今日の臨床サポート

糖尿病性神経障害

著者: 壁谷悠介 そうわクリニック

監修: 野田光彦 国際医療福祉大学市川病院 糖尿病・代謝・内分泌内科

著者校正/監修レビュー済:2021/09/08
参考ガイドライン:
  1. 日本糖尿病学会:糖尿病診療ガイドライン2019
患者向け説明資料

概要・推奨   

  1. 糖尿病性神経障害の発症・進展には血糖コントロールの状態が関与するため、できる限り厳格な血糖コントロールを行うことが推奨される(推奨度1)。
  1. 糖尿病性神経障害の予防のためには、血糖値のコントロールのみならず、高血圧、脂質異常症の是正、禁煙、節酒などの生活習慣の改善が推奨される(推奨度1)。
  1. 足の診察・フットケアは糖尿病患者に定期的に行うべきである(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
壁谷悠介 : 未申告[2021年]
監修:野田光彦 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 糖尿病診療ガイドライン2019に基づき、主に有痛性神経障害の治療について改訂を行った。
  1. 米国糖尿病学会のポジションステートメントに基づき確認を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 糖尿病性神経障害とは、糖尿病によって誘発される神経障害のことである。多発神経障害(広汎性左右対称性神経障害)と単神経障害がある。日常臨床では多発神経障害に遭遇する頻度のほうが高い。多発神経障害は、感覚神経障害と自律神経障害を呈する。
  1. 感覚神経障害で多い症状は、下肢を主体とした異常知覚、知覚鈍麻である。自律神経障害の症状は多岐にわたり、日常生活に大きな影響を与えることがある。単神経障害の代表的なものは、急な単一脳神経の麻痺である。頭蓋内病変との鑑別を要する。
  1. 多発神経障害の疾患頻度は、過去の報告の診断基準や対象患者が多様であるため明確に把握されていないが、糖尿病合併症のなかで最も頻度が高いといわれる。一方、単神経障害の頻度は低い。
  1. 糖尿病性神経障害の治療の基本は血糖コントロールであり、良好な血糖コントロールを長期間維持することにより神経障害の発症・進展が抑制されることが明らかにされている[1]
 
糖尿病神経障害の分類一覧とその主な症状:
  1. 広汎性左右対称性神経障害(代謝障害が主な原因と考えられる)
  1. 感覚・運動神経障害:
  1. 頻度が最多である。異常感覚(しびれ感、じんじん感)自発痛、感覚鈍麻、こむら返りなどを認める。特に糖尿病性神経痛。
  1. 自律神経障害:
  1. 発汗の異常、起立性低血圧、胃不全麻痺、便通異常(便秘・下痢)、胆のう無力症、膀胱障害、勃起障害、無自覚低血糖などを認める。
  1. 単神経障害(血管閉塞が主な原因と考えられる)
  1. 脳神経障害:
  1. 外眼筋麻痺(動眼神経麻痺・滑車神経麻痺・外転神経麻痺など)、顔面神経麻痺などを認める。
  1. 単神経障害で、臨床的に多く認めるのは、動眼神経障害である。臨床的には、脳動脈瘤による動眼神経への圧迫、脳梗塞との鑑別が必要になる。通常、散瞳を認めるのが脳動脈瘤の圧迫で、糖尿病性単神経障害では、散瞳を認めない傾向がある。
  1. 体幹・四肢の神経障害:
  1. 尺骨神経麻痺、腓骨神経麻痺、体幹の単神経障害などを認める。
  1. 糖尿病性筋萎縮
問診・診察のポイント  
病歴:
  1. 糖尿病の罹病期間、血糖コントロールの状態を確認する。

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文献 

著者:
雑誌名: N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
Abstract/Text BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

