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1、 2011 AMERICAN ACADEMY OF NEUROLOGYAAN指南PPT-治疗痛性糖尿病神经病Stillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望 2011 AMERICAN ACADEMY OF NEUROLOGYIf you have questions, comments, or feedback regarding this slide presentation, or would like to modify the contents for presentati
2、on in a lecture, please contact 2011 AMERICAN ACADEMY OF NEUROLOGYPresentation 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
3、present evidence-based recommendations 2011 AMERICAN ACADEMY OF NEUROLOGYOverview BackgroundGaps in careAmerican Academy of Neurology (AAN) guideline processAnalysis of evidence, conclusions, recommendationsRecommendations for future research 2011 AMERICAN ACADEMY OF NEUROLOGYBackground Diabetic sen
4、sorimotor 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 un
5、treated (39%).3PDN 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 phar
6、macologic and nonpharmacologic treatments to reduce pain and improve physical function and QOL in patients with PDN. 2011 AMERICAN ACADEMY OF NEUROLOGYBackground, cont. Pharmacologic Agents:Anticonvulsants, antidepressants, opioids, antiarrhythmics, cannabinoids, aldose reductase inhibitors, protein
7、 kinase C beta inhibitors, antioxidants (-lipoic acid), transketolase activators (thiamines and allithiamines), topical medications (analgesic patches, anesthetic patches, capsaicin cream, clonidine), and othersNonpharmacologic Modalities:Infrared therapy, shoe magnets, exercise, acupuncture, extern
8、al stimulation (transcutaneous electrical nerve stimulation), spinal cord stimulation, biofeedback and behavioral therapy, surgical decompression, and intrathecal baclofen 2011 AMERICAN ACADEMY OF NEUROLOGYGaps in Care The chronic effect of drug therapies is not known (how long to treat, when or whe
9、ther 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.Estim
10、ated 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 NEUROLOGYGaps in Care, cont. Practitioners dont identify pain enough in peripheral neuropathy or diabetic neuropathy.P
11、atients with diabetes often arent 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 NEUROLOGYAAN Guideline Process Clinical QuestionEvidenceConclusionsRecommendations 2011 AMERICA
12、N ACADEMY OF NEUROLOGYClinical 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 th
13、e potential to improve care/patient outcomes. 2011 AMERICAN ACADEMY OF NEUROLOGY Literature Search/Review RelevantCompleteSearchReview abstractsReview full textSelect articlesRigorous, Comprehensive, Transparent 2011 AMERICAN ACADEMY OF NEUROLOGYAAN Classification of Evidence All studies rated Class
14、 I, II, III, or IVFive different classification systems:TherapeuticRandomization, control, blindingDiagnosticComparison to gold standardPrognosticScreeningCausation 2011 AMERICAN ACADEMY OF NEUROLOGY AAN Level of RecommendationsA = Established as effective, ineffective or harmful (or established as
15、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 (
16、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 NEUROLOGYTr
17、anslating Class to RecommendationsA = 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 I
18、II. 2011 AMERICAN ACADEMY OF NEUROLOGYTranslating 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 conf
19、idence interval is 2). 2011 AMERICAN ACADEMY OF NEUROLOGYApplying This Processto the Issue We will now turn our attention to the guidelines. 2011 AMERICAN ACADEMY OF NEUROLOGYClinical Questions1. In patients with PDN, what is the efficacy of pharmacologic agents to reduce pain and improve physical f
20、unction 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 NEUROLOGYMethodsMEDLINE and EMBASE 1960 to August 2008Relevant, fully published, peer-reviewed articlesMeSH term “diabetic neurop
21、athies” 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 NEUROLOGYMethods, cont.At least two authors reviewed each article for inclusion.Risk of bias was determined using the classificatio
22、n of evidence for each study (Classes IIV).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 NEUROLOGYLiterature Review 79 articles2234 abstractsInclusion criteria: - Articles dealing
23、 with PDN, describing the intervention clearly, reporting study completion rates, defining the outcome measures clearlyExclusion criteria: - Case reports and review papers 2011 AMERICAN ACADEMY OF NEUROLOGYAAN Classification of Evidencefor Therapeutic InterventionClass I: A randomized, controlled cl
24、inical 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
25、are also required:concealed allocationprimary outcome(s) clearly definedexclusion/inclusion criteria clearly defined 2011 AMERICAN ACADEMY OF NEUROLOGYAAN Classification of Evidencefor Therapeutic Intervention, cont.adequate accounting for drop-outs (with at least 80% of enrolled subjects completing
26、 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
27、 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
28、 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 upo
29、n a per protocol analysis that takes into account dropouts or crossovers. 2011 AMERICAN ACADEMY OF NEUROLOGYAAN Classification of Evidencefor Therapeutic Intervention, cont.Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or
30、objective outcome assessment that lacks one criteria ae above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets be above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or t
31、here is appropriate statistical adjustment for differences. 2011 AMERICAN ACADEMY OF NEUROLOGYAAN Classification of Evidencefor Therapeutic Intervention, cont.Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representat
32、ive 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 13 in Class I, item 5 are required for Class II in equivalence trials
33、. If any one of the three are missing, the class is automatically downgraded to Class III. 2011 AMERICAN ACADEMY OF NEUROLOGYAnalysis of EvidenceQuestion 1: In patients with PDN, what is the efficacy of pharmacologic agents to reduce pain and improve physical function and QOL? 2011 AMERICAN ACADEMY
34、OF NEUROLOGYConclusions/RecommendationConclusions: 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, prega
