AANEM PRACTICE TOPIC
EVIDENCE-BASED GUIDELINE: TREATMENT OF PAINFUL DIABETIC
NEUROPATHY—REPORT OF THE AMERICAN ASSOCIATION OF
NEUROMUSCULAR AND ELECTRODIAGNOSTIC MEDICINE, THE
AMERICAN ACADEMY OF NEUROLOGY, AND THE AMERICAN ACADEMY
OF PHYSICAL MEDICINE & REHABILITATION
VERA BRIL, MD, FRCP(C),1JOHN D. ENGLAND, MD, FAAN,2GARY M. FRANKLIN, MD, MPH,3MIROSLAV BACKONJA, MD,4
JEFFREY A. COHEN, MD, FAAN,5DAVID R. DEL TORO, MD,6EVA L. FELDMAN, MD, PhD,7DONALD J. IVERSON, MD, FAAN,8
BRUCE PERKINS, MD, FRCP(C),1JAMES W. RUSSELL, MD, MS,9and DOUGLAS W. ZOCHODNE, MD10
1University Health Network, University of Toronto, Toronto, Ontario, Canada
2Department of Neurology, Louisiana State University School of Medicine, New Orleans, Louisiana, USA
3University of Washington, Seattle, Washington, USA
4University of Wisconsin, Madison, Wisconsin, USA
5Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
6Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
7University of Michigan, Ann Arbor, Michigan, USA
8Humboldt Neurological Medical Group, Inc., Eureka, California, USA
9Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
10University of Calgary, Calgary, Alberta, Canada
Accepted 28 February 2011
entifically sound and clinically relevant evidence-based guideline
for the treatment of painful diabetic neuropathy (PDN). The ba-
sic question that was asked was: ‘ ‘What is the efficacy of a
given treatment (pharmacological: anticonvulsants, antidepres-
sants, opioids, others; non-pharmacological: electrical stimula-
tion, 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?’ ’ A sys-
tematic review of literature from 1960 to August 2008 was per-
formed, and studies were classified according to the American
Academy of Neurology classification of evidence scheme for a
therapeutic article. Recommendations were linked
strength of the evidence. The results indicate that pregabalin is
established as effective and should be offered for relief of PDN
(Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, val-
proate, opioids (morphine 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 nega-
tive. Effective treatments for PDN are available, but many have
The objective of this report was to develop a sci-
side effects that limit their usefulness. Few studies have suffi-
cient information on their effects on function and QOL.
Muscle Nerve 000: 000–000, 2011
Diabetic sensorimotor polyneuropathy represents
injury to peripheral nerves that has major implica-
tions with regard to quality of life (QOL), morbid-
ity, and costs from a public health perspective.1,2
Painful diabetic neuropathy (PDN) affects 16% of
patients with diabetes, and it is frequently unre-
ported (12.5%) and more frequently untreated
(39%).3PDN presents an ongoing management
problem for patients, caregivers, and physicians.
There are many treatment options available, and a
rational therapeutic approach to the patient with
This article is a joint report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the
American Academy of Physical Medicine & Rehabilitation. It was approved by the AANEM Board of Directors on February 15, 2011. This report did not
undergo further editorial review by Muscle & Nerve.
Abbreviations: EQ-5D, Euro-QOL (5 dimensions); NNT, number needed to treat; PDN, painful diabetic neuropathy; QOL, quality of life; RCT, randomized, con-
trolled trial; SF-MPQ, Short Form of the McGill Pain Questionnaire; SF-QOL, Short Form of the Quality of Life Assessment; TENS, transcutaneous electrical
nerve stimulation; VAS, visual-analog pain scale
Key words: efficacy; neuropathic pain; painful diabetic neuropathy; quality of life; treatment options
Disclaimer: This report is provided as an education service of the AANEM, the AAN, and the AAMP&R. It is based on an assessment of current scientific and
clinical information. It is not intended to include all possible proper methods of care for a particular neurological problem or all legitimate criteria for choosing to use a
specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AANEM, AAN, and AAPM&R recognize that specific care
decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.
