对难治性偏头痛需考虑“合理的联合治疗”

科罗拉多州埃斯蒂斯帕克——科罗拉多大学的Chantal O’Brien博士在由该校主办的一场内科学会议上报告称，对于曲坦类单药治疗无效的急性偏头痛发作，合理的联合治疗常常是正确选择。关键是要确定能同时作用于头痛相关性中枢和外周通路的联合治疗方案。如果能够找到这样的方案，就能中止头痛并降低短期复发率。

一种曲坦类药物加一种非甾体抗炎药(NSAID)，必要时再加一种止呕药物，就是一个合理的联合用药方案。在近年来的多项随机研究中，上述种类药物的多种组合已在难治性偏头痛的治疗中显示出疗效。

O’Brien博士例举了哈佛大学的一项研究。这项研究招募了28例偏头痛患者，均伴有皮肤疼痛和触摸痛。半数受试者在偏头痛发作开始4 h后皮下注射舒马曲坦。这些受试者在2 h后仍疼痛，并在此时静脉注射酮咯酸。结果有71%的受试者在注射酮咯酸后60 min内头痛和触摸痛消失。另一半受试者在开始发作后4 h时静脉注射酮咯酸，结果有64%的患者在60 min内不再头痛和触摸痛(Headache 2005;45:850-61)。酮咯酸的给药剂量为10 mg肌内注射，之后根据需要可每4~6 h口服10 mg，单日最大剂量为40 mg。

双氯芬酸溶液(Cambia)也是一种已获得FDA批准且已应用多年的急性偏头痛治疗药物，且使用更方便、能迅速起效。患者可在杯中将双氯芬酸粉末与水混合后服用，从而使药物被迅速吸收。此外，萘普生钠的吸收速度比其他所有口服NSAID都更快，包括布洛芬和酮洛芬。萘普生钠的使用剂量为220~550 mg，24 h内不得超过1,100 mg。

O’Brien解释称，目前认为无先兆的偏头痛是一种神经元兴奋过度性疾病，其病理生理学机制非常复杂。发作由脑干开始，一旦这一区域被激活，就会在脑膜中启动两种外周疼痛机制：脑膜血管舒张和神经性炎症。来自外周的疼痛信号上升至脑干中的三叉神经尾核，在此处使中枢敏化。这是一种神经元兴奋过度，而曲坦类药物常常无法应付这种情况。

曲坦类药物通过预防降钙素基因相关肽(一种非常强力的内源性血管舒张剂)的释放而作用于外周偏头痛通路，但不能遏制外周疼痛信号激活三叉神经尾核的过程，也就不能阻止中枢敏化。而NSAID类药物可通过影响脊髓中升高的环氧合酶水平而阻止中枢敏化。

另一类合理的联合治疗是一种麦角类药物加一种NSAID。与曲坦类药物相似，麦角类药物锁定关键的外周靶点——降钙素基因相关肽。Migranal是一种可选用的双氢麦角胺，兼有皮下注射和鼻腔喷雾两种剂型。一种名为Levadex的在研口腔吸入性双氢麦角胺被认为将在不久的将来进入临床。

O’Brien博士报告称无相关利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: BRUCE JANCIN, Internal Medicine News Digital Network
ESTES PARK, COLO. – Rational combination therapy is often the answer for the acute treatment of migraine attacks not successfully relieved by a triptan alone, according to Dr. Chantal O’Brien, a neurologist at the University of Colorado, Denver.

The goal is to identify a combination regimen that addresses both the central and peripheral pathways involved in the headaches. When successful, this strategy aborts the headache and reduces the rate of headache recurrence hours later, she said at a conference on internal medicine sponsored by the University of Colorado.

One rational combination therapy is a triptan and a nonsteroidal anti-inflammatory drug (NSAID), with an antinausea medication added as needed. Various combinations of drugs in these medication classes have been shown effective in the treatment of refractory migraine in multiple randomized studies in recent years.

Dr. O’Brien cited as one example a Harvard University study of 28 patients exhibiting migraine with the associated cutaneous pain and tenderness known as allodynia. Half received subcutaneous sumatriptan 4 hours after their attack was underway. All continued to have pain 2 hours later, at which point they received intravenous ketorolac. Seventy-one percent were free of head pain and allodynia within 60 minutes after ketorolac infusion.

The other half of the subjects received intravenous ketorolac monotherapy 4 hours after onset of the attack; 64% were pain- and allodynia-free within 60 minutes (Headache 2005;45:850-61).

This approach is readily adaptable to primary care settings, albeit with administration of the NSAID by routes other than intravenous infusion.

"I have quite a few patients who actually present to their primary care physician’s office for IM ketorolac when they’ve gone past that stage of response to their triptan agents. And they’ve had good success with that," according to the neurologist.

The ketorolac dose is a single 10-mg IM injection followed by 10 mg orally every 4-6 hours as needed to a maximum of 40 mg per day.

A far more convenient, fast-acting alternative that received Food and Drug Administration approval for acute migraine several years ago is solubilized diclofenac (Cambia). The patient can mix the diclofenac powder in a glass of water and drink it down for quick absorption.

Alternatively, naproxen sodium is more rapidly absorbed than other oral NSAIDs, such as ibuprofen or ketoprofen. The dose is 220-550 mg, with a maximum of 1,100 mg in 24 hours.

Dr. O’Brien explained that the current understanding of migraine without aura is that it’s a condition of neuronal hyperexcitability. The pathophysiology is complex. The initiating event occurs centrally in the brainstem. Once this central generator is activated, it initiates two peripheral pain mechanisms in the meninges: vasodilation of meningeal blood vessels and neurogenic inflammation. Pain signals from the periphery ascend to the trigeminal nucleus caudalis in the brainstem, at which point central sensitization occurs. This is a state of neuronal hyperexcitability, and triptans are often unable to quell it.

Triptans address the peripheral migraine pathway by preventing release of calcitonin gene–related peptide, an extremely potent endogenous vasodilator that also activates mast cells, triggering release of histamine, serotonin, and proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha. But if the triptan is unable to curb this process and ascending pain signals activate the trigeminal nucleus caudalis, it’s game on: The resultant central sensitization is beyond the reach of that medication class.

In contrast, NSAIDs tackle central sensitization by addressing the increased levels of cyclooxygenase present in the spinal cord, she continued.

Another rational combination therapy is an ergot plus an NSAID. Like the triptans, ergots address the key peripheral target, calcitonin gene–related peptide. Migranal is a dihydroergotamine available in formulations for subcutaneous injection and as a nasal spray. An investigational, orally inhaled dihydroergotamine known as Levadex is thought to be close to marketing approval.

Dr. O’Brien reported having no relevant financial conflicts.