Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy
Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy
Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy
Reviews
Diabetic Peripheral Neuropathy: Epidemiology,
Diagnosis, and Pharmacotherapy
Zohaib Iqbal, MRCP1; Shazli Azmi, MRCP, PhD2; Rahul Yadav, MRCP, MD3;
Maryam Ferdousi, PhD2; Mohit Kumar, MRCP4; Daniel J. Cuthbertson, FRCP, PhD5;
Jonathan Lim, MRCP5; Rayaz A. Malik, FRCP, PhD2,6; and Uazman Alam, MRCP, PhD5,7,8
1
Department of Endocrinology, Pennine Acute Hospitals NHS Trust, Greater Manchester, United
Kingdom; 2Institute of Cardiovascular Science, University of Manchester and the Manchester Royal
Infirmary, Central Manchester Hospital Foundation Trust, Manchester, United Kingdom; 3Department of
Endocrinology, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, United Kingdom;
4
Department of Endocrinology, Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, United
Kingdom; 5Diabetes and Endocrinology Research, Department of Eye and Vision Sciences and Pain
Research Institute, Institute of Ageing and Chronic Disease, University of Liverpool and Aintree University
Hospital NHS Foundation Trust, Liverpool, United Kingdom; 6Weill Cornell Medicine–Qatar, Doha,
Qatar; 7Department of Diabetes and Endocrinology, Royal Liverpool and Broadgreen University NHS
Hospital Trust, Liverpool, United Kingdom; and 8Division of Endocrinology, Diabetes and
Gastroenterology, University of Manchester, Manchester, United Kingdom
(Clin Ther. 2018;40:828–849) & 2018 Elsevier HS studies that were not considered relevant to the aims
Journals, Inc. All rights reserved. of this article. Further appraisal of selected articles
Key words: diabetes, diagnosis, epidemiology, neu- were undertaken and any relevant explanatory data
ropathy, pharmacotherapy. from said articles were included in the present review
as descriptive prose.
INTRODUCTION
Diabetes has reached epidemic proportions world- Epidemiology
wide, with International Diabetes Federation estimates Epidemiologic studies of diabetic neuropathy have
suggesting a prevalence of 425 million people world- provided heterogeneous results, owing to different pa-
wide in 2017, rising to 628 million by 2045.1 This rise tient populations, definitions of neuropathy used, and
will be accompanied by an increase in the prevalence methods of assessments. Prediabetes is also associated
of the complications of diabetes.2 DPN is the most with neuropathy.11 In the San Luis Valley cohort,12 the
common cause of neuropathy worldwide, and is prevalence of peripheral neuropathy in patients with
estimated to affect around half of people with diabetes was 25.8%, as compared to 11.2% in subjects
diabetes.3,4 It causes considerable morbidity, impairs with impaired glucose tolerance (IGT) and 3.9% in
quality of life, and increases mortality.5,6 Indeed, control subjects. The MonItoring trends and
approximately one fourth of the US health care determinants in CArdiovascular/Cooperative Research
expenditure on diabetes is spent on DPN.7 in the Region of Augsburg (MONICA/KORA)13
Diabetic neuropathy refers to a collection of clin- investigators found the prevalence of neuropathic pain
ically diverse disorders affecting the nervous system, to be 13.3% in patients with diabetes versus 8.7%,
with differing anatomic features, clinical courses, and 4.2%, and 1.2% in subjects with IGT, impaired fasting
phenotypes. The common underlying pathophysiology glucose, and controls, respectively. PROMISE
is a consequence of hyperglycemia and microangiop- (Prospective Metabolism and Islet Cell Evaluation)14
athy.8 The commonest form is distal symmetric followed up patients longitudinally who were at risk for
sensorimotor polyneuropathy9; however, most body developing diabetes. At 3 years, the prevalence of
systems can be affected through involvement of the neuropathy (as assessed using the Michigan
autonomic nerves. Despite the considerable, health Neuropathy Screening Instrument) was 50% in
care–related economic burden and effect on quality patients who developed diabetes, 49% in those with
of life in DPN, treatment options are limited and prediabetes, and 29% in controls.15
prevention remains the key goal.10 The purpose of this In a Spanish study, the reported prevalence of DPN
review was to critically review the current literature on in primary care was 21% compared to 27% in-
the diagnosis and treatment of DPN, with a focus on hospital.16 The Rochester Neuropathy Study evaluated
the treatment of neuropathic pain in DPN. data from 380 participants16; DPN, diagnosed using a
multifaceted approach, including the neuropathy
symptom score, neuropathy disability score, and nerve
MATERIALS AND METHODS conduction studies, was found in 66% and 59% of
A comprehensive literature review was undertaken, patients with type 1 and 2 diabetes, respectively.
