CGRP Under the Magnifying Glass
There is now widespread agreement that vasodilation is neither necessary nor of a magnitude to be responsible for migraine pain; migraine is a complex neuronal disorder with vascular epiphenomenon.1
Interest in calcitonin gene-related peptide (CGRP) comes from research which suggests that CGRP could play an important role of migraine pathophysiology. It has been demonstrated that CGRP levels rise during spontaneous migraine episodes,2 and decrease concomitantly with symptomatic relief after administration of triptans.3,4 in addition, CGRP levels are elevated interictally in chronic and episodic migraine,5 and migrainous episodes can be precipitated by intravenous infusion of CGRP.6,7
Consequently, targeting the calcitonin gene-related peptide (CGRP) pathway has been pursued as a new strategy for both acute and preventive treatment of migraine with promising results.8,9
Four monoclonal anti-CGRP antibodies are currently being developed igalcanezumab, eptinezumab, and fremanezumab acting against CGRP one against the CGRP receptor, erenumab.
In the most recent Phase III studies,10 administration of erenumab demonstrated a reduction of monthly migraine days 2.9 days (placebo 1.8), a 50% reduction in monthly migraine days in 40% (placebo 30%) and migraine specific medication 1.2 days (placebo 0.6 days) of patients in episodic migraine.10 In a Phase III study of chronic migraine,11 in which fremanezumab was administered, a reduction in average number of headache days per month by 4.3 (administered quarterly), 4.6 (administered monthly) compared to placebo 2.5 (both comparisons). Thirty-eight per cent and 41% (quarterly and monthly respectively) experienced a 50% reduction in number of headache days per month compared to eighteen percent in the placebo group for both comparisons.11
Whilst in the scientific/research community, it is recognised that a group of patients (relative size is hard to establish) were excluded from clinical trials because they ‘… failed more than two preventive categories…’ i.e. those who had not responded to at least two clusters of preventive medications or who had continuous headache and that, ‘… their exclusion from initial trials may be warranted to maximize sensitivity to detecting efficacy…’ (of CGRP anti bodies),9(p8) this was not evident in the media launch. Perhaps then, because only a specific group of migraine patients were enrolled in the afore-mentioned Phase III trials,10,11 the results cannot be extrapolated to all migraine patients. Indeed, ‘…it is unknown what benefit this (excluded group of patients) population would derive.’9(p8)
Nevertheless, these trials provide prima facie evidence for these anti-CGRP antibodies providing more (than triptans) temporary relief for those whose lives are blighted by migraine.
However, much remains to be understood as to the site of (CGRP) action in migraine prevention – it is not clear. Furthermore, the long-term safety is entirely unknown.9 Open-label clinical trials lasting at least 12 months are required for the necessary longer-term safety and tolerability.9
CGRP is a 37-amino acid neuropeptide that is widely distributed throughout the central and peripheral nervous systems,12,13 with widespread, complex physiologic functions.
Theoretically, being a potent vasodilator,14 CGRP blockade could inhibit vasodilatation in situations where vasodilatation is required. Animal data15 demonstrates that CGRP protects against cerebrovascular ischaemia, vasospasm after subarachnoid haemorrhage and cardiac ischaemia. Furthermore, any adverse reactions, could not be readily reversed as antibodies have a relatively long half-life. In addition, the possibility of long-term effects with ongoing CGRP inhibition without obvious ischaemia, is unknown.9 This can only be assessed in much larger populations and probably only possible with post-marketing monitoring.9
Moreover, CGRP receptors are not exclusive to the nervous and vascular systems. They are also found in the adrenal glands, kidneys, pancreas, and bone; the effect of ongoing anti-CGRP antibodies on these organs is unknown.9
Lastly, it is recognised, that anti-CGRP antibodies will be expensive.9 This cost will need to be weighed up with the magnitude of relief and the absence of a long-term safety profile and tolerability.
Comment: This research and developments are well-meaning; I am just not sure that the benefit – partial relief – is worth it, but then I am fortunate, for whilst I have experienced very severe headache, I do not experience migraine or chronic headache. So, who am I to say it is not worth it, any relief, albeit temporary and partial, is welcome.
I am bemused though, by this systemic (pharmaceutical) approach to a unilateral disorder (migraine is defined as unilateral head pain16), which is driven by a unilateral disorder and in 80 percent of migraine this disorder ‘alternates’.17,18 Does CGRP choose one side of the head (and in 80 per cent of cases choose to affect the other side)? No.
The underlying disorder in migraine is a sensitised trigemino cervical nucleus (TCN).1 If the primary reason for sensitisation was an issue with CGRP, why isn’t migraine global?
CGRP can only mitigate the migraine process because it does not address the reason for sensitisation of the TCN. One cannot expect dramatic (and enduring) relief from migraine unless the reason for sensitisation is identified and targeted directly. This the reason why pharmaceutical intervention is sub optimal and perhaps not worth the risk of potential adverse reactions.
As serendipity would have it, at the time of this commentary, a migraineur contacted the Watson Headache® Institute and communicated her migraine experience. What is pertinent to this discussion is that she explored the new CGRP drug with her General Practitioner who responded, and I paraphrase ‘… it might be promising but I am not prepared to prescribe this until we know what the long-term effects are…’.
Manipulating CGRP is not/will not be the answer to significant relief from migraine but let’s recognise that for some, a few extra days in their lives without migraine, is an improved life.
But there is more to this; because i) migraine is unilateral (possibly cervical) ii) alternates (hands down musculoskeletal!) and iii) upper cervical afferents can sensitise the TCN, it is irresponsible to not educate and offer the headache and migraine population a skilled examination of the upper cervical spine to determine or otherwise cervical relevancy.
- Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiological reviews. Apr 2017;97(2):553-622.
- Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. Aug 1990;28(2):183-187.
- Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. Jan 1993;33(1):48-56.
- Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia. Mar 2005;25(3):179-183.
- Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. Oct 1 2013;81(14):1191-1196.
- Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. Feb 2002;22(1):54-61.
- Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. Oct 2010;30(10):1179-1186.
- Goadsby PJ. Bench to bedside advances in the 21st century for primary headache disorders: migraine treatments for migraine patients. Brain. Oct 2016;139(Pt 10):2571-2577.
- Tso AR, Goadsby PJ. Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention? Curr Treat Options Neurol. Aug 2017;19(8):27.
- Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. May 2018;38(6):1026-1037.
- Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. Nov 30 2017;377(22):2113-2122.
- Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. Jul 15 1982;298(5871):240-244.
- Rosenfeld MG, Mermod JJ, Amara SG, et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature. Jul 14-20 1983;304(5922):129-135.
- Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. Dec 1987;7(6):720-728.
- MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping Out CGRP: Potential Cardiovascular Risks. Trends in pharmacological sciences. Sep 2016;37(9):779-788.
- Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. Jan 2018;38(1):1-211.
- Prakash S, Rathore C. Side-locked headaches: an algorithm-based approach. J Headache Pain. Dec 2016;17(1):95.
- Ramon C, Mauri G, Vega J, Rico M, Para M, Pascual J. Diagnostic distribution of 100 unilateral, side-locked headaches consulting a specialized clinic. Eur Neurol. 2013;69(5):289-291.