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Anticonvulsants 治療 diabetic neuropathic pain 的效果

Anticonvulsants 治療 diabetic neuropathic pain 的效果. 小港醫院 R2 董錦松. 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？. 背景說明.

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Anticonvulsants 治療 diabetic neuropathic pain 的效果

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  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 (Rull 1969) and Chadda (Chadda 1978) found that with two weeks' treatment between 30 and 50% more patients improved on anticonvulsant than on placebo. • Saudek 1977, using phenytoin (300 mg/day) for 23 weeks of treatment found no difference in mean pain intensity compared with placebo • 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. • 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 improved • 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

  17. 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

  18. 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。

  19. 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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