Disclosures: V.B. has received research support from Talecris, Eisai, and Johnson & Johnson. J.D.E. has received honoraria from Talecris for consulting work and
speaking; holds financial interests in Pfizer; and has received research support from Wyeth, the NIH, Astra Zeneca, and Pfizer. M.B. is on the editorial boards of Pain,
Journal of Pain, Clinical Journal of Pain, European Journal of Pain, and Pain Medicine; he provided consultation to and holds corporate appointments with Allergan,
Astellas, J&J, Lilly, Merck, Neurogesx, and Pfizer, and conducted clinical research with Neurogesx. J.A.C. has received funding for travel from the National ALS
Association; has received honoraria from a neurology practice in Massachusetts; serves on the speakers’ bureau of Athena Diagnostics; and has given expert
testimony, prepared an affidavit, and acted as a witness in a legal proceeding with regard to vaccine-related injuries and peripheral nerve injuries. E.L.F. has served as
a journal editor for the Journal of the Peripheral Nervous System, Endocrinology, and Neurobiology of Disease; has received royalties from UpToDate; has received
honoraria from the Neurological Institute of New York, the Detroit Medical Center, and the University of Pennsylvania; is on the Data Safety Monitoring Board of
Novartis; and receives research support from the NIH. D.J.I. has been a treating expert witness with regard to a legal proceeding. J.W.R. has received financial
compensation from Exelexis Corp. and Baxter Corp.; has received honoraria from the AAN and several hospitals and academic institutions; and has received
research support from Baxter Corporation, the NIH, the VA, the American Diabetes Association, and the Juvenile Diabetes Association. D.W.Z. serves on the advisory
board for Aegera, Inc.; has received honoraria from ONO, Japan; and holds stock options in and receives research support from Aegera.
Correspondence to: AANEM, 2621 Superior Drive NW, Rochester, MN 55901; e-mail: email@example.com
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.22092
C2011 American Association of Neuromuscular and Electrodiagnostic Medicine.
AANEM Practice Topic: Treatment of PDNMUSCLE & NERVEMonth 20111
PDN requires an understanding of the evidence
for each intervention.
This evidence-based guideline addresses the effi-
cacy of pharmacological and non-pharmacological
treatments for reducing pain and improving physi-
cal function and QOL in patients with PDN. The
pharmacological agents reviewed include anticon-
vulsants, antidepressants, opioids, anti-arrhythmics,
cannabinoids, aldose reductase inhibitors, protein
kinase C beta inhibitors, antioxidants (alpha-lipoic
acid), transketolase activators (thiamines and allithi-
amines), topical medications (analgesic patches, an-
esthetic patches, capsaicin cream, clonidine), and
others. The non-pharmacological modalities include
infrared therapy, shoe magnets, exercise, acupunc-
ture, external stimulation (TENS), spinal cord stim-
ulation, biofeedback and behavioral therapy, surgi-
cal decompression, and intrathecal baclofen.
DESCRIPTION OF THE ANALYTIC PROCESS
In January 2007, the American Association of Neuro-
muscular and Electrodiagnostic Medicine (AANEM),
the American Academy of Neurology (AAN), and
the American Academy of Physical Medicine and
Rehabilitation (AAPM&R) convened an expert panel
from the USA and Canada, selected to represent a
broad range of relevant expertise. In August 2008, a
literature search of MEDLINE and EMBASE was per-
formed in all languages using the MeSH term dia-
betic neuropathies and its text word synonyms and
key words for the therapeutic interventions of inter-
est (see Appendix E1 for a full list of search terms).
The search identified 2234 citations, the titles and
abstracts of which were reviewed by at least two inves-
tigators 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 two investigators
according to the AAN criteria for the classification
of therapeutic articles (Appendix E2), and recom-
mendations were linked to the strength of evidence
(Appendix E3) 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
treatment of PDN, described the intervention
clearly, reported the completion rate of the study,
and defined the outcome measures clearly. The
panel also considered the side effects of the treat-
ment and measures of function and QOL, if any.
