560

Diabetic Neuropathy
Elina Zakin, MD1 Rory Abrams, MD2 David M. Simpson, MD, FAAN2

1 Division of Neuromuscular Medicine, Department of Neurology, Address for correspondence Elina Zakin, MD, Department of
NYU Langone School of Medicine, New York, New York Neurology, Division of Neuromuscular Medicine, NYU Langone School
2 Division of Neuromuscular Medicine, Department of Neurology, of Medicine, 222 East 41st Street, New York, NY 10017
Icahn School of Medicine at Mount Sinai, New York, New York (e-mail: [email protected]).

Semin Neurol 2019;39:560–569.

Abstract Diabetes mellitus is becoming increasingly common worldwide. As this occurs, there
will be an increase in the prevalence of known comorbidities from this disorder of
glucose metabolism. One of the most disabling adverse comorbidities is diabetic
neuropathy. The most common neuropathic manifestation is distal symmetric poly-

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neuropathy, which can lead to sensory disturbances, including diminished protective
sense, making patients prone to foot injuries. However, focal, multifocal, and auto-
nomic neuropathies are also common. Diabetic nerve pain and Charcot osteoarthro-
pathy are advanced neuropathic conditions that portend a severe deterioration in
quality of life. To combat these symptoms, along with glycemic control and establish-
ment of health care systems to educate and support patients with the complexities of
Keywords diabetes, there are pharmacologic remedies to ameliorate the neurologic symptoms.
► diabetic neuropathy Several guidelines and review boards generally recommend the use of tricyclic
► distal symmetric antidepressants, serotonin/norepinephrine-reuptake inhibitors, α-2-delta ligands,
polyneuropathy and anticonvulsants as medications to improve painful diabetic neuropathy and quality
► neuropathic pain of life.

Diabetes is an increasingly prevalent disease that has sys- They include cardiovascular disease, stroke, peripheral
temic implications for health and quality of life. According to artery disease, nephropathy, retinopathy, neuropathy, dental
the World Health Organization (WHO), as many as 422 disease, as well as a reduced ability to fight infection.4 It is
million adults globally were living with diabetes in 2014.1 likely that these complications will be increasingly common,
This number is expected to increase; by some estimates as and affect both the local and global burden of disease. Of
many 642 million adults worldwide between the ages of 20 these systemic manifestations of disease, this article will
and 79, a prevalence rate of 8.8% of the population, may be focus on the impact, symptomatology, diagnosis, and man-
afflicted with diabetes by 2040.2 The highest rates of diabetes agement of diabetic peripheral neuropathy.
are expected to be in North America and the Caribbean
region, at a prevalence of approximately 11.5%, as compared
Epidemiology and Disease Burden
with those in Africa, with the lowest rates at approximately
3.8%.2 The Centers for Disease Control and Prevention (CDC) Diabetic peripheral neuropathy occurs in upwards of 50% of
reported that as of 2015, 30.2 million adults living in the individuals with diabetes and is the most common cause of
United States aged 18 years or older, making up approxi- neuropathy worldwide.5,6 The development of diabetic neu-
mately 12.2% of the U.S. adult population. Of those 65 years ropathy seems to be tied to the duration of disease, and
and older, the prevalence increases to more than 25% of causes significant morbidity and disability, manifesting in
adults living with diabetes in the United States.3 Complica- the forms of pain, ulcer formation, poor sleep, and depres-
tions of both type I and type II diabetes are thought to result sion.7,8 As a result, the neuropathy of diabetes is more
both from the vascular and metabolic effects of the disease. common in older adults (>50 years), due to the time it takes

Issue Theme Peripheral Neuropathies; Copyright © 2019 by Thieme Medical DOI https://doi.org/
Guest Editors, Michelle Kaku, MD, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1688978.
Peter Siao, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
 Diabetic Neuropathy Zakin et al. 561

