治疗偏头痛的神经刺激仪疗法受青睐

伦敦——目前，头痛专科医生对于治疗急性偏头痛的无创性治疗仪热情高涨。

在欧洲头痛与偏头痛信托国际会议上，英国头痛研究学会主席/神经科高级顾问Fayyaz Ahmed博士说：“我平时其实是一个爱持怀疑态度的人，但我相信10年内头痛诊所一半的患者将不再需要服用任何药物来治疗头痛了，而是会使用某种类型的电子治疗仪。在偏头痛确诊后，患者可以将治疗仪放在裤兜里随身带着。”他预测道：“我想大约10年之后，就会有针对这类神经刺激治疗仪的SIM卡，患者将SIM卡插入一个类似于ATM的机器，这种机器可能就放在各大超市里，充值后就可以开始充电了。”


这种Spring TMS治疗仪由美国eNeura Therapeutics公司制造，现已向美国食品药品管理局提交了上市申请。

这次会议上讨论最多的无创性神经刺激治疗仪是一种名为Spring TMS的单脉冲经颅磁刺激治疗仪，该产品已于2011年在欧洲获准用于急性偏头痛的治疗。Spring TMS治疗仪由美国eNeura Therapeutics公司制造，现已向美国食品药品管理局提交了上市申请。

在这次国际会议上，来自比利时列日大学的Jean Schoenen博士也报告了Cefaly无创性治疗仪通过眶上经皮神经刺激预防偏头痛的首个多中心、随机、假对照研究。他总结道：“这不是一种革命性的治疗。其效应量属于中等，比不上那些最有效的预防药物。其最大的优势就是没有任何副作用。我认为Cefaly治疗仪可以成为预防偏头痛的另一种工具。”

Ahmed博士称，医生和患者之所以对无创性治疗仪感兴趣，主要是因为有相当大一部分偏头痛患者经药物治疗后效果不够好、不能耐受药物治疗或者存在药物治疗的禁忌证。此外，有些患者就是不想用药。

Ahmed博士解释道，针对头痛的神经刺激治疗也经历了一个演变的过程，从高侵袭性到微创性再到现在的无创性治疗仪。

 
Spring TMS单脉冲经颅磁刺激治疗仪已于2011年在欧洲获准用于急性偏头痛的治疗。

最早问世的是通过植入电极对下丘脑核进行深部脑刺激的治疗仪，这类仪器已被证实能有效治疗帕金森病。在头痛领域，现已发表了14项关于深部脑刺激下丘脑腹后外侧核治疗慢性难治性丛集性头痛的研究，总共涉及患者64例。2/3的患者对这种治疗有应答，疼痛至少减轻了50%。但是这种侵袭性很高的治疗方法作为急性期治疗无效，只能用于头痛的预防，而且还会使大约3%的患者出现颅内出血。

之后又研发出了微创性枕大神经刺激系统。在已发表的10项研究中，总共约有500例慢性偏头痛患者接受了这种治疗，应答率相差很大。此外，这类治疗仪价格非常昂贵，而且容易出现电极移位或破损以及电池耗尽等问题。Ahmed博士称：“目前只有英国的几家医院在开展枕大神经刺激治疗。”

不过，开发微创性神经刺激头痛治疗仪仍有一定的商业价值。在这次伦敦头痛会议上，圣犹达医疗公司(St. Jude Medical)就宣布其开发的Eon系列神经刺激仪刚刚通过了欧盟监管机构的批准，可以用于难治性慢性偏头痛的治疗。在刚刚获批的新产品中有一种名为Eon Mini的治疗仪，其重量只有1盎司左右，直径只有10 mm。

在最近发表的一项由圣犹达医疗公司资助的12周、双盲、多中心、关键研究中，共有157例慢性偏头痛患者以2:1的比例被随机分配至周围神经刺激组或者假对照组。在接受了阳性治疗的患者中，35%疼痛至少减轻了30%，这一比例比对照组高2倍以上。阳性治疗组患者的头痛发作天数也从基线时的每月22天平均减少了6.1天，而对照组患者只减少了3天(Cephalalgia 2012 Oct. 3 [doi: 10.1177/0333102412462642])。