PMID 8366922  N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/・・・
著者: Rodica Pop-Busui, Andrew J M Boulton, Eva L Feldman, Vera Bril, Roy Freeman, Rayaz A Malik, Jay M Sosenko, Dan Ziegler
雑誌名: Diabetes Care. 2017 Jan;40(1):136-154. doi: 10.2337/dc16-2042.
Abstract/Text
PMID 27999003  Diabetes Care. 2017 Jan;40(1):136-154. doi: 10.2337/dc1・・・
著者: A J Boulton, J Drury, B Clarke, J D Ward
雑誌名: Diabetes Care. 1982 Jul-Aug;5(4):386-90.
Abstract/Text Nine patients with diabetic neuropathy were treated as outpatients with continuous subcutaneous insulin infusion (CSII). Painful symptoms were scored on a 10-cm horizontal graphic rating scale; motor conduction velocity (MCV) was measured in the median and peroneal nerves; and vibration perception threshold (VPT) was recorded in the great toes. All investigations were repeated after 6 wk and at the completion of 4 mo of CSII. Improved diabetic control was confirmed by significantly lower mean blood glucose levels, M-values, and glycosylated hemoglobin. Symptomatic relief was noted by all patients and was accompanied by a significant improvement in pain scores. There was also significant improvement in VPT and MCV after 6 wk of CSII, which was maintained throughout the 4-mo period. However, sensory studies in the median nerve showed no significant changes during the study. It is concluded that strict glucoregulation is indicated in all cases of symptomatic diabetic neuropathy. It remains to be seen whether strict diabetic control from diagnosis will lead to a reduction in the incidence of this complication.

PMID 7151654  Diabetes Care. 1982 Jul-Aug;5(4):386-90.
著者: D A Greene, M J Brown, S N Braunstein, S S Schwartz, A K Asbury, A I Winegrad
雑誌名: Diabetes. 1981 Feb;30(2):139-47.
Abstract/Text The use of electrophysiological (EP) tests as the primary basis for determining outcome in clinical trials of therapy for symptomatic diabetic polyneuropathy, and the frequently short duration of such trials, is based on assumptions at variance with the pathology and natural history of this disorder and with the evidence that the commonly employed EP tests predominantly reflect the status of the large myelinated nerve fibers. The course of painful, distal symmetrical, primarily sensory polyneuropathy was studied in nine chronic diabetics, aged 21--59 yr, selected for the absence of other forms of diabetic neuropathy, other causes of neuropathy, and other significant illness. All were treated with modifications of diet, insulin, and a daily multivitamin tablet, and, on a randomized basis, also received either placebo or myo-inositol tablets. Initially, and after 2, 4, and 6 mo, a standardized questionnaire was used to assess symptoms, and a standardized neurological examination and battery of EP tests were performed. A minimum of 6 mo was found necessary to assess the clinical course of this syndrome. Clinical improvement occurred in both legs and arms in four patients, as judged by improvement both in symptoms and in the extent of deficits in pinprick and temperature perception; abnormalities in sensory modalities mediated by large myelinated fibers, however, were generally unaltered after 6 mo. A nonuniform distribution of abnormal EP tests of sensory components of the commonly studied nerves of the leg and arm was demonstrated in the study group at the outset, and clinical improvement was not accompanied by evidence of any consistent pattern of improvement in the initially abnormal EP tests. A significant fraction of chronic diabetics with painful, distal symmetrical, primarily sensory polyneuropathy selected by standard criteria appear to have potential for clinical improvement over 6 mo, but primarily in sensory modalities that make it inappropriate to use the common EP tests as the primary basis of judging outcome.

PMID 7202858  Diabetes. 1981 Feb;30(2):139-47.
著者: A Tolaymat, J L Roque, L S Russo
雑誌名: South Med J. 1982 Feb;75(2):185-9.
Abstract/Text A 16-year-old girl with insulin dependent (Type I) diabetes since age 9 and painful sensory neuropathy for two months was treated with a portable insulin infusion pump, allowing strict control of hyperglycemia. Within 28 days the distal motor latency in all nerves tested had improved and painful incapacitating dysesthesias disappeared. The findings suggest that strict control of hyperglycemia with a portable insulin infusion pump can successfully reverse the changes of recent onset diabetic neuropathy.

