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Anticonvulsants 治療 diabetic neuropathic pain 的效果 小港醫院 R2 董錦松.

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Presentation on theme: "Anticonvulsants 治療 diabetic neuropathic pain 的效果 小港醫院 R2 董錦松."— Presentation transcript:

1 Anticonvulsants 治療 diabetic neuropathic pain 的效果 小港醫院 R2 董錦松

2 臨床問題 Anticonvulsants 對 diabetic neuropathic pain 的治療效果如何? 若 anticonvulsants 治療 diabetic neuropathic pain 有效,那一種 anticonvulsant 為最佳選 擇?

3 背景說明 1960 年代起,即開始使用 anticonvulsants 來治療 neuropathic pain ,如 diabetic neuropathy , trigeminal neuralgia , post-herpetic neuralgia 等。 Diabetic neuropathic pain 是臨床上常見之病症,困 擾許多 DM 病人,近年來多種新的 anticonvulsants 上 市,是否也代表治療 diabetic neuropathic pain 的選 擇更多,副作用更少,因此找尋文獻比較各種 anticonvulsants 對 diabetic neuropathic pain 的療效。

4 Diabetic peripheral neuropathy 15% DM p’t have S/S of neuropathy –DM>25 years  affect nearly 50% p’t Pathogenesis: unknown –Hyperglycemia –Microvascular diasease Treatment: TCAs, NSAID, anticonvulsants, opioids, topical anesthetic agents, nerve block

5 期待目標 anticonvulsants 對 diabetic neuropathic pain 的治療效果,並找出何種 anticonvulsants 是 最佳的選擇。

6 搜尋步驟 搜尋字串: –Neuropathy –anticonvulsant, anticonvulsants, carbamazepine, oxcarbazepine, valproate, phenytoin, lamotrigine, vigabatrin, gabapentin, topiramate –Clinical trial (PubMed) 搜尋範圍: –ACP Journal Club -- 1 –Cochrane Database of Systematic Reviews -- 1 –Cochrane Central Register of Controlled Trials, PubMed -- 15

7 結 果

8 結果摘要 (I) Cochrane Database of Systematic Reviews Anticonvulsant drugs for acute and chronic pain (2000) –Diabetic Neuropathy: Four placebo-controlled studies one with carbamazepine (Rull 1969), two with phenytoin (Chadda 1978, Saudek 1977), and one with gabapentin (Backonja 1998)).Rull 1969Chadda 1978 Saudek 1977Backonja 1998 Rull (Rull 1969) and Chadda (Chadda 1978) found that with two weeks' treatment between 30 and 50% more patients improved on anticonvulsant than on placebo.Rull 1969Chadda 1978 Saudek 1977, using phenytoin (300 mg/day) for 23 weeks of treatment found no difference in mean pain intensity compared with placeboSaudek 1977 Backonja (Backonja 1998) reported a 60% improvement on a global scale for patients on gabapentin (up to 3.6 grams per day) after four weeks' treatment in a study of 165 participants.Backonja 1998 one active control study comparing carbamazepine 200 mg versus a nortriptyline 10 mg/fluphenazine 0.5 mg combination (Gomez -Perez 1996). Only mean data were reported and the authors could not show a difference between the two treatments although it is stated that all patients improvedGomez -Perez 1996 –Conclusion: gabapentin is effective in post-herpetic neuralgia and diabetic neuropathy but does not appear to be superior to carbamazepine, a cheaper alternative in many countries. There were, however, no direct comparisons between these two drugs

9 結果摘要 (II) ACP journal (2002) Review: Anticonvulsant drugs relieve chronic but not acute pain –6 drugs: carbamazepine (12 trials), phenytoin (6 trials), sodium valproate (2 trials), gabapentin (2 trials), clonazepam (1 trial), and lamotrigine (1 trial) –Carbamazepine, phenytoin, and gabapentin were more effective than was placebo in relieving the pain of diabetic neuropathy –all caused such minor side effects as drowsiness, dizziness, constipation, nausea, and ataxia (numbers needed to harm [NNHs] ranged from 3 to 4). The NNHs for major harm were not statistically significant for any drug

10 結果摘要 -Carbamazepine 3 randomized clinical trial 2 with placebo (Rull, 1969; Wilton, 1974) –More effective then placebo 1 with nortriptyline and fluphenazine (Gomez- Perez, 1996) –Both drugs: improvements from baseline, but no significant difference between 2 drugs Dose: 300-1000mg/d Adverse events (up to 70%): Somnolence, dizziness, gait disturbance Withdrawal rate: 0-7%