公司发言人明确表示，圣犹达医疗公司正在计划向美国FDA提交Eon神经刺激治疗仪的上市申请。

研究数据最为充分的无创性神经刺激偏头痛治疗仪是Spring TMS单脉冲经颅磁刺激治疗仪。英国伦敦国家神经内科与神经外科医院的神经病学专家Kevin G. Shields博士称，临床试验表明这种治疗仪在首次出现偏头痛疼痛征兆时能在不到1分钟的时间内完成治疗，并且其副作用特征与假对照组观察到的情况类似。

Shields博士指出，单脉冲经颅磁刺激技术已经在临床使用了30年，最初是用于疾病诊断，后来也作为一种治疗手段。其效应机制现已明确，安全性也得到了充分的证实；事实上，FDA已将其归类为一种无重大风险的技术。近年来，单脉冲经颅磁刺激的主要技术进步在于电容器尺寸大大缩小。这种仪器已经从研发初期的冰箱大小(见于伦敦)缩小到了如今的便携式Spring TMS治疗仪，患者可以把它装进手提包里，工作时也能方便地使用。

这种治疗仪的使用禁忌包括有癫痫病史；头颈部或上半身带有金属物体；置入了心脏起搏器或其他心脏仪器。

支持Spring TMS治疗仪安全性和疗效的证据基础包括一项已发表的在先兆型偏头痛患者中开展的随机、双盲、假对照临床试验(Lancet Neurol. 2010;9:373-80)。


Fayyaz Ahmed博士
 
此外，在这次国际会议上，来自苏格兰爱丁堡大学的Mark W. Weatherall博士还报告了一项关于这种单脉冲经颅磁刺激治疗仪用于临床实践的英国上市后研究的初步结果，该试验目前仍在进行中。受试人群由13例无先兆型偏头痛和24例先兆型偏头痛患者组成，所有患者均使用了这种治疗仪至少3个月，总共治疗了777次头痛发作。

疗效报告包括：

·73%的患者认为这种治疗仪的疗效好或者非常好，减轻甚至消除了偏头痛带来的疼痛感。63%的患者称这种治疗还能有效缓解其他偏头痛症状。

·55%的患者称每月头痛发作的天数减少。

Weatherall博士报告称，在经颅磁刺激治疗前头痛发作的平均持续时间为2.46天，而在受试者开始使用这种治疗仪之后缩短至了0.77天。在3个月的试验期间这些疗效可以复制，并且患者没有报告任何不良事件。

Schoenen博士则报告了关于Cefaly治疗仪的首个随机试验数据。这种眶上经皮神经刺激治疗仪已经在欧洲上市5年了，但到目前为止也没有来自对照试验的支持数据。


Jean Schoenen博士
 
这种治疗仪由一根薄薄的银带子组成，像是电影《星际旅行》里的东西。将带子挂在耳朵上，然后绕过前额，就像是未来派的太阳镜一样。患者每天使用一次，每次20分钟。研究者会对这种可设定程序的治疗仪设置参数：方波脉冲，频率60 Hz，波宽300微秒，最大电流强度14.99 mA。

Schoenen博士报告称，这项3个月、多中心、双盲、假对照、比利时研究总共纳入了67例发作性偏头痛患者。结果显示，Cefaly组患者每月头痛发作的平均天数显著减少，从基线的6.9天减少至第3个月时的4.9天，而对照组无变化。Cefaly组38%的患者的每月头痛发作天数至少减少了50%，而在对照组中这一比例只有12%。在所有接受了Cefaly治疗的患者中，用于急性期治疗的曲坦类药物的每月用量减少了36%；在Cefaly应答者中则减少了75%。

为了大致了解这种眶上经皮神经刺激治疗仪较之标准预防性药物治疗的利弊，Schoenen博士对有关托吡酯的已发表随机试验文献进行了全面的分析。结果显示，在Cefaly试验中获得了≥50%应答率的患者占38%，而托吡酯的合并分析数据为45%。此外，托吡酯与每月偏头痛发作次数平均减少48%相关，而Cefaly治疗仪只能减少19%。他指出，另一方面，在随机试验中接受了托吡酯治疗的患者大约有1/4因为副作用而停药；但所有接受Cefaly治疗的患者都没有出现任何不良反应。

这是一项由研究者发起的研究，由比利时头痛学会负责实施，STX-Med公司(Cefaly治疗仪在欧洲市场的经销商)提供资助。Schoenen博士声明担任了圣犹达医疗、Allergan和ATI公司的顾问委员会成员。Shields博士和Weatherall博士声明担任了eNeura Therapeutics公司的讲演团成员。

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By: BRUCE JANCIN, Internal Medicine News Digital Network

LONDON – Enthusiasm is mounting among headache specialists for noninvasive device therapy for acute migraine.