incorporating article searches in electronic databases Importantly, approximately 10% of participants had
(EMBASE, PubMed, OVID) and reference lists of
a nondiabetic etiology of the neuropathy.16
relevant articles with the authors' expertise in DPN. A large-scale, multicenter study (N ¼ 6500) re-
Articles published from inception of databases to vealed DPN (based on questionnaire and examina-
December 2017 were identified. Data from articles
tion) in 28.5%.4 A community-based study in
that were felt not relevant by authors with the ~15,000 patients with diabetes showed that 34% of
guidance of the senior reviewers (R.A.M., U.A.) were patients had symptoms of painful neuropathy, with an
excluded from the review. increased risk in patients with type 2 diabetes, women,
and people of South Asian origin.17
RESULTS The prevalence of DPN is considered to be low
Databases searches were undertaken and 188 papers in patients with early type 1 diabetes; however,
were cited in the final manuscript. Authors excluded among participants in the Diabetes Control and
Complications Trial (DCCT), the prevalences of ab- angiotensin-converting enzyme inhibitors,29 and therefore
normal neurologic exam results were almost 20% in trials need to be of longer duration.
those on conventional treatment and almost 10% in
those on intensive treatment, after ~5 years of follow- Glycemic Control
up.18 In the EURODIAB IDDM complications Glycemic control has been shown to prevent or
study,19 which evaluated over 3000 patients across delay the progression of neuropathy in patients with
16 countries, there was a 28% baseline neuropathy type 1 diabetes.30 The Pittsburgh Epidemiology of
prevalence, which rose by 23.5% after 7 years. The Diabetes Complications Study suggested that duration
risk factors for the development of neuropathy of diabetes, HbA1c, smoking status, and high-density
included age, duration of diabetes, poor glycemic lipoprotein cholesterol are associated with
control, elevated low-density lipoprotein cholesterol neuropathy.31,32 The Wisconsin Epidemiologic Study
and triglycerides, hypertension, obesity, and of Diabetic Retinopathy reported a 20% decrease in
smoking.19 The EDIC (Epidemiology of Diabetes the prevalence of DPN for a 2% decrease in HbA1c
Interventions and Complications) study, following over 4 years of follow-up.33 In DCCT, HbA1c values
up patients up for 13 years after the initial 6.5 years were 7.4% in the intensive group and 9.1% in the
of the DCCT,8 showed an initial 64% reduction in the conventional group, and the risk reduction for incident
risk for DPN in those on intensive compared to DPN with intensive glucose control was 64% after 6.5
conventional treatment during the DCCT period and years of follow-up.8 By the 5th year of the EDIC study,
a 30% risk reduction was maintained in the follow-up despite HbA1c values in the 2 groups being similar
EDIC study period.8 (8.1% vs 8.2%), the prevalences of DPN and cardiac
More recently, the prevalence of DPN in youth with a autonomic neuropathy remained significantly lower in
shorter duration of diabetes has been reevaluated. In patients who had been on intensive therapy compared
SEARCH (the Search for Diabetes in Youth Study),20 a to standard therapy during DCCT.34 This phenomenon
cohort of young people (aged o20 years) who had a has been termed metabolic memory.
duration of diabetes of over 5 years were evaluated using In type 2 diabetes, the evidence for the role of
the Michigan Neuropathy Screening Instrument.21 Data improved glycemic control in slowing the progression
from 1374 patients with type 1 diabetes and 258 with of neuropathy in patients is limited.35–37 ACCORD
type 2 diabetes were studied, revealing prevalence rates of (Action to Control Cardiovascular Risk in
DPN of 7% and 22%, respectively,21 suggesting an Diabetes )36 showed a significant reduction in loss of
excessive burden of DPN even in adolescents. sensation to light touch, which was only 1 of 4
neuropathy end points after a follow-up of 5 years.