Case reports and review studies 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
reporting a >30–50% change from baseline on
a Likert or visual-analog pain scale (VAS) as
compared with 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/her pain level on this scale.4–6
2. The percent change from baseline on a Likert
or VAS as compared with no treatment (pla-
cebo) or the comparative treatment.6
3. Any other quantitative measure of pain reduc-
tion provided by the investigators.
For studies reporting the difference in the pro-
portion of patients reporting a >30–50% reduction
in pain, we considered a risk difference of >20%
to be a large effect [number needed to treat
(NNT) <5], a risk difference of >10–20% (NNT
>5–10) a moderate effect, and a risk difference of
?10% (NNT >10) a small effect, where risk differ-
ence is the reduction in pain in the active treat-
ment group minus the reduction in the control
group. For studies using a mean reduction from
baseline on a Likert scale or VAS as compared
with no treatment (placebo) or a comparative
treatment, we considered a reduction difference of
>30% a large effect, >15% to 30% a moderate
effect, and ?15% a small effect. For any other
quantitative measure of pain reduction, we consid-
ered a reduction of >30% a large effect, >15% to
30% a moderate effect, and ?15% a small effect.
The panel recognized that older studies gener-
ally lacked measures of QOL and function com-
pared with more recent studies. Furthermore, the
panel was aware that a standardized QOL measure
for PDN or a standardized assessment of function
are not available, and multiple instruments were
used to measure QOL, such as the 36-item Short
Form (SF-36) Health Survey, subsections 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
others are shown in the tables. Details of Class I,
II, and III studies are presented in the evidence
ANALYSIS OF EVIDENCE
In patients with PDN, what is the efficacy of phar-
macological agents to reduce pain and improve
physical function and QOL?
to anticonvulsants graded higher than Class IV
(Supplementary table 1). Most of the randomized,
controlled trials (RCTs) rated as Class II instead of
Class I had completion rates of < 80%, or the
completion rate was not identified.
We identified 20 articles relevant
2 AANEM Practice Topic: Treatment of PDNMUSCLE & NERVEMonth 2011
Four studies (three Class I and one Class II)
evaluated the efficacy of pregabalin.7–10All of the
studies found that pregabalin relieved pain, but
the effect size was small relative to placebo, reduc-
ing 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
with placebo) was observed in the Class II study.10
The NNT for a 50% reduction in pain was 4 at 600
g/day.7–10In the QOL measures, social function-
ing, mental health,bodily
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.11,12In the Class I
study,11gabapentin had a small effect of net pain
reduction from baseline of 11% on the 11-point
Likert scale compared with the change in placebo-
treated patients, whereas a Class II gabapentin
study showed no effect.12Gabapentin had no
effect on overall QOL in the single study reporting
this measure, but it did show an improvement in
subsets of mental health and vitality.11
Two Class I trials evaluated the efficacy of lamo-
trigine.13,14There was no difference in the primary
outcome measures in the lamotrigine and placebo
Two studies (both Class II) evaluated the effi-
cacy of sodium valproate.15,16Both showed a 27–
30% pain reduction (moderate) in the Short Form
McGill Pain Questionnaire (SF-MPQ) with sodium
valproate compared with placebo, and QOL was
not measured. Both studies were conducted at the
same center with the same principal investigator in
patients in each study and were 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
One Class II study evaluated the efficacy of top-
iramate.17The study reported a small effect com-
pared with 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.18–20Two studies showed no bene-
fit,18,20but a third showed a moderate benefit—
17% more patients on oxcarbazepine had a >50%
pain reduction compared with placebo, with an
NNT of 6.023.19The study showing a positive
response had a slightly higher completion rate
(73%19compared with 67%).20Short Form Quality
of Life (SF-QOL) was not improved.
