a class is influenced
by the patient's age, preferences with regard to dosing frequency, side effects, and
cost/formulary considerations. (See 'Choice of agent' above and 'Administration and
efficacy' above.)

● None of the first-line choices are universally effective or tolerated, even with appropriate
titration. A two- to three-month trial is generally required to titrate to effect and assess response
to initial therapy. For patients who do not respond to or tolerate the initial drug, we try an
alternative first-line agent or use a combination of drugs from different classes. (See
'Inadequate response to initial therapy' above.)

● For patients who do not tolerate any of the first-line medications or who prefer
nonpharmacologic therapies, we discuss capsaicin cream, lidocaine patch, alpha-lipoic acid
(ALA), and transcutaneous electrical nerve stimulation (TENS). (See 'Nonpharmacologic or
topical therapies' above and 'Possibly effective' above.)

● We avoid use of opioids for the treatment of painful diabetic neuropathy because of the lack of
evidence regarding long-term effectiveness; the potential for tolerance, addiction, and
overdose; and the availability of multiple safer alternative therapies. (See 'Not recommended'
above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge David K McCulloch, MD, who contributed
to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 13/19

9/28/2020 Management of diabetic neuropathy - UpToDate

1. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by
the American Diabetes Association. Diabetes Care 2017; 40:136.

2. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and
Complications Trial. Ann Neurol 1995; 38:869.

3. Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group. Neuropathy and related
findings in the diabetes control and complications trial/epidemiology of diabetes interventions
and complications study. Diabetes Care 2014; 37:31.

4. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing
and treating diabetic neuropathy. Cochrane Database Syst Rev 2012; :CD007543.

5. Cortez M, Singleton JR, Smith AG. Glucose intolerance, metabolic syndrome, and neuropathy.
Handb Clin Neurol 2014; 126:109.

6. Müller-Stich BP, Fischer L, Kenngott HG, et al. Gastric bypass leads to improvement of
diabetic neuropathy independent of glucose normalization--results of a prospective cohort
study (DiaSurg 1 study). Ann Surg 2013; 258:760.

7. O'Brien R, Johnson E, Haneuse S, et al. Microvascular Outcomes in Patients With Diabetes

After Bariatric Surgery Versus Usual Care: A Matched Cohort Study. Ann Intern Med 2018;
169:300.

8. Bönhof GJ, Herder C, Strom A, et al. Emerging Biomarkers, Tools, and Treatments for
Diabetic Polyneuropathy. Endocr Rev 2019; 40:153.

9. American Diabetes Association. 4. Lifestyle Management: Standards of Medical Care in

Diabetes-2018. Diabetes Care 2018; 41:S38.

10. Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12
Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab
2016; 101:1754.

11. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful
diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006; 29:1518.

12. Ziegler D, Rathmann W, Dickhaus T, et al. Neuropathic pain in diabetes, prediabetes and
normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med 2009;
10:393.

uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 14/19

9/28/2020 Management of diabetic neuropathy - UpToDate

13. Young RJ, Ewing DJ, Clarke BF. Chronic and remitting painful diabetic polyneuropathy.
Correlations with clinical features and subsequent changes in neurophysiology. Diabetes Care
1988; 11:34.

14. Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful
diabetic neuropathy: An umbrella systematic review and comparative effectiveness network
meta-analysis. Ann Intern Med 2014; 161:639.

15. Dy SM, Bennett WL, Sharma R, et al. Preventing complications and treating symptoms of diab
etic peripheral neuropathy. Comparative Effectiveness Review No. 187. AHRQ Publication No.
17-EHC005-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2017. htt
ps://effectivehealthcare.ahrq.gov/ehc/products/612/2436/diabetic-neuropathy-report-170324.p
df (Accessed on April 06, 2017).

16. Boyle J, Eriksson ME, Gribble L, et al. Randomized, placebo-controlled comparison of

amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral
neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of
life. Diabetes Care 2012; 35:2451.

17. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in
painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes
Care 2011; 34:818.

18. Boulton AJ. Is duloxetine more effective than amitriptyline for painful diabetic neuropathy?
Curr Diab Rep 2011; 11:230.

19. Majdinasab N, Kaveyani H, Azizi M. A comparative double-blind randomized study on the

effectiveness of Duloxetine and Gabapentin on painful diabetic peripheral polyneuropathy.
Drug Des Devel Ther 2019; 13:1985.

20. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic
neuropathy: report of the American Academy of Neurology, the American Association of
Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical
Medicine and Rehabilitation. Neurology 2011; 76:1758.

21. Bymaster FP, Lee TC, Knadler MP, et al. The dual transporter inhibitor duloxetine: a review of
its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr
Pharm Des 2005; 11:1475.

22. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine vs. placebo in patients with painful diabetic
neuropathy. Pain 2005; 116:109.
uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 15/19
9/28/2020 Management of diabetic neuropathy - UpToDate

23. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing
duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med
2005; 6:346.

24. Wernicke JF, Pritchett YL, D'Souza DN, et al. A randomized controlled trial of duloxetine in
diabetic peripheral neuropathic pain. Neurology 2006; 67:1411.

25. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or
fibromyalgia. Cochrane Database Syst Rev 2014; :CD007115.

26. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of
painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004; 110:697.

27. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults.
Cochrane Database Syst Rev 2015; :CD011091.

28. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in
patients with normal or depressed mood. Neurology 1987; 37:589.

29. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain
in diabetic neuropathy. N Engl J Med 1992; 326:1250.

