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Headache


Table 1: International Headache Society Criteria for Migraine Without Aura


With Aura


Five or more attacks lasting 4–72 hours


Like migraine without aura but with two


or more attacks with three or more of the following characteristics: • one or more fully reversible aura symptoms indicating brain dysfunction;


• at least one aura symptom develops gradually over more than four minutes or two more symptoms occur in succession;


• no single aura symptom lasts more than one hour; and/or


• headache follows aura with free interval of less than one hour


Two or more of the following


headache symptoms: • unilateral location; • pulsating quality; • moderate to severe intensity; and/or • aggravated by routine activity At least one of the following associated symptoms: • nausea or vomiting; and/or • phonophobia and photophobia Other causes for headache excluded


Source: Bigal et al., 2009.6


Table 2: Safety Results from a European Study on Cambia® in Acute Migraine


Most Common Treatment-assigned Adverse Events (ITT Population) Total number of patients


Total number of adverse events Vomiting


Abdominal pain (upper) Dyspepsia Dizziness Diarrhea Nausea


Somnolence


291 20 3 2 2 2 1 1 1


Cambia (n) Diclofenac Placebo (n) Potassium Tablet (n) 298 17 1 0 1 1 1 1 1


299 32 1 3 1 0 4 3 3


ITT = intention-to-treat. Source: Diener et al., 2006.27


Sensation from the head and neck is then relayed orthodromically to cortical pain and sensory processing areas. When the trigeminal system is activated during the migraine event it triggers a reflex that sends electrical signals antidromically to the periphery,13 the trigeminovascular response.14


the trigeminal nucleus caudalis in the pons and descending spinal trigeminal tracts.11,12


known as Peripheral nerve endings then release


an ‘inflammatory soup’ of substances including prostaglandins, histamine, cytokines, substance P, calcitonin gene-related peptide, and bradykinin, which results in inflammation and swelling of peripheral tissues (meningeal, blood vessels, muscle, skin).15


Migraine pain is a result of the


sensitization of the peripheral tissues leading to allodynia, resulting from a non-painful stimulus. Once the process begins, the pain derived


140 Other causes for headache excluded


In addition to the peripheral release of prostaglandins, the cortical event in migraine, cortical spreading depression, not only results in a wave of depolarization with the cortex but also prostaglandin release centrally.17,18 The use of prostaglandin-inhibiting medication that acts via inhibition of cyclo-oxygenase (COX) can suppress cortical spreading depression. COX- 1/COX-2 inhibitors exhibit this effect but aspirin and COX-2 inhibitors alone do not.19,20


from the inflammation is transmitted back to trigeminal neurons where the loop is completed and reinforces the trigeminal-vascular response, enhancing the pain event and making it more difficult to treat.16


An effort was made by Sarchielli et al. to establish a link between the animal evidence and clinical migraine. Five patients with migraine were assessed with assays for neurokinin A (NKA), prostaglandin E2, and nitrites after onset of migraine attacks at 30 minutes, one hour, two hours, four hours, and six-hours. Maximum prostaglandin levels were achieved two hours after an attack with sustained elevation through the sixth hour time point. The levels were assessed again after the end of the attack, with prostaglandin levels falling below those recorded 30 minutes after headache onset. Levels of nitrites, NKA and the intracellular messengers cyclic guanosine monophosphate (cGMP), calcitonin gene-related peptide (CGRP) peaked at the first hour then gradually decreased to levels lower than those at headache onset. These data suggest a relationship between the activation of the L-arginine/nitric oxide pathway, the release of vasoactive peptides from trigeminal endings, and a late rise in the synthesis of prostanoids which may be involved in maintaining the headache phase.21


Acute Migraine Treatment


For several years, treatment of acute migraine has been based on a stratified approach utilizing more-‘specific’ therapy targeted to migraine pathophysiology depending on the severity of headache. This approach has been validated as not only more effective for headache treatment but more cost effective as well. Treatment with analgesics such as acetaminophen or the use of over the counter non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for patients with only mild headache. For patients with moderate to severe headaches, approved therapeutic options include selective serotonin receptor (5-HT1) agonists (triptans),22


Cambia® (diclofenac potassium for oral solution) and ergot alkaloids. The latter are


non-selective 5-HT1 agonists that have a wider spectrum of receptor affinities outside of the 5-HT1 system, including dopamine receptors.


Although triptans, ergot alkaloids and Cambia have been approved by the FDA as effective for migraine treatment, more than 25 % of patients with migraine are dissatisfied with their current treatment23 would be willing to try an alternative.24


and nearly 80 % Triptans are generally considered


superior to ergot alkaloids from both an efficacy and side-effect perspective.25


However, intolerance of side effects (blood vessel constriction, chest pain/pressure/tightness, esophageal spasm, dizziness, fatigue, nausea, light headedness, etc.) is also a major source of dissatisfaction with triptans, leading to the need for a viable alternative.26 It is for this reason that certain NSAIDs, such as Cambia, have been re-examined as a potential treatment alternative for acute migraine.


Diclofenac has a long history of use in a variety of forms.27 As a member


of the NSAID class, it not only suppresses peripheral inflammation in migraine but also acts centrally to limit central sensitization.28,29


In US NEUROLOGY


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