Transcript Slide 1

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
Vera Bril, MD, FRCP(C); John England, MD, FAAN; Gary M. Franklin, MD,
MPH, FAAN; Miroslav Backonja, MD; Jeffrey Cohen, MD, FAAN; David Del
Toro, MD; Eva Feldman, MD, PhD, FAAN; Donald J. Iverson, MD, FAAN;
Bruce Perkins, MD, FRCP(C), MPH; James W. Russell, MD, MS, FRPC;
Douglas Zochodne, MD
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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© 2011 AMERICAN ACADEMY OF NEUROLOGY
Presentation Objectives
• To present analysis of the efficacy of pharmacologic and
nonpharmacologic treatments to reduce pain and
improve physical function and quality of life (QOL) in
patients with painful diabetic neuropathy (PDN)
• To present evidence-based recommendations
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Overview
• Background
• Gaps in care
• American Academy of Neurology (AAN) guideline
process
• Analysis of evidence, conclusions, recommendations
• Recommendations for future research
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Background
•
•
•
•
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Diabetic sensorimotor polyneuropathy represents a diffuse symmetric and
length-dependent injury to peripheral nerves that has major implications for
QOL, morbidity, and cost from a public health perspective.1,2
PDN affects 16% of patients with diabetes; it is frequently unreported
(12.5%) and more frequently untreated (39%).3
PDN presents an ongoing management problem for patients, caregivers,
and physicians.
Many treatment options are available, and a rational approach to treating
patients with PDN requires an understanding of the evidence for each
intervention.
This guideline addresses the efficacy of pharmacologic and
nonpharmacologic treatments to reduce pain and improve physical function
and QOL in patients with PDN.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Background, cont.
• Pharmacologic Agents:

Anticonvulsants, antidepressants, opioids, antiarrhythmics,
cannabinoids, aldose reductase inhibitors, protein kinase C beta
inhibitors, antioxidants (α-lipoic acid), transketolase activators
(thiamines and allithiamines), topical medications (analgesic patches,
anesthetic patches, capsaicin cream, clonidine), and others
• Nonpharmacologic Modalities:

Infrared therapy, shoe magnets, exercise, acupuncture, external
stimulation (transcutaneous electrical nerve stimulation), spinal cord
stimulation, biofeedback and behavioral therapy, surgical
decompression, and intrathecal baclofen
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Gaps in Care
• The chronic effect of drug therapies is not known (how
long to treat, when or whether to withdraw treatment).
• There is an insufficient number of comparative studies
among high-quality studies (most were Class II or lower).
• There is no uniformity in how to measure pain, QOL, and
function across the studies examined.
• Lack of cost effectiveness is apparent in all of the
studies.
• Estimated numbers needed to treat are available, but
numbers needed to harm are not available.
• The AAN classifies studies by quality of the evidence,
not by cost.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Gaps in Care, cont.
• Practitioners don’t identify pain enough in peripheral
neuropathy or diabetic neuropathy.

Patients with diabetes often aren’t aware that nerve pain is a symptom.
• Most neuropathy therapies treat pain but not numbness.
• There is a lack of attention to PDN as a disease entity.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Questions
• The first step in developing guidelines is to clearly
formulate questions to be answered.
• Questions address areas of controversy, confusion, or
variation in practice.
• Questions must be answerable with data from the
literature.
• Answering the question must have the potential to
improve care/patient outcomes.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of
Evidence
• All studies rated Class I, II, III, or IV
• Five different classification systems:
 Therapeutic
− Randomization, control, blinding
 Diagnostic
− Comparison to gold standard
 Prognostic
 Screening
 Causation
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Level of
Recommendations
• A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
• B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
• C = Possibly effective, ineffective or harmful (or possibly
useful/predictive or not useful/predictive) for the given
condition in the specified population.
• U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.
Note that recommendations can be positive or negative.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Translating Class to Recommendations
• A = Requires at least two consistent Class I
studies.*
• B = Requires at least one Class I study or two
consistent Class II studies.
• C = Requires at least one Class II study or two
consistent Class III studies.
• U = Studies not meeting criteria for Class I
through Class III.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Translating Class to Recommendations,
cont.
*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).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Applying This Process
to the Issue
We will now turn our attention to the guidelines.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Questions
1. In patients with PDN, what is the efficacy of
pharmacologic agents to reduce pain and
improve physical function and QOL?
2. In patients with PDN, what is the efficacy of
nonpharmacologic modalities to reduce
pain and improve physical function and
QOL?
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Methods
• MEDLINE and EMBASE
 1960 to August 2008
 Relevant, fully published, peer-reviewed articles
 MeSH term “diabetic neuropathies” and its text word
synonyms and key words for the therapeutic
interventions of interest (see published guideline for full
list of terms)
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Methods, cont.