PMID 7036357  South Med J. 1982 Feb;75(2):185-9.
著者: N H White, S R Waltman, T Krupin, J V Santiago
雑誌名: J Pediatr. 1981 Jul;99(1):41-5.
Abstract/Text Two adolescents with insulin-dependent diabetes mellitus developed unusually severe diabetic neuropathy which responded to intensive measures to achieve improved metabolic control. Employing home blood glucose monitoring and either frequent insulin injections or a portable insulin infusion pump, painful peripheral neuropathy and autonomic gastrointestinal neuropathy improved after five and 12 months of therapy, respectively. During this period of time, abnormal ocular fluorophotometry, an early change in the eye of diabetic patients, also returned to normal. These patients demonstrate the reversibility of unusually severe neuropathy and early ocular changes in adolescents with diabetes when treated with intensive measures designed to improve metabolic control.

PMID 7019402  J Pediatr. 1981 Jul;99(1):41-5.
著者: Solomon Tesfaye, Nish Chaturvedi, Simon E M Eaton, John D Ward, Christos Manes, Constantin Ionescu-Tirgoviste, Daniel R Witte, John H Fuller, EURODIAB Prospective Complications Study Group
雑誌名: N Engl J Med. 2005 Jan 27;352(4):341-50. doi: 10.1056/NEJMoa032782.
Abstract/Text BACKGROUND: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study.
METHODS: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (+/-SD) follow-up of 7.3+/-0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory.
RESULTS: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors.
CONCLUSIONS: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.

Copyright 2005 Massachusetts Medical Society.
PMID 15673800  N Engl J Med. 2005 Jan 27;352(4):341-50. doi: 10.1056/N・・・
著者: K Y Forrest, R E Maser, G Pambianco, D J Becker, T J Orchard
雑誌名: Diabetes. 1997 Apr;46(4):665-70.
Abstract/Text The pathogeneses of diabetic neuropathy is still unclear. This study prospectively investigated the risk factors for distal symmetrical polyneuropathy (DSP) in a cohort of childhood-onset IDDM patients. Subjects from the Epidemiology of Diabetes Complications (EDC) Study were clinically examined at baseline and then biennially. DSP was diagnosed by a combination of clinical criteria, symptoms and signs (Diabetes Control and Complications Trial [DCCT] exam), and quantitative sensory threshold (QST). Among the 463 (70.4%) subjects who were free of DSP at baseline, 453 (97.8%) participated in at least one biennial reexamination during the first 6 years of follow-up and were included in the current analysis. A total of 68 (15.0%) subjects developed DSP in 6 years, giving a cumulative probability of 0.29. The Cox proportional hazards model shows that longer IDDM duration, hypertension, poor glycemic control, height, and smoking were all independent predictors of the incidence of DSP (all P < 0.0001, except for smoking for which P = 0.03). Hypertension showed the greatest impact on the development of DSP for individuals with either short or long IDDM duration. This study confirms some risk factors for DSP found in cross-sectional studies and suggests a strong relationship between hypertension and DSP. The results indicate that in addition to good glycemic control, avoidance of smoking and good blood pressure control may be helpful in preventing or delaying the onset of DSP in IDDM patients.

