Page 133 - The clinical aspects and management of chronic migraine Judith Anne Pijpers

the context of migraine chronification cutaneous allodynia should not only be studied as one entity, but the extension of sensitization should be taken into account.
This division might shed light on a recently stated hypothesis of different underlying mechanisms of central sensitization. The hypothesis was evoked by the observation in clinical studies that some patient become unresponsive to triptans once cutaneous allodynia manifested17,18, and some patients remain responsive to triptans despite of cutaneous allodynia.19–21 Acknowledging different stages of central sensitization (second and third order), and considering that triptans act both peripherally and post-synaptic on second order neurons,19 but not third order neurons, could explain this discrepancy: Patients with second order sensitization (cephalic allodynia) alone remain responsive to triptans, whereas patients with extension to third order sensitization (extracephalic allodynia) are unresponsive.
Alternatively, two hypotheses on the origin of central sensitization can be stated: i) central sensitization is initiated by peripheral activation of the trigeminal afferents, and sequentially causes second and third order sensitization (triptan responsive allodynia);10,13,22 ii) central sensitization is initiated by central changes, for instance the hypothalamus as part of the descending pain pathway, directly causing both second and third order sensitization (triptan unresponsive allodynia). The second hypothesis is supported by imaging studies, suggesting an important role of the hypothalamus in migraine chronification and brainstem as generator of migraine attacks.16,23 Although not directly studied, the dose- response relationship between cephalic versus extracephalic allodynia and response in chapter 6, suggests a sequential gradual extension of central sensitization. Nonetheless, the difference is small, and does not exclude a central origin. These mechanisms (sequential events of sensitization extension initiated by peripheral sensitization or central sensitization directly caused by central changes) might even coincide and facilitate each other. In this thesis, I propose a role for both mechanisms. In episodic migraine, central sensitization may mainly originate from a peripheral stimulus, and is reversible after removal of this stimulus (i.e. the end of migraine attack). In the process of migraine chronification, the recurrent attacks and medication intake may lead to central changes by both functional and structural neuroplasticity24, increasing the importance of a persistent state of central sensitization caused by central changes.
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Summary and general discussion
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