• At least two authors reviewed each article for
inclusion.
• Risk of bias was determined using the
classification of evidence for each study (Classes
I–IV).
• Strength of practice recommendations were linked
directly to levels of evidence (Levels A, B, C, and
U).
• Conflicts of interest were disclosed.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Literature Review
Inclusion criteria:
2234 abstracts
- Articles dealing with
PDN, describing the
intervention clearly,
reporting study completion
rates, defining the
outcome measures clearly
Exclusion criteria:
- Case reports and review
papers
79 articles
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention
• 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 presented and substantially
equivalent among treatment groups or there is appropriate
statistical adjustment for differences. The following are
also required:
 concealed allocation
 primary outcome(s) clearly defined
 exclusion/inclusion criteria clearly defined
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
 adequate accounting for drop-outs (with at least 80% of enrolled
subjects completing the study) and cross-overs with numbers
sufficiently low to have minimal potential for bias.
 For noninferiority or equivalence trials claiming to prove efficacy for
one or both drugs, the following are also required**:
– The authors explicitly state the clinically meaningful difference to be excluded by
defining the threshold for equivalence or noninferiority.
– The standard treatment used in the study is substantially 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).
– 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 standard treatment.
– The interpretation of the results of the study is based upon a per protocol analysis
that takes into account dropouts or crossovers.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
• Class II: A randomized controlled clinical trial of the
intervention of interest in a representative population with
masked or objective outcome assessment that lacks one
criteria ae above or a prospective matched cohort study
with masked or objective outcome assessment in a
representative population that meets be above. Relevant
baseline characteristics are presented and substantially
equivalent among treatment groups or there is appropriate
statistical adjustment for differences.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for Therapeutic Intervention, cont.
• Class III: All other controlled trials (including well-defined
natural history controls or patients serving as own controls)
in a representative population, where outcome is
independently assessed, or independently derived by
objective outcome measurement.**
• Class IV: Studies not meeting Class I, II or III criteria
including consensus or expert opinion.
**Note that numbers 13 in Class I, item 5 are required for Class II in equivalence trials. If
any one of the three are missing, the class is automatically downgraded to Class III.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 1: In patients with PDN, what is
the efficacy of pharmacologic agents to
reduce pain and improve physical function
and QOL?
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
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.
Recommendation:
• If clinically appropriate, pregabalin should be offered for the treatment of
PDN (Level A).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• Based on 1 Class I study, gabapentin is probably effective in lessening the
pain of PDN.
• Based on 2 Class II studies, sodium valproate is probably effective in
treating PDN.
Recommendation:
• Gabapentin and sodium valproate should be considered for the treatment of
PDN (Level B).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
• There is conflicting Class III evidence for the effectiveness of topiramate in
treating PDN.
Recommendation:
• There is insufficient evidence to support or refute the use of topiramate for
the treatment of PDN (Level U).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• Lamotrigine is probably not effective in treating PDN.
• Based on Class II evidence, oxcarbazepine is probably not effective 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.
Recommendation:
•
Oxcarbazepine, lamotrigine, and lacosamide should probably not be
considered for the treatment of PDN (Level B).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
• Although sodium valproate 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, this drug is unlikely to be
the first treatment choice for PDN.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendations
Conclusions:
• Based on 3 Class I and 5 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 superior to placebo in relieving pain when added to
gabapentin.
Recommendations:
• 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.
• Venlafaxine may be added to gabapentin for a better response (Level C).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
• There is insufficient evidence to determine whether desipramine,
imipramine, fluoxetine, or the combination of nortriptyline and fluphenazine
are effective for the treatment of PDN.
Recommendation:
• 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 (Level U).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• Based on one Class I study, dextromethorphan is probably effective in
lessening the pain of PDN and improving QOL.
• Based on Class II evidence, morphine sulphate, 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.
Recommendation:
• Dextromethorphan, morphine sulphate, tramadol, and oxycodone should be
considered for the treatment of PDN (Level B). Data are insufficient to
recommend one agent over the other.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
• The use of opioids for chronic nonmalignant pain has gained
credence over the last decade due to the studies reviewed in this
article.
• Both tramadol and dextromethorphan were associated 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 associated with the development of novel
pain syndromes such as rebound headache.
• Chronic use of opioids leads to tolerance and frequent escalation of
dose.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• Based on Class I and Class II evidence, capsaicin cream is probably
effective in lessening the pain of PDN.
• Based on Class I evidence, isosorbide dinitrate spray is probably effective
for the treatment of PDN.
Recommendation:
• Capsaicin and isosorbide dinitrate spray should be considered for the
treatment of PDN (Level B).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• Based on Class III studies, there is insufficient evidence to determine if IV
lidocaine 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.
