DOI 10.1212/WNL.0b013e3182166ebe
; Prepublished online April 11, 2011;Neurology
V. Bril, J. England, G.M. Franklin, et al.
Rehabilitation
Medicine, and the American Academy of Physical Medicine and
American Association of Neuromuscular and Electrodiagnostic
neuropathy : Report of the American Academy of Neurology, the
Evidence-based guideline: Treatment of painful diabetic
April 13, 2011This information is current as of
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rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
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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
V. Bril, MD, FRCP(C)
J. England, MD, FAAN
G.M. Franklin, MD,
MPH, FAAN
M. Backonja, MD
J. Cohen, MD, FAAN
D. Del Toro, MD
E. Feldman, MD, PhD,
FAAN
D.J. Iverson, MD, FAAN
B. Perkins, MD,
FRCP(C), MPH
J.W. Russell, MD, MS,
FRPC
D. Zochodne, MD
ABSTRACT
Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for
the treatment of painful diabetic neuropathy (PDN).
Methods: We performed a systematic review of the literature from 1960 to August 2008 and
classified the studies according to the American Academy of Neurology classification of evi-
dence scheme for a therapeutic article, and recommendations were linked to the strength of
the evidence. The basic question asked was: “What is the efficacy of a given treatment (phar-
macologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electri-
cal stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage,
others) to reduce pain and improve physical function and quality of life (QOL) in patients with
PDN?”
Results and Recommendations: Pregabalin is established as effective and should be offered for
relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (mor-
phine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective
and should be considered for treatment of PDN (Level B). Other treatments have less robust
evidence or the evidence is negative. Effective treatments for PDN are available, but many have
side effects that limit their usefulness, and few studies have sufficient information on treatment
effects on function and QOL. Neurology® 2011;76:1–1
GLOSSARY
AAN� American Academy of Neurology; NNT� number needed to treat; PDN� painful diabetic neuropathy; QOL� quality
of life; RCT� randomized controlled trial; SF-MPQ� Short Form–McGill Pain Questionnaire; SF-QOL� Short Form–Quality
of Life; VAS� visual analog pain scale.
Diabetic sensorimotor polyneuropathy represents a
diffuse symmetric and length-dependent injury to
peripheral nerves that has major implications on
quality of life (QOL), morbidity, and costs from a
public health perspective.1,2 Painful diabetic neu-
ropathy (PDN) affects 16% of patients with diabe-
tes, and it is frequently unreported (12.5%) and
more frequently untreated (39%).3 PDN presents
an ongoing management problem for patients,
caregivers, and physicians. There are many treat-
ment options available, and a rational approach to
treating the patient with PDN requires an under-
standing of the evidence for each intervention.
This guideline addresses the efficacy of phar-
macologic and nonpharmacologic treatments to
reduce pain and improve physical function and
QOL in patients with PDN. The pharmacologic
agents reviewed include anticonvulsants, antide-
pressants, opioids, anti-arrhythmics, cannabi-
noids, aldose reductase inhibitors, protein kinase
Supplemental data at
www.neurology.org
Address correspondence and
reprint requests to American
Academy of Neurology, 1080
Montreal Avenue, St. Paul, MN
55116
guidelines@aan.com
e-Pub ahead of print on April 11, 2011, at www.neurology.org.
From the University Health Network (V.B., B.P.), University of Toronto, Toronto, Canada; Department of Neurology (J.E.), LSU School of
Medicine, New Orleans, LA; University of Washington (G.M.F.), Seattle; University of Wisconsin (M.B.), Madison; Dartmouth Hitchcock Medical
Center (J.C.), Lebanon, NH; Department of PM&R (D.D.), Medical College of Wisconsin, Milwaukee; University of Michigan (E.F.), Ann Arbor;
Humboldt Neurological Medical Group, Inc. (D.J.I.), Eureka, CA; Department of Neurology (J.W.R.), University of Maryland School of Medicine,
Baltimore; and University of Calgary (D.Z.), Calgary, Canada.
Appendices e-1–e-5 and References e1–e46 are available on the Neurology�Web site at www.neurology.org.
Approved by the AAN Quality Standards Subcommittee on November 13, 2010; by the AAN Practice Committee on December 15, 2010; by the
AAN Board of Directors on February 10, 2011; by the Neuromuscular Guidelines Steering Committee on October 8, 2010; by the AANEM Practice
Issues Review Panel on January 15, 2011; by the AANEM Board of Directors on February 15, 2011; by the AAPM&R Quality Practice & Policy
Committee on February 6, 2011; and by the AAPM&R Board of Governors on March 11, 2011.