Three Class III studies evaluated the efficacy of
lacosamide.21–23All the studies showed a small
reduction in pain with 400 mg/day lacosamide
(3%, 6%, and 6% compared with placebo), but in
small numbers of
two studies no significant differences compared
with placebo were observed with 600 mg/day laco-
samide.22,23In one study, benefits on general activ-
ity and sleep interference QOL measures were
Based on consistent Class I evi-
dence, pregabalin is established as effective in less-
ening the pain of PDN. Pregabalin also improves
QOL and lessens sleep interference, although the
effect size is small. Based on one Class I study,
gabapentin is probably effective in lessening the
pain of PDN. Based on two Class II studies, sodium
valproate is probably effective in treating PDN.
Lamotrigine is probably 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 associated with
improved physical function.
1. If clinically appropriate, pregabalin should be
offered for the treatment of PDN (Level A).
2. Gabapentin and sodium valproate should be
considered 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).
should probably not be considered for the treat-
ment of PDN (Level B).
may be effective in treating PDN, it is potentially
teratogenic and should be avoided in diabetic
women of childbearing age. Due to potential
adverse effects, such as weight gain and potential
worsening of glycemic control, it is unlikely to be
the first drug to use in treating PDN.
Although sodium valproate
to antidepressants rated higher than Class IV
(Supplementary table 2). Seventeen articles were
excluded. Most of the RCTs rated as Class II
instead of Class I had completion rates of <80%.
Two studies (one Class I and one Class II) eval-
uated the efficacy of venlafaxine.24,25The Class I
study reported a moderate effect of venlafaxine,
with 23% more pain relief than placebo on the
VAS-PI (0–100) scale and an NNT of 5.24In the
Class II study, venlafaxine plus gabapentin showed
a moderate effect in relieving pain on the 11-point
Likert scale in PDN, with 18% more relief than
We identified 14 articles relevant
AANEM Practice Topic: Treatment of PDN MUSCLE & NERVE Month 20113
placebo plus gabapentin.25The QOL measures of
bodily pain, mental health, and vitality improved
on the SF-36.
Three studies (one Class I and two Class II)
evaluated the efficacy of duloxetine in PDN.26–28
The Class I study showed that duloxetine had a
small effect compared with placebo, reducing pain
by 8% on the 11-point Likert scale26; QOL was not
assessed. Intwo Class
reduced pain (measured by VAS) 13% more than
placebo,27,28but in one study a moderate effect
was shown in the responder analysis, with 26%
more responders on duloxetine 120 mg/day (total
52%) than placebo (26%) (responders defined as
those patients having 50% reduction in their 24-
hour average pain score).27The completion rate
in both studies was about 75%.27,28Duloxetine
reduced interference with general activity and the
SF-36 and Euro-QoL (EQ-5D).27,28
Three studies (one Class I and two Class II)
evaluated the efficacy of amitriptyline.29–31The
Class I study showed a large responder effect with
amitriptyline, with 43% more responders with ami-
triptyline than with placebo (requiring at least
20% pain reduction for responder status). A third
group in this study that was treated with maproti-
line had 18% more responders than the placebo
group.29In two Class II studies amitriptyline had a
large effect, reducing pain on a verbal 13-item
descriptor list converted to a numeric 5-point scale
by 63% and 58%, respectively, more than pla-
cebo.30,31In one of these Class II studies an active
placebo was used.30
Two Class III trials evaluated other tricyclic
line).32,33One Class III study showed that 47%
more subjects on imipramine improved on a
global evaluation compared with the placebo
group, but there was no difference on a 6-point
symptom scale.32Another Class III study showed a
large effect with the combination of nortriptyline
plus fluphenazine compared with placebo; 63%
more patients had a ?50% VAS reduction in the
combination group.33One Class III study com-
pared desipramine, amitriptyline, fluoxetine, and
placebo and found a small effect on a 13-word
scale converted to 5 points for amitriptyline and
desipramine (both had 6% pain reduction), but
not for fluoxetine.34
Based on three Class I and five
Class II studies, the antidepressants amitriptyline,
venlafaxine, and duloxetine are probably effective
in lessening the pain of PDN. Venlafaxine and
duloxetine also improve QOL. Venlafaxine is supe-
rior to placebo in relieving pain when added to
gabapentin. There is insufficient evidence to deter-
mine whether desipramine, imipramine, fluoxe-
tine, or the combination of nortriptyline and flu-
phenazine are effective for the treatment of PDN.
