Headache Currents

David W. Dodick, M.D., UCLA

Department of Neurology,
710 Westwood Plazz, BOX 951769,
Los Angeles, CA 90095–1769;
E-mail: rwbaloh@ucla.edu
Headache Currents
Chief Editor
David W. Dodick, Scottsdale, AZ
Managing Editor
Wendy Krank, Scottsdale, AZ
Clinical Science Associate Editors
Richard B. Lipton, Bronx, NY
Julio Pascual, Santander, Spain
R. Allan Purdy, Halifax, Nova Scotia
Stephen D. Silberstein, Philadelphia, PA
Basic Science Associate Editors
Rami Burstein, Boston, MA
Michel D. Ferrari, Leiden, The Netherlands
Peter J. Goadsby, London, UK
Clinical Science Contributing Editors
Werner J. Becker, Calgary, Alberta
Marcelo E. Bigal, Bronx, NY
David F. Black, Rochester, MN
Christopher J. Boes, Rochester, MN
David J. Capobianco, Jacksonville, FL
Carl G.H. Dahlof, Gothenburg, Sweden
Kathleen B. Digre, Salt Lake City, UT
Eric J. Eross, Scottsdale, AZ
Randolph W. Evans, Houston, TX
Deborah I. Friedman, Rochester, NY
Jonathan P. Gladstone, Toronto, Ontario
Steven B. Graff-Radford, Los Angeles, CA
James W. Lance, Sydney, Australia
Massimo Leone, Milan, Italy
Elizabeth W. Loder, Boston, MA
Ninan T. Mathew, Houston, TX
Lawrence C. Newman, New York, NY
Alan M. Rapoport, Stanford, CT
K. Ravishankar, Bombay, India
John F. Rothrock, Mobile, AL
Todd Rozen, Ann Arbor, MI
Joel R. Saper, Ann Arbor, MI
Fred D. Sheftell, Stanford, CT
Todd J. Schwedt, St. Louis, MO
Jerry W. Swanson, Rochester, MN
Frederick R. Taylor, Minneapolis, MN
Stewart J. Tepper, Stamford, CT
Paul Winner, West Palm Beach, FL
William B. Young, Philadelphia, PA
Basic Science Contributing Editors
Sheena K. Aurora, Seattle, WA
F. Michael Cutrer, Rochester, MN
H.C. Diener, Essen, Germany
Marie Germaine-Bousser, Paris, France
Volker Limmroth, Essen, Germany
Peggy Mason, Chicago, IL
Manjit S. Matharu, London, UK
Arne May, Regensburg, Germany
Michael A. Moskowitz, Charlestown, MA
Frank Porecca, Tuscon, AZ
Nabih M. Ramadan, North Chicago, IL
Fumihiko Sakai, Kanagawa, Japan
Margarita Sanchez del Rio, Madrid, Spain
Peter S. Sandor, Zurich, Switzerland
Jean Schoenen, Liege, Belgium
Irene Tracey, Oxford, UK
CURRENT REVIEW: CLINICAL SCIENCE
Clinical and Preclinical Rationale for CGRP-Receptor
Antagonists in the Treatment of Migraine
Stewart J. Tepper, MD; Mark J. Stillman, MD
Calcitonin gene-related peptide (CGRP) is linked to migraine
and other primary headache disorders. It is found in every
location described in migraine genesis and processing, including
meninges, trigeminal ganglion, trigeminocervical complex,
brainstem nuclei, and cortex. It is released in animal models
following stimulation of the CNS similar to that seen in
migraine, and triptans inhibit this release. Injection of CGRP
into migraineurs results in delayed headache similar to migraine.
Elevation of CGRP occurs during migraine, resolving following
migraine-specific treatment. Finally, and most importantly,
CGRP receptor antagonists terminate migraine with efficacy
similar to triptans. Both intravenous olcegepant (BIBN 4096 BS)
and oral telcagepant (MK-0974) have been effective, safe, and
well tolerated in phase I and II studies. Telcagepant is currently
in phase III trials, and preliminary results are favorable.The
potential for a migraine-specific medication without
vasoconstrictive or vascular side effects is enormous. CGRP
receptor blockade may also have applications in other pathologic
and pain syndromes.
Key words: calcitonin-gene related peptide, RAMP1, migraine, BIBN4096,
olcegepant, MK-0974, telcagepant
The concept that a calcitonin gene-related peptide (CGRP)-
receptor antagonist would be of clinical utility in migraine goes
back to the late 1980s. Relief of migraine corresponds to reduc-
tion of blood CGRP, and migraine pharmacotherapies decrease
CGRP. A CGRP-receptor antagonist could block vasodilation
and avoid vasoconstriction in the meninges, as well as alter
CGRP action in the trigeminal ganglion and reduce pain trans-
mission. Two CGRP-receptor antagonists, olcegepant (BIBN
4096 BS) and telcagepant (MK-0974), have been tested in phase
II trials in humans and showed clinical benefit and excellent
tolerability, with recent presentation of phase III data on tel-
cagepant suggesting that proof of concept is positive.
PATHOPHYSIOLOGY OF MIGRAINE
AND CGRP
The genesis of migraine is either in brainstem aminergic nuclei or
in the cortex, and is due to firing of hyperexcitable neurons.1,2
From the Center for Headache and Pain, Department of Neurology, Neurological Institute,
Cleveland Clinic Foundation, Cleveland, OH, USA.
Address all correspondence to S.J. Tepper, T33 Cleveland Clinic, 9500 Euclid Avenue, Cleve-
land, OH 44195, USA.
Accepted for publication June 16, 2008.
.............
Headache
© 2008 the Authors
Journal compilation © 2008 American Headache Society
1259
Headache Currents
Following initiation of migraine, peripheral meningeal pain
mechanisms are activated, as neurons release vasoactive, neuroin-
flammatory peptides, such as substance P and CGRP. Vasodilation
results in fenestration of meningeal blood vessels and further
plasma extravasation, while mast cells and other pro-inflammatory
cells are called in and release their contents in and around the
meninges. These processes further sensitize peripheral nociceptors
(primary sensitization), which, in turn, transduce noxious stimuli
into impulses. The impulses then travel centrally along the
trigeminal axon to the brainstem for processing in the trigeminal
nucleus caudalis and the trigeminocervical complex, and from
there rostrally through brainstem and thalamus to cortex.3,4
Calcitonin gene-related peptide is located at each juncture in
the genesis and processing of migraine. Activation of CGRP
receptors leads to increased levels of cyclic AMP (cAMP) which
modulates the intracellular activity of calicum-dependent kinase
enzymes such as protein kinase A (PKA) and C (PKC).5-7 PKA
and PKC are involved in phosphorylation and subsequent acti-
vation of glutamate receptors such as kainate Gluk6 and NMDA/
NR1. In particular, phosphorylation of the NR1 subunit results
in a configurational change in the ionotropic channel leading to
the removal of the magnesium plug, perhaps through an inter-
action with the glycine site of the receptor, and excitatory
postsynaptic potential (EPSP)-causing ionic influx. This postsyn-
aptic excitability may contribute to the generation, and mainte-
nance, of cortical spreading depression in aura, and possibly in
migraine without aura. Furthermore, such peripheral
stimulation-dependent activation can contribute to persistent
NMDA currents which would windup and eventual central sen-
sitization, expressed as allodynia.2-4,8-16 Additionally, selective
CGRP1 receptor antagonists (CGRP8-37 and olcegepant) in the
amygdala reverse arthritis pain-related plasticity through a PKA-
dependent postsynaptic mechanism that involves NMDA recep-
tors. CGRP receptor antagonists inhibited synaptic plasticity in
the laterocapsular division of the central nucleus of the amygdala
in brain slices from arthritic rats compared with normal controls,
further suggesting an interplay between CGRP and the
glutamatergic system.17
.............
Conflict of Interest: Dr. Tepper has received grants and research support from Allergan, Alexza,
ANS/Advanced Bionics, AstraZeneca, Eisai, Endo, Forrest, GSK, King, MAP, Merck,
Medtronix, Minster, Neurochem, NMT, Novartis, Nupathe, OrthoMcNeil, Pfizer, Pozen, Pro-
ethic, Takeda, Winston, and Vernalis; has been a consultant for Allergan, AstraZeneca, Coherex,
Elan, Endo, Forrest, GSK, Merck, NMT, OrthoMcNeil, and Vernalis; has been on the speakers
bureau of Allergan, AstraZeneca, Endo, GSK, Merck, NMT, OrthoMcNeil, Pfizer, and Valeant;
and is on the advisory boards of GSK and Merck. Dr. Stillman has received grants and research
support from GSK and MAP; is on the speakers bureau of Allergan, GSK, Merck, OrthoMcNeil,
Pfizer, and Valeant; and is on the advisory boards of GSK and Pfizer.

