The market approval of CGRP antibodies has revolutionized the treatment options for migraine. It is a therapy option that is very popular with patients and whose efficacy
is supported by a broad evidence base. At this year’s Pain Congress, experts discussed the relevance of comorbidities for migraine treatment and how these should be taken into account as part of individualized therapy.
Migraine is a widespread illness and often leads to considerable limitations for those affected. The headaches, which occur in attacks of moderate to severe intensity, are accompanied by throbbing pain and usually last from a few hours to several days. The prevalence of migraine is most common in the 20-50 age group, with women being affected almost three times more often than men [1]. We speak of episodic migraine when the typical migraine symptoms occur on less than 15 days a month. If the headache attacks exceed 15 migraine days per month, this is chronic migraine. It is now known that migraine is associated with numerous comorbidities, including anxiety disorders, depression, back pain and vascular diseases (Fig. 2) [2,6,10].
Migraine prophylaxis with erenumab and fremanezumab has proven its worth
The current guideline recommends considering migraine prophylaxis with medication for frequent migraine attacks or migraine attacks with severe symptoms or persistent aura [16]. In general, CGRP antibodies have proven to be a very effective treatment option for migraine, according to Dr. Sebastian Strauss, Department of Neurology, Greifswald (Germany) [4]. The guideline also attests to the very good efficacy and tolerability of monoclonal antibodies against CGRP receptors, and in recent years this group of drugs has experienced a real upswing in migraine treatment. CGRP (Calcitonin Gene-Related Peptide) is a vasoactive neuropeptide that is released by primary afferent nerve fibers and can trigger headache attacks in migraine patients. CGRP levels are typically elevated during an attack. Erenumab specifically targets the CGRP receptor to reduce the transmission of pain signals and fremanezumab is a CGRP receptor antagonist that inhibits the binding of the neuropeptide to the CGRP receptor [5,21]. The success of the treatment should be checked after about three months. Prophylactic treatment for episodic and chronic migraine is successful in around half of all cases [3]. Both erenumab and fremanezumab are available as pre-filled pens for subcutaneous administration [21].
Subpopulation of depressive migraine patients also benefited
Effective treatment of migraine can also have a positive effect on comorbid depressive symptoms, reported PD Dr. med. Carl H. Göbel, Pain Clinic Kiel (Germany) [6]. This was shown in a subgroup analysis of the HALO CM study published in 2021, in which the effects of fremanezumab were investigated in comparison to placebo [7]. Fremanezumab or placebo was administered quarterly in one treatment group (675 mg at baseline and in weeks 4 and 8) and monthly in the other (675 mg at baseline and 225 mg in weeks 4 and 8). The subgroup analysis included 219 of 1121 migraine patients who suffered from moderate to severe depression at the start of the study (PHQ**-9 sum score ≥10). At week 12, fremanezumab was not only associated with a significant reduction in the monthly number of headache days compared to placebo, but PHQ-9 scores also improved to a greater extent. In the fremanezumab study arm with quarterly dosing (n=96), the LSM values were -10.9 (p=0.113), in the monthly dosing -9.8 (p=0.558) and with placebo -9.2 [7]. Mc Allister et al. investigated the effects of fremanezumab in migraine patients with severe depression in the UNITE study, which also showed that the CGRP antibody performed better than placebo at week 12 not only in terms of reducing the number of headache days (MMD), but also with regard to the secondary endpoints HIT$-6 and CGI-S& [8].
** PHQ-9=Patient Health Questionnaire
$ HIT-6=Headache Impact Test
& CGI-S=Clinical Global Impression Severity Scale
High blood pressure – risk assessment and monitoring are crucial
When CGRP is released, vasodilation is induced via the activation of the CGRP receptors, explained Dr. Göbel [11]. If this effect is inhibited by a CGRP blockade, vasoconstriction occurs. Theoretically, therefore, there is a risk of high blood pressure, but the study situation on this is inconsistent. Hypertension did not occur significantly more frequently in the approval study of erenumab, reported the speaker [11,17]. In order to be able to make a statement based on real-world data, the US Food and Drug Administration (FDA) analyzed the Adverse Event Reporting System for erenumab: of 81 blood pressure-related reports, 61 were hypertension (BP >140 mm Hg or diastolic BP >90 mm Hg) and 41 patients experienced serious complications. These findings prompted the FDA to formulate a safety recommendation in the drug information for ereneumab, which states that patients treated with ereneumab should be monitored for new hypertension or worsening of existing hypertension and, if necessary, discontinuation of treatment should be considered if the medical examination does not reveal an alternative etiology for the hypertension [12]. Dr. Göbel pointed out that those patients who had experienced hypertensive side effects already had relevant comorbidities prior to erenumab treatment. Whether there are indications of a risk of high blood pressure with fremanezumab in addition to erenumab was investigated by de Vries Lentsch et al. [9]. The conclusion of this study is that it appears to be a CGRP-specific effect, although there may be some differences between erenumab and fremenezumab in this regard due to different mechanisms of action.