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 fluphenazine in the treatment of PDN
opioids graded higher than Class IV (Supplemen-
tary table 3). Most of the RCTs rated as Class II
instead of Class I had completion rates of <80%.
One Class I study showed that dextromethor-
phan relieved pain moderately by 16% more than
placebo on a 20-point Gracely Box scale in PDN
and improved the SF-36.35In one Class II study,
dextromethorphan with benztropine reduced pain
by 24% more than placebo on a 6-point scale, a
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 the SF-36
and the Beck Depression Inventory.37
In two Class II studies, tramadol relieved pain mod-
erately (16% and 20% more than placebo on a Likert
scale) in PDN38,39and improved physical function.38
In three Class II studies, oxycodone controlled-
release and Ultracet (tramadol þ acetaminophen)
relieved pain in PDN.40e1,e2Oxycodone had a
small effect, with 9% more pain relief on the Pain
Inventory than placebo. It also improved sleep
quality by 7% more than placebo, but did not
change SF-36.40Ultracet improved pain by 13% on
the VAS, a small effect, and also improved SF-36
scores by 10%.e1Oxycodone controlled-release had
a moderate effect on pain (27% reduction in the
VAS compared with placebo), improved disability
by 10%, and improved most SF-36 subscores.e2
Based on one Class I study, dextro-
methorphan is probably effective in lessening the
pain of PDN and improving QOL. Based on Class II
evidence, morphine sulfate, tramadol, and oxycodone
controlled-release are probably effective in lessening
the pain of PDN. Dextromethorphan, tramadol, and
oxycodone controlled-release have moderate effect
sizes, reducing pain by 27% compared with placebo.
phine sulfate, tramadol, and oxycodone should be
considered for the treatment of PDN (Level B).
We identified nine articles relevant to
4 AANEM Practice Topic: Treatment of PDNMUSCLE & NERVEMonth 2011
Data are insufficient to recommend one agent
over the other.
The use of opioids for chronic,
nonmalignant pain has gained credence over the last
decade due to the studies reviewed in this study.
Both tramadol and dextromethorphan were associ-
ated with substantial adverse events (e.g., sedation in
18% on tramadol and 58% on dextromethorphan,
nausea in 23% on tramadol, and constipation in
21% on tramadol). The use of opioids can be associ-
ated with the development of novel pain syndromes
such as rebound headache. Chronic use of opioids
leads to tolerance and frequent escalation of dose.
Other Pharmacological Agents.
articles relevant to other pharmacological agents
rated higher than Class IV (Supplementary table 4).
Thirteen other articles were excluded. Most of the
RCTs rated Class II instead of Class I had comple-
tion rates of <80%, and those rated Class III often
lacked predefined endpoints.
One Class I study of 0.075% capsaicin showed a
large effect, with 40% more pain reduction on the
VAS compared with vehicle cream.e3One Class II
study showed that 0.075% capsaicin reduced pain
in PDN with a small effect size of 13% on the VAS
compared with vehicle cream.e4
One Class I study of isosorbide dinitrate spray
showed a moderate effect, with an 18% reduction
in VAS pain compared with placebo.e5
One Class I study of clonidine and pentoxifyl-
line compared with placebo did not show an effect
of these drugs on PDN.e6
One Class I study of mexiletine did not show
an effect on PDN.e7Two Class II studies showed
pain reduction with mexiletine: one with a large
effect (37% more pain reduction than placebo)e8
and one with a small effect (5% difference com-
pared to placebo).e9In the first Class II study,
sleep disturbance was reduced,e8but this was not
found in the other Class II study.e9
In a single Class I study of sorbinil, pain relief
was not observed.e10
One Class I and two Class II studies showed
benefit from alpha-lipoic acid in reducing pain in
PDN, but pain was not a predefined endpoint in
these studies.e11–e13The effect size in pain reduc-
tion was moderate (20–24% superior to placebo).