1260 | Headache | September 2008
Calcitonin gene-related peptide is present in some brainstem
aminergic nuclei implicated in migraine, including the periaque-
ductal grey and dorsal raphe area of the upper brainstem, believed
to be another possible candidate for the generator of
migraine.18,19 CGRP is found in the trigeminal ganglion, the
activation of which causes CGRP release from perivascular nerve
endings at the peripheral nociceptor level. CGRP is an important
mediator of neurogenic inflammation via vasodilation and mast
cell degranulation, and to a lesser extent, plasma extravasation in
the meninges.
PRECLINICAL WORK ON CGRP
CGRP is a 37 amino acid neuropeptide expressed in subsets of
peripheral and central nervous system neurons. It was first
described in 1982 by Amara and colleagues, who discovered it
when alternative processing of RNA transcripts from the calcito-
nin gene was shown to result in the production of distinct
mRNAs encoding CGRP.20,21 CGRP and its peptide family
members mediate their physiological effects through heteromeric
receptors composed of a G protein-coupled receptor and a recep-
tor activity-modifying protein, or RAMP. Specifically, dimeriza-
tion of calcitonin receptor-like receptor (CLR) with RAMP1
produces a CGRP receptor.22
CONTROVERSY ON CGRP IN THE EXTERNAL
JUGULAR DURING MIGRAINE
Goadsby and colleagues reported elevation of CGRP levels in
external jugular blood in 7 of 9 patients with trigeminal neuralgia
treated with thermocoagulation. A parallel experiment in cat also
found CGRP elevations following electrical stimulation of the
trigeminal ganglion.23
However, Tvedskov and colleagues could not replicate similar
elevations of CGRP levels in human external jugular during
migraine in their 2005 study, and they suggested several reasons
for the discrepancy. They considered possible confounding
factors such as physical exertion, stress, and previous opiate use in
Goadsby et al’s earlier study, which was conducted in the pre-
triptan era. In laboratory models, opiates have been found to
induce the release of CGRP from rat dorsal rat ganglia.24
The preponderance of evidence, though, continues to suggest
that the CGRP elevation is not spurious, and is related to migrain-
ous processes. Zagami and colleagues reported in 1990 that stimu-
lation of cat superior sagittal sinus (SSS) resulted in elevation of
CGRP levels in external jugular by 85%, suggesting that activation
of the trigeminovascular system, by selective stimulation of noci-
ceptive craniovascular afferents, caused release of CGRP.25 In
another experiment, the same laboratory sampled human external
jugular blood ipsilateral to the side of migraine ictally and found
marked elevations of CGRP.26
In a more recent set of studies, Goadsby and Edvinsson
studied the effects of dihydroergotamine (DHE) and the triptans
Headache Currents
sumatriptan, zolmitriptan, and avitriptan on CGRP levels in
cats. Stimulation of trigeminal ganglion led to a significant
CGRP release into the cranial circulation, which was markedly
antagonized by both sumatriptan and DHE.27 These results
merely spawned greater controversy, and other labs have ques-
tioned the conclusions. Tvedskov et al drew attention to the fact
that open-label investigation of migraine patients described the
levels of CGRP in patients with migraine attacks lasting up to 3.5
weeks, and external jugular CGRP levels could not be correlated
specifically to a discrete migraine attack. Goadsby and Edvins-
son’s findings, however, demonstrated a reduction in jugular
CGRP levels after sumatriptan administration.24,27
In their 1994 Wolff Award study, Goadsby and Edvinsson
described the stimulation of cat trigeminal ganglion, leading to
increased CGRP in the external jugular vein blood, and its
attenuation by administration of intravenous (IV) zolmitriptan.28
This concurred with a previous study from 1999, in which these
researchers stimulated cat SSS, resulting in increased CGRP
levels in external jugular vein. Avitriptan IV blocked this CGRP
release in the cat.29 When they restudied human patients during
migraine, elevated CGRP returned to normal in 7 of 8 migraine
patients who responded to subcutaneous sumatriptan.27
FURTHER EVIDENCE FOR CGRP IN ANIMAL
MODELS AND MIGRAINE
Using an in vitro trigeminal ganglion neuronal model, Durham
and Russo reported a large increase in CGRP release when neurons
were exposed to KCl, and exposure to capsaicin, which stimulates
trigeminal sensory fibers, also caused marked CGRP release. The
group then dosed the neurons with an inflammatory cocktail, in
an attempt to mimic neurogenic inflammation, which resulted in
augmented CGRP release, at least as large as that produced by KCl
or capsaicin. These researchers concluded that trigeminal ganglia
neuronal release of CGRP under conditions mimicking neuro-
genic inflammation is consistent with a role for CGRP in
migraine. In a third part to the experiment, Durham and Russo
reported that after trigeminal sensory neurons were stimulated
with KCl or inflammatory cocktail, sumatriptan inhibited the
release of CGRP, providing a link to migraine treatment.4,30
Gallai et al measured ictal and interictal levels of CGRP in the
plasma of 30 young migraine patients with aura (MA) and 45
migraine patients without aura (MO) and compared the results
with those of 30 age-matched controls. An elevation of CGRP
levels in plasma was found during attacks in MA and, to
a lesser extent, in MO (P < .03 and P < .05, respectively), once
again suggesting a role for CGRP in migraine attacks, at least in
juvenile migraine patients.31
Lassen et al described the effect of injecting CGRP into
humans in a double-blind, placebo-controlled, crossover study.
Intravenous CGRP was given to 10 migraine patients over 20
minutes and caused headache in virtually all migraine sufferers,
whereas placebo did not. The headache occurred during the
 Headache Currents
1261 | Headache | September 2008

