The sense of stopping migraine prophylaxis

Abstract

Introduction Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making. Methods Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar. Discussion Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month. There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated. Conclusion Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine. Graphical Abstract

Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia

“…54 In rats with hHCY, the excitability of meningeal afferents was higher compared to naive rats which may be associated with changes in the expression and/or function of ion channels responsible for the maintenance of the resting membrane potential and AP generation, possibly including two-pore K + channels, voltage-gated Na + and voltage-gated K + channels. 55,56 However, at the level of TG neurons, we did not observe changes in the RMP, threshold, amplitude, and duration of APs between control and hHCY animals, which does not confirm participation of background or voltage-gated K currents and tetrodotoxinsensitive Na + channels. At the same time, we found that lower values of injection currents capable of causing a single AP (rheobase)…”

“…Moreover, meningeal elevation of KCl was suggested to activate dural afferents during cortical spreading depression 54 . In rats with hHCY, the excitability of meningeal afferents was higher compared to naive rats which may be associated with changes in the expression and/or function of ion channels responsible for the maintenance of the resting membrane potential and AP generation, possibly including two‐pore K + channels, voltage‐gated Na + and voltage‐gated K + channels 55,56 …”

Evaluation of the concomitant use of prophylactic treatments in patients with migraine under anti‐calcitonin gene‐related peptide therapies: The PREVENAC study

“…In clinical practice, attempts should be made to limit the exposure time to preventive drugs due to the prevalence of adverse effects [24]. This is particularly significant for older patients, who typically require multiple concomitant medications.…”

RE‐START: Exploring the effectiveness of anti‐calcitonin gene‐related peptide resumption after discontinuation in migraine

“…Patients were included if: (i) they were aged over 18 years; (ii) they had a diagnosis of high‐frequency episodic migraine (HFEM) or chronic migraine (CM) according to the International Classification of Headache Disorders 3rd edition (ICHD‐3) criteria [18]; (iii) they were treated with anti‐CGRP MAb treatment after fulfilling the national prescription criteria for this, which include eight or more MMDs and lack of response to at least three preventive medications, each taken at sufficient doses for a minimum of 3 months, one of these medications being onabotulinumtoxinA in the case of CM [10, 19]. Patients could have received galcanezumab, erenumab or fremanezumab; eptinezumab was not yet commercialized during this study); (iv) they were receiving anti‐CGRP MAb treatment for at least 12 months and had good clinical response according to the responsible physician; and (v) they had migraine worsening after discontinuation that led to restarting the anti‐CGRP MAb.…”