Pathogenetic Treatments It should be noted that the intensive glucose-lowering
Numerous pathogenetic treatments that target the regimen was associated with increased mortality
underlying molecular and cellular mechanisms involved (hazard ratio ¼ 1.22; 95% CI, 1.01–1.46; P ¼ 0.04),
in DPN, including aldose reductase inhibitors, benfoti- suggesting harm associated with tight glycemic control,6
amine, and protein kinase C inhibitors, have undergone and self-reported DPN conferred a higher risk for
clinical trials over the past 4 decades.10 All have failed in mortality in the intensive glycemic control group than
Phase III clinical trials, and none have been approved by in those with a higher HbA1c and those on aspirin.38
the US Food and Drug Administration (FDA) as disease-
modifying treatments for DPN.22,23 Multiple reasons Lipids
have been cited for this failure. In part, the end points There is an association between plasma triglycerides/
selected, including composite clinical scores and quanti- remnant lipoproteins and the risk for DPN.19 In animal
tative sensory testing (QST), which relies on patients' models, treatment with specific fatty acids, such as
responses, are deemed to be subjective24 and prone to docosahexaenoic acid, have been shown to exhibit a
high variability, and even objective measures such as protective effect and potentially even can reverse DPN.39
neurophysiology have been shown to have high It has been suggested that cholesterol-lowering treatments
interobserver variability.25–28 It is now also evident that (statins and ezetimibe)40,41 and triglyceride-lowering treat-
the rate of DPN progression is slower than predicted,23 in ments (fibrates)40 may reduce the progression and severity
part due to concomitant use of routine therapies such as of DPN. Well-planned randomized trials are needed to
evaluate the impact of intensive plasma lipid normaliza- the bariatric surgery group as compared to a non-
tion on DPN. surgical treatment group in patients with type 2
diabetes after at least 5 years of follow-up.46 In a
Diet and Lifestyle Interventions study of bariatric surgery in patients with and without
In patients with IGT, lifestyle intervention could diabetes, there were improvements in body mass
arrest the underlying process that leads to neuropathy. index, systemic inflammation, metabolic parameters,
The Diabetes Prevention Program study42 and small nerve fibers, as measured by corneal
demonstrated that lifestyle changes and treatment confocal microscopy (CCM).47
with metformin reduced the prevalence of diabetes Micronutrient deficiencies after bariatric surgery
in those with IGT. Lifestyle intervention may also be are associated with an acute neuropathy,48,49 and
effective in preventing DPN, as shown in the IGT longer longitudinal studies that accurately phenotype
Causes Neuropathy study,43 in which diet and neuropathy are required to delineate potential risk
exercise counselling in subjects with IGT resulted in factors for this condition.
increased intraepidermal nerve fiber density (IENFD)
and an improvement in neuropathic pain.
Diagnosis of DPN
Weight Loss The American Diabetes Association's position state-
Experimental studies have shown that incretin-based ment on diabetic neuropathy (2017) advises that the
therapies have valuable effects on diabetic complications, early recognition of neuropathy and initiation of
independent of their glucose-lowering abilities, mainly appropriate management are essential to the manage-
mediated by their antiinflammatory and antioxidative ment of patients with diabetes.50 Alternative etiologies
stress properties.44 However, in a pilot study in patients of neuropathy should be actively diagnosed and treated.
with type 2 diabetes and mild to moderate DPN, 18 These include chronic inflammatory demyelinating
months of treatment with exenatide, compared with polyneuropathy, B12 deficiency, hypothyroidism, and
glargine, had no effect on neuropathy.45 uremia, which may concomitantly occur in diabetes.51
In a meta-analysis of data from 10 studies, there The tests frequently used to diagnose DPN have been
was greater remission and lower risks for micro- listed in Table I, along with their advantages &
vascular and macrovascular disease and mortality in disadvantages and type of nerve fiber they assess.
CCM ¼ corneal confocal microscopy; NCS ¼ nerve conduction studies; NDS ¼ neuropathy disability score; QST ¼
quantitative sensory testing.