infusion and disappeared or diminished after infusion stopped. might sensitize susceptible migrainous individuals to the action
After a median of 5 hours, there was a delayed, stronger head- of CGRP.39
ache, with most of the characteristics of migraine in 9 subjects,
while the headaches in 3 met strict IHS criteria for MO. CGRP
appeared to have caused migraine-like headaches in a delayed LOCATION OF CGRP RECEPTORS AND
fashion in these migraineurs.32 Furthermore, IV CGRP caused CLINICAL EFFECTS
only mild, non-migraine headache in non-migraineurs.33 Location of CGRP receptors along nociceptive pathways:
In a very similar fashion, migraineurs treated with nitroglyc- agonist, antagonist, and modulatory effects
erin (NTG) also develop an initial headache and then a delayed CGRP receptors are localized in virtually every one of the brain-
headache meeting criteria for MO. Juhasz and colleagues studied stem nuclei implicated in migraine genesis or processing. In
15 women with MO and 8 controls administered 0.5 mg of experiments described below, Storer and Goadsby found that
sublingual NTG. Plasma CGRP concentrations did not change iontophoresis of triptans, ergots, and CGRP receptor antagonists
during the immediate headaches and in the subjects without on the trigeminocervical complex inhibited spontaneous and
delayed migraine attacks. Plasma CGRP concentration increased evoked firing of that region central to migraine pathophysiol-
significantly (P < .01) during the delayed migraine attacks and ogy.40,41 In rats, Ma and colleagues found the anatomical distri-
returned to baseline after the attacks stopped. In addition, both bution of CGRP receptor component protein (RCP)
the change and peaks showed significant positive correlations immunoreactivity widely and selectively distributed in the cere-
with migraine headache intensity (P < .001).34 bral cortex, septal nuclei, hippocampus, various hypothalamic
The synthesis of CGRP involves a complex CGRP promoter nuclei, amygdala, nucleus colliculus, periaqueductal gray (PAG),
with multiple sites that regulate and enhance the process. For parabrachial nuclei, locus coeruleus (LC), cochlear nuclei, dorsal
example, nerve growth factor (NGF) has been shown to stimulate raphe nuclei, solitary tractus nucleus and gracile nucleus, cerebellar
CGRP synthesis by activating enhancer elements. Durham and cortex, various brainstem motor nuclei, spinal dorsal and ventral
Russo demonstrated that sumatriptan suppressed NGF- and horns, and in dorsal root ganglia and trigeminal ganglia.14
MAPK-stimulated CGRP promoter activity in rat trigeminal Although RCP is only a component, these data suggest the
ganglion culture, suggesting multiple sites of action for triptans possibility that there are functional CGRP receptors in those
in preventing CGRP effects in models for migraine processes.30 regions, pending demonstrating CLR and RAMP1.
Adding to these in vitro data, Durham and colleagues used
recombinant adenovirus containing rat CGRP promoter to dem-
onstrate CGRP-expressing neurons. Promoter activity was
decreased by sumatriptan, eletriptan, and rizatriptan (see figure
below [figure 3]).4,35
Investigating the potential role of botulinum neurotoxin, type
A in preventing chronic daily headache or frequent episodic
migraine,36,37 Durham and colleagues demonstrated that botuli-
num neurotoxin type A inhibited release of CGRP from rat
trigeminal cultures stimulated with KCl or capsaicin. They
speculated that the possible prophylactic efficacy of botulinum
toxin type A, like the acute efficacy of triptans, may be partly
attributed to the toxin’s inhibitory effect on release of CGRP
from trigeminal neurons.38
Zhang and colleagues demonstrated that activation of CGRP
receptors on cultured trigeminal ganglion neurons increased
CGRP mRNA levels and CGRP promoter activity. The pro-
moter activation was cAMP dependent, and gene transfer using
an adenoviral hRAMP1 expression vector increased production
of cAMP. To establish whether RAMP1 was limiting in vivo, a
transgenic mouse expressing hRAMP1 in the nervous system was
generated. After CGRP injection into the whisker pad, the
hRAMP1 transgenic mice displayed 2.2-fold greater plasma
extravasation, a measure of neurogenic inflammation. The
authors speculated that, as the rate-limiting step for CGRP
receptor activity in trigeminal neurons, elevated RAMP1 activity

