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Tough migraines may warrant combined Tx.


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, Dr. O'Brien said at the conference.

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.

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.

Dr. O'Brien reported having no relevant financial conflicts of interest.
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Title Annotation:NEUROLOGY
Author:Jancin, Bruce
Publication:Internal Medicine News
Date:Dec 1, 2012
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