Quantitative Sensory Testing with QST. An inverse correlation has also been shown
QST, which includes a thermal threshold assess- between IENFD and the duration of diabetes,
ment for cold sensation (A-δ fibers) and warm sensa- neurologic impairment score, and results of sensory
tion (c fibers), assesses small fiber dysfunction and evaluation.70,71
therefore can detect early neuropathy, but is highly
subjective. However, QST is a sensitive method of Novel Surrogate Imaging Markers of DPN
detecting SFN, particularly in those patients with Corneal Confocal Microscopy
normal nerve conduction study results,64 and may Over the past 2 decades, the significance of evalu-
be used where no definitive quantitative structural ating corneal nerve morphology as a surrogate marker
assessment of small nerve fibers (skin biopsy or CCM) for peripheral neuropathies has been established.
can be undertaken. CCM has been suggested as a surrogate end point
Also, vibration perception threshold, assessed using for the assessment of DPN, as it allows direct visual-
a biothesiometer, correlates with the severity of DPN, ization of peripheral nerves and is a rapid, non-
and a vibration perception threshold of 425 V is a invasive, and objective technique,72,73 with high
strong predictor of foot ulceration.65 sensitivity and specificity to diagnose early nerve fiber
damage23 and repair.74 Several studies have shown
Nerve Conduction Studies that CCM is highly correlated with IENFD loss23 and
Nerve conduction studies (NCSs) are commonly is comparable to the diagnostic ability of skin
used to assess the severity of DPN and are considered biopsy.75,76 A number of parameters are used to
to be sensitive and specific for DPN.66 Interestingly, quantify the corneal sub-basal nerve plexus and
Dyck et al24 compared NCS to individual physicians' include corneal nerve fiber length, corneal nerve
clinical diagnosis of DPN and found that clinician's branch density, and corneal nerve fiber density.
diagnoses were excessively variable and frequently CCM has been extensively used to identify small
inaccurate, with an overestimation of DPN. Vinik nerve fiber damage in a range of peripheral neuro-
et al67 conducted a study in 205 patients with both pathies, including DPN,77,78 HIV neuropathy,79
type 1 and 2 diabetes and mild DPN and showed that chemotherapy-induced peripheral neuropathy,80
81 82
sural nerve conductivity correlated well with the CIDP, Fabry disease, and idiopathic SFN.83
severity of DPN. However, NCSs evaluate only large CCM can detect subclinical small nerve fiber
myelinated nerve fibers and cannot detect an early damage in patients with IGT84 and has been shown
SFN as commonly seen in prediabetes and short- to predict the development of DPN85 and the end
duration diabetes. The ADA's position statement points of foot ulceration and Charcot foot.86 CCM
does not advocate the routine use of NCS, and it may be an ideal technique to monitor the progression
should be reserved for patients with atypical features of DPN, as it is noninvasive and hence reiterative.87
in whom the diagnosis is unclear.50
Optical Coherence Tomography
Skin Biopsy Optical coherence tomography is a noninvasive,
Skin biopsy enables direct visualization of thinly reproducible ophthalmic imaging technique that was
myelinated and nonmyelinated nerve fibers that are recently introduced as a surrogate end point for the
the earliest to be affected in DPN. Skin biopsy can be assessment of retinal nerve fiber loss in neurologic
used to diagnose SFN.68 The European Federation for conditions.88,89 Retinal nerve fiber layer (RNFL)
Neurological Societies' guidance recommends a punch thinning is reported in patients with DPN associated
skin biopsy at the distal leg or proximal thigh for the with the severity of neuropathy, particularly in pa-
diagnosis of SFN.69 The assessments of intraepidermal tients with a higher risk for foot ulceration.90 Previous
nerve fibers and IENFD are currently advocated in studies have suggested that RNFL loss in patients with
clinical practice in the United States43 and are diabetes may be independent of diabetic retinopathy
recommended as an end point in clinical trials.23 and represents a distinct type of neuropathy.91,92
Pittenger et al70 showed a reduction in IENFD in Measuring RNFL thickness has also been suggested
patients with SFN, with a sensitivity between 74% as a potentially useful means to assess and monitor
and 87.5%, and that IENFD was inversely correlated axonal loss in patients with DPN, as RNFL thinning
was greater in patients with DPN compared to those number needed to treat (NNT) (6.9 vs 3.9).99 In a
without DPN over the course of 4 years.93 However, smaller-scale study, the relative efficacy of 5%
larger-scale, longitudinal prognostic and interven- lignocaine was assessed in 15 patients with IN and
tional studies using optical coherence tomography as 25 patients with non-IN, a greater effect on pain
a surrogate marker are required before routine use of paroxysms and deep aching pain was found in those
this modality can be recommended. with IN.100 We have also demonstrated preclinical
The use of optical coherence tomography as a evidence on the physiology and pharmacology of rate-
possible diagnostic modality is still in its infancy and dependent depression of the spinal H-reflex as a
requires longitudinal studies alongside established marker for spinal disinhibition in painful diabetic
biomarkers, such as electrophysiology and skin bi- neuropathy,101 and recently translated the use of
opsy. CCM has a wealth of research, particularly in rate-dependent depression as a biomarker of spinally
DPN. However, the availability of CCM as a diag- mediated pain to a personalized-medicine approach in
nostic modality is limited due to a lack of expertise the treatment of painful DPN.102 In this section, we
in its use as a surrogate marker in peripheral consider the current pharmacologic treatments for
neuropathies. alleviating pain in DPN, the most frequently used of
which are highlighted in Table II.