11 結果摘要 -Phenytoin 2 randomized clinical trial(Chadda, 1978; Saude, 1977) Conflicting result

12 結果摘要 -Sodium valproate 2 randomized clinical trial(91 p’t)(Kochar, 2002; 2004) –Significant improvement then placebo SF-MPQ: 5  3.41 (1 month) VAS: 6  3, SF-MPQ: 19.47  9.66, PPI: 2.71  1.33 (3 months) –Side effect: nausea:2, sedation:1, liver change:2 –Dose: 1200mg, 1000mg/d

13 結果摘要 -Gabapentin I 4 randomized clinical trial –3 with placebo, 1 with morphine, 1 with amitriptyline Backonja, 1998 (165p’t) –900 titrated to 3600mg/d –Significant pain relief than placebo, improvement of sleep, mood (pain score: 6.4  3.9; placebo:6.5  5.1) –Pain relief was observed during 2nd week when dose reached 1800mg/d –Dizziness 24%, somnolence 23%, headache 11%, diarrhea 11% Gorsen, 1999 (40 p’t) –900mg/d –Ineffective at dose of 900mg/d

14 結果摘要 -Gabapentin II Morello, 1999 (28 p’t) –Gabapentin 900-1800mg, or Amitriptyline 25-75 mg /d –No significant different in pain relief –No significant difference in occurrence of adverse effects (17 in amitriptyline, 18 in gabapentin) Gilron, 2005 (57p’t) –Gabapentin (3200mg), Morphine(120mg), combine(G 2400mg, M 60mg), placebo –Gabapentin and Morphine combined achieved better analgesia at lower dose of each drug –Adverse effect: Combination: contipation↑than gabapentin, dry mouth↑than morphin

15 結果摘要 -Lamotrigine 1 randomized clinical trial (53 p’t)(Eisenberg, 2001) Lamotrigine attenuates painful diabetic neuropathy at a daily dose of 200-400mg then placebo (NPS: 6.4  4.2, MPQ, PDI, BDI: unchanged) Maximal pain reduction:37%, 12 p’t 50% pain reduction Adverse events: similar to placebo (exception 2 rash developed)

16 結果摘要 -Topiramate 2 randomized clinical trial Topiramate diabetic neuropathic pain study group, 2004 (3 trial)(1259 p’t) –100mg, 200mg, 300mg –1 effective, 2 no significant (placebo effect high, 38% and 48%) –Overall: no significant more effective than placebo –16 ~ 31% discontinuation due to adverse events Raskin, 2004 (12weeks, 323 p’t, 400mg) –½ - 30%, 1/3 - 50% pain reduction –Reduced pain and body weight more effective than placebo –Adverse event: nausea, somnolence, dizziness, paresthesia, cognition dysfunction, appetite decrease –48% dropout rate


18 結果摘要 -Oxcarbazepine 1 open-label trial (30p’t)(Beydoun, 2004) –Significant improvement in total pain score, and present pain intensity (VAS score: 66.3  34.3, 48.3%) –Dose: up to 1200mg/d (mean 814mg) –Adverse events(>10%): drowsiness, dizziness, headache, nausea, vomiting, diarrhea

19 總結 (I) 目前證據顯示 carbamazepine, sodium valproate, lamotrigine, gabapentin 在治療 diabetic neuropathic pain 可 以顯著改善臨床症狀,但並無試驗直接比較不同 anticonvulssants 間的差別。 Topiramate, phenytoin 在不同的臨床試驗出現不同的結果, 對於 diabetic neuropathic pain 的效果尚無定論。 Oxcarbazepine, vigabatrin 並無 RCT 來支持治療 diabetic neuropathic pain 的效果。 新的 anticonvulsants (gabapentin, topiramate, oxcarbazepine) ,仍有許多常見 adverse effects 如 dizziness, somnolence, sedation 的作用。 Sodium valproate 及 Lamitrigine 的小型試驗中,有較少的副 作用。

20 總結 (II) 對於治療 diabetic neuropathic pain , anticonvulsants 可以有效減緩疼痛症狀,但需 注意治療所引起的不適及副作用。 目前無證據顯示何種 anticonvusants 為最佳選 擇,若考量花費,傳統 anticonvulsants 仍是優 先選擇,若病患不能忍受副作用或是有過敏 反應,則可給予不同的 anticonvulsants 。

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