1262 | Headache | September 2008
With respect to the role of CGRP, further evidence for the
importance of the PAG in pain processing was demonstrated by
Yu et al. They noted that rat hindlimb withdrawal latencies to
thermal and mechanical stimulation increased significantly after
intra-PAG administration of CGRP. The anti-nociceptive effects
induced by CGRP were significantly blocked by intra-PAG
administration of the CGRP receptor antagonist CGRP8-37.42 The
aforementioned studies by Durham and colleagues on CGRP
synthesis, release, and the inhibition of both in rat trigeminal
ganglia culture by triptans and botulinum neurotoxin type A,
suggest that CGRP clinical effects involve the trigeminal gan-
glion as well.30,35,38,43 If confirmed, CGRP may be active in all the
areas of the central nervous system thought to be involved in the
induction, propagation, and modulation of migraine headaches,
italicized above: cortex, PAG, LC, dorsal raphe, spinal dorsal
horn, and root ganglia.
RELIEF OF MIGRAINE
Relief of migraine corresponds to reduction of blood CGRP.
Migraine pharmacotherapies decrease CGRP release, concentra-
tions, transcription, and promoter activity. Anti-migraine medi-
cations tested include sumatriptan, rizatriptan, eletriptan, and
botulinum neurotoxin type A. CGRP release in the meninges
results in vasodilation and plasma extravasation, which may con-
tribute to the peripheral pain mechanisms of migraine, although
subsequent studies suggest that CGRP effects in migraine are also
central (see pp. 20-21).
As noted above, the controversy about whether CGRP is
increased during migraine in human external jugular, and
whether triptans reduce CGRP as part of their mechanism of
action was addressed by Tvedskov et al who felt that the blood-
brain barrier may prevent intracerebral CGRP from entering the
venous circulation of the brain.24 They also felt that the experi-
mental construct in laboratory animals, published by Goadsby
and Edvinsson,27 may have spuriously induced systemic CGRP
elevation in stressed animals. However, given that CGRP recep-
tor antagonists work clinically, as described below, the likelihood
is that these antagonists work at one or more of the sites in which
CGRP release, binding, and effects play a role in migraine.
In the work of Zhang et al, the CGRP promoter activation
shown to be cAMP dependent was blocked by olcegepant, a
CGRP receptor antagonist described below. Russo, summarizing
the preclinical work on CGRP, suggested that CGRP, its receptor
and RAMP1, the modifying protein necessary to bind CGRP to
its receptor, be considered as candidate genes for migraine suscep-
tibility.39 On the basis of Tvedskov et al’s failure to demonstrate
elevation of CGRP during migraine attacks,24 the fact that IV
CGRP triggers delayed migraines in migraineurs and only mild
headaches in non-migraineurs,24 in addition to a few other dis-
crepancies in animal models, Russo speculated that migraineurs
may be sensitized to the actions of CGRP through increased
receptor activity.44
Headache Currents
Several lines of evidence suggest that RAMP1 is pivotal in
migraine: (1) The overexpression of RAMP1 in transgenic mice
resulted in doubling CGRP-induced plasma extravasation, a
manifestation of neurogenic inflammation; (2) Increased RAMP
increased auto-activation of CGRP synthesis, which might
explain the time delay in CGRP-induced migraine;28 (3) Elevated
RAMP1 can sensitize the trigeminal ganglion and potentially
sustain and intensify the nociceptive actions of CGRP in
migraine.44
THE CGRP RECEPTOR ANTAGONISTS
The search for a CGRP receptor antagonist began with the
synthesis of 2 short peptides, a and bCGRP8-37, each containing
all but the first 7 amino acids of CGRP. These antagonists have
been extensively studied .45,46 Studies using CGRP8-37 have also
helped in elucidating CGRP effects in causing vasodilation and
neurogenic inflammation in animals.3,21,47 Although useful for
research, CGRP8-37 was not clinically effective, due to short half-
life and low in vivo potency.48
Rudolph, Doods, and colleagues in Germany used high
throughput screening to find small molecule CGRP receptor
antagonists, and number 19, first called BIBN4096, and later
named olcegepant, was selected for clinical trials. Olcegepant
inhibited the effects of CGRP released by stimulation of the
trigeminal ganglion on facial blood flow in marmoset mon-
keys.49,50 Olcegepant is a large hydrophilic molecule, and a ques-
tion on its location of action was raised. Edvinsson felt that it was
not likely to pass the blood-brain barrier, but this has been
challenged. Olcegepant has a high affinity for the clinically
important CGRP receptor. Its half-life is 2.5 hours, and 15% of
the drug appears in urine.51
In an early trial fully published on olcegepant
in healthy volunteers, the drug was administered at varying IV
doses in a single-center, double-blind (within dose levels),
placebo-controlled, randomized, single-rising dose design, and
41 received olcegepant, 14 placebo. Sixteen adverse events were
seen in 8 of the 41 subjects treated with olcegepant, compared
with adverse events in 4/14 treated with placebo. Two-thirds of
the adverse events occurred at the highest dose, 10 mg. All of the
adverse events at 10 mg were in 3 women treated with olcege-
pant. A statistically significant increase in standing systolic blood
pressure of 3 mmHg was seen compared with placebo, which
showed a drop of blood pressure at 10 mmHg; this was not
considered clinically meaningful. The most common adverse
events were transient and mild paresthesias, including flushing,
feeling of facial warmth, head and body crawling sensations,
numb and cold feelings in hand and forearm infusion site, stab-
bing in throat and head, and congestion in the head. “No clini-
cally relevant” drug-induced changes in blood pressure, pulse
rate, respiratory rate, EKG, lab tests, or forearm blood flow” were
seen.52

1263 | Headache | September 2008
In another early trial of olcegepant, 10 participants in a double-
blind placebo-controlled crossover study received either olcege-
pant 2.5 mg IV or placebo as pretreatment. Then, they were given
h-aCGRP. Six of 10 placebo subjects, and none of the olcegepant
patients, experienced an h-aCGRP-induced headache. The
researchers concluded that olcegepant effectively prevented
CGRP-induced headache and extracerebral vasodilation, but did
not significantly affect induced cerebral hemodynamic changes.33
As noted above, Storer and Goadsby used the model of SSS
stimulation to activate cat trigeminocervical pathways critical to
migraine pathophysiology. In a study published in 1997, anti-
migraine medications such as ergotamine, sumatriptan, and
zolmitriptan iontophoresed onto this region inhibited evoked
and spontaneous firing.40 The team then demonstrated that cell
firing was increased by microiontophoresis of L-glutamate into
the same region, and microiontophoresis of CGRP excited 7/17
tested neurons. Olcegepant inhibited the majority of units acti-
vated by L-glutamate, demonstrating a non-presynaptic site of
action for CGRP. CGRP8-37 inhibited a similar proportion of
cells. Using the SSS stimulation model to activate the nociceptive
pathways, IV olcegepant also resulted in inhibition of trigemi-
nocervical activity.41 These studies are critical in understanding
central effects of both CGRP and their receptor antagonists.
The large phase IIB trial on IV olcegepant was published in the
New England Journal of Medicine in 2004. This was an interna-
tional, multicenter, double-blind, randomized proof of concept
clinical trial in which 126 migraine patients received placebo or
one of 6 doses of olcegepant IV at 16 centers in Denmark,
Germany, Netherlands, and the UK from February to December
1999.
Inclusion criteria were ages 18-65, IHS diagnosis of migraine
for at least 1 year, 1-6 migraines per month, and prophylaxis was
excluded. A total of 127 patients were randomized, and 126
received medication. Patients were required to present for treat-
ment with worsening migraine of 6 or less hours duration, and
they received IV infusion of placebo or olcegepant. The primary
end point was headache response or relief 2 hours after treatment.
Secondary end points included response at other time points,
headache-free rates, rates of sustained response over 24 hours,
relief of associated symptoms, time to meaningful relief, degree of
clinical disability, use of rescue medication, and frequency and
types of adverse events.
The study used a “group-sequential adaptive treatment-
assignment design.” This involved an up-and-down dosing
process designed to minimize the number of patients exposed.
Groups of 6 received olcegepant or placebo, starting with 1-mg
olcepepant. If 3/4 in the active group responded, the dose was
reduced; otherwise, the dose was increased. The optimal dose was
established when there was response in ⱖ4 groups in ⱖ3/4
treated and ⱖ20 were treated with the selected dose, while at
least 18 had been treated with placebo. The best dose found using
this novel method was 2.5-mg IV olcegepant.
Headache Currents
Headache response was 66% (21/32) for the 2.5-mg dose vs
27% (11/41) for placebo (P = .001). Statistical separation from
placebo for headache response was first seen at 30 minutes with
doses from 2.5 to 10 mg, and was still increasing at 1, 2, and 4
hours.
Pain-free response rate from 2.5-mg olcegepant was 44% at 2
hours and 56% at 4 hours (placebo pain-free responses were 2%
and 10%). Sustained response rate was 47% (placebo 15%).
Nausea, phonophobia, and photophobia all improved in parallel
with pain response. Rate of recurrence was 19% (placebo 46%).
Adverse event rate was 20% for the olcegepant group and 12%
in the placebo group. The most common adverse event was mild
paresthesias, seen in 7 patients (8%) who received active drug,
none on placebo. Nausea occurred in 2% of both active and
treatment groups. Headache, dry mouth, and “abnormal vision”
occurred in 2% of the olcegepant group, but none with placebo.
Thus, proof of concept for a CGRP receptor antagonist in epi-
sodic migraine was established.53
A second CGRP receptor antagonist has also been tested in
phase I-III trials in oral formulation. At the time of this writing,
the Phase III data were presented only in a platform presentation
and are not published. The medication, telcagepant, was given in
a rhesus dermal vasodilation assay, which relies on the CGRP-
mediated response to topically applied capsaicin as a pharmaco-
dynamic measure, and the new drug inhibited the capsaicin-
induced dermal perfusion.21,54
Telcagepant was administered in phase I studies to 330 human
subjects as of 2007. No drug-related serious adverse experiences
have been reported; all nonserious clinical adverse experiences
were transient and mild or moderate in intensity. There was no
reported adverse event frequency dose response curve, and no
significant effect of gender or age.55
Another phase I study on telcagepant has also been reported in
abstract form, a 3-period crossover design in 12 healthy males
receiving telcagepant 300 mg, 800 mg, or placebo, followed by 2
topical doses of 300 and 1000 mg liquid capsaicin to the forearms
30 minutes and 3.5 hours post-dosing. As in the animal model,
both doses inhibited capsaicin-induced dermal microvascular
blood flow, establishing that the drug works in both primates and
humans using this model.56
The same group also evaluated telcagepant in a phase I ran-
domized, double-blind, placebo-controlled, 2-period fixed
sequence study in 23 otherwise healthy migraineurs to establish
the effect of reduced gastric motility on pharmacokinetic param-
eters. Once again, the data are only available in abstract form at
the time of writing. Fifteen patients received 300 mg of tel-
cagepant in both treatment periods, and 8 received placebo. In
the first period, patients received study drug in a research unit
within approximately 2 hours of the onset of a moderate to severe
migraine attack, but at least 4 hours after their last meal. In the
second period, patients received study drug in-house after at least
a 4 hour fast, at a similar time of day to their Period I dosing
 Headache Currents
1264 | Headache | September 2008