for nerve damage and pain to occur. This raises the question The generalized diabetic peripheral neuropathies are sub-
of how this disorder affects children with diabetes.9 Accord- classified into typical and atypical forms. The typical form is
ing to the SEARCH for diabetes in youth study, the prevalence defined as a “chronic, symmetrical, length-dependent sensor-
of diabetic peripheral neuropathy in children under 20 years imotor polyneuropathy” and is believed to be the most frequent
is 7% in those with type I diabetes, and 22% in those with type manifestation, and the most commonly recognized variety.
II diabetes. Given that the incidence of diabetes is expected to Colloquially, the sensory symptoms in this form have been
increase amongst adolescents in the United States, and that described as following a “stocking and glove” distribution.7,16,19
they would be expected to live for more of their life with Neuropathic pain from diabetes is often used interchangeably
diabetes, the disease would expectedly yield a greater bur- in the literature with DSPN from diabetes, especially in regards
den of associated complications.10 to the management of pain relief and glycemic control.6,11
Along with the medical burden of disease from diabetes, Atypical diabetic peripheral neuropathies are less studied,
there is a tremendous economic loss to people coping with but may present with either an acute, subacute, or chronic
diabetic neuropathy, in the form of direct medical costs, as presentation. Atypical forms may also present as either a
well as indirect costs, in the form of lost opportunity from monophasic or fluctuating illness, and tend to involve both
work and wages.1 A recent U.S. study of the economic costs of small sensory and autonomic fibers.18 For example, one aty-
diabetic neuropathy estimated a per person annualized pical variant presents acutely with allodynia, hyperesthesia,
direct cost of $4,841, and indirect cost of $9,730.11 In 2003, and pain, and is believed to be triggered by abrupt weight loss
and strict glycemic control.15,20 Another important variant that

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the national economic burden of diabetic peripheral neuro-
pathy, and its related complications, was estimated to be has been attributed to both type I and II diabetes presents in
between $4.6 and 13.7 billion annually.12 recurrent clinical episodes as chronic inflammatory demyeli-
Diabetic peripheral neuropathy is not only a costly disease nating polyneuropathy (CIDP), and will meet electrophysiolo-
in terms of morbidity to patients and its broad financial gic criteria for CIDP on nerve conduction studies. Interestingly,
impact, but it is also medically challenging for physicians to it has additionally been noted that CIDP occurs more frequently
manage this chronic condition. The underlying management in diabetic than in nondiabetic individuals.21,22
of diabetes-related hyperglycemia and diabetic foot ulcers
typically requires an interdisciplinary team of experts to
Clinical Manifestations
optimize medical outcomes.13,14 Primary care providers may
feel comfortable diagnosing and managing uncomplicated The most common symptoms of DSPN from diabetes present in
presentations of diabetic neuropathy. However, in patients a slowly progressive, length-dependent manner. This implies
with multiple medical comorbidities and atypical presenta- that the most distal aspects of the lower and upper extremities
tions of diabetic peripheral neuropathy, recognition of this are usually involved first, and then slowly progress or “ascend”
diagnosis may be difficult. Atypical presentations of diabetic proximally over the span of years. Sensory complaints are most
neuropathy, including focal, multifocal, and mononeuropa- frequently reported in this disorder. However, motor symp-
thies, warrant referral to a specialist. The focus herein will be toms can become prominent as the disease advances.23 Symp-
on the most common presentation of diabetic peripheral toms can be classified as a “positive” complaint, such as
neuropathy, which is distal symmetric polyneuropathy tingling, burning, or dysesthesia. Painful DSPN may also be
(DSPN), and the treatment of diabetic nerve pain. described as a sensation of electricity, shooting pain, or contact
hyperalgesia, which tend to occur most prominently at
night.8,19 Sensory symptoms may alternatively be described
Types of Neuropathy
as a “negative” complaint, such as loss of sensation, numbness,
Diabetic neuropathy was first described in the late 1800s, “weakness,” or unsteady gait. Negative symptoms can be
and at the time, was divided into a form with predominantly equally, if not more disabling than, positive or painful com-
patchy motor involvement, and two sensory varieties, plaints, as they can affect the ability to safely ambulate.8 Some
described characteristically with either a predominantly patients with diabetic neuropathy have insensate feet and are
painful or an ataxic picture.15 Since then, the classification thus more prone to injury, are less aware when injuries happen,
of diabetes-related neuropathies has become more specific, and are at greater risk of developing foot ulcerations.23,24
with recognition that patients may be heterogeneous in the Charcot or diabetic foot syndrome, first described in 1883, is
symptomatology, the extent, and the severity of disease.16 a dreaded complication of DSPN, due to the greatly elevated risk
The Toronto Consensus Panel on Diabetic Neuropathy in of lower extremity amputation. This syndrome has been
2009 helped to establish a formal classification and defini- defined as the development of foot injuries and ulcerations
tion schemes for diabetic peripheral neuropathy. in association with peripheral neuropathy, peripheral arterial
The panel first distinguished diabetic peripheral neuropa- disease, localized trauma, inflammation, and acquisition of
thies by pattern of involvement, categorizing the disorders into infection.4 Although pain and discomfort may have been pre-
focal, multifocal, or generalized forms. Focal presentations sent leading up to this stage of disease, there is an inappropri-
include cranial mononeuropathies, such as a third nerve palsy, ately attenuated pain response, when compared with what is
or median neuropathy/carpal tunnel syndrome. Multifocal experienced with a similar injury in others with normal
forms included multiple mononeuropathies, as well as lumbo- sensation. In addition to the loss of protective sensation, the
sacral, thoracic, and cervical radiculoplexus neuropathies.17,18 coincident motor neuropathy is thought to result in