Symptomatic Treatment of DPN
Neuropathic pain is a debilitating feature of DPN Antidepressants
resulting in significant morbidity.94 Current guidelines Neurologic pathways implicated in mood disorders
advocate the use of therapies targeting the symptoms of share neurotransmitters with pathways associated
painful DPN, particularly as there is a lack of with pain processing.103 It is therefore not surprising
treatments targeting the pathogenetic mechanisms. that there is a dual utility in alleviating neuropathic
Although measures such as tight glycemic control pain.
may prevent the progression of diabetic neuropathy,
there is no evidence that improved glycemic control Tricyclic Antidepressants
improves pain in DPN. Moderate improvements in The precise mechanism of action of TCAs in
pain are considered to be ~30% to 50% pain relief, analgesic efficacy is unclear, but they are thought to
whereas 450% pain relief is considered a good indirectly modulate the opioid system in the brain via
outcome.95 A recent systematic review concluded that serotonergic and norepinephrine neuromodulation,
duloxetine, venlafaxine, pregabalin, oxcarbazepine, among other properties.104–106 TCAs require up-titra-
tricyclic antidepressants (TCAs), atypical opioids, and tion to effective doses, often over a period of 6 to 8
botulinum toxin were more effective than placebo for weeks before reasonable effects are noted; hence,
relieving neuropathic pain, but quality of life was compliance may sometimes be compromised.107 A
poorly reported. Studies were however short term and meta-analysis by Rudroju et al108 concluded that
drugs had substantial discontinuation rates of ~10%.96 amitriptyline was the least effective but a well-
The limited benefit of any one agent alone reflects tolerated agent compared to other antidepressant
the complex etiologic basis of neuropathic pain. Thus, agents used to treat painful DPN. In a joint report
there is an increasing recognition that "one size does on painful DPN from the American Academy of
not fit all," and rather than having an agnostic Neurology, the American Association of
approach (ie, blindly trying different therapies until Neuromuscular and Electrodiagnostic Medicine, and
one works), we should consider better clinical pheno- the American Academy of Physical Medicine and
typing and targeted therapies.97 However, superficial Rehabilitation, published in 2011, it was concluded
clinical phenotyping in relation to symptomatology that amitriptyline has the greatest efficacy among the
has not been shown to improve the response to TCAs.109 Despite studies showing the efficacy of
therapy.98 More detailed phenotyping using QST imipramine,110 it was also concluded that there is
has shown that patients with an irritable nociceptor currently insufficient evidence for the routine use of
(IN) phenotype (n ¼ 31) compared to a non-IN imipramine.
phenotype (n ¼ 52) had a significantly greater TCAs remain as the first- or second-line recom-
response to oxcarbazepine and a reduced overall mendations in all 5 international guidelines on pain
Table II. Commonly used therapies for painful diabetic peripheral neuropathy.
Common
Initial Maintenance Adverse
Drug Class Agent Dose Dose Reactions Common Drug Interactions
Common
Initial Maintenance Adverse
Drug Class Agent Dose Dose Reactions Common Drug Interactions
Anorexia
Nausea
Urinary
retention
Constipation
Blurred vision
Mydriasis
Weight gain
Xerostomia
Somnolence
Opioids Tramadol 50 mg 200– 400 mg Constipation Concurrent use with MAOIs and
QID QID linezolid increases risk for serotonin
syndrome.