time. Telcagepant pharmacokinetics were generally similar. No
serious adverse experiences occurred in either period, and the
drug was generally well tolerated.57
The phase II trial of telcagepant was a computer simulation
adaptive design. The study was a randomized, double-blind,
placebo and active-controlled (rizatriptan), parallel-group study,
with a 2-stage adaptive design. A total of 420 patients were
randomized, and 330 patients treated for a migraine were
included in primary and secondary efficacy analyses. The primary
end point was relief of headache at 2 hours after one dose of
telcagepant compared with placebo and the safety and tolerability
of telcagepant in the treatment of acute migraine. Secondary end
points included pain-free response and sustained pain-free
response, the selection of 2 doses for phase III, the establishment
a dose-response curve, and a comparison with the efficacy results
to the active comparator, rizatriptan.
Stage 1 of the trial used 16 patients per active groups and 8
patients per placebo groups to a total of 64. Sixteen patients
received rizatriptan, and there was a rizatriptan placebo group of 8.
In an interim analysis step, the 4 lowest dose telcagepant groups
(25, 50, 100, and 200 mg) were discontinued due to insufficient
efficacy. In stage 2 of the trial, telcagepant groups were equally
randomized to the remaining dose levels, 98 in the active groups,
49 in the placebo group, 34 in the active rizatriptan group, and 17
in the placebo rizatriptan group. The efficacy data are contained in
Table 1.
Once again, as with olcegepant, adverse events with tel-
cagepant as reported in the phase IIB trial were mild (see
Table 2).55,58
A single-randomized, double-blind, phase III clinical trial of
telecagepant was published in abstract form only at the time of
this writing, with data presented orally at the American Head-
ache Society meeting in 2008. Patients treated with oral
telecagepant 150 mg, telecagepant 300 mg, zolmitriptan 5 mg,
or placebo. The primary end points were 2-24 hour sustained
pain free and 2 hour pain relief, pain free, photophobia, phono-
phobia, and nausea. telecagepant 300 mg was significantly more
effective than placebo on all primary end points. The efficacy of
telecagepant 300 mg was comparable to that of zolmitriptan
5 mg; telecagepant 150 mg was slightly less effective than both
telecagepant 300 mg and zolmitriptan 5 mg. The actual efficacy
numbers were not published in the abstract.
Both doses of telecagepant were generally well tolerated. For
telecagepant 150 mg, 300 mg, zolmitriptan 5 mg and placebo,
respectively, the overall rates of adverse events were 31.4%,
37.2%, 50.7%, and 32.1%; the rates of drug-related adverse
events were 21%, 24.7%, 40.9%, and 18.6%. There were no
serious adverse events, but the actual adverse events were not
published in the abstract.60-62
Two other important abstracts on telecagepant were presented
at the American Headache Society meeting in 2008, both sug-
gesting safety for telecagepant. One study abstracted assessed the

Table 1.—Phase IIB Telcagepant Efficacy58

Telcagepant Telcagepant Telcagepant Rizatriptan

300 mg 400 mg 600 mg 10 mg Placebo
2-hour pain relief 68.1* 48.2* 67.5* 69.5 46.3
2-hour pain free 45.2** 24.3** 32.1** 33.4 14.3
24-hour sustained pain relief 52.6** 37.8** 52.5** 35.3 23.5
24-hour sustained pain free 39.6** 22.0** 32.0** 18.4 11.0
*P = .015, **P < .001; Comparison of mean response rate of 300, 400, and 600 mg doses to the placebo.

Table 2.—Adverse Events (AEs) from Phase IIB, Telcagepant58,59

MK-0974 300 mg MK-0974 400 mg MK-0974 600 mg Rizatriptan 10 mg

Placebo (N = 47) (N = 51) (N = 52) (N = 49) (N = 50)
Any AEs 17 (36.2%) 18 (35.3%) 19 (36.5%) 20 (40.8%) 21 (42.0%)
Any drug-related AEs 11 (23.4%) 13 (25.5%) 14 (26.9%) 12 (24.5%) 14 (28.0%)
Common AEs
Dry mouth 1 2 2 1 1
Nausea 6 3 4 5 1
Fatigue 0 0 1 1 2
Dizziness 2 3 1 4 1
Somnolence 0 2 1 4 2
Paresthesia 0 0 0 1 2

