GENERAL DISCUSSION 215 10 headache, which suggests that either the compound was not effective for full blockage of the receptor or that EP4 is not the only receptor involved in PGE2 induced headache. 53 Regarding the endocannabinoid system, medical marijuana is used as a preventive treatment of migraine, although controlled research on the effectiveness is lacking,47, 54 Chemical compounds targeting the endocannabinoid catabolic enzymes are new treatment targets and allosteric ligands of the CB1 and CB2 receptor are gaining interest and are currently being investigated in animal studies. 47 The newest treatment avenue entails incorporating the interplay of these systems is dual therapy, whereby components of different pathways are blocked/stimulated with one medicine. Currently, there is development of combined FAAH/TRPV1 and FAAH/COX-2 inhibitors.55 Other upcoming targeted medication are the ditans and gepants. Ditans are selective 5-HT-1F receptor agonists, such as lasmiditan. Gepants are small molecules that work as antagonists of CGRP receptors, examples are ubrogepant and rimegepant. Both can be used as medication during an attack, ditans can also be used to prevent attacks. Based on these pathways thus far no effective treatment has been found for migraine, a consecutive question would be: why that is and are we looking at the right targets, given that no difference in concentration was found in either Chapter 4 or Chapter 5? The answer could be that the absence of significance does not prove the absence of an effect. In addition, a difference might be too subtle to be detected or only occur at the cellular level. There is still a lot of evidence pointing to the involvement of these systems in pain and migraine, this should not be disregarded. However, given the large clinical heterogeneity in migraine there might be an equally large heterogeneity in the components of the pathways that are involved. To truly understand the mechanisms involved, we might have to change the way we investigate migraine. Finding biochemical differences in case-control studies Often the central aim of metabolomics studies is to test for the association between (specific) metabolites and a trait of interest, in our case migraine. Once a difference is found this can provide biological insight into the disease, be it the cause or consequence of a disease process. In this thesis, we set out to investigate the biochemical aspects of migraine. For both Chapters 3 and 5 we performed a robust analysis to compare plasma levels of endocannabinoids and PGE2, respectively, between cases and controls. Contrary to what other studies have found, we did not detect differences in migraineurs compared to controls. Notably, our sample sizes were larger than in most previous studies that did find differences between migraineurs and controls. The lack of replicability and comparability is a major and challenging issue when investigating metabolites. One reason underlying the contradictory findings might be related to the study design. As stated above, both the endocannabinoid system and the pathways involving PGE2 are complex and can be influenced by numerous possibly confounding factors apart from the presence or absence of migraine. Confounding occurs when there is a distortion of the association between the exposure and the outcome. The problem of confounding arises when the study groups differ with respect to variables that can influence the outcome, such as age, sex,
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