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562 Diabetic Neuropathy Zakin et al.

deformations of foot structure, which further increases the A close evaluation should be performed to establish an early
likelihood of trauma.23,25 diagnosis of DSPN, so as to prevent the occurrence of advanced
Autonomic dysfunction in diabetic neuropathy, while damage from underlying neuropathy.8 However, establishing
distinct from typical DSPN and painful diabetic neuropathy, an early diagnosis of DSPN can be challenging, as more than
poses significant effects on quality of life. Autonomic invol- half of patients may be asymptomatic. In these cases, careful
vement of the gastrointestinal and genitourinary systems examination is crucial for establishing the diagnosis.
may be associated with the extent of diabetic peripheral Bedside testing may focus on the sensory examination,
neuropathy, and also causes marked morbidity. Delayed assessing sensation to multiple modalities, including vibra-
esophageal transit and gastroparesis occur in approximately tion, pinprick or pain, temperature (hot or cold), and light
50 and 40% of long-standing diabetics, respectively. This may touch.7 The loss of vibratory sensation may be the earliest
promote dysphagia, regurgitation, esophageal erosion, and sign of underlying neuropathy.8 Vibration testing should be
strictures. This may also impair medication absorption. performed using a 128-Hz tuning fork. Detailed testing
Erectile dysfunction can also be mediated by autonomic should be performed, assessing either the ability to detect
dysfunction and occurs in approximately 35 to 90% of men the duration of a vibratory stimulus, or using a more quan-
with diabetes. Bladder dysfunction including dysuria, fre- titative approach, measuring vibratory sensation with a
quency, urgency, nocturia, incomplete voiding, and urinary Rydel-Seifer tuning fork. The greatest sensitivity is achieved
incontinence can be attributable to neuronal dysfunction, when the tuning fork is placed over the dorsum of the distal
phalanx of the hallux.33 Light touch sensation can vary

