CGRP and migraine
J Neurol
CGRP and migraine
M. Cauchi 0 1
N. P. Robertson 0 1
0 Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University , Cardiff , UK
1 & N. P. Robertson
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Migraine has been estimated to be the seventh highest
cause of disability worldwide, and the third most common
disease worldwide after dental caries and tension type
headache. However, the use of currently available acute
and prophylactic medications to control this condition,
such as 5-HT1 agonists (triptans) and beta-blockers, is
limited by side effects and efficacy so that alternative and
more specific treatments are required. More recently, an
improved understanding of the pathophysiology of disease
has allowed investigation of new therapeutic targets.
The 37 amino acid neuropeptide calcitonin gene-related
peptide (CGRP) has been shown to play a crucial role in
the trigeminocervical complex pathway for nociception in
the head. Studies have demonstrated elevated levels in the
external jugular vein during the headache phase of
migraine, with reduction following headache resolution.
Furthermore, CGRP infusion triggers migraine type
headache and subsequent treatment with triptans results in
normalization of CGRP levels. This neuropeptide is
therefore thought to have a central role in pain modulation
as it participates in the neurovascular pathway and
contributes to the vasodilation and neurogenic inflammation,
which leads to migrainous attacks. Targeting CGRP may
provide the ideal therapeutic tool needed for control of this
common and debilitating illness.
The three studies chosen for this month’s journal club
are a small sample of the large amount of research being
performed on CGRP. The first investigates whether its
measurement can be used to classify migraine. The second
and third articles are phase II clinical trials which
investigate the use of CGRP antagonists and a monoclonal
antibody CGRP.
Interictal increase in CGRP levels in peripheral
blood as a biological marker for chronic migraine
In this study, the authors investigated the possible use of
CGRP as a marker for chronic migraine. 103 female
patients diagnosed with chronic migraine according to
international headache society criteria were recruited.
Cases reported an average of 9.5 ± 3.4 years of chronic
migraine and attempted detoxification at least once for a
minimum of 2 months if diagnosed with analgesic overuse
migraine. The control groups consisted of 31 healthy
women with no headaches and on no medications, 43
females with episodic migraine, and 14 patients with
cluster headaches (13 female, 1 male).
Morning blood samples were taken from all patients on
days without moderate/severe headaches. No symptomatic
medications were allowed in the previous 24 h and
prophylactic medications were continued. CGRP was found to
be significantly higher in chronic migraine as compared to
all control groups interictally. The authors subsequently
analyzed the potential of CGRP as a biomarker for chronic
migraine and concluded that for a CGRP concentration of
43.45 ng/ml, 90.38 % of CM, and 80.64 % of controls
would be correctly classified. They also propose that it is
possible to distinguish between chronic migraine and
episodic migraine on the CGRP level alone.
Comment. Although these findings demonstrate
considerable potential for CGRP levels as a disease biomarker,
considerably more evidence is required before it could be
used in clinical practice. Sensitivity and specificity remains
poor, and its value in the clinical setting remains unclear
particularly as the IHS guidelines appear to provide clear
guidance for the clinician. Furthermore, the choice of
control groups is limited and it would be of interest to
extend these groups to include cases more representative of
general clinical practice. However, the study underlines the
relevance of CGRP in pathophysiology and holds promise
as an objective measure of response and of treatment
stratification for future therapeutic trials and also those
trials specifically targeting this molecule.
Cernuda-Morollo´n V et al (2013) Neurology
81:1191–1196.
BMS-927711 for the acute treatment of migraine:
a double-blind, randomized, placebo controlled,
dose-ranging trial
Previous studies of CGRP antagonists have been limited by
early termination due to liver toxicity. This well-designed,
single-dose, double-blind, randomized, multicenter
evaluation of the CGRP antagonist BMS-927711 measures
efficacy as an acute migraine therapy. 1026 patients were
enrolled and 885 randomized to receive a single dose of
placebo, 100 mg sumatriptan, or one of 6 different doses of
BMS-927711 (10, 25, 75, 150, 300 or 600 mg). Exclusion
criteria included a history of vascular disease and the
concomitant use of drugs metabolized by CYP3A.
Prophylactic migraine therapy was allowed but the use of other
acute therapies was prohibited 2 days prior to
randomization. A Bayesian analysis of the observed response rates
allocated group (...truncated)