Recommendation:
• The Lidoderm patch may be considered for the treatment of PDN (Level C).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendation
Conclusions:
• 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 contradictory; however,
the only Class I study of this agent indicates that mexiletine is probably
ineffective for the treatment of PDN.
Recommendation:
• Clonidine, pentoxifylline, and mexiletine should probably not be considered
for the treatment of PDN (Level B).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
• There is insufficient evidence to determine whether vitamins and α-lipoic
acid are effective for the treatment of PDN.
Recommendation:
• There is insufficient evidence to support or refute the usefulness of vitamins
and α-lipoic acid in the treatment of PDN (Level U).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
• Although capsaicin has been 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.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 2: In patients with PDN, what is
the efficacy of nonpharmacologic modalities
to reduce pain and improve physical
function and QOL?
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusions/Recommendations
Conclusions:
• Based on a Class I study, electrical stimulation is probably effective in
lessening the pain of PDN and improving QOL.
• Based on single Class I studies, electromagnetic field treatment, lowintensity laser treatment, and Reiki therapy are probably not effective for the
treatment of PDN.
Recommendations:
• Percutaneous electrical nerve stimulation should be considered for the
treatment of PDN (Level B).
• Electromagnetic field treatment, low-intensity laser treatment, and Reiki
therapy should probably not be considered for the treatment of PDN (Level
B).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
• There is not enough evidence to support or exclude a benefit of
amitriptyline plus electrotherapy in treating PDN.
Recommendation:
• Evidence is insufficient to support or refute the use of amitriptyline plus
electrotherapy for treatment of PDN (Level U).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Comparison Studies:
• Studies with 2 active treatment arms and without a placebo arm were
considered separately and graded using active control equivalence criteria
(see appendix e-2 and table e-6 of the published guideline).
• We identified 6 comparison studies of agents (gabapentin to amitriptyline,4
venlafaxine to carbamazepine, nortriptyline + fluphenazine to
carbamazepine, capsaicin to amitriptyline, and benfotiamine +
cyanocobalamin with conventional vitamin B) but did not find evidence to
recommend one over the other. 5–10
• None of the studies defined the threshold for equivalence or noninferiority.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
• 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 the 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 common.11
• The 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.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Future Research
• A formalized process for rating pain scales for use in all clinical trials should be
developed.
• Clinical trials should be expanded to include effects on QOL and physical
function when evaluating efficacy of new interventions for PDN; the measures
should be standardized.
• Future clinical trials should include head-to-head comparisons of different
medications and combinations of medications.
• Because PDN is a chronic disease, trials of longer duration should be done.
• Standard metrics for side effects to qualify effect sizes of interventions need to
be developed.
• Cost-effectiveness studies of different treatments should be done.
• The mechanism of action of electrical stimulation is unknown; a better
understanding of its role, mode of application, and other aspects of its use
should be studied.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
References
1.
2.
3.
4.
5.
6.
Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the
American Diabetes Association. Diabetes Care 2005;28:956–962.
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of
diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:1790–1795.
Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ.
Chronic painful peripheral neuropathy in an urban community: a controlled
comparison of people with and without diabetes. Diabet Med 2004;21:976–982.
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of
diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:1790–1795.
Dallocchio C, Buffa C, Mazzarello P, Chiroli S. Gabapentin vs. amitriptyline in painful
diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage
2000;20:280–285.
Jia H, Li Q, Song D, et al. Effects of venlafaxine and carbamazepine for painful
peripheral diabetic neuropathy: A randomized, double-blind and double-dummy,
controlled multi-center trial. Chin J of Evid-based Med 2006;6.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
References, cont.
7.
Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. Randomized
double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic
peripheral neuropathy pain. Arch Intern Med 1999;159:1931–1937.
8. Gomez-Perez FJ, Choza R, Rios JM, et al. Nortriptyline-fluphenazine vs.
carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med Res
1996;27:525–529.
9 Biesbroeck R, Bril V, Hollander P, et al. A Double-blind Comparison of Topical
Capsaicin and Oral Amitriptyline in Painful Diabetic Neuropathy. Adv Ther
1995;12:111–120.
10. Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev D. Therapeutic efficacy of
"Milgamma" in patients with painful diabetic neuropathy. Folia Med (Plovdiv)
1997;39:5–10.
11. Perkins BA, Bril V. Emerging therapies for diabetic neuropathy: a clinical overview.
Curr Diabetes Rev 2005;1:271–280.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
References, cont.
For a complete list of references, please access the full
guideline at www.aan.com/guidelines
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Questions/Comments
© 2011 AMERICAN ACADEMY OF NEUROLOGY
Thank you for your participation!
© 2011 AMERICAN ACADEMY OF NEUROLOGY