"Normally I’m quite a cynical person, but I think within 10 years time half of my people in the headache clinic won’t be using any medications for their headaches. They’ll have an electronic device of some kind. You get your migraine sorted out, you put your device back in your pants pocket, and you carry on," Dr. Fayyaz Ahmed said at the European Headache and Migraine Trust International Congress.

"I think in about 10 years time you’ll have SIM cards for these neurostimulatory devices, you’ll put the card in an ATM-like machine – perhaps in a supermarket – and you’ll top it up and recharge it," predicted Dr. Ahmed, a consultant neurologist in Hull, England, and chair of the British Association for the Study of Headache.

The noninvasive neurostimulatory therapy most discussed at the congress was the Spring TMS single-pulse transcranial magnetic stimulation device, which since 2011 has been approved in Europe for the acute treatment of migraine. The Spring TMS device is manufactured by U.S.-based eNeura Therapeutics, which is seeking marketing approval from the Food and Drug Administration.

The international congress also saw the presentation of the first multicenter, randomized, sham-controlled study of the noninvasive Cefaly device for prevention of migraine via supraorbital transcutaneous neurostimulation.

"It’s not a revolutionary therapy. The effect size is moderate and inferior to that of the most effective preventive drugs. Its great advantage is that it’s devoid of side effects. I think the Cefaly device is another tool we can use for preventing migraine," Dr. Jean Schoenen concluded in presenting the study data.

Dr. Ahmed said physician and patient interest in noninvasive device therapy is being driven by the sizable proportion of migraine patients who don’t respond adequately to drug therapy, can’t tolerate it, or have contraindications to its use. Plus, some patients would just rather be drug free.

Neurostimulatory therapy for headache has followed an evolutionary process, progressing from highly invasive to minimally invasive and now to noninvasive devices, the neurologist observed.

First came deep brain stimulation of the subthalamic nucleus via implanted electrodes, which proved useful in treating Parkinson’s disease.

In the field of headache, there are 14 published studies of deep brain stimulation of the ventroposterior hypothalamus for treatment of intractable chronic cluster headache in a collective total of 64 patients. Two-thirds responded with at least a 50% decrease in pain. But this highly invasive form of therapy is not effective as acute therapy, only for prevention, and it entails a 3% rate of intracranial bleeding.

Next came minimally invasive systems for occipital nerve stimulation. Response rates have been variable in 10 published studies totaling roughly 500 patients treated for chronic migraine. In addition, the devices are quite expensive and are susceptible to lead migration or breakage and battery depletion.

"Only a couple of centers in the U.K. are doing occipital nerve stimulation now," according to Dr. Ahmed.

Yet there is still commercial interest in developing minimally invasive neurostimulatory therapy for headache. During the London headache congress, St. Jude Medical announced that its Eon family of neurostimulators had just received European regulatory approval for treatment of intractable chronic migraine. Among the newly approved devices is the Eon Mini, which weighs about an ounce and has a 10-mm profile.

The recently published 12-week, double-blind, multicenter pivotal study sponsored by St. Jude Medical involved 157 patients with chronic migraine randomized 2:1 to peripheral nerve stimulation or sham control. Of patients on active therapy, 35% achieved at least a 30% reduction in pain, a rate more than twice that in controls. The active treatment group also had a mean 6.1-day reduction in headache days per month from a baseline of 22 days, compared with a 3-day reduction in controls (Cephalalgia 2012 Oct. 3 [doi: 10.1177/0333102412462642]).

A company spokesperson said St. Jude Medical definitely plans to seek U.S. marketing approval for its Eon neurostimulators.