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and is estimated to occur in up to 87% of type I diabetics, and
25% of type II diabetics.16,17 greatly when manually palpating the skin. For this reason,
the use of a 1 g Semmes–Weinstein monofilament, applied
to the plantar or dorsal aspects of the hallux, can be useful in
Pathophysiology
identifying subtle changes in sensitivity, with reasonable
The pathophysiology of diabetic neuropathy is not well specificity for diabetic neuropathy, when compared with
understood, and its etiology is most likely multifactorial. nerve conduction studies. The loss of sensation in response
Several putative mechanisms involving derangements of to a heavier 10 g monofilament may also be useful in
normal metabolic homeostasis, autoimmunity, and micro- predicting ulcer risk.34,35
vascular insufficiency have been implicated.26 The metabolic Examination of the feet should include evaluation of
mechanisms have included oxidative and nitrosative stress, peripheral pulses, as well as a visual and tactile inspection
accumulation of glycation end products, calcium handling for swelling, skin temperature changes, erythema, bony
dysregulation, increased polyol pathway function, and mito- deformities, and frank ulcerations.17,25 Bedside evaluation
chondrial dysfunction.26–30 These mechanisms are believed should also include assessment of deep tendon reflexes,
to affect both the peripheral sensory neuronal cells and the which are usually diminished or absent in DSPN.36 Gait
supportive glial cells.28 Nerve biopsies have revealed degen- evaluation may reveal signs suggestive of sensory ataxia
eration of both unmyelinated fibers, early in the course of including waddling gait, hammertoe deformities, and wast-
neuropathy, and damage to the myelinated fibers, seen in ing, or weakness of the intrinsic muscles of the feet;
more advanced disease.15,17,31 Over time, as these peripheral weakness and atrophy of the hands may be seen in late
lesions relay their signals to the central nervous system, stages of disease.26 ►Fig. 1 below demonstrates the various
central sensitization of nociceptive neurons may occur.32 diagnostic techniques for the diagnosis of diabetic periph-
eral neuropathy.
The prevention and treatment of neurologic conse-
The Diagnostic Evaluation
quences from diabetes should involve a multidisciplinary
Physical Examination team.13,14 These patients should undergo annual or semi-
The diagnosis of DSPN is primarily based on the clinical annual ophthalmologic evaluations for diabetic retinopathy.
evaluation, as provided by a comprehensive history and Joint guidelines established by the American Academy of
physical examination.7,8 The patient’s symptoms should be Ophthalmology, the American Diabetes Association, and the
evaluated in a systematic manner, with a focus on pain. The American College of Physicians recommend annual screen-
clinician should identify the onset of symptoms (whether ing for all postpubertal type I diabetics, and all patients with
sudden or gradual), the pattern and distribution of symptom type II diabetes with disease duration of more than 5 years.
involvement, any progression of symptoms over time, and Critically, fewer than half of such patients undergo the
any therapies that have been attempted.16 The focus of the recommended screening, putting them at a greatly increased
physical examination should be on neurologic tests and risk of vision loss from diabetic retinopathy and macular
evaluation of the feet. Toe and foot amputations may be edema.37 There should also be cardiovascular assessment
the most obvious sign of neurovascular compromise. The due to the elevated risk of morbidity and mortality from
observation of Charcot neuropathic osteoarthropathy in the cardiovascular disease in these patients, estimated at two- to
feet is often overlooked by clinicians, due to the perceived fourfold increase amongst type II diabetics compared with
rarity; however, when recognized early, it indicates the nondiabetics.38 Additionally, concomitant cardiac auto-
occurrence of advanced damage from longstanding nomic neuropathy from diabetes may predispose patients
neuropathy.23,25 to cardiovascular events and dysrhythmias.39,40

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 Diabetic Neuropathy Zakin et al. 563

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Fig. 1 Diagnostic techniques for diabetic peripheral neuropathy.