In two Class III studies, intravenous (IV)
infusion.e14,e15In one study, a transient decrease
of 75% was observed on a 5-point symptom scale,
compared with a decrease of 50% with placebo
infusion.e14In the other study, the McGill Pain
Questionnaire improved by a small amount (9%
reduction in present pain intensity) with ligno-
caine, and the differences with placebo were signif-
We identified 18
icant due to worsening in the placebo group.e15
The baseline values were not provided.
In two Class III studies, the lidoderm patch
improved pain scores with a moderate to large
effect (20–30% reduction in pain scores from base-
line and 70% of patients experienced >30% relief
Based on Class I and Class II evi-
dence, capsaicin cream is probably effective in lessen-
ing the pain of PDN. Based on Class III studies, there
is insufficient evidence to determine whether IV lido-
caine is effective in lessening the pain of PDN. Based
on Class III evidence, the lidoderm patch is possibly
effective in lessening the pain of PDN. Based on
Class I evidence, clonidine and pentoxifylline are
probably not effective for the treatment of PDN. The
evidence for the effectiveness of mexiletine is contra-
dictory; however, the only Class I study of this agent
indicates that mexiletine is probably ineffective for
the treatment of PDN. There is insufficient evidence
to determine whether vitamins and alpha-lipoic acid
are effective for the treatment of PDN. Based on
Class I evidence, isosorbide dinitrate spray is probably
effective for the treatment of PDN.
1. Capsaicin and isosorbide dinitrate spray should be
considered for the treatment of PDN (Level B).
2. Clonidine, pentoxifylline, and mexiletine should
probably not be considered for the treatment of
PDN (Level B).
3. The lidoderm patch may be considered for the
treatment of PDN (Level C).
4. There is insufficient evidence to support or
refute the usefulness of vitamins and alpha-
lipoic acid in the treatment of PDN (Level U).
effective in reducing pain in PDN clinical trials,
many patients are intolerant of the side effects,
mainly burning pain on contact with warm/hot
water or in hot weather.
In patients with PDN, what is the efficacy of
non-pharmacological modalities to reduce pain and
improve physical function and QOL?
Although capsaicin has been
We identified 11 articles relevant to non-phar-
macological treatment of PDN graded higher than
Class IV (Supplementary table 5). Only articles on
electrical stimulation, Reiki therapy, low-intensity
laser therapy, and magnetized shoe insoles reached
evidence levels sufficient for discussion in the text.
Surgical decompression was addressed in a previ-
ous AAN practice advisorye18and will not be con-
sidered further in this report.
that percutaneous electrical nerve stimulation reduced
One Class I study reported
AANEM Practice Topic: Treatment of PDNMUSCLE & NERVE Month 20115
pain in PDN by a large magnitude (42% on the VAS)
compared with the reduction observed with sham
treatment, and also improved sleep.e19One Class II
study reported no effect with electrical stimulation,e20
and one Class II study of frequency-modulated electro-
magnetic neural stimulation showed a small degree of
pain relief (11% on the VAS) in a crossover design,
but with no improvement in the placebo group.e21
The addition of electrotherapy to amitriptyline
was more effective than amitriptyline alone, based
on one Class III study.e22
Magnetic Field Treatment.