PMID 9075809  Diabetes. 1997 Apr;46(4):665-70.
著者: A I Adler, E J Boyko, J H Ahroni, V Stensel, R C Forsberg, D G Smith
雑誌名: Diabetes Care. 1997 Jul;20(7):1162-7.
Abstract/Text OBJECTIVE: To identify risk factors for diabetic lower-extremity peripheral sensory neuropathy prospectively in a cohort of U.S. veterans with diabetes.
RESEARCH DESIGN AND METHODS: General medicine clinic outpatients with diabetes were followed prospectively for the development of insensitivity to the 5.07 monofilament on the foot.
RESULTS: Of 775 subjects, 388 (50%) had neuropathy at baseline. Of the 387 subjects without neuropathy at baseline, 288 were followed up, and of these, 58 (20%) developed neuropathy. Multivariate logistic regression modeling of prevalent neuropathy controlling for sex and race revealed independent and significant associations with age, duration of diabetes, glycohemoglobin level, height, history of lower-extremity ulceration, callus, and edema; an independent and inverse correlation was noted with ankle-arm index. Risk factors for incident neuropathy in multivariate logistic regression included age, baseline glycohemoglobin level, height, history of ulcer, and CAGE screening instrument alcohol score; current smoking and albumin level were inversely associated with risk.
CONCLUSIONS: Poorer glycemic control increases the risk of neuropathy and is amenable to intervention. Height and age directly increase risk of neuropathy and may help identify patients at risk. A proportion of neuropathy in diabetic veterans is probably due to or worsened by alcohol ingestion. Neuropathy was less common in current smokers than subjects not currently smoking.

PMID 9203456  Diabetes Care. 1997 Jul;20(7):1162-7.
著者: Harjot Kaur, Debasish Hota, Anil Bhansali, Pinaki Dutta, Dipika Bansal, Amitava Chakrabarti
雑誌名: Diabetes Care. 2011 Apr;34(4):818-22. doi: 10.2337/dc10-1793. Epub 2011 Feb 25.
Abstract/Text OBJECTIVE: To compare the efficacy and safety of duloxetine and amitriptyline in painful diabetic neuropathy (PDN).
RESEARCH DESIGN AND METHODS: In this randomized, double-blind, cross-over, active-control trial, 58 patients received amitriptyline and duloxetine orally once daily at bedtime, each for 6 weeks with optional dose uptitration fortnightly. Single-blinded placebo washout was given for 2 weeks between the two treatments and a single-blinded placebo run-out phase of 4 weeks was given at the end of the treatment period. Pain relief was measured by the patient's global assessment of efficacy, using a visual analog scale (0-100) as a primary end point, and overall improvement and adverse events were assessed as secondary outcome measures. Median pain score reductions of >50%, 25-50%, and <25% were considered good, moderate, and mild responses, respectively.
RESULTS: There was a significant improvement in pain with both treatments compared with their baseline values (P < 0.001 for both). Good, moderate, and mild pain relief was achieved in 55, 24, and 15% of patients, respectively, on amitriptyline and 59, 21, and 9% of patients, respectively, on duloxetine. There were no significant differences in various other outcome measures between the groups. Of the reported adverse events, dry mouth was significantly more common with amitriptyline than duloxetine (55 vs. 24%; P < 0.01). Although, numerically, more patients preferred duloxetine, overall this was not statistically significant (48 vs. 36%; P = 0.18).
CONCLUSIONS: Both duloxetine and amitriptyline demonstrated similar efficacy in PDN. A large, multicentric clinical trial in other populations could possibly demonstrate the superiority of either drug.

PMID 21355098  Diabetes Care. 2011 Apr;34(4):818-22. doi: 10.2337/dc10・・・
著者: Julia Boyle, Malin E V Eriksson, Laura Gribble, Ravi Gouni, Sigurd Johnsen, David V Coppini, David Kerr
雑誌名: Diabetes Care. 2012 Dec;35(12):2451-8. doi: 10.2337/dc12-0656. Epub 2012 Sep 18.
Abstract/Text OBJECTIVE: Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP.
RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period.
RESULTS: All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group.
CONCLUSIONS: There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.