Laboratory Studies temic vasculitides would be characterized by multifocal or

Evaluation of glycemic control can support the diagnosis of asymmetric pain with one or more attacks.43 Paraproteinemic
DSPN. Measuring fasting glucose levels and noting the pre- neoplasms and paraneoplastic syndromes may also present
sence of glycosuria can be supportive of a diagnosis of diabetes with length-dependent neuropathies.22
and diabetic neuropathy.9 A 2-hour oral glucose tolerance test
increases the sensitivity of the diagnosis of impaired glycemic Nerve Conduction Studies and Skin Biopsy
control. Serial measurements of the hemoglobin A1c levels can While the diagnosis of diabetic neuropathy is predominantly a
be used to track improvement in response to dietary and clinical diagnosis, ancillary studies may be helpful especially in
antiglycemic intervention over time.7 complex and atypical presentations. Nerve conduction studies
Exclusion of alternative etiologies of polyneuropathy is are often a part of the evaluation for diabetic neuropathy,
crucial as disease-specific correction or treatment may be particularly given the variability in symptomatology and
available. Additionally, up to 50% of individuals with diabetes examination, and the broad differential for mimics of DSPN
may have additional, concomitant causes of their peripheral as discussed above. While these studies are well standardized
neuropathy. Assessment should include environmental and and validated for the evaluation of large fiber neuropathy, a
metabolic causes, including alcohol use, thyroid dysfunction, normal examination does not exclude small fiber peripheral
uremia, and heavy metal exposure, if clinically suggested.7 The neuropathy, which can also occur in diabetes.26 In these cases,
most common vitamin deficiencies that cause peripheral intraepidermal quantitation of nerve fibers and small-fiber
neuropathy include vitamin B12 (cobalamin) and vitamin B1 morphology can be ascertained via skin biopsy.44–46
(thiamine). Deficiency of vitamin B6 (pyridoxine) can also Decreased intraepidermal nerve fiber density has been iden-
cause peripheral neuropathy but is unlikely in the absence tified as an early marker of diabetic neuropathy, and corre-
of exposure to provoking pharmacotherapy such as isoniazid, sponds to certain markers of disease.47 Quantitative sensory
penicillamine, and hydralazine.22 testing may also be helpful in documenting and quantifying
Length-dependent symmetric peripheral neuropathy is the both large- and small-fiber pathology.7,16 In general, imaging
most common neurologic manifestation of human immuno- modalities such as computer tomography or magnetic reso-
deficiency virus (HIV) infection, due in part to the prolonged nance imaging are not indicated unless there is a clinical
survival time, as a result of neurotoxic antiretroviral therapies suspicion for nerve entrapment or vertebral disc structural
(ARTs); however, the use of neurotoxic ART has become far less pathology.8 The guidelines presented by the Toronto Consen-
common, particularly in the developed world.41 Other infec- sus Panel on Diabetic Neuropathy provide unifying criteria that
tious etiologies of peripheral neuropathy include hepatitis C, combine a patient’s symptom heterogeneity and severity,
with or without cryoglobulinemia, and Lyme disease.42 CIDP clinical examination, and supporting studies that may be
should be considered in cases of relapsing and remitting helpful in establishing the diagnosis.17,18
episodic disease, or with proximal shoulder and hip girdle
pain. This warrants nerve conduction testing and possibly Symptom Screening Questionnaires
cerebrospinal fluid analysis.7,21,22,26 Vasculitic neuropathies Providers may find it helpful to use questionnaires to quantify
can mimic DSPN, and may be suspected when there is evidence the neuropathy and its impact on quality of life. These include
of systemic symptoms. Laboratory screening would reveal an the short-form McGill Pain Questionnaire, the Michigan Neuro-
elevated erythrocyte sedimentation rate (ESR), while nonsys- pathy Screening Instrument, the Brief Pain Inventory, the

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564 Diabetic Neuropathy Zakin et al.

Neuropathic Pain Questionnaire, the Neuropathic Pain Symp- TCAs are their anticholinergic and cardiac side effects,
tom Inventory, the Norfolk Quality of Life Questionnaire-Dia- including dry mouth, orthostatic hypotension, constipation,
betic Neuropathy Questionnaire, and the Neuropathy and Foot and urinary retention. Other TCAs, such as norpramin and
Ulcer-specific Quality of Life Instrument.48–54 These standar- desipramine, likely have a lower anticholinergic adverse
dized scaling instruments can be used to track therapy response effect profile than amitriptyline. Providers should prescribe
and can be readily adapted to be self-performed or conducted by TCAs with caution to patients with cardiac disease, making
any member on a treatment team. sure to obtain an electrocardiogram for patients receiving
>100 mg per day, or those over the age of 40.60 Both the
NeuPSIG and NICE guidelines recommend TCAs as first-line
Treatment
agents for treatment in diabetic nerve pain.60,61
To date, there is no treatment that can reverse or reliably
prevent disease progression. Treatment modalities focus on Serotonin/Norepinephrine-Reuptake Inhibitors
optimized diabetic management and symptomatic relief. SNRIs, including duloxetine and venlafaxine, are effective in
Glycemic control is the first step in the approach to disease maintaining sustained pain relief for 1 year in an open-label
management, and has been shown to improve occurrence of trial in patients with painful diabetic neuropathy.62 The
falls and presence of foot ulcers. There is evidence that mechanism of drug action is regulation of the descending
pancreas transplant, topiramate, and diet with exercise inhibitory pathways of pain via inhibition of serotonin and
may result in small-fiber regeneration.55–57 Many clinical