pulsed electromagnetic fields compared with a
sham device failed to demonstrate an effect in
patients with PDN.e23
One Class II study of the use of magnetized
shoe insoles in patients with PDN showed a small
effect (14% VAS decrease) at 4 months compared
with non-magnetized insoles, but the endpoint of
burning pain was not predetermined.e24
One Class I study using
of low-intensity laser treatment compared with
sham treatment did not show an effect on pain.e25
Reiki therapy is defined as the transfer of
energy from the practitioner to the patient to ena-
ble the body to heal itself through balancing
energy. One Class I study of Reiki therapy did not
show any effect on PDN.e26
Other interventions such as exercise and acu-
puncture do not have any evidence of efficacy in
One Class I study on the use
ulation is probably effective in lessening the pain of
PDN and improving QOL. Based on single Class I
studies, electromagnetic field treatment, low-intensity
laser treatment, and Reiki therapy are probably not
effective for the treatment of PDN. There is not
enough evidence to support or exclude a benefit of
amitriptyline plus electrotherapy in treating PDN.
Based on a Class I study, electrical stim-
1. Percutaneous electrical nerve stimulation should
be considered for the treatment of PDN (Level B).
2. Electromagnetic field treatment, low-intensity laser
treatment, and Reiki therapy should probably not
be considered for the treatment of PDN (Level B).
3. Evidence is insufficient to support or refute the
use of amitriptyline plus electrotherapy for treat-
ment of PDN (Level U).
ment arms and without a placebo arm were consid-
ered separately and graded using active control equiv-
alence criteria (Appendix E2 and Supplementary
table 6). We identified six comparison studies of
Studies with two active treat-
agents but did not find sufficient evidence to recom-
mend one over the other.e27–e32The comparisons
were gabapentin to amitriptyline (two), venlafaxine
to carbamazepine, nortriptyline þ fluphenazine to
carbamazepine, capsaicin to amitriptyline, and ben-
fothiamine þ cyanocobalamine to conventional vita-
min B. None of the studies defined the threshold for
equivalence or non-inferiority.
CLINICAL CONTEXT SUMMARY FOR ALL EVIDENCE
It is notable that the placebo effect varied from
0% to 50% pain reduction in these studies.
Adjuvant analgesic agents are drugs primarily
developed for an indication other than treatment of
PDN (e.g., anticonvulsants and antidepressants) that
have been found to lessen pain when given to patients
with PDN. Their use in the treatment of PDN is com-
mon.e33The panel recognizes that PDN is a chronic
disease and that there are no data on the efficacy of
the chronic use of any treatment, as most trials have
durations of 2–20 weeks. It is important to note that
the evidence is limited, the degree of effectiveness can
be minor, the side effects can be intolerable, the
impact on improving physical function is limited, and
the cost is high, particularly for novel agents.
A summary of Level A and B recommendations
for the treatment of PDN is provided in Table 1.
RECOMMENDATIONS FOR FUTURE RESEARCH
1. A formalized process for rating pain scales for
use in all clinical trials should be developed.
2. Clinical trials should be expanded to include
effects on QOL and physical function when
evaluating efficacy of new interventions for PDN
and the measures should be standardized.
Table 1. Summary of recommendations
Pregabalin, 300–600 mg/day
Gabapentin, 900–3600 mg/day
Sodium valproate, 500–1200 mg/d
Venlafaxine, 75–225 mg/day
Duloxetine, 60–120 mg/day
Amitriptyline, 25–100 mg/day
Morphine sulfate, titrated
to 120 mg/day
Tramadol, 210 mg/day
Reiki therapy Oxycodone, mean
37 mg/day, max. 120 mg/day
four times per day
Isosorbide dinitrate spray
stimulation for 3–4 weeks
6 AANEM Practice Topic: Treatment of PDN MUSCLE & NERVE Month 2011
3. Future clinical trials should include head-to-
head comparisons of different medications and
combinations of medications.
4. Because PDN is a chronic disease, trials of lon-
ger duration should be done.
5. Standard metrics for side effects to qualify effect
sizes of interventions need to be developed.
6. Cost-effectiveness studies of different treatments
should be done.