PMID 22991449  Diabetes Care. 2012 Dec;35(12):2451-8. doi: 10.2337/dc1・・・
著者: Masayuki Baba, Norimitsu Matsui, Masanori Kuroha, Yosuke Wasaki, Shoichi Ohwada
雑誌名: J Diabetes Investig. 2019 Sep;10(5):1299-1306. doi: 10.1111/jdi.13013. Epub 2019 Feb 28.
Abstract/Text AIMS/INTRODUCTION: This study evaluated the efficacy and safety of mirogabalin, a novel, potent, selective ligand of the α2 δ subunit of voltage-dependent Ca2+ channels, for the treatment of diabetic peripheral neuropathic pain (DPNP).
MATERIALS AND METHODS: During this double-blind, multisite, placebo-controlled phase III study, Asian patients aged ≥20 years with type 1 or 2 diabetes and DPNP were randomized 2:1:1:1 to a placebo, mirogabalin 15, 20 or 30 mg/day for up to 14 weeks, with a 1- to 2-week titration (NCT02318706). The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 14, defined as a weekly average of daily pain (0 = no pain to 10 = worst possible pain, for the past 24 h).
RESULTS: Of 834 randomized patients, 330, 164, 165 and 165 received placebo, mirogabalin 15, 20 or 30 mg/day, respectively, and were included in analyses (modified intention-to-treat population, n = 824); 755 (90.5%) completed the study. At week 14, the least squares mean average daily pain score change from baseline was -1.31, -1.34, -1.47 and -1.81, respectively, showing statistical significance for mirogabalin 30 mg/day versus placebo (P = 0.0027). The treatment-emergent adverse events observed were mostly mild-to-moderate in all mirogabalin doses, and the most frequent treatment-emergent adverse events were nasopharyngitis, somnolence, dizziness, peripheral edema and weight increase.
CONCLUSIONS: Mirogabalin relieved DPNP in a dose-dependent manner; mirogabalin 30 mg/day showed statistically significant pain relief (vs placebo) in Asian DPNP patients. All doses of mirogabalin tested were well tolerated.

© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
PMID 30672128  J Diabetes Investig. 2019 Sep;10(5):1299-1306. doi: 10.・・・
著者: R J Young, D J Ewing, B F Clarke
雑誌名: Diabetes Care. 1988 Jan;11(1):34-40.
Abstract/Text Twenty-nine diabetic patients (19 men, 10 women) aged 19-71 yr with newly developed painful polyneuropathy were studied prospectively for 12-18 mo. Pain remitted completely in 16 patients within 12 mo, but continued in the other 13 patients. At presentation, no differences were found in the type or prevalence of symptoms or neurophysiological measurements (electrophysiology and cardiovascular autonomic function tests) between the patients whose pain remitted and those whose pain continued. Most electrophysiological measurements improved slightly in remitting patients but deteriorated slightly in those whose pain continued to reveal a significant difference (P less than .05) between the groups on final review. Similarly, abnormal autonomic nerve function improved slightly when pain remitted but worsened or persisted in patients whose pain continued, again revealing a significant difference between the groups (P less than .05) on final review. We also observed that pain remission usually occurred if the onset of symptoms shortly followed some sudden metabolic change (e.g., rapid improvement in glycemic control, ketoacidosis, anorexia nervosa) when the duration of diabetes was relatively short or when considerable weight loss preceded the onset of pain. We suggest that remitting and chronic painful diabetic polyneuropathy have distinctive clinical features at presentation and detectable neurophysiological differences during their symptomatic evolution.

