AAN指南PPT-治疗痛性糖尿病神经病.ppt

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,If you have questions, comments, or feedback regarding this slide presentation, or would like to modify the contents for presentation in a lecture, please contact ,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,Overview,Background Gaps in care American Academy of Neurology (AAN) guideline process Analysis of evidence, conclusions, recommendations Recommendations for future research,Background,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.,Background, cont.,Pharmacologic Agents: Anticonvulsants, antidepressants, opioids, antiarrhythmics, cannabinoids, aldose reductase inhibitors, protein kinase C beta inhibitors, antioxidants (-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,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.,Gaps in Care, cont.,Practitioners dont identify pain enough in peripheral neuropathy or diabetic neuropathy. Patients 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.,AAN Guideline Process,Clinical Question Evidence Conclusions Recommendations,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.,Literature Search/Review,Rigorous, Comprehensive, Transparent,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,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.,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.,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).,Applying This Process to the Issue,We will now turn our attention to the guidelines.,Clinical Questions,1. In patients with PDN, what is the efficacy of pharmacologic agents to reduce pain and improve physical function and QOL? In patients with PDN, what is the efficacy of nonpharmacologic modalities to reduce pain and improve physical function and QOL?,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),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 IIV). Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.,Literature Review,Inclusion criteria: Articles dealing with PDN, describing the intervention clearly, reporting study completion rates, defining the outcome measures clearly Exclusion criteria: Case reports and review papers,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,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.,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 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 there is appropriate statistical adjustment for differences.,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 13 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.,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?,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).,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).,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).,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).,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.,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).,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).,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.,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.,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).,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).,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).,Conclusion/Recommendation,Conclusion: There is insufficient evidence to determine whether vitamins and -lipoic acid are effective for the treatment of PDN. Recommendation: There is insufficient evidence to support or refute the usefulness of vitamins and -lipoic acid in the treatment of PDN (Level U).,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.,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?,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, low-intensity 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).,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).,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. 510 None of the studies defined the threshold for equivalence or noninferiority.,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 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 agents.,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