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norepinephrine reuptake. Duloxetine can also be used for
trials have been performed to evaluate the efficacy of phar- treatment of comorbid depression and anxiety, with a starting
macologic agents in the management of pain from diabetic dose of 30 mg daily. Duloxetine is safe in patients with comor-
neuropathy. The remainder of this article will focus on the bid cardiac disease, but can result in nausea as an adverse side
pharmacologic management of painful diabetic neuropathy. effect. It is best to initiate at 30 mg, and titrate further to 60 mg
Guidelines from professional societies and expert panels once daily, as gastrointestinal side effects may be less frequent
have been created for the management of neuropathic pain with this slower titration. In contrast to duloxetine (which is
from diabetes mellitus. Societies such as the Toronto Con- recommended as first line), venlafaxine, a different SNRI, is not
sensus Panel on Diabetic Neuropathy, the Neuropathic Pain recommended by the NICE guidelines.61 According to the AAN
Special Interest Group (NeuPSIG), the European Federation guidelines, there are no existing data to suggest superiority of a
of Neurological Societies Task Force, the National Institute for single agent over another, when comparing amitriptyline (TCA)
Health and Care Excellence (NICE), the American Association to venlafaxine and duloxetine.63
of Neurology (AAN) with the American Association of Neu-
romuscular and Electrodiagnostic Medicine (AANEM), and Anticonvulsants
the American Academy of Physical Medicine and Rehabilita- Anticonvulsants have been used for neuropathic pain of many
tion (AAPMR) with several other societies have put together etiologies. Studies show varying degrees of efficacy of this drug
guidelines for the management of painful diabetic neuro- class in the management of neuropathic pain. Specifically,
pathy. Spallone performed a review and comparison of the sodium channel blocking agents, such as carbamazepine,
guidelines put forth by the aforementioned groups.58 This oxcarbazepine, and lamotrigine, function to reduce neuronal
review recommends that the general classes of pharmaco- excitability in the peripheral and central nervous system.
logic agents that should be considered as first-line therapy Though limited data exist, there is a single randomized,
for the management of neuropathic pain from diabetes are placebo-controlled trial that showed the maximum titrated
tricyclic antidepressants (TCAs), serotonin/norepinephrine- dose of oxcarbazepine of 1,800 mg per day to be effective in the
reuptake inhibitors (SNRIs), and α-2-delta ligands. Duloxe- treatment of painful diabetic neuropathy.64 Carbamazepine
tine is also recommended in other guidelines as a first-line showed modest clinical success in small trials for the treat-
agent in the treatment of DSPN.59 ►Table 1 shows the various ment of painful diabetic neuropathy.65 It is important to titrate
pharmacologic agents that can be trialed for management of these medications slowly, and to inform patients that possible
diabetic neuropathic pain. side effects include dizziness, ataxia, sedation, hyponatremia,
as well as confusion in the elderly.
Tricyclic Antidepressants Data on lamotrigine are conflicting, with some studies
TCAs, such as amitriptyline, are cost-effective, may be admi- reporting significant relief of painful diabetic neuropathy,
nistered once daily, and are used to treat comorbid depres- while other studies show no significant benefit as either
sion. The analgesic effects are thought to be mediated by a monotherapy or when combined as an adjunctive treat-
pathway that is different from that which mediates the ment.66–69 The most serious side effect of lamotrigine, though
antidepressant effect. They work by inhibiting the reuptake not common, is Stevens–Johnson syndrome. The more com-
of monoamine neurotransmitters (serotonin and norepi- mon drug side effects include sedation, dizziness, and ataxia.
nephrine) from presynaptic terminals and blockade of ion Topiramate, also used as an anticonvulsant, as well as a
channels. It is advisable to initiate amitriptyline at a low dose migraine prophylactic agent, has been shown in one study to
(i.e., 10–20 mg), and subsequently increase by 25 mg every 3 significantly reduce pain when compared with placebo in a
to 7 days as tolerated. An adequate trial can take 6 to 8 weeks population of patients with painful diabetic neuropathy.70
for efficacy. Perhaps the greatest factors limiting the use of Additional evidence also suggests that topiramate can induce