PMID 3338378  Diabetes Care. 1988 Jan;11(1):34-40.
著者:
雑誌名: Ann Neurol. 1995 Dec;38(6):869-80. doi: 10.1002/ana.410380607.
Abstract/Text The Diabetes Control and Complications Trial demonstrated that intensive diabetes therapy effectively delays the onset of clinically apparent neuropathy in patients with insulin-dependent diabetes mellitus. A total of 1,441 patients with insulin-dependent diabetes mellitus were randomly assigned to receive intensive treatment or conventional treatment. Of these, 1,290 were randomized at least 4 1/2 years or more prior to study termination. Nerve conduction studies were performed at baseline and repeated after approximately 5 years for 1,243 of these patients, 96% of the eligible population. After 5 years of treatment, significant nerve conduction differences were observed between the intensive and conventional treatment groups, all favoring better performance (faster sensory and motor conduction velocities and shorter F-wave latencies) in the intensive treatment group. Moreover, while performance generally deteriorated among the conventionally treated patients, most attributes remained stable or showed modest improvement in the intensively treated group. Treatment group differences were consistent across strata defined by duration of diabetes and the presence of neuropathy at baseline. A nonparametric multivariate test of all ten nerve conduction measures established a strong effect in favor of intensive treatment. These data confirm that the electrophysiological abnormalities associated with diabetic neuropathy are delayed or prevented by intensive diabetes treatment.

PMID 8526459  Ann Neurol. 1995 Dec;38(6):869-80. doi: 10.1002/ana.410・・・
著者: Roy Freeman, Edith Durso-Decruz, Birol Emir
雑誌名: Diabetes Care. 2008 Jul;31(7):1448-54. doi: 10.2337/dc07-2105. Epub 2008 Mar 20.
Abstract/Text OBJECTIVE: To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN).
RESEARCH DESIGN AND METHODS: Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.
RESULTS: Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P < or = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P < or = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (> or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.
CONCLUSIONS: Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.

PMID 18356405  Diabetes Care. 2008 Jul;31(7):1448-54. doi: 10.2337/dc0・・・
著者: Hitoshi Yasuda, Nigishi Hotta, Kazuwa Nakao, Masato Kasuga, Atsunori Kashiwagi, Ryuzo Kawamori
雑誌名: J Diabetes Investig. 2011 Apr 7;2(2):132-9. doi: 10.1111/j.2040-1124.2010.00073.x.
Abstract/Text UNLABELLED: Aims/Introduction:  Duloxetine has been suggested to exert analgesic effects by activating the descending inhibitory system through inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake. This randomized controlled trial investigated the efficacy and safety of duloxetine in Japanese patients with diabetic neuropathic pain (DNP).
MATERIALS AND METHODS:   Duloxetine 40 or 60 mg/day or placebo was given orally once daily for 12 weeks. The primary efficacy measure was weekly mean 24-h average pain severity score on the 11-point Numerical Rating Scale.
RESULTS:   At 12 weeks vs baseline, the 24-h average pain score (adjusted mean ± SE) was significantly improved in the combined duloxetine (-2.47 ± 0.18) and duloxetine 40 mg (-2.41 ± 0.21) and 60 mg groups (-2.53 ± 0.21) as compared with the placebo group (-1.61 ± 0.18). Duloxetine also exerted significant improvements over the placebo in nearly all secondary outcome measures including 24-h worst pain, night pain, Brief Pain Inventory (BPI) pain scores, Patient's Global Impression of Improvement (PGI-I) and health outcome measures, namely, various BPI interference scores. The incidence of adverse events (AE) was higher in the duloxetine groups than in the placebo group (duloxetine overall, 84.8%; duloxetine 40 mg, 84.7%; duloxetine 60 mg, 84.9%; placebo, 73.7%). Most AE were mild or moderate in severity, and resolved or relieved. There were no clinically significant safety concerns.
CONCLUSIONS:   Duloxetine 40 or 60 mg/day showed superiority over the placebo at reducing pain scores in patients with DNP. Duloxetine is safe, efficacious and clinically useful in the management of DNP. This trial was registered with ClinicalTrials.gov (no. NCT-00552175). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00073.x, 2010).

