Headache
an NSAID. Such combination therapies produce more benefits than either monotherapy or placebo and also reduce headache recurrence, as shown in recent placebo-controlled trials of sumatriptan–naproxen sodium36 combinations.37
and almotriptan–aceclofenac
The sumatriptan–naproxen sodium combination is moderately superior to sumatriptan or naproxen monotherapy38 and theoretically able to abort migraine in its initial stages, i.e. at the level of the trigeminal ganglion, and prevent the slow central sensitisation phenomenon.39
For headache recurrence, a second dose of the triptan is effective in most cases.40 Other Drugs
One of the most interesting products under development is a sumatriptan patch: NP101 is an iontophoretic patch that delivers sumatriptan transdermally (using a small electric current to drive the compound across the skin) and keeps its plasma levels above the target level of 10 ng/ml for longer than seven hours.41
Transdermal
iontophoretic delivery of sumatriptan via NP101 may offer significant clinical benefits for migraine patients, for example, circumventing the gastrointestinal disturbances, including nausea and gastric stasis, that are associated with migraine. The patch also provides consistent, predictable delivery of desired drug levels over a four-hour period. This offers the potential to avoid atypical pain, pressure and other sensations commonly associated with current triptan formulations.42
The combination of triptans with antiemetics is little studied, with only small studies indicating the benefits of this approach. Although one might expect this combination to be helpful, there is no clear clinical evidence that this is the case.43
The Newest Acute Treatment
Calcitonin Gene-related Peptide Antagonists (‘Gepants’) When specific anti-migraine therapies, i.e. triptans or ergot derivatives, have failed or their use is restricted (by the presence of multiple vascular risk factors or major adverse effects), other non-vasoactive therapeutic alternatives must be offered.
In view of the complex pathogenic mechanisms involved in the migraine attack, considerable efforts have been made to identify other targets for acute therapies.
The most recent experimental and clinical studies have focused on CGRP antagonists. Considering that CGRP receptor antagonists are the first non-serotoninergic, migraine-specific drugs without a vasoconstrictor action, it has been suggested that they may be suitable for patients with vascular disease, such as coronary artery disease and peripheral vascular disease.44
CGRP, one of the most potent vasodilators known, is released from trigeminal sensory nerve fibres. Data from a recent randomised controlled trial confirmed that CGRP antagonists are a potentially useful target in acute migraine treatment.45
Two CGRP antagonists have been studied: olcegepant (BIBN4096), a parenteral preparation, and telcagepant (MK-0974), the first oral formulation. Olcegepant proved to be effective at aborting migraine attacks in a Phase II trial,45
while a Phase IIB study and a
Phase III study found telcagepant to work well in migraine. Preclinical studies suggest that telcagepant is not a vasoconstrictor – the vasoconstrictor effect is, as mentioned, a major limitation in the use of triptans – and its efficacy is comparable with that of certain
268 5-HT1F Agonists (‘Lasmiditan’)
Clinically, LY334370 is the prototype selective 5-HT1F agonist and also the first one to reach Phase II clinical development.49,50
There are several lines of evidence that implicate the 5-HT1F receptor in migraine. Animal experiments indicate that 5-HT1F agonists are effective in preclinical models of migraine and are not vasoconstrictors.12 LY334370, which is a selective 5-HT1F agonist, inhibits single-cell firing in the trigeminal nucleus caudalis without having any effect on the cerebral vessel lumen as measured by intravital microscopy.48 Anatomically, 5-HT1F mRNA is located in the trigeminal ganglion. Functionally, 5-HT1F, 5-HT1B and 5-HT1D agonists can presynaptically inhibit the release of glutamate, which may participate in the migraine cascade.49
Adverse
events found to be more common on oral LY334370 than on placebo were asthenia, somnolence, dizziness and paraesthesias.51
5-HT1D Agonists (PNU-109291 and PNU-142633) 5-HT1D receptor agonists are potent inhibitors of dural plasma protein extravasation and possess no vasoactive properties. Two 5-HT1D selective agonists (PNU-109291 and PNU-142633) have shown some promise in animal models of migraine. In one human randomised controlled trial, PNU-142633 failed to achieve significance and subjects reported cardiovascular symptoms such as chest pain.52
The
PNU-142633 programme was abandoned. Also, the non-vasoactive hypothesis of 5-HT1D agonism needs further elucidation in view of the complaints of chest symptoms on PNU-142633. One tantalising hypothesis is that 5-HT1D agonists are cardioactive but not vasoactive and the chest symptoms are valvular in origin since 5-HT1D receptors are found on cardiac valves.53
Another explanation is that the chest symptoms are of pulmonary origin.54 Glutamate Modulators
Ramadan et al., in 2003, discussed the role of glutamate in migraine pathophysiology.49
The fact that neurons in the trigeminal
ganglion that are 5-HT1B, 5-HT1D and 5-HT1F receptor-positive are also glutamate receptor-positive could indicate that 5-HT1 autoreceptors inhibit the release of glutamate presynaptically.55
Two
studies demonstrated elevated plasma levels of glutamate in migraine patients, particularly in migraine-with-aura patients, but these results were not confirmed by other studies.
Beyond their vascular effects, drugs modifying glutamate neurotransmission and modulation are promising in migraine therapy for other reasons: one need only consider the multiple stages in the pathophysiological cascade of migraine in which glutamate and its receptors have a pivotal action in experimental models, from CSD to processing of nociceptive information in the trigeminovascular pathway.56
NXN-188 is a new oral agent with a dual mechanism of action: inhibition of neuronal NO synthase and binding to 5-HT1B/1D
EUROPEAN NEUROLOGICAL REVIEW triptans (rizatriptan and zolmitriptan).46 However, a Phase IIa clinical
trial of telcagepant for the prophylaxis of episodic migraine was stopped on 26 March 2009 after the “identification of two patients with significant elevations in serum transaminases”.47
A memorandum
to the study centres stated that telcagepant had preliminarily been reported to increase the liver enzyme alanine transaminase levels in “11 out of 660 randomised (double-blinded) study participants”. All study participants were told to stop taking the medication. In July 2011, Merck terminated the clinical development of telcagepant.
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