AAN 糖尿病神经痛指南 2011

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 http://www.neurology.org/content/early/2011/04/08/WNL.0b013e3182166ebe located on the World Wide Web at: The online version of this article, along with updated information and services, is rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Allsince 1951, it is now a weekly with 48 issues per year. Copyright © 2011 by AAN Enterprises, Inc. ® is the official journal of the American Academy of Neurology. Published continuouslyNeurology by guest on April 13, 2011www.neurology.orgDownloaded from 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 Published Ahead of Print on April 11, 2011 as 10.1212/WNL.0b013e3182166ebe by guest on April 13, 2011www.neurology.orgDownloaded from 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 by guest on April 13, 2011www.neurology.orgDownloaded from 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 Neurology 76 May 17, 2011 3 by guest on April 13, 2011www.neurology.orgDownloaded from 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