Somnolence Combination therapy with SSRIs,
Nausea SNRIs, TCAs, or antipsychotics can
Headache lower seizure threshold, leading to
Dizziness convulsions. Combination use with
caution is advised.
Tapentadol 50–100 600 mg daily Same as Concurrent use with SSRIs or SNRIs
(immedi- mg 4–6 above may increase risk for serotonin
ate times syndrome. Use with caution is
release) per day advised.
Can take Concurrent use with MAOIs can result
700 mg in hypertensive crisis.
on first Use with enzyme inducers such as
day rifampicin or St John's wort may
reduce efficacy.
MAOIs ¼ monoamine oxidase inhibitors; SNRIs ¼ serotonin norepinephrine re-uptake inhibitors; SSRIs ¼ selective serotonin
re-uptake inhibitors; TCAs ¼ tricyclic antidepressants.
management in DPN, with most citing amitriptyline as extent, venlafaxine, which does not have FDA appro-
the drug of choice among the TCAs (Table III). The val for use in the treatment of painful DPN. A third
2017 position statement from the ADA stated that, serotonin–norepinephrine reuptake inhibitor is des-
although effective for the treatment of neuropathic venlafaxine, which was evaluated in a single random-
pain, TCAs should be used with caution given ized, controlled trial and showed some efficacy.114
their higher-risk profile, particularly in elderly These drugs primarily exert their effect via inhibiting
populations.50 serotonin and norepinephrine reuptake, resulting in
the excitation of inhibitory descending pathways with
Serotonin–Norepinephrine Reuptake Inhibitors alleviation of neuropathic pain.115
Two serotonin–norepinephrine reuptake inhibitors Duloxetine at both 40 mg and 60 mg has shown
are used in painful DPN, duloxetine and, to a lesser efficacy in treating painful DPN.116 A Cochrane review
Line of Treatment EFNS (2010)111 AAN (2011)109 NICE (2013)112 AACE (2015)113 ADA (2017)50
AACE ¼ American Association of Clinical Endocrinologists; AAN ¼ American Academy of Neurology; ADA ¼ American
Diabetes Association; EFNS ¼ European Federation of Neurological Societies; NICE ¼ National Institute of Clinical
Excellence (UK); SNRI ¼ serotonin norepinephrine reuptake inhibitor; TCA ¼ tricyclic antidepressant.
including 8 trials (n ¼ 2728) showed that 60 mg of amitriptyline.123 Venlafaxine has shown superiority to
duloxetine daily was more efficacious compared with duloxetine in some studies; however, there is a lack of
placebo, with a 50% pain reduction by 12 weeks (NNT larger-scale trials showing this effect.124 Additionally, it
¼ 5; 95% CI, 4–9).117 Tanenberg et al118 showed that is important to note that venlafaxine must be slowly
duloxetine was noninferior to pregabalin in treating weaned to reduce the potential for adverse events,124
painful DPN in patients exhibiting an inadequate and it has not been approved by the FDA for use in
response to gabapentin. Duloxetine has a superior treating neuropathic pain.
safety profile compared to amitriptyline, owing to the
comparably lower rates of anticholinergic side effects. Anticonvulsants
However, one study found a 20% and 14% respective Similarities in the mechanisms of neuropathic pain
prevalence of somnolence and constipation in a cohort and epilepsy led to the use of anticonvulsant medi-
of patients treated with 60 mg of duloxetine daily.119 A cations in the treatment of painful DPN.125
post hoc analysis of 3 pooled, double-blind, placebo- Carbamazepine has been used efficaciously in the
controlled trials evaluating the use of duloxetine in management of trigeminal neuralgia for many years;
older patients (aged 465 years) advocated the however, a Cochrane Collaboration review found that
tolerability and efficacy of this drug in the older it had limited utility in the treatment of painful
population.120 DPN,126 and it is not recommend for painful DPN.
