AAN 2009:Levetiracetam對於慢性日常頭痛並未顯著優於安慰劑


  May 15, 2009(西雅圖) — 抗癲癇藥物levetiracetam (Keppra,UCB藥廠)可以適度增加沒有頭痛的天數,減少某些病患因為慢性日常頭痛引起的失能和疼痛,但是在最近的隨機試驗中,該藥物的效果並未顯著優於安慰劑。
  
  這項研究是levetiracetam用於慢性日常頭痛病患的首度雙盲、安慰劑控制試驗,慢性日常頭痛定義為,每月有15天出現疼痛持續至少4小時的頭痛、至少有6個月。
  
  雖然研究結果是負面的,主要作者、澳洲新南威爾斯大學的Roy Beran醫師表示,在當時未加確認的一小組病患中,該藥依舊有用。他表示,不能說它沒用;用它試試,如果它有用,它就有用,如果它沒效,你有何損失?
  
  這項研究發現發表於美國神經學會第61屆年會中,看來似乎和之前有關levetiracetam用於治療頭痛之效果的報告不相同。
  
  【很難治的一群人】
  這篇研究包括了七個地區、忍受頭痛達平均20年的病患;Beran醫師認為我們聚焦在很難治的一群人;該研究隨機分派88位病患接受安慰劑、89位病患服用levetiracetam。
  
  27週研究結束時,相較於安慰劑組的主要終點,服用levetiracetam病患的無頭痛率增加3.9%。作者表示,這表示每個月多1天不受頭痛所苦的日子。不過,儘管有此趨勢,並未達統計上的顯著意義。
  
  該藥的效果並沒有像另一個抗癲癇藥物gabapentin (Neurontin,輝瑞藥廠)一樣好,gabapentin已經顯示可用於慢性日常頭痛病患。之前一篇研究發現,相較於安慰劑,gabapentin每個月可多3天不受頭痛所苦的日子。
  
  Beran醫師表示,還不清楚抗癲癇藥物對於慢性頭痛的作用機轉如何,但這些藥物的確可以治療疼痛。
  
  【很大的安慰劑效果】
  Beran醫師表示,levetiracetam的負面結果很可能是因為安慰劑效果。服用此藥物的病患比開始時出現100%的改善,但是卻未達統計上的顯著意義。
  
  不過,該研究的確顯示服用levetiracetam的病患顯著降低失能(P = .0487)與降低疼痛嚴重度(P = .0162)。 Beran醫師表示,我們在疼痛嚴重度上有戲劇性的降低,P值小於.02,這是相當令人印象深刻的。
  
  Beran醫師表示,重要的是,將近10%服用此藥的病患每月頭痛天數少於15天,與安慰劑組相較之P值為.0325)。他向Medscape Neurology & Neurosurgery表示,這是相當戲劇性的,如果你認為我們的平均無頭痛率是零的話。
  
  Beran醫師表示,這表示,該藥顯然對一小組我們未區分的病患有用。
  
  【偏頭痛變成緊張性頭痛】
  他指出,本研究的一個有趣推論是,開始時是偏頭痛的病患,最後變成了緊張性頭痛。研究中,當病患首次發生頭痛時,其中74.1%有偏頭痛、36.5%有緊張性頭痛,但是在20多年後的研究,56.3%有偏頭痛、43.8%有緊張性頭痛。
  
  Beran醫師表示,他還不確定有關levetiracetam的下一步研究,因為該藥的病患人數減少,這會影響到研究資金。
  
  【最後的選項】
  賓州大學神經科教授、Jefferson頭痛中心主任、美國頭痛協會前任主席Stephen Silberstein醫師被要求對此研究評論時表示,該研究並未提供levetiracetam有效治療慢性頭痛的證據。
  
  Silberstein醫師指出,這和完全無用是不一樣的。可能有一小組病患有用,但目前來說,我們沒有相關證據。
  
  Silberstein醫師表示,該藥不是他前三順位的頭痛藥物選項,我可能會在每種藥物都失敗後作為最後的選項。
  
  他指出,為了幫助確認哪些病患對該藥有反應,必須改變試驗設計。他表示,例如,研究者先找出哪些人對該藥有反應,之後讓他們的半數接受藥物治療、半數使用安慰劑。
  
  UCB藥廠教育資金資助本研究。Beran醫師接受Strategic Health Evaluators提供的個人活動津貼,接受UCB、Biogen Idec、 Ovations、Bayer-Schering、 Novartis以及 Mundipharm a等藥廠的研究支持。
  
  美國神經學會第61屆年會。摘要LB2.001。發表於2009年4月29日。
  

AAN 2009: Levetiracetam Not Significantly Better Than Placebo in Chronic Daily Headache

By Pauline Anderson
Medscape Medical News

May 15, 2009 (Seattle, Washington) — The antiepileptic drug levetiracetam (Keppra, UCB) may provide a modest increase in headache-free days and reduced disability and pain for some patients with chronic daily headache, but its superiority over placebo did not reach statistical significance in a recent randomized trial.

