Migraine and Calcitonin Gene-Related Peptide

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.

References:

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2. 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.
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