Disclosure: Author disclosures are provided at the end of the article.
SPECIAL ARTICLE
Copyright © 2011 by AAN Enterprises, Inc. 1
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C beta inhibitors, antioxidants (�-lipoic acid),
transketolase activators (thiamines and allithia-
mines), topical medications (analgesic patches, an-
esthetic patches, capsaicin cream, clonidine), and
others. The nonpharmacologic modalities include
infrared therapy, shoe magnets, exercise, acupunc-
ture, external stimulation (transcutaneous electri-
cal nerve stimulation), spinal cord stimulation,
biofeedback and behavioral therapy, surgical de-
compression, and intrathecal baclofen.
DESCRIPTION OF THE ANALYTIC PROCESS
In January 2007, the American Academy of Neurol-
ogy (AAN), the American Association of Neuromus-
cular and Electrodiagnostic Medicine, and the
American Academy of Physical Medicine and Reha-
bilitation convened an expert panel from the United
States and Canada, selected to represent a broad
range of relevant expertise. In August 2008, a litera-
ture search of MEDLINE and EMBASE was per-
formed in all languages using the MeSH term
diabetic neuropathies and its text word synonyms
and key words for the therapeutic interventions of
interest (see appendix e-1 on the Neurology® Web
site at www.neurology.org for a full list of search
terms). The search identified 2,234 citations, the ti-
tles and abstracts of which were reviewed by at least 2
authors for relevance, resulting in 463 articles. All of
these articles were reviewed in their entirety, and of
these, the panel identified 79 relevant articles. Each
of these articles was rated by at least 2 authors ac-
cording to the AAN criteria for the classification of
therapeutic articles (appendix e-2), and recommen-
dations were linked to the strength of evidence (ap-
pendix e-3) and to effect size of the intervention.
Disagreements regarding classification were arbi-
trated by a third reviewer.
Articles were included if they dealt with the treat-
ment of PDN, described the intervention clearly, re-
ported the completion rate of the study, and defined
the outcome measures clearly. The panel also consid-
ered the side effects of the treatment and measures of
function and QOL, if any. Case reports and review
articles were excluded.
We anticipated that studies would use varying
measures for quantifying pain reduction. For the
purposes of this guideline we preferred the following
outcome measures, listed in order of preference:
1. The difference in the proportion of patients re-
porting a greater than 30% to 50% change from
baseline on a Likert or visual analog pain scale
(VAS) as compared to no treatment (placebo) or
the comparative treatment. The Likert scale is an
11-point linear scale ranging from 0 (no pain) to
10 (maximum pain), and the patient rates his or
her pain level on this scale.4–6
2. The percent change from baseline on a Likert or
VAS as compared to no treatment (placebo) or
the comparative treatment.6
3. Any other quantitative measure of pain reduction
provided by the investigators.
For studies reporting the difference in the propor-
tion of patients reporting a greater than 30% to 50%
reduction in pain, we considered a risk difference of
�20% a large effect (number needed to treat [NNT]
�5), a risk difference of�10% to 20% (NNT�5 to
10) a moderate effect, and a risk difference of�10%
(NNT �10) a small effect, where risk difference is
the reduction in pain in the active treatment group
minus the reduction in the control group. For studies
using a mean reduction from baseline on a Likert
scale or VAS as compared to no treatment (placebo)
or a comparative treatment, we considered a reduc-
tion difference of �30% a large effect, �15% to
30% a moderate effect, and �15% a small effect.
For any other quantitative measure of pain reduc-
tion, we considered a reduction of �30% a large
effect, �15% to 30% a moderate effect, and
�15% a small effect.
The panel recognized that older studies generally
lacked measures of QOL and function compared to
more recent studies. Furthermore, the panel was
aware that a standardized QOL measure for PDN or
a standardized assessment of function is not avail-
able, and multiple instruments were used to measure
QOL, such as the SF-36® Health Survey, subsec-
tions of the SF-36, and function (such as sleep
interference).
Studies with the highest levels of evidence for
each intervention are discussed in the text, and data
from other studies are shown in the tables. Details of
Class I, II, and III studies are presented in the evi-
dence tables.
ANALYSIS OF EVIDENCE In patients with PDN,
what is the efficacy of pharmacologic agents to reduce pain
and improve physical function and QOL? Anticonvulsants.