The study was the first double-blind, placebo-controlled trial of levetiracetam in patients with chronic daily headache, defined as a headache lasting at least 4 hours, 15 days of the month, for a minimum of 6 months.

While the results of the study were negative, its lead author, neurologist Roy Beran, MD, from the University of New South Wales, in Australia, still feels the drug does work in an as-yet-to-be-defined subgroup of patients. "You don't [dismiss it] as useless; you give it a try and if it works, it works, and if it doesn't work, what have you lost?" he said.

The findings, released here during the American Academy of Neurology 61st Annual Meeting, appear to be at odds with previous reports on the efficacy of levetiracetam in treating headaches.

Very Refractory Population

The 7-site study included patients who had endured headaches for a mean of about 20 years. "So we're looking at a very refractory population," commented Dr. Beran.

The study randomized 88 patients to receive placebo and 89 to take levetiracetam.

At the end of the 27-week study, patients taking levetiracetam achieved a 3.9% increase in the headache-free rate, the primary end point, compared with placebo. The authors said this translates into 1 extra day of headache freedom per month. However, although this showed a trend, it failed to reach statistical significance, they said.

The drug did not appear to perform as well as gabapentin (Neurontin, Pfizer), another antiepilepsy drug, has been shown to do in patients with chronic daily headache. One previous study found that gabapentin provided 3 more headache-free days per month than placebo.

It's not clear how antiepileptic drugs might work in chronic headaches, although these drugs do treat pain, said Dr. Beran.

Large Placebo Effect

A possible reason for the negative outcome with levetiracetam is the placebo effect, said Dr. Beran. Patients on the drug demonstrated a 100% improvement from baseline, but with a large placebo effect, the improvement was not enough to provide statistical significance, he said.

However, the study did show that patients on levetiracetam had significantly reduced disability (P = .0487) and reduced pain severity (P = .0162) "We had a very dramatic decrease in headache severity, coming down to a P value of less than .02, which is impressive stuff," said Dr. Beran

Importantly, said Dr. Beran, close to 10% of patients on the drug fell below the 15 days/month criteria for chronic daily headache compared with placebo (P = .0325). "That is quite dramatic, if you think that our median headache-free rate was zero," he told Medscape Neurology & Neurosurgery.

This demonstrates, he added, that the drug "obviously works well in a subgroup population that we haven't defined," said Dr. Beran.

Migraines Morph Into Tension Headaches

An interesting corollary to this study, he added, is the number of patients who start with migraine headaches, which eventually morph into tension headaches. When patients in the study first started getting headaches, 74.1% of them had migraines and 36.5% had tension-type headaches, but leading up to the study 20 or so years later, 56.3% had migraines and 43.8% had tension type headaches.

Dr. Beran said he is not certain of his next research steps with levetiracetam since the drug's patent is set to run out, which might affect research funding.

Last Resort

Asked for his comment on this study, Stephen Silberstein, MD, professor of neurology at Thomas Jefferson University, in Philadelphia, Pennsylvania, director of the Jefferson Headache Center, and past president of the American Headache Society, said the research provides no evidence that levetiracetam is effective in chronic headache.

"That's not the same as saying it's totally useless," Dr. Silberstein added. "There may be a subset of the population in which it works, but at the current time, we have no evidence that it's useful."

Dr. Silbertein said the drug would not be his first, second, or even third choice of headache medication. "I might use it if everything in the world failed, as a last resort."

He added that to help determine which patients respond to the drug, trial designs would have to be changed. For example, he said, researchers could first find who responds to the drug and then put half of those on the drug and the other half on placebo.

The study was funded by an educational grant from UCB. Dr. Beran has received personal compensation for activities with Strategic Health Evaluators and has received research support from UCB, Biogen Idec, Ovations, Bayer-Schering, Novartis, and Mundipharma.

American Academy of Neurology 61st Annual Meeting. Abstract LB2.001. Presented April 29, 2009.

    
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