1265 | Headache | September 2008
effect of telcagepant on 28 patients with stable coronary artery
disease (CAD) who received two double-blind doses of 300 mg 2
hours apart or placebo, with a minimum 5-day washout between
periods. The investigators collected clinical and lab evaluations,
and spontaneous ischemic events quantified using continuous
high-fidelity digital 12-lead EKG monitoring during each treat-
ment period and analyzed in a blinded eEKG core lab. Each
patient was his own control. Ischemic ST events occurred in 2
patients during placebo and in one following telecagepant. No
one experience a serious adverse event. There was no chest pain
from drug or placebo. The conclusion was that telecagepant did
not exacerbate spontaneous ischemia.63
The second study abstracted the effect of telecagepant on the
hemodynamic responses to sublingual nitroglycerin (NTG) of
22 healthy males.64 The subjects received a single dose of
telecagepant 500 mg or placebo, followed in 90 minutes by
0.4 mg sublingual NTG. Central augmentation index (Aix), a
measure of arterial stiffness and brachial artery diameter (BAD),
was measured at multiple times post doses, and there was no
alteration in NTG effects, specifically in its vasdodilatory
response. This suggests that vasodilation mediated by nitric oxide
is unlikely to be affected by CGRP-receptor blockade.
CLINICAL IMPLICATIONS FOR A CGRP
RECEPTOR ANTAGONIST
Given the positive phase II trials on 2 different CGRP receptor
antagonists, the orally reported phase III data on one of them,
and their excellent tolerability, the possibility of a new class of
specific anti-migraine medications become a reality. This pros-
pect necessitates a few thoughts on the clinical potential for this
class if the efficacy approaches or exceeds that of the triptans, and
the drugs have clinically acceptable adverse effect profiles. Trip-
tans are contraindicated clinically in patients with vascular
disease. CGRP receptor antagonists do not appear to exhibit the
vasoconstrictive properties seen with the triptan class and may
have no contraindications with this important group of patients.
Taken in their entirety, it is possible that the clinical effects of
telcagepant are primarily central rather than peripheral. That is,
although CGRP antagonists block vasodilation, it appears from
several converging pieces of evidence that the central blockade of
CGRP is necessary for clinical effect:
1. CGRP by itself is not sufficient to excite or sensitize
meningeal nociceptors in rats.65 If the primary effect of
CGRP is meningeal vasodilation, why are these nocice-
ptors not activated?
2. Trigeminocervical complex activation initiated by
glutamate and SSS stimulation can be blocked by microi-
ontophoretic application of olcegepant onto neurons of
this region, demonstrating a non-presynaptic site of
action for CGRP, ie, central.41
Headache Currents
3. Intravenous olcegepant but not local peripheral CGRP
blockade inhibits postsynaptic nociceptive trigeminal
transmission in the rat spinal trigeminal nucleus.66
4. Finally, and most importantly, the effective dose of tel-
cagepant suggests central action. That is, small dosages
sufficient to block peripheral CGRP receptors did not
work clinically, while larger, presumably central penetrant
dosages did work. The Ki of telcagepant = 0.8 nM in a
I125-CGRP binding assay, and the IC50 = 2 nM in a
cAMP functional assay for telcagepant, which has 94%
protein binding. The optimal clinical dose for telcagepant
appears to be 300 mg, establishing a Cmax of ~3-5 mM.
This dose is markedly higher than would be needed for
peripheral, meningeal effects.54,58 This establishment of
central mechanisms of action raises the prospect of using
CGRP receptor antagonists in other pain syndromes.
Could a CGRP antagonist work in other primary headaches in
which CGRP levels are elevated? Goadsby and colleagues first
described CGRP elevation in cluster in 1994,67 and Fanciullacci
et al confirmed this by demonstrating an increase in CGRP from
the extracerebral circulation during NTG-induced cluster head-
ache attacks, also suggesting cluster as a potential target.68
Goadsby and Edvinsson also showed increase in CGRP in par-
oxysmal hemicrania, and CGRP may play an important role in
the genesis of the trigeminal autonomic cephalalgias.69,70
Other disease states associated with elevated levels of CGRP
include hypertension,71 sepsis,72 TMD disorders,73,74 periodontal
disease,75 and eye conditions following laser or ocular surgery or
trauma.76 In addition, there are alterations in RAMP1 genes in
hypoxia and preecclampsia.44,77 It is tempting to speculate what
effect a CGRP receptor antagonist might have on other pain
syndromes mediated by the trigeminovascular system, where
CGRP receptors are numerous, and on other neurovascular pain
syndromes where CGRP is released.
CONCLUSIONS
Calcitonin gene-related peptide is involved in the genesis of
migraine and other primary headache disorders. It is found in
every location described in migraine propagation and processing,
including the meninges, trigeminal ganglion, trigeminocervical
complex, ascending brainstem aminergic nuclei, and cortex.
CGRP is released in animal models following stimulation of the
CNS similar to that seen in migraine, and triptans inhibit its
release. Injection of CGRP into migraineurs results in delayed
headache similar to migraine. Multiple studies show elevation of
CGRP during migraine, resolving following migraine-specific
treatment. Finally, and most importantly, CGRP receptor antago-
nists terminate migraine with efficacy similar to triptans. Both
olcegepant, a potent IV CGRP antagonist, and oral telcagepant