We identified 20 articles relevant to anticonvulsants
graded higher than Class IV (table e-1). Most of the
randomized controlled trials (RCTs) rated as Class II
instead of Class I had completion rates of less than
80% or the completion rate was not identified.
Four studies (3 Class I and 1 Class II) evaluated
the efficacy of pregabalin.7–10 All studies found that
pregabalin relieved pain, but the effect size was small
relative to placebo, reducing pain by 11%–13% on
the 11-point Likert scale in the Class I studies. A
large dose-dependent effect (24%–50% reduction in
Likert pain scores compared to placebo) was ob-
2 Neurology 76 May 17, 2011
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served in the Class II study.10 The NNT for a 50%
reduction in pain was 4 at 600 g/day.7–10 In the QOL
measures, social functioning, mental health, bodily
pain, and vitality improved, and sleep interference
decreased, all changes with p � 0.05.
Two studies (1 Class I and 1 Class II) evaluated the
efficacy of gabapentin.11,12 In the Class I study,11 gabap-
entin had a small effect of net pain reduction from base-
line of 11% on the 11-point Likert scale compared to
the change in placebo-treated patients, while a Class II
gabapentin study showed no effect.12 Gabapentin had
no effect on overall QOL in the single study reporting
this measure, but did show an improvement in subsets
of mental health and vitality.11
Two Class I trials evaluated the efficacy of lam-
otrigine.13,14 There was no difference in the primary
outcome measures in the lamotrigine and placebo
groups.
Two studies (both Class II) evaluated the efficacy of
sodium valproate.15,16 Both showed a 27%–30% pain
reduction (moderate) in the Short Form–McGill Pain
Questionnaire (SF-MPQ) with sodium valproate com-
pared to placebo, and QOL was not measured. Both
studies were conducted by the same principal investiga-
tor at the same center but in separate populations with
small numbers of patients; each study was remarkable
for the lack of any change in placebo patients and for
the lack of side effects typically attributed to sodium
valproate. Treatment allocation concealment was not
described.
One Class II study evaluated the efficacy of topi-
ramate.17 The study reported a small effect compared
to placebo, 7% net pain reduction on the VAS, and
an NNT of 6.6 for �30% pain reduction.
Three Class II studies evaluated the efficacy of
oxcarbazepine.18–20 Two studies showed no bene-
fit,18,20 but a third showed a moderate benefit—17%
more patients on oxcarbazepine had a �50% pain
reduction compared to placebo, with an NNT of
6.023.19 The study showing a positive response had a
slightly higher completion rate (73%19 compared to
67%).20 Short Form–Quality of Life (SF-QOL)
scores were not improved.
Three Class III studies evaluated the efficacy of
lacosamide.21–23 All the studies showed a small reduc-
tion in pain with 400 mg/day of lacosamide (3%,
6%, and 6% compared to placebo), but in 2 studies
no significant differences compared to placebo were
observed with 600 mg/day of lacosamide.22,23 In one
study, benefits on general activity and sleep interfer-
ence QOL measures were observed.21
Conclusions. Based on consistent Class I evidence,
pregabalin is established as effective in lessening the
pain of PDN. Pregabalin also improves QOL and
lessens sleep interference, though the effect size is
small. Based on one Class I study, gabapentin is
probably effective in lessening the pain of PDN.
Based on 2 Class II studies, sodium valproate is prob-
ably effective in treating PDN. Lamotrigine is prob-
ably not effective in treating PDN. Based on Class II
evidence, oxcarbazepine is probably not effective in
treating PDN. There is conflicting Class III evidence
for the effectiveness of topiramate in treating PDN.
Based on Class III evidence, lacosamide is possibly
not effective in treating PDN. The degree of pain
relief afforded by anticonvulsant agents is not associ-
ated with improved physical function.
Recommendations
1. If clinically appropriate, pregabalin should be of-
fered for the treatment of PDN (Level A).
2. Gabapentin and sodium valproate should be con-
sidered for the treatment of PDN (Level B).
3. There is insufficient evidence to support or refute
the use of topiramate for the treatment of PDN
(Level U).
4. Oxcarbazepine, lamotrigine, and lacosamide
should probably not be considered for the treat-
ment of PDN (Level B).
Clinical context. Although sodium valproate may be
effective in treating PDN, it is potentially teratogenic
and should be avoided in diabetic women of child-
bearing age. Due to potential adverse effects such as
weight gain and potential worsening of glycemic
control, this drug is unlikely to be the first treatment
choice for PDN.