PMID 24843472  J Diabetes Investig. 2011 Apr 7;2(2):132-9. doi: 10.111・・・
著者: Man-chun Wong, Joanne W Y Chung, Thomas K S Wong
雑誌名: BMJ. 2007 Jul 14;335(7610):87. doi: 10.1136/bmj.39213.565972.AE. Epub 2007 Jun 11.
Abstract/Text OBJECTIVE: To evaluate the effects of treatments for the symptoms of painful diabetic neuropathy.
DESIGN: Systematic review.
DATA SOURCES: Articles (English and full text) on double blind randomised trials found by searching with the key words anticonvulsant, antidepressant, non-steroidal anti-inflammatory drugs, tramadol, opioid, ion channel blocker, diabetic neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, and neuropathy. The search included Medline, Embase, EMB reviews-AP Journal club, and the Cochrane central register of controlled trials.
STUDY SELECTION: Randomised controlled trials comparing topically applied and orally administered drugs with a placebo in adults with painful diabetic neuropathy.
DATA EXTRACTION: Data were extracted to examine quality of methods, characteristics of studies and patients, efficacy, and side effects. The primary outcome was dichotomous information for 50% or moderate reduction of pain. Secondary outcomes were 30% reduction of pain and withdrawals related to adverse events.
RESULTS: Odds ratios were calculated for achievement of 30%, 50%, or moderate pain relief and for withdrawals related to adverse effects. Twenty five reports were included and seven were excluded. The 25 included reports compared anticonvulsants (n=1270), antidepressants (94), opioids (329), ion channel blockers (173), N-methyl-D-aspartate antagonist (14), duloxetine (805), capsaicin (277), and isosorbide dinitrate spray (22) with placebo. The odds ratios in terms of 50% pain relief were 5.33 (95% confidence interval 1.77 to 16.02) for traditional anticonvulsants, 3.25 (2.27 to 4.66) for newer generation anticonvulsants, and 22.24 (5.83 to 84.75) for tricylic antidepressants. The odds ratios in terms of withdrawals related to adverse events were 1.51 (0.33 to 6.96) for traditional anticonvulsants, 2.98 (1.75 to 5.07) for newer generation anticonvulsants, and 2.32 (0.59 to 9.69) for tricylic antidepressants. Insufficient dichotomous data were available to calculate the odds ratios for ion channel blockers.
CONCLUSION: Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. Oral tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants. Evidence of the long term effects of oral antidepressants and anticonvulsants is still lacking. Further studies are needed on opioids, N-methyl-D-aspartate antagonists, and ion channel blockers.

PMID 17562735  BMJ. 2007 Jul 14;335(7610):87. doi: 10.1136/bmj.39213.5・・・
著者: Y Goto, N Hotta, Y Shigeta, N Sakamoto, R Kikkawa
雑誌名: Biomed Pharmacother. 1995;49(6):269-77. doi: 10.1016/0753-3322(96)82642-4.
Abstract/Text The clinical efficacy of epalrestat (150 mg/day, 50 mg tid, po; A group), an aldose reductase inhibitor, was evaluated in 196 patients with diabetic neuropathy by a double-blind study using placebo (9 mg/day, 3 mg tid, po; P group) as a control for 12 weeks. The disappearance rates of upper limb spontaneous pain were 42.9% and 12.0% in the A and P groups, respectively, and those of lower limb spontaneous pain 48.6% and 22.6%, thus being significantly higher in the A group (p < 0.05, logrank-test). The motor nerve conduction velocity of the peroneal nerve significantly increased only in the A group (delta 1.6 +/- 0.6 m/sec, p < 0.01, paired t-test), and the extent of increase in that of the median nerve was significantly greater in the A group than in the P group (p < 0.05). Thresholds of vibratory sensation and autonomic nerve function were also significantly improved in the A group (p < 0.05). The data were reanalyzed by dividing patients into two groups according to their HbA1c values. The improvement ratings of subjective symptoms and of nerve function tests for cases with HbA1c > or = 7.5% were both significantly different between the A and P groups, with the improvement rate being higher in the A group, and also higher as compared to the analysis for cases with HbA1c < 7.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7579007  Biomed Pharmacother. 1995;49(6):269-77. doi: 10.1016/07・・・

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