1266 | Headache | September 2008
are effective, safe, and well tolerated in phase I and II studies. At
the time of writing, telcagepant is in phase III trials, but prelimi-
nary results are favorable.
The potential for a migraine-specific medication without vaso-
constrictive or vascular side effects is enormous. CGRP receptor
blockade may also have applications in other pathologic and pain
syndromes.
Acknowledgments: The authors would like to thank Dr. Paul
Durham for his review of and suggestions for this manuscript prior to
submission and to Dr. Nabih Ramadan for his erudite teaching and
editing.
References
1. Dodick DW. Brainstem dysfunction in chronic migraine as evi-
denced by neurophysiological and positron emission tomography
(PET) studies – an editorial comment. Headache. 2007;47:1004-
1007.
2. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neu-
rosci. 2003;4:386-398.
3. Durham PL. CGRP receptor antagonists – a fresh approach to
migraine therapy? N Engl J Med. 2004;350:1073-1074.
4. Durham PL. Emerging neural theories of migraine pathogenesis:
Calcitonin gene-related peptide (CGRP) and migraine. Headache.
2006;46(Suppl. 1):S3-S8.
5. Michelangeli VP, Findlay DM, Fletcher A, Martin TJ. Calcitonin
gene-related peptide (CGRP) acts independently of calcitonin on
cyclic AMP formation in clonal osteogenic sarcoma cells (UMR
106-01). Calcif Tissue Int. 1986;39:44-48.
6. Fiscus RR, Zhou HL, Wang X, et al. Calcitonin gene-related
peptide (CGRP)-induced cyclic AMP, cyclic GMP and vasorelaxant
responses in rat thoracic aorta are antagonized by blockers of
endothelium-derived relaxant factor (EDRF). Neuropeptides.
1991;20:133-143.
7. Wang X, Han C, Fiscus RR. Calcitonin gene-related peptide
(CGRP) causes endothelium-dependent cyclic AMP, cyclic GMP
and vasorelaxant responses in rat abdominal aorta. Neuropeptides.
1991;20:115-124.
8. Raymond LA, Tingley WG, Blackstone CD, Roche KW, Huganir
RL. Glutamate receptor modulation by protein phosphorylation. J
Physiol Paris. 1994;88:181-192.
9. Hatt H. Modification of glutamate receptor channels: Molecular
mechanisms and functional consequences. Naturwissenschaften.
1999;86:177-186.
10. Swope SL, Moss SJ, Raymond LA, Huganir RL. Regulation of
ligand-gated ion channels by protein phosphorylation. Adv Second
Messenger Phosphoprotein Res. 1999;33:49-78.
11. Sexton PM, McKenzie JS, Mason RT, Moseley JM, Martin TJ,
Mendelsohn FA. Localization of binding sites for calcitonin gene-
related peptide in rat brain by in vitro autoradiography. Neuro-
science. 1986;19:1235-1245.
12. Kawai Y, Takami K, Shiosaka S, et al. Topographic localization of
calcitonin gene-related peptide in the rat brain: An immunohis-
tochemical analysis. Neuroscience. 1985;15:747-763.
Headache Currents
13. Oliver KR, Wainwright A, Kinsey AM, Heavens RP, Sirinathsinghji
DJ, Hill RG. Regional and cellular localization of calcitonin
gene-related peptide-receptor component protein mRNA in the
guinea-pig central nervous system. Brain Res Mol Brain Res.
1999;66:205-210.
14. Ma W, Chabot JG, Powell KJ, Jhamandas K, Dickerson IM, Quirion
R. Localization and modulation of calcitonin gene-related peptide-
receptor component protein-immunoreactive cells in the rat central
and peripheral nervous systems. Neuroscience. 2003;120:677-694.
15. Ramadan NM, Buchanan TM. New and future migraine therapy.
Pharmacol Ther. 2006;112:199-212.
16. Buldyrev I, Tanner NM, Hsieh H, Dodd EG, Nguyen LT, Balkow-
iec A. Calcitonin gene-related peptide enhances release of native
brain-derived neurotrophic factor from trigeminal ganglion
neurons. J Neurochem. 2006;99:1338-1350.
17. Han JS, Li W, Neugebauer V. Critical role of calcitonin gene-
related peptide 1 receptors in the amygdala in synaptic plasticity
and pain behavior. J Neurosci. 2005;25:10717-10728.
18. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from
perturbation of brain. Headache 1987;27:416-420.
19. Weiller C, May A, Limmroth V, et al. Brain stem activation in
spontaneous human migraine attacks. Nat Med. 1995;1:658-660.
20. Amara SG, Jonaas V, Jonas V, Rosenfeld MG, Ong ES, Evans RM.
Alternative RNA processing in calcitonin gene expression generates
mRNAs encoding different polypeptide products. Nature.
1982;298:240-244.
21. Brain SD. Calcitonin gene-related peptide (CGRP) antagonists:
Blockers of neuronal transmission in migraine. Br J Pharmacol.
2004;142:1053-1054.
22. Kane SA, Salvatore CA, Hershey JC, et al. Profile of MK-0974, the
first orally bioavailable CGRP receptor antagonist. Headache.
2007;47:812 (abstract).
23. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides
in the extracerebral circulation of humans and the cat during acti-
vation of the trigeminovascular system. Ann Neurol. 1988;23:
193-196.
24. Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J.
No increase of calcitonin gene-related peptide in jugular blood
during migraine. Ann Neurol. 2005;58:561-568.
25. Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior
sagittal sinus in the cat causes release of vasoactive peptides. Neu-
ropeptides. 1990;16:69-75.
26. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in
the extracerebral circulation of humans during migraine headache.
Ann Neurol. 1990;28:183-187.
27. Goadsby PJ, Edvinsson L. The trigeminovascular system and
migraine: Studies characterizing cerebrovascular and neuropeptide
changes seen in humans and cats. Ann Neurol. 1993;33:48-56.
28. Goadsby PJ, Edvinsson L. Joint 1994 Wolff Award Presentation.
Peripheral and central trigeminovascular activation in cat is blocked
by the serotonin (5HT)-1D receptor agonist 311C90. Headache.
1994;34:394-399.
29. Knight YE, Edvinsson L, Goadsby PJ. Blockade of calcitonin gene-
related peptide release after superior sagittal sinus stimulation in
cat: A comparison of avitriptan and CP122,288. Neuropeptides.
1999;33:41-46.