Antidepressants. We identified 14 articles relevant
to antidepressants rated higher than Class IV (table
e-2). Seventeen articles were excluded. Most of the
RCTs rated as Class II instead of Class I had comple-
tion rates of less than 80%.
Two studies (1 Class I and 1 Class II) evaluated
the efficacy of venlafaxine.24,25 The Class I study re-
ported a moderate effect of venlafaxine, with 23%
more pain relief than with placebo on the VAS-PI
(0–100) scale and an NNT of 5.24 In the Class II
study, venlafaxine plus gabapentin showed a moder-
ate effect in relieving pain on the 11-point Likert
scale in PDN, with 18% more relief than with pla-
cebo plus gabapentin.25 The QOL measures of
bodily pain, mental health, and vitality improved on
the SF-36.
Three studies (1 Class I and 2 Class II) evaluated
the efficacy of duloxetine in PDN.26–28 The Class I
study showed that duloxetine had a small effect com-
pared to placebo, reducing pain by 8% on the 11-
point Likert scale26; QOL was not assessed. In 2
Class II studies, duloxetine reduced pain (measured
by VAS) 13% more than placebo,27,28 but in one
study, a moderate effect was shown in responder
analysis, with 26% more responders on duloxetine
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120 mg/day (total 52%) than placebo (26%) (re-
sponders defined as those patients having 50% re-
duction in their 24-hour average pain score).27 The
completion rate in both studies was about 75%.27,28
Duloxetine reduced interference with general activity
and improved SF-36 and EQ-5D™ scores.27,28
Three studies (1 Class I and 2 Class II) evaluated
the efficacy of amitriptyline.29–31 The Class I study
showed a large responder effect with amitriptyline,
with 43% more responders with amitriptyline than
with placebo (requiring at least 20% pain reduction
for responder status). A third group in this study that
was treated with maprotiline had 18% more re-
sponders than the placebo group.29 In 2 Class II stud-
ies, amitriptyline had a large effect, reducing pain by
63% and 58% more than placebo on a verbal 13-
item descriptor list converted to a numeric 5-point
scale.30,31 In one of these Class II studies, an active
placebo was used.30
Two Class III trials evaluated other tricyclic anti-
depressants (imipramine and nortriptyline).32,33 One
Class III study showed that 47% more subjects on
imipramine improved on a global evaluation com-
pared to the placebo group, but there was no differ-
ence on a 6-point symptom scale.32 Another Class III
study showed a large effect with the combination of
nortriptyline plus fluphenazine compared to placebo;
63% more patients had a 50% or greater VAS reduc-
tion in the combination group.33 One Class III study
compared desipramine, amitriptyline, fluoxetine,
and placebo and found a small effect (6% pain reduc-
tion) for both amitriptyline and desipramine but not
for fluoxetine on a 13-word scale converted to 5
points.34
Conclusions. Based on 3 Class I and 5 Class II stud-
ies, the antidepressants amitriptyline, venlafaxine,
and duloxetine are probably effective in lessening the
pain of PDN. Venlafaxine and duloxetine also im-
prove QOL. Venlafaxine is superior to placebo in
relieving pain when added to gabapentin. There is
insufficient evidence to determine whether desipra-
mine, imipramine, fluoxetine, or the combination of
nortriptyline and fluphenazine are effective for the
treatment of PDN.
Recommendations
1. Amitriptyline, venlafaxine, and duloxetine should
be considered for the treatment of PDN (Level
B). Data are insufficient to recommend one of
these agents over the others.
2. Venlafaxine may be added to gabapentin for a
better response (Level C).
3. There is insufficient evidence to support or refute
the use of desipramine, imipramine, fluoxetine,
or the combination of nortriptyline and flu-
phenazine in the treatment of PDN (Level U).
Opioids. We identified 9 articles relevant to opi-
oids graded higher than Class IV (table e-3). Most of
the RCTs rated as Class II instead of Class I had
completion rates of less than 80%.
One Class I study showed that dextromethorphan
relieved pain moderately by 16% more than placebo
on a 20-point Gracely Box scale in PDN and im-
proved SF-36 results.35 In one Class II study, dextro-
methorphan with benztropine reduced pain by 24%
more than placebo on a 6-point scale, a moderate
reduction.36
A Class II study showed that morphine sulfate
had a small effect and reduced pain from baseline by
15% on the SF-MPQ and improved SF-36 and Beck
Depression Inventory results.37
In 2 Class II studies, tramadol relieved pain
moderately (16% and 20% more than placebo on
a Likert scale) in PDN3
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