The best-studied noninvasive neurostimulatory device therapy for migraine is the single-pulse transcranial magnetic stimulation Spring TMS device. It delivers a complete treatment in less than a minute at the first sign of migraine pain and has a side effect profile similar to that of sham therapy in clinical trials, according to Dr. Kevin G. Shields, a neurologist at the National Hospital for Neurology and Neurosurgery in London.

Single-pulse transcranial magnetic stimulation has been in clinical use for 30 years, first diagnostically, then as therapy. The mechanism of benefit has been mapped out. The treatment’s safety is very well established; indeed, the FDA has classified it as a nonsignificant risk technology, he noted.

The major technical advance that’s occurred in single-pulse transcranial magnetic stimulation has been a radical reduction in capacitor size. The equipment has shrunk from refrigerator-size in the therapy’s early development, which took place in London, to the highly portable Spring TMS device that patients can stick in a briefcase and utilize unobtrusively at work, Dr. Shields observed.

The contraindications to use of the device are a history of epilepsy; the presence of metal objects in the head, neck, or upper body; and pacemakers or other cardiac devices.

The evidence base supporting the safety and efficacy of the Spring TMS device includes a published randomized, double-blind, sham-controlled clinical trial conducted in patients with migraine with aura (Lancet Neurol. 2010;9:373-80).
 
In addition, at the international congress Dr. Mark W. Weatherall of the University of Edinburgh, Scotland, presented the first results of an ongoing multicenter U.K. postmarketing study of the single-pulse transcranial magnetic stimulation device as used in clinical practice. The study population consisted of 13 patients with migraine without aura and 24 having migraine with aura who had been using the device for at least 3 months and collectively had treated 777 attacks.

Efficacy reports were:

·73% of patients said the device showed good to excellent efficacy, reducing or even alleviating migraine pain. Sixty-three percent pronounced the therapy effective in diminishing other migraine symptoms.

·55% reported a reduction in the number of headache days per month.

The mean attack duration was 2.46 days before transcranial magnetic stimulation therapy and 0.77 days after subjects started using the device. The benefits were reproducible over the 3-month study period and beyond, and no adverse events were reported, he said.

Dr. Jean Schoenen presented the first randomized trial data on the Cefaly device. The supraorbital transcutaneous neurostimulation device has been available in Europe for 5 years, but until now it had no supporting data from controlled trials.
 
The device consists of a thin silver band that looks like something out of Star Trek. It is hooked over the ears and worn across the forehead like futuristic sunglasses. Patients don it once daily for 20 minutes. The investigators set the programmable device to deliver a square pulse at 60 Hz, 300 microseconds, and a maximum of 14.99 mA.
                                                                                                                                                                             
The 3-month, multicenter, double-blind, sham-controlled Belgian study involved 67 patients with episodic migraine. The mean number of headache-days per month dropped significantly, from 6.9 at baseline to 4.9 at 3 months in the Cefaly group but was unchanged in controls. Thirty-eight percent of patients using the active device experienced at least a 50% reduction in their number of headache-days per month, compared with 12% of controls. Monthly consumption of triptans for acute therapy was reduced by 36% in the Cefaly-treated patients as a whole and by 75% in the Cefaly responders, reported Dr. Schoenen of the University of Liege, Belgium.

To get a crude idea of how supraorbital transcutaneous neurostimulation stacks up against standard prophylactic drug therapy, Dr. Schoenen turned to the extensive published randomized trial literature on topiramate. While the 50% or greater responder rate in the Cefaly trial was 38%, in the pooled topiramate data it’s 45%. Moreover, topiramate was associated with an impressive average 48% reduction in the number of migraine attacks per month, compared with a 19% decrease with the Cefaly device.

On the other hand, one in four patients assigned to topiramate in the randomized trials dropped out due to side effects. No one experienced any adverse effects from the device therapy, he noted.

This was an investigator-initiated study carried out by the Belgian Headache Society and sponsored by STX-Med, which markets the Cefaly device in Europe. Dr. Schoenen is on the advisory boards of St. Jude Medical, Allergan, and ATI. Dr. Ahmed, Dr. Shields, and Dr. Weatherall are on the speakers bureau for eNeura Therapeutics.