7. The mechanism of action of electrical stimula-
tion is unknown and a better understanding of
its role, mode of application, and other aspects
of its use should be studied.
APPENDIX E1: SEARCH TERMS USED
Search term used included painful diabetic neu-
ropathy OR neuropathic pain OR diabetes AND:
anticonvulsant, anti-epileptic, anti-depressant, anti-
arrthymic, spinal cord stimulation, infra-red ther-
apy, acupuncture, opioids, topical patches, lido-
caine, intra-thecal baclofen, TENS, vitamins, life-
style modification, metabolic control, baclofen.
APPENDIX E2: AAN CLASSIFICATION OF
EVIDENCE FOR RATING OF A
Class I: A randomized, controlled clinical trial
of the intervention of interest with masked or
objective outcome assessment, in a representative
population. Relevant baseline characteristics are
treatment groups or there is appropriate statistical
adjustment for differences.
The following are also required:
a. Concealed allocation.
b. Primary outcome(s) clearly defined.
c. Exclusion/inclusion criteria clearly defined.
d. Adequate accounting for dropouts (with at least
80% of enrolled subjects completing the study)
and crossovers with numbers sufficiently low to
have minimal potential for bias.
e. For non-inferiority or equivalence trials claiming
to prove efficacy for one or both drugs, the fol-
lowing are also required (note that 1–3 are
required for Class II in equivalence trials. If any
one of the three are missing, the class is auto-
matically downgraded to Class III).
1. The authors explicitly state the clinically mean-
ingful difference to be excluded by defining the
threshold for equivalence or non-inferiority.
2. The standard treatment used in the study is sub-
stantially similar to that used in previous studies
establishing efficacy of the standard treatment
(e.g., for a drug, the mode of administration,
dose, and dosage adjustments are similar to
those previously shown to be effective).
3. The inclusion and exclusion criteria for patient
selection and the outcomes of patients on the
standard treatment are comparable to those of
previous studies establishing efficacy of the
4. The interpretation of the results of the study is
based upon a per-protocol analysis that takes
into account dropouts or crossovers.
Class II: A randomized, controlled clinical trial of
the intervention of interest in a representative pop-
ulation with masked or objective outcome assess-
ment that lacks one of the criteria a–e listed above
masked or objective outcome assessment in a rep-
resentative population that meets b–e above. Rele-
vant baseline characteristics are presented and
substantially equivalent among treatment groups
or there is appropriate statistical adjustment for
Class III: All other controlled trials (including
well-defined natural history controls or patients
serving as own controls) in a representative popu-
lation, where outcome is independently assessed,
or independently derived by objective outcome
measurement [i.e., an outcome measure that is
unlikely to be affected by an observer’s (patient,
treating physician, investigator) expectation or bias
(e.g., blood tests, administrative outcome data)].
Class IV: Studies not meeting Class I, II, or III cri-
teria including consensus or expert opinion.
APPENDIX E3: CLASSIFICATION OF
A ¼ Established as effective, ineffective or harmful
(or established as useful/predictive or not useful/
predictive) for the given condition in the specified
population. (Level A rating requires at least two
consistent Class I studies.) [In exceptional cases,
one convincing Class I study may suffice for an
‘‘A’’ recommendation if: (1) all criteria are met;
(2) the magnitude of effect is large (relative rate
improved outcome >5 and the lower limit of the
confidence interval is >2.]
B ¼ Probably effective, ineffective, or harmful (or
probably useful/predictive or not useful/predic-
tive) for the given condition in the specified popu-
lation. (Level B rating requires at least one Class I
study or two consistent Class II studies.)
C ¼ Possibly effective, ineffective, or harmful
(or possibly useful/predictive or not useful/pre-
dictive) for the given condition in the specified
AANEM Practice Topic: Treatment of PDN MUSCLE & NERVE Month 20117
population. (Level C rating requires at least one Download full-text
Class II study or two consistent Class III studies.)
U ¼ Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
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