35、balin should be offered for the treatment of PDN (Level A). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusions/RecommendationConclusions: 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 treatin
36、g PDN. Recommendation:Gabapentin and sodium valproate should be considered for the treatment of PDN (Level B). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusion/RecommendationConclusion: There is conflicting Class III evidence for the effectiveness of topiramate in treating PDN. Recommendation:There is i
37、nsufficient evidence to support or refute the use of topiramate for the treatment of PDN (Level U). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusions/RecommendationConclusions: Lamotrigine is probably not effective in treating PDN. Based on Class II evidence, oxcarbazepine is probably not effective in t
38、reating 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 f
39、or the treatment of PDN (Level B). 2011 AMERICAN ACADEMY OF NEUROLOGYClinical ContextAlthough 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 potenti
40、al worsening of glycemic control, this drug is unlikely to be the first treatment choice for PDN. 2011 AMERICAN ACADEMY OF NEUROLOGYConclusions/RecommendationsConclusions: Based on 3 Class I and 5 Class II studies, the antidepressants amitriptyline, venlafaxine, and duloxetine are probably effective
41、 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 rec
42、ommend one of these agents over the others.Venlafaxine may be added to gabapentin for a better response (Level C). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusion/RecommendationConclusion: There is insufficient evidence to determine whether desipramine, imipramine, fluoxetine, or the combination of nor
43、triptyline 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 NEUR
44、OLOGYConclusions/RecommendationConclusions: 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
45、.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 recommen
46、d one agent over the other. 2011 AMERICAN ACADEMY OF NEUROLOGYClinical ContextThe 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.
47、, 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
48、 dose. 2011 AMERICAN ACADEMY OF NEUROLOGYConclusions/RecommendationConclusions: 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. Recommendat
49、ion:Capsaicin and isosorbide dinitrate spray should be considered for the treatment of PDN (Level B). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusions/RecommendationConclusions: Based on Class III studies, there is insufficient evidence to determine if IV lidocaine is effective in lessening the pain of
50、 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 NEUROLOGYConclusions/RecommendationConclusions: Based on Class I evidence, clonid
51、ine 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, pentoxify
52、lline, and mexiletine should probably not be considered for the treatment of PDN (Level B). 2011 AMERICAN ACADEMY OF NEUROLOGYConclusion/RecommendationConclusion: There is insufficient evidence to determine whether vitamins and -lipoic acid are effective for the treatment of PDN. Recommendation:Ther
53、e is insufficient evidence to support or refute the usefulness of vitamins and -lipoic acid in the treatment of PDN (Level U). 2011 AMERICAN ACADEMY OF NEUROLOGYClinical ContextAlthough capsaicin has been effective in reducing pain in PDN clinical trials, many patients are intolerant of the side eff
54、ects, mainly burning pain on contact with warm/hot water or in hot weather. 2011 AMERICAN ACADEMY OF NEUROLOGYAnalysis of EvidenceQuestion 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 NEURO
55、LOGYConclusions/RecommendationsConclusions: 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, low-intensity laser treatment, and Reiki therapy are probably not effec
56、tive 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). 201
57、1 AMERICAN ACADEMY OF NEUROLOGYConclusion/RecommendationConclusion: 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 treatme
58、nt of PDN (Level U). 2011 AMERICAN ACADEMY OF NEUROLOGYAnalysis of EvidenceComparison 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). W
59、e 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
60、. 510None of the studies defined the threshold for equivalence or noninferiority. 2011 AMERICAN ACADEMY OF NEUROLOGYClinical ContextIt 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 ot
61、her 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.11The panel recognizes that PDN is a chronic disease and that there are no data on the efficacy of the chronic us
62、e of any treatment, as most trials have durations of 220 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 agen
63、ts. 2011 AMERICAN ACADEMY OF NEUROLOGYFuture ResearchA 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 s
64、hould 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
65、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 NEUROLOGYReferences1.Boulton
66、AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956962. 2.Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:17901795. 3.Daousi
67、 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;21:976982. 4.Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of d
68、iabetic peripheral neuropathy in the US. Diabetes Care 2003;26:17901795.5.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;20:280285.6.Jia H, Li Q, Song D, et al. Effects of venlafaxine
69、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 NEUROLOGYReferences, cont.7. Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. Randomized d
70、ouble-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999;159:19311937. 8. Gomez-Perez FJ, Choza R, Rios JM, et al. Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med
71、Res 1996;27:525529. 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;12:111120. 10. Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev D. Therapeutic efficacy of Milgamma in patients with p
72、ainful diabetic neuropathy. Folia Med (Plovdiv) 1997;39:510. 11. Perkins BA, Bril V. Emerging therapies for diabetic neuropathy: a clinical overview. Curr Diabetes Rev 2005;1:271280. 2011 AMERICAN ACADEMY OF NEUROLOGYReferences, cont.For a complete list of references, please access the full guideline at 2011 AMERICAN ACADEMY OF NEUROLOGYQuestions/Comments 2011 AMERICAN ACADEMY OF NEUROLOGYThank you for your participation!