Venlafaxine showed efficacy in treating painful DPN Similarly, in a recent Cochrane review, oxcarbazepine
in a double-blind placebo controlled trial in which showed little evidence for efficacy in painful diabetic
pain-intensity visual analog scale (VAS) scores were neuropathy.127
used as the primary outcome measure.121 A Cochrane
Collaboration systematic review122 of venlafaxine for α2δ Ligands
the treatment of neuropathic pain reported an NNT of Gabapentin is a lipophilic analogue of γ-amino-
3.1 (95% CI, 2.2–5.1), which is comparable to that of butyric acid that binds to the α2δ1 subunit of the
voltage-gated calcium channel on the presynaptic treatment of painful DPN are pregabalin and dulox-
membranes and reduces excitability of chiefly gluta- etine. The COMBO-DN study was designed to com-
minergic neurones.128 pare the efficacy and tolerability between high-dose
Backonja et al129 investigated its use in neuropathic monotherapy and standard-dose combination therapy
pain in a double-blind, placebo-controlled trial of patients with both pregabalin and duloxetine.139 This
randomized to either gabapentin or placebo. Significant multinational, randomized, double-blind, parallel-
improvement in pain scores were seen 8 weeks after the group trial was conducted in patients with painful
start of treatment.129 A systematic review of 35 studies (n DPN resistant to standard-dose monotherapy. After
¼ 727) in patients with unselected neuropathic pain randomization and elimination of noneligible patients,
concluded that gabapentin was an effective agent in 173 received high-dose monotherapy with either
alleviating pain; however, its effectiveness may be duloxetine 120 mg daily or pregabalin 600 mg daily,
reduced if administered at low doses.130 Rudroju and 170 patients received combination therapy with
et al108 compared the efficacy and tolerability of 6 duloxetine 60 mg daily and pregabalin 300 mg
agents used in the management of painful DPN in a daily.139 A 2-point reduction in the Brief Pain
meta-analysis of data from 21 trials and concluded that Inventory score was the primary outcome measure;
gabapentin provided a good balance between tolerability no significant difference was shown when comparing
and efficacy for the treatment of painful DPN. the standard-dose combination therapy to the high-
Pregabalin, another analogue of γ-aminobutyric dose monotherapy therapy in those who did not
acid has higher potency and has been approved achieve adequate pain relief on standard-dose
by the FDA for use in treating painful DPN duloxetine or pregabalin.139
based on several robust randomized, controlled trials In a secondary analysis, duloxetine 60 mg was
that have shown its efficacy in the treatment of found to be more efficacious compared with pregaba-
painful DPN.131–133 Snedecor et al134 undertook a lin 300 mg/day in the initial 8-week run in phase. To
comparative meta-analysis of data from studies of a date, this is the only head to head trial of duloxetine
number of agents in the treatment of painful DPN and and pregabalin. A further exploratory post hoc anal-
found pregabalin to be the most efficacious in ysis of data from Combination vs. Monotherapy of
reducing pain VAS scores. pregaBalin and duloxetine in Diabetic Neuropathy
Somnolence is listed as a common side effect of (COMBO-DN) showed that high-dose monotherapy
pregabalin, as studies in healthy volunteers have was favorable in patients with severe pain, whereas
shown that it enhances slow-wave sleep. A placebo- combination therapy was more beneficial in patients
controlled trial evaluated the efficacy of pregabalin, with moderate and mild pain.140 Also, patients who
amitriptyline, and duloxetine in pain relief and the received duloxetine (60 mg/d) as initial therapy had a
effects on sleep.135 Duloxetine increased sleep better response to combined duloxetine and
fragmentation, while pregabalin promoted sleep.135 pregabalin for evoked or severe tightness and a
These findings are in agreement with those from greater benefit with high-dose duloxetine (120 mg/d)
previous studies showing that pregabalin improves for paresthesia–dysaesthesia.140,141
subjective sleep and quality of life in patients with
painful DPN.136,137 Side effects include edema and
mood disturbance, and it is important to warn Other Anticonvulsants
patients not to abruptly discontinue its use, as this The use of topiramate has been evaluated in several
has been linked to the development of seizures, placebo-controlled trials, with differing results. Raskin
cerebral edema, and encephalopathy.138 Both et al142 randomized 323 subjects to topiramate versus
gabapentin and pregabalin are commonly prescribed placebo and found a significant 30% reduction in pain
as first-line agents for treating painful DPN, and this is VAS scores with topiramate.142 A recent smaller study