Seminars in Neurology Vol. 39 No. 5/2019

 Table 1 Pharmacologic therapies for diabetic peripheral sensory neuropathy

Drug class Agent Route Initial dose Dose increment Typical effective dose Adverse side effects
Tricyclic Amitriptyline PO 10–20 mg daily Increase by 25 mg every 25–100 mg daily • Anticholinergic effects: dry mouth, orthostatic hypotension,
antidepressants Desipramine 3–7 d urinary retention
Nortriptyline • Use with caution in patients with cardiac disease
• Obtain EKG if >40 years old and receiving >100 mg/d
Serotonin– Duloxetine PO 20–60 mg daily Increase from 30 to 60 mg daily • Nausea
norepinephrine 60 mg after 7 d • Gastrointestinal upset
reuptake
Venlafaxine PO 37.5 mg daily 37.5–75 mg every 4 d 150–225 mg taken • Cardiac conduction derangements in patients with cardiac disease
inhibitors
daily (extended release) • Should be tapered on discontinuation due to concern for
or three times daily withdrawal syndrome
(immediate release)
Calcium Gabapentin PO 100–300 mg daily to 100–300 mg every 1–5 d 300–1,200 mg three • Administer in reduced doses for patients with renal insufficiency
channel three times/d times daily • Dose-related dizziness and sedation, therefore recommended
α2-δ ligands to start at low dose and titrate with caution
Pregabalin PO 25–75 mg daily to 25–50 mg every 3 d 50–200 mg three times
• Edema, weight gain
three times/d daily or 75–300 mg
• Delayed onset to analgesic effect
twice daily
Sodium Lamotrigine PO 25 mg daily or every Increase by 25–50 mg 100–200 mg once or • Rash (Steven–Johnson syndrome involving oral mucosa)
channel other day for 2 wk per wk twice daily • Gastrointestinal symptoms
antagonists • Headache
• Somnolence
• Dizziness
Topiramate PO 25–50 mg daily Increase by 25–50 mg 50–200 mg twice daily • Weight loss
every wk • Nausea
• Somnolence
• Dizziness
• Paresthesias (due to carbonic anhydrase inhibitor activity)
Oxcarbazepine PO 300 mg twice daily 300 mg every 3 d 1,200–1,800 mg daily • Somnolence
• Ataxia
• Nausea/vomiting
• Up to 23% of patients may develop hyponatremia
Carbamazepine PO 100–200 mg daily 100–200 mg every 2 d 200–400 mg three • Drowsiness
times per day • Difficulties with balance
• Skin rash
• Dizziness
• Rarely, can cause leukopenia, thrombocytopenia, and liver damage
Topical 5% lidocaine Topical 4 patches daily for maximum 12–18 h • Local erythema and rash
agents patch
Capsaicin Topical 0.025–0.075% (low) • Erythema, burning and pain at application site

Seminars in Neurology
patch OR
Diabetic Neuropathy

8% (high)

Vol. 39
Abbreviations: EKG, electrocardiogram; PO, per os (orally).
Zakin et al.

No. 5/2019
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566 Diabetic Neuropathy Zakin et al.

skin intraepidermal nerve fiber regeneration, and enhance are currently FDA approved for postherpetic neuralgia, and
neurovascular function.56 The AAN concludes that there is can be applied up to four times daily. Combination of
insufficient evidence to either support or refute the use of lidocaine 5% patches with pregabalin has been shown to
topiramate in the management of painful diabetic neuro- provide additional relief from pain due to postherpetic
pathy. Additionally, the AAN guidelines conclude that neuralgia, as well as diabetic polyneuropathy in an 8-week
sodium valproate should be considered for the treatment combination phase treatment of 229 patients (68 with post-
of peripheral diabetic neuropathy, whereas lamotrigine, herpetic neuralgia and 161 with diabetic polyneuropathy).77
oxcarbazepine, and lacosamide should probably not be con- Current AAN guidelines recommend the use of lidocaine
sidered for use.63 patches for the treatment of pain from diabetic polyneuro-
pathy with a level C recommendation. Side effects are largely
Calcium Channel α2-δ Ligands related to local skin reactions.
Gabapentin and pregabalin are considered the first-line class
of medications in the treatment of neuropathic pain. They bind Opioids
to voltage-gated calcium channels at the α2-δ subunit and Most consensus panel guidelines for the treatment of neuro-
produce changes in neurotransmitter release. The presumed pathic pain relegate opioid use to those patients that are
mechanism of action of gabapentin and pregabalin is by way of refractory to other first- and second-line therapies, particu-
inhibiting the calcium-channel activation of excitatory trans- larly due to their adverse effect profile and potential for
mitter release and spinal sensitization.71 These drugs are abuse.78 According to the NeuPSIG guidelines, opioids may