1267 | Headache | September 2008
30. Durham PL, Russo AF. Regulation of calcitonin gene-related
peptide secretion by a serotonergic antimigraine drug. J Neurosci.
1999;19:3423-3429.
31. Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptide levels in
the plasma of young migraine patients with and without aura
assessed both interictally and ictally. Cephalalgia. 1995;15:384-390.
32. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B,
Olesen J. CGRP may play a causative role in migraine. Cephalalgia.
2002;22:54-61.
33. Petersen KA, Birk S, Lassen LH, et al. The CGRP-antagonist,
BIBN4096BS does not affect cerebral or systemic haemodynamics
in healthy volunteers. Cephalalgia. 2005;25:139-147.
34. Juhasz G, Zsombok T, Modos EA, et al. O-induced migraine
attack: Strong increase in plasma calcitonin gene-related peptide
(CGRP) concentration and negative correlation with platelet sero-
tonin release. Pain. 2003;106:461-470.
35. Durham PL, Dong PX, Belasco KT, et al. Neuronal expression and
regulation of CGRP promoter activity following viral gene transfer
into cultured trigeminal ganglia neurons. Brain Res. 2004;997:103-
110.
36. Silberstein SD, Mauskop A, Dodick DW, et al. Program to assess
headache treatment strategies: An observational study of botulinum
toxin type A in the preventive treatment of headache. Headache.
2006;46:846-847 (abstract).
37. Silberstein SD, Mauskop A, Dodick DW, et al. Predictors of out-
comes with botulinum toxin type A in the preventive treatment of
headache. Cephalalgia. 2006;26:1371 (abstract).
38. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related
peptide secretion from trigeminal nerve cells by botulinum toxin
type A: Implications for migraine therapy. Headache. 2004;44:35-
43.
39. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. Sensitiza-
tion of calcitonin gene-related peptide receptors by receptor
activity-modifying protein-1 in the trigeminal ganglion. J Neuro-
science. 2007;27:2693-2703.
40. Storer RJ, Goadsby PJ. Microiontophoretic application of serotonin
(5HT)1B/1D agonists inhibits trigeminal cell firing in the cat.
Brain. 1997;120:2171-2177.
41. Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide
(CGRP) modulates nociceptive trigeminovascular transmission in
the cat. Br J Pharmacol. 2004;142:1171-1181.
42. Yu LC, Weng XH, Wang JW, Lundeberg T. Involvement of calci-
tonin gene-related peptide and its receptor in anti-nociception in
the periaqueductal grey of rats. Neurosci Lett. 2003;349:1-4.
43. Durham PL, Russo AF. Stimulation of the calcitonin gene-related
peptide enhancer by mitogen-activated protein kinases and repres-
sion by an antimigraine drug in trigeminal ganglia neurons. J Neu-
rosci. 2003;23:807-815.
44. Russo AF. Ramping it up: RAMP1 and the implications for
migraine. Pharmacogenomics. 2007;8:687-690.
45. Wisskirchen FM, Doyle PM, Gough SL, Harris CJ, Marshall I.
Conformational restraints revealing bioactive b-bend structures for
ha CGRP8-37 at the CGRP2 receptor of the rat prostatic vas defer-
ens. Br J Pharmacol. 1999;126:1163-1170.
46. Wisskirchen FM, Gray DW, Marshall I. Receptors mediating
CGRP-induced relaxation in the rat isolated thoracic aorta and
Headache Currents
porcine isolated coronary artery differentiated by ha CGRP8-37. Br
J Pharmacol. 1999;128:283-292.
47. Escott KJ, Beattie DT, Connor HE, Brain SD. Trigeminal ganglion
stimulation increases facial skin blood flow in the rat: A major role
for calcitonin gene-related peptide. Brain Res. 1995;69:93-99.
48. Longmore J, Hogg JE, Hutson PE, Hill RG. Effects of two trun-
cated forms of human calcitonin-gene related peptide: Implications
for receptor classification. Eur J Pharmacol. 1994;265:53-59.
49. Rudolf K, Eberlein W, Engel W, et al. Development of
human calcitonin gene-related peptide (CGRP) receptor antago-
nists. 1. Potent and selective small molecule CGRP antagonists.
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-
yl) - 1 - piperidinyl]carbonyl] - D - tyrosyl] - L - lysyl] - 4 -(4-pyridinyl)
piperazine: The first CGRP antagonist for clinical trials in acute
migraine. J Med Chem. 2005;48:5921-5931.
50. Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of
BIBN4096BS, the first selective small molecule CGRP antagonist.
Br J Pharmacol. 2000;129:420-423.
51. Edvinsson L. Clinical data on the CGRP antagonist BIBN4096BS
for treatment of migraine attacks. CNS Drug Rev. 2005;11:69-76.
52. Iovino M, Feifel U, Yong CL, Wolters JM, Wallenstein G. Safety,
tolerability and pharmacokinetics of BIBN 4096 BS, the first selec-
tive small molecule calcitonin gene-related peptide receptor antago-
nist, following single intravenous administration in healthy
volunteers. Cephalalgia. 2004;24:645-656.
53. Olesen J, Diener H-C, Husstedt IW, for the BIBN 4096 BS Clini-
cal Proof of Concept Study Group, et al. Calcitonin gene-related
peptide receptor antagonist BIBN 4096 BS for the acute treatment
of migraine. N Engl J Med. 2004;350:1104-1110.
54. Salvatore CA, Hershey JC, Corcoran HA, et al. Pharmacological
characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-
2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1
H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent
and orally active calcitonin gene-related peptide receptor antagonist
for the treatment of migraine. J Pharmacol Exp Ther. 2008;324:416-
421.
55. Fan X (F), Assaid CA, Ho T. An adaptive two-stage design in a
Phase 2 dose-finding trial to treat acute migraine. Neurology.
2007;68(Suppl. 1):A195 (abstract).
56. Sinclair SR, Kane SA, Xiao A, et al. MK-0974 oral CGRP antago-
nist inhibits capsaicin-induced increase in dermal microvascular
blood flow. Neurology. 2007;68(Suppl. 1):A307 (abstract), also in
Headache 2007;47:811 (abstract).
57. Sinclair SR, Boyle JE, de Lepeleire I, et al. MK-0974, a novel oral
CGRP antagonist, exhibits similar pharmacokinetics during and
between migraine attacks. Headache. 2007;47:811-812 (abstract).
58. Ho TW, Mannix LK, Fan X, et al., on behalf of the MK- 0974
Protocol 004 study group. Randomized controlled trial of an oral
CGRP receptor antagonist, MK-0974, in acute treatment of
migraine. Neurology. 2008;70:1304-1312.
59. Ho TW. Platform presentation. American Headache Society
meeting, Chicago, 2007.
60. Ho TW, Ferrari MD, Dodick DW, et al. Antimigraine efficacy and
tolerability of the novel oral CGRP receptor antagonist MK-0974:
A Phase III clinical trial versus placebo and zolmitriptan. Headache.
2008;48:S7-8 (abstract).

1268 | Headache | September 2008
61. Dodick DW, Galet V, Kost J, Assaid C, Ho TW. “Sustained pain
freedom and no adverse events” as an endpoint in clinical trials of
acute migraine treatments: Application to patient-level data from a
trial of the CGRP receptor antagonist, MK-0974, and zolmitriptan.
Headache. 2008;48:S41-42 (abstract).
62. TW H. Platform presentation, American Headache Society meeting.
Boston. 2008.
63. Behm MO, Blanchard RL, Murphy MG, et al. Assessment of the
effect of MK-0974, and oral CGRP receptor antagonist, on spon-
taneous ischemia in patients with stable cardiovascular disease.
Headache. 2008;48:S39.
64. Van dr Schueren BJ, Blanchard R, Murphy MG, et al. Effect of
MK-0974, an oral CGRP antagonist, on the hemodynamic
response to sublingual nitroglycerin. Headache. 2008;48:S63-64.
65. Levy D, Burstein R, Strassman AM. Calcitonin gene-related
peptide does not excite or sensitize meningeal nociceptors: Impli-
cations for the pathophysiology of migraine. Ann Neurol.
2005;58:698-705.
66. Fischer MJ, Koulchitsky S, Messlinger K. The nonpeptide calcito-
nin gene-related peptide receptor antagonist BIBN4096BS lowers
the activity of neurons with meningeal input in the rat spinal
trigeminal nucleus. J Neurosci. 2005;25:5877-5883.
67. Goodsby PJ, Edvinsson L. Human in vivo evidence for trigemi-
novascular activation in cluster headache. Neuropeptide changes
and effects of acute attack therapies. Brain. 1994;117(Pt. 3):427-
434.
Headache Currents
68. Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S.
Increase in plasma calcitonin gene-related peptide from the extrac-
erebral circulation during nitroglycerin-induced cluster headache
attack. Pain. 1995;60:119-123.
69. Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of
chronic paroxysmal hemicrania—evidence for trigemino-
parasympathetic activation. Cephalalgia. 1996;16:448-450.
70. Edvinsson L. A pathophysiological view of primary headaches.
Funct Neurol. 2000;15(Suppl. 3):50-60.
71. Goto K, Miyauchi T, Homma S, Ohshima N. Calcitonin gene-
related peptide in the regulation of cardiac function. Ann N Y Acad
Sci. 1992;657:194-203.
72. Joyce CD, Fiscus RR, Wang X, Dries DJ, Morris RC, Prinz RA.
Calcitonin gene-related peptide levels are elevated in patients with
sepsis. Surgery. 1990;108:1097-1101.
73. Kopp S. Neuroendocrine, immune, and local responses related to
temporomandibular disorders. J Orofac Pain. 2001;15:9-28.
74. Sessle BJ. New insights into peripheral chemical mediators of
temporomandibular pain and inflammation. J Orofac Pain.
2001;15:5.
75. Byers MR. Dynamic plasticity of dental sensory nerve structure and
cytochemistry. Arch Oral Biol. 1994;39(Suppl.):13S-21S.
76. Belmonte C, Acosta MC, Gallar J. Neural basis of sensation in
intact and injured corneas. Exp Eye Res. 2004;78:513-525.
77. Hay DL, Poyner DR, Sexton PM. GPCR modulations by RAMPs.
Pharmacol Ther. 2006;109:173-197.