indeed a reflection of the current recommendations. from Iran143 showed that gabapentin and topiramate
equally reduced pain scores.143 However, a Cochrane
COMBO-DN Study Collaboration review of data from 3 placebo-
The only 2 medications with both FDA and Euro- controlled, parallel-group trials showed that
pean Medicines Agency approval for use in the topiramate lacks evidence of efficacy in painful DPN.144
Lamotrigine is chemically unrelated to other anti- patients and a 50% pain reduction in 34.9% of
epileptic agents. It is thought to exert its antiepileptic patients.150 A subsequent 12-week study confirmed
effect via sodium channels. Lamotrigine has been these earlier data, and in 2012 the FDA approved the
assessed in painful DPN. Eisenberg et al145 observed use of modified-release tapentadol for the treatment of
a significant reduction in the numeric pain scale in neuropathic pain.151
83% of patients randomized to lamotrigine compared
to 73% receiving placebo, but this study was relatively Opioid Agonists
small-scale (n ¼ 59). In an analysis of data from 2 There is increasing concern for opioid dependency,
randomized trials, lamotrigine (300 and 400 mg daily) especially during long-term use, despite the efficacy of
showed inconsistent effects in DPN, and while it was opioids in treating neuropathic pain.152 A Cochrane
well tolerated,146 it cannot be advocated for use in Collaboration review153 evaluated the use of
painful DPN.147 oxycodone modified release, morphine, levorphanol,
A double-blind, placebo-controlled trial of lacosa- and methadone in the treatment of neuropathic pain
mide found it to be efficacious compared to placebo; and found that, in studies lasting 12 weeks or less,
however, the cohort receiving 600 mg daily had a opioids exhibited a significant analgesic effect
much higher withdrawal rate due to adverse reactions, compared to placebo, but the results were subject to
such as nausea, tremor, headache, and fatigue.148 The bias due to relatively small sample sizes and short
efficacy of lacosamide over placebo was also marginal, duration of studies.153 Additional data are needed to
and it is therefore currently not recommended for use characterize long-term efficacy and the safety profile
in painful DPN.147 of opioids in neuropathic pain.
Table IV. Emerging therapies for the treatment of painful diabetic peripheral neuropathy.
COX ¼ cyclooxygenase; ER ¼ extended release; SNRI ¼ serotonin–norepinephrine reuptake inhibitor; SR ¼ sustained release;
TRPV1 ¼ transient receptor potential vanilloid 1.
quinidine was significantly more efficacious compared repair receptor–mediating tissue protection176 and
with placebo, with a reasonable safety profile. also antagonizes the transient receptor potential
Desvenlafaxine is the most potent metabolite of the vanilloid 1 receptor,177 mediating disease-modifying
parent compound venlafaxine and has been evaluated and analgesic effects, respectively. It has shown
in patients with painful DPN.114,173 In a Phase III significantly increased small nerve fiber abundances
multicenter, randomized placebo-controlled trial (n = in the cornea and skin, with improved neuropathic
412), graduated doses of 200 and 400 mg/d desvenla- pain in patients with DPN178 and sarcoid
faxine were found to be effective in relieving pain and neuropathy.179
improving activity.114 Tanezumab is a fully humanized anti–nerve growth
EMA401 is an angiotensin II type 2 receptor factor monoclonal antibody. However, this class of
antagonist that was evaluated in a multicenter, drugs has a long and checkered history, with the FDA
randomized, placebo-controlled trial in 183 patients placing a clinical hold on clinical studies of anti–nerve
with postherpetic neuralgia over 28 days and showed growth factor monoclonal antibody in late 2010,
benefit.174 Anand et al175 showed angiotensin 2 because of reports of serious joint-related adverse
immunostaining in 75% of small- to medium- events and sympathetic nerve damage tolerability
diameter human dorsal root ganglia neurons and concerns. However, the FDA lifted its hold in March
that this was the major ligand for angiotensin II type 2015, and in 2017 granted fast-track status as a
2 receptor.175 Angiotensin 2–mediated angiotensin II nonopioid pain medication,180 particularly for hip
type 2 receptor signaling was reversed by EMA401, and knee osteoarthritis.181 In the only reported
establishing a mechanism for its action in neuropathic study in DPN, 20 mg of SC tanezumab was
pain.175 administered on day 1 and week 8 and showed a
Cibinetide (ARA290), a nonhematopoietic peptide reduction in DPN pain but no improvement in
of erythropoietin, interacts selectively with the innate patients' global assessment of pain.182
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