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eliminated by the kidney, and not by the liver, which makes be deemed appropriate for first-line therapy in certain circum-
them favorable agents for use when concern for drug–drug stances, such as for the treatment of acute neuropathic pain,
interaction exists. The adverse side effects include dose- exacerbations of severe neuropathic pain episodes, neuro-
related dizziness and sedation; therefore, it is recommended pathic cancer pain, or during a titration of a first-line medica-
that these drugs are started at a low dose and titrated with tion, when immediate pain relief is required. Opioids provide
caution. AAN guidelines recommended the use of pregabalin rapid relief of pain and thus are commonly used in the
in diabetic neuropathic pain management as a level A recom- community as first line for pain control. However, this practice
mendation; gabapentin was given a level B recommenda- has come under severe scrutiny from many quarters, particu-
tion.63 The NICE guidelines also recommend gabapentin and larly in the setting of the current opioid epidemic.79
pregabalin as initial therapies for neuropathic pain.61 Another Tramadol is an agonist of the opioid μ-receptor, but also
study showed that in patients with chronic pain due to diabetic works to inhibit the reuptake of serotonin and norepinephrine.
painful neuropathy or painful herpetic neuralgia, improve- It is similar to other opioid analgesics as it is effective in
ments in patient function and quality of life were correlated achieving quick analgesic efficacy and has the same recom-
with the extent of pain relief, measured in response to treat- mendations by the NeuPSIG as opioids for appropriateness in
ment with pregabalin. This study suggested that these treatment of neuropathic pain.60 Side effects include constipa-
improvements were not mediated solely by relief from pain, tion, sedation, and nausea. It can also lower seizure threshold,
but also from the combined effect on pain and sleep distur- though potential for abuse is less with tramadol as compared
bance, with a direct effect on patient function.72 with other opioids. Tapentadol, which is approved for painful
diabetic neuropathy, is a dual-acting opioid agonist and nor-
epinephrine antagonist, and has been shown to be an effective
Topical Agents
analgesic in patients with painful diabetic neuropathy.80,81
Capsaicin There are significant concerns for safety of use with this
Capsaicin is a transient receptor potential vanilloid type 1 class of drugs. Opioid use could have many deleterious
(TRPV1) agonist. Capsaicin creams of lower strengths, ranging consequences including opioid-associated hyperalgesia,
from 0.025 to 0.075%, have been shown to reduce pain in although extrapolation of animal to human data is contro-
diabetic polyneuropathy.73,74 The AAN recommendations sug- versial. Additionally, there are concerns for opioid abuse and
gest the use of capsaicin for the treatment of diabetic neuro- addiction in patients who suffer from chronic pain, thus
pathy with level B recommendations, while the NICE opioids should be reserved for patients who fail to respond to
guidelines recommend capsaicin cream for the treatment of first-line therapy.
localized neuropathic pain, especially in those individuals who
cannot tolerate systemic side effects of oral treatments.60,61
Conclusion
High-concentration (8% capsaicin) patch has been shown to
provide 12weeks of pain relief, with studies performed in DSPN is the most common form of diabetic neuropathy,
postherpetic neuralgia and HIV-associated neuropathic resulting in significant burden both to the affected individual
pain.75,76 Side effects reported include erythema, burning, or and to society as a whole. Several complications can follow,
pain that is localized to the site of application. including poor sleep, depression, foot ulcers, loss of function,
inability to ambulate, and subsequent limb amputation. The
Lidocaine Patches diagnosis should be made as early as possible, though
Lidocaine is a sodium-channel antagonist, and acts to reduce recognition of neuropathy may be difficult given the extre-
ectopic discharges mediating nociception. Lidocaine patches mely mild symptoms at onset. Treatment typically focuses on

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 Diabetic Neuropathy Zakin et al. 567

pain control, along with modification of risk factors. Glyce- 16 Vinik A, Casellini C, Nevoret ML. Diabetic neuropathies. In: De
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research definition, diagnostic criteria and estimation of severity.
Conflict of Interest
Diabetes Metab Res Rev 2011;27(07):620–628
None.
19 Vinik A. The approach to the management of the patient with
neuropathic pain. J Clin Endocrinol Metab 2010;95(11):
4802–4811
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