30. Kvinesdal B, Molin J, Frøland A, Gram LF. Imipramine treatment of painful diabetic
neuropathy. JAMA 1984; 251:1727.

31. Vrethem M, Boivie J, Arnqvist H, et al. A comparison a amitriptyline and maprotiline in the
treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997; 13:313.

32. Dooley DJ, Mieske CA, Borosky SA. Inhibition of K(+)-evoked glutamate release from rat
neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000; 280:107.

33. Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of
substance P and CGRP from rat spinal tissues only after inflammation or activation of protein
kinase C. Pain 2003; 105:133.

34. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment
for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials
across a range of doses. Diabetes Care 2008; 31:1448.

35. Derry S, Bell RF, Straube S, et al. Pregabalin for neuropathic pain in adults. Cochrane
Database Syst Rev 2019; 1:CD007076.

uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 16/19

9/28/2020 Management of diabetic neuropathy - UpToDate

36. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia
in adults. Cochrane Database Syst Rev 2014; :CD007938.

37. Gilron I, Bailey JM, Tu D, et al. Nortriptyline and gabapentin, alone and in combination for
neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009;
374:1252.

38. Effect of treatment with capsaicin on daily activities of patients with painful diabetic
neuropathy. Capsaicin Study Group. Diabetes Care 1992; 15:159.

39. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind,
vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med 1991; 151:2225.

40. Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in painful diabetic neuropathy.
Controlled study with long-term follow-up. Diabetes Care 1992; 15:8.

41. Simpson DM, Robinson-Papp J, Van J, et al. Capsaicin 8% Patch in Painful Diabetic
Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. J Pain 2017;
18:42.

42. Barbano RL, Herrmann DN, Hart-Gouleau S, et al. Effectiveness, tolerability, and impact on
quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol 2004; 61:914.

43. Dubinsky RM, Miyasaki J. Assessment: efficacy of transcutaneous electric nerve stimulation in
the treatment of pain in neurologic disorders (an evidence-based review): report of the
Therapeutics and Technology Assessment Subcommittee of the American Academy of
Neurology. Neurology 2010; 74:173.

44. Kumar D, Marshall HJ. Diabetic peripheral neuropathy: amelioration of pain with
transcutaneous electrostimulation. Diabetes Care 1997; 20:1702.

45. Forst T, Nguyen M, Forst S, et al. Impact of low frequency transcutaneous electrical nerve
stimulation on symptomatic diabetic neuropathy using the new Salutaris device. Diabetes Nutr
Metab 2004; 17:163.

46. Ahn AC, Bennani T, Freeman R, et al. Two styles of acupuncture for treating painful diabetic
neuropathy--a pilot randomised control trial. Acupunct Med 2007; 25:11.

47. Garrow AP, Xing M, Vere J, et al. Role of acupuncture in the management of diabetic painful
neuropathy (DPN): a pilot RCT. Acupunct Med 2014; 32:242.

uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 17/19

9/28/2020 Management of diabetic neuropathy - UpToDate

48. Abuaisha BB, Costanzi JB, Boulton AJ. Acupuncture for the treatment of chronic painful
peripheral diabetic neuropathy: a long-term study. Diabetes Res Clin Pract 1998; 39:115.

49. Chao MT, Schillinger D, Nguyen U, et al. A Randomized Clinical Trial of Group Acupuncture
for Painful Diabetic Neuropathy Among Diverse Safety Net Patients. Pain Med 2019; 20:2292.

50. Chen W, Yang GY, Liu B, et al. Manual acupuncture for treatment of diabetic peripheral
neuropathy: a systematic review of randomized controlled trials. PLoS One 2013; 8:e73764.

51. Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant
thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 1999;
16:1040.

52. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are
improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003; 26:770.

53. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with
the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 2004; 21:114.

54. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves
symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006; 29:2365.

55. Kochar DK, Jain N, Agarwal RP, et al. Sodium valproate in the management of painful
neuropathy in type 2 diabetes - a randomized placebo controlled study. Acta Neurol Scand
2002; 106:248.

56. Kochar DK, Rawat N, Agrawal RP, et al. Sodium valproate for painful diabetic neuropathy: a
randomized double-blind placebo-controlled study. QJM 2004; 97:33.

57. Rull JA, Quibrera R, González-Millán H, Lozano Castañeda O. Symptomatic treatment of

peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial.
Diabetologia 1969; 5:215.

58. Chakrabarti AK, Samantaray SK. Diabetic peripheral neuropathy: nerve conduction studies
before, during and after carbamazepine therapy. Aust N Z J Med 1976; 6:565.

59. Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for neuropathic pain and fibromyalgia in
adults. Cochrane Database Syst Rev 2013; :CD008314.

60. Busse JW, Wang L, Kamaleldin M, et al. Opioids for Chronic Noncancer Pain: A Systematic
Review and Meta-analysis. JAMA 2018; 320:2448.

uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 18/19

9/28/2020 Management of diabetic neuropathy - UpToDate

61. Chou R, Ballantyne JC, Fanciullo GJ, et al. Research gaps on use of opioids for chronic
noncancer pain: findings from a review of the evidence for an American Pain Society and
American Academy of Pain Medicine clinical practice guideline. J Pain 2009; 10:147.

62. McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database Syst
Rev 2013; :CD006146.

63. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose:
a cohort study. Ann Intern Med 2010; 152:85.

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uptodate.searchbox.science/contents/management-of-diabetic-neuropathy?search=diabetic neuropathy&source=search_result&selectedTitle=1~15… 19/19