Is there an association between migraine and autoimmune diseases?
In addition to depression and hypertension, other comorbidities were discussed at the pain congress. Dr. Armin Scheffler, Department of Neurology, University Hospital Essen (Germany) reported on a possible association between autoimmune diseases and migraine [13]. There are individual studies that point to an increased prevalence of multiple sclerosis (MS) [18], rheumatoid arthritis [19], and psoriasis [20], but overall the data on this is contradictory. It is possible that a greater willingness to react to inflammation is an underlying factor for a possible association, but this is only a vague hypothesis at this stage. With regard to chronic inflammatory bowel disease (IBD), around 500,000 data records from the UK Biobank were analyzed for an association between bowel disease and migraine in one of the few larger studies, whereby a significant association was only found for irritable bowel syndrome (OR 2.24, p<0.001) and peptic ulcers (OR 1.55, p<0.001) [13].
Congress: German Pain Congress, October 18-21, 2023
Literature:
- Stovner LJ, Andrée C: Prevalence of headache in Europe: a review for the Eurolight project. The Journal of Headache and Pain 2010; 11(4): 289-299.
- Buse DC, et al: Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in america symptoms and treatment (MASI) study. J Headache Pain 2020; 21(23).
- Diener HC: Therapy of migraine. Guidelines for diagnostics and therapy in neurology: German Society of Neurology 2012, www.dmkg.de, (last accessed 10/31/2023)
- “Common pathophysiological aspects between primary headaches and complex regional pain syndrome (CRPS)”, Dr. Sebastian Strauss, German Pain Congress 18-21.10.2023.
- Swissmedic: Medicinal product information, www.swissmedicinfo.ch,(last accessed 31.10.2023)
- “Comorbid depression: Does the depression also improve if I get the migraine under control?”, PD Dr. med. Carl H. Göbel, German Pain Congress 18-21.10.2023.
- Lipton RB, et al: Effects of fremanezumab in patients with chronic migraine and comorbid depression: Soubgroup analysis of the randomized HALO CM study. Headache 2021; 61(4): 662-672.
- Mc Allister P, et al: Impact of Fremanezumab Treatment on Disability Outcomes in Patients with Migraine and Major Depressive Disorder: Results of the UNITE Study. Poster presented at the 65th Annual Scientific Meeting of the American Headache Society (AHS), June 15-18, 2023; Austin, TX, United States.
- de Vries Lentsch S, et al: Blood Pressure in Patients With Migraine Treated With Monoclonal Anti-CGRP (Receptor) Antibodies: A Prospective Follow-up Study. Neurology 2022; 99(17): e1897-e1904.
- “Live debate: CGRP & the relevance of comorbidities for migraine prophylaxis”, Dr. Zaza Katsarava, German Pain Congress, 18-21.10.2023.
- “Hypertension: Is the FDA correctly assessing the risk of anti-CGRP antibodies?”, PD Dr. med. Carl H. Göbel, German Pain Congress 18-21.10.2023.
- Prescribing information, www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Aimovig/aimovig_pi_hcp_english.pdf,(last accessed 10/31/2023)
- “Migraine and its association with autoimmune diseases”, Dr. med. Armin Scheffler, Pain Congress, 18-21.10.2023.
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- DGN/DMKG: Therapy of migraine attacks and prophylaxis of migraine, S1 guideline, AWMF register number: 030/057, as of 18.10.2022.
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- Kim YH, et al: Bidirectional association between migraine and rheumatoid arthritis: two longitudinal follow-up studies with a national sample cohort. BMJ Open 2021 Jun 8;11(6): e046283.
- Egeberg A, Mallbris L, Hilmar Gislason G, et al: Increased risk of migraine in patients with psoriasis: A Danish nationwide cohort study. J Am Acad Dermatol 2015; 73(5): 829-835.
- Swissmedic: Medicinal product information, www.swissmedicinfo.ch,(last accessed 02.11.2023)
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