SEARCH

SEARCH BY CITATION

Keywords:

  • calcitonin-gene related peptide;
  • RAMP1;
  • migraine;
  • BIBN4096;
  • olcegepant;
  • MK-0974;
  • telcagepant

Abstract

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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.

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 reduction 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 transmission. 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 telcagepant suggesting that proof of concept is positive.

PATHOPHYSIOLOGY OF MIGRAINE AND CGRP

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

The genesis of migraine is either in brainstem aminergic nuclei or in the cortex, and is due to firing of hyperexcitable neurons.1,2 Following initiation of migraine, peripheral meningeal pain mechanisms are activated, as neurons release vasoactive, neuroinflammatory 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 activation 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 interaction with the glycine site of the receptor, and excitatory postsynaptic potential (EPSP)-causing ionic influx. This postsynaptic excitability may contribute to the generation, and maintenance, 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 sensitization, 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 receptors. 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

Calcitonin gene-related peptide is present in some brainstem aminergic nuclei implicated in migraine, including the periaqueductal 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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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 calcitonin 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 receptor activity-modifying protein, or RAMP. Specifically, dimerization of calcitonin receptor-like receptor (CLR) with RAMP1 produces a CGRP receptor.22

CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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 migrainous processes. Zagami and colleagues reported in 1990 that stimulation 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 nociceptive 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 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 questioned 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 Edvinsson'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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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 neurogenic 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 infusion and disappeared or diminished after infusion stopped. After a median of 5 hours, there was a delayed, stronger headache, 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 fashion in these migraineurs.32 Furthermore, IV CGRP caused only mild, non-migraine headache in non-migraineurs.33

In a very similar fashion, migraineurs treated with nitroglycerin (NTG) also develop an initial headache and then a delayed headache meeting criteria for MO. Juhasz and colleagues studied 15 women with MO and 8 controls administered 0.5 mg of sublingual NTG. Plasma CGRP concentrations did not change during the immediate headaches and in the subjects without delayed migraine attacks. Plasma CGRP concentration increased significantly (P < .01) during the delayed migraine attacks and returned to baseline after the attacks stopped. In addition, both the change and peaks showed significant positive correlations with migraine headache intensity (P < .001).34

The synthesis of CGRP involves a complex CGRP promoter with multiple sites that regulate and enhance the process. For example, nerve growth factor (NGF) has been shown to stimulate CGRP synthesis by activating enhancer elements. Durham and Russo demonstrated that sumatriptan suppressed NGF- and MAPK-stimulated CGRP promoter activity in rat trigeminal ganglion culture, suggesting multiple sites of action for triptans in preventing CGRP effects in models for migraine processes.30 Adding to these in vitro data, Durham and colleagues used recombinant adenovirus containing rat CGRP promoter to demonstrate 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 botulinum 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 promoter 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 might sensitize susceptible migrainous individuals to the action of CGRP.39

LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

Location of CGRP receptors along nociceptive pathways: agonist, antagonist, and modulatory effects CGRP receptors are localized in virtually every one of the brainstem nuclei implicated in migraine genesis or processing. In experiments described below, Storer and Goadsby found that iontophoresis of triptans, ergots, and CGRP receptor antagonists on the trigeminocervical complex inhibited spontaneous and evoked firing of that region central to migraine pathophysiology.40,41 In rats, Ma and colleagues found the anatomical distribution of CGRP receptor component protein (RCP) immunoreactivity widely and selectively distributed in the cerebral cortex, septal nuclei, hippocampus, various hypothalamic nuclei, amygdala, nucleus colliculus, periaqueductal gray (PAG), parabrachial nuclei, locus coeruleus (LC), cochlear nuclei, dorsal raphe nuclei, solitary tractus nucleus and gracile nucleus, cerebellar cortex, various brainstem motor nuclei, spinal dorsal and ventral horns, and in dorsal root ganglia and trigeminal ganglia.14 Although RCP is only a component, these data suggest the possibility that there are functional CGRP receptors in those regions, pending demonstrating CLR and RAMP1.

inline image

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 ganglion 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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

Relief of migraine corresponds to reduction of blood CGRP. Migraine pharmacotherapies decrease CGRP release, concentrations, transcription, and promoter activity. Anti-migraine medications tested include sumatriptan, rizatriptan, eletriptan, and botulinum neurotoxin type A. CGRP release in the meninges results in vasodilation and plasma extravasation, which may contribute 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 experimental construct in laboratory animals, published by Goadsby and Edvinsson,27 may have spuriously induced systemic CGRP elevation in stressed animals. However, given that CGRP receptor 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 susceptibility.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 discrepancies in animal models, Russo speculated that migraineurs may be sensitized to the actions of CGRP through increased receptor activity.44

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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

The search for a CGRP receptor antagonist began with the synthesis of 2 short peptides, α and βCGRP8-37, 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 monkeys.49,50 Olcegepant is a large hydrophilic molecule, and a question 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 olcegepant. 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, stabbing in throat and head, and congestion in the head. “No clinically relevant” drug-induced changes in blood pressure, pulse rate, respiratory rate, EKG, lab tests, or forearm blood flow” were seen.52

In another early trial of olcegepant, 10 participants in a double-blind placebo-controlled crossover study received either olcegepant 2.5 mg IV or placebo as pretreatment. Then, they were given h-αCGRP. Six of 10 placebo subjects, and none of the olcegepant patients, experienced an h-αCGRP-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 activated 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 trigeminocervical 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 international, 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 treatment 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 ≥4 groups in ≥3/4 treated and ≥20 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 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 episodic 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 pharmacodynamic 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 µg 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 randomized, double-blind, placebo-controlled, 2-period fixed sequence study in 23 otherwise healthy migraineurs to establish the effect of reduced gastric motility on pharmacokinetic parameters. Once again, the data are only available in abstract form at the time of writing. Fifteen patients received 300 mg of telcagepant 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 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.

Table 1.—. Phase IIB Telcagepant Efficacy58
 Telcagepant 300 mgTelcagepant 400 mgTelcagepant 600 mgRizatriptan 10 mgPlacebo
  • *

    P = .015,

  • **

    P < .001; Comparison of mean response rate of 300, 400, and 600 mg doses to the placebo.

2-hour pain relief68.1*48.2*67.5*69.546.3
2-hour pain free45.2**24.3**32.1**33.414.3
24-hour sustained pain relief52.6**37.8**52.5**35.323.5
24-hour sustained pain free39.6**22.0**32.0**18.411.0

Once again, as with olcegepant, adverse events with telcagepant as reported in the phase IIB trial were mild (see Table 2).55,58

Table 2.—. Adverse Events (AEs) from Phase IIB, Telcagepant58,59
 Placebo (N = 47)MK-0974 300 mg (N = 51)MK-0974 400 mg (N = 52)MK-0974 600 mg (N = 49)Rizatriptan 10 mg (N = 50)
Any AEs17 (36.2%)18 (35.3%)19 (36.5%)20 (40.8%)21 (42.0%)
Any drug-related AEs11 (23.4%)13 (25.5%)14 (26.9%)12 (24.5%)14 (28.0%)
Common AEs
Dry mouth12211
Nausea63451
Fatigue00112
Dizziness23141
Somnolence02142
Paresthesia00012

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 Headache 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, phonophobia, 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 suggesting safety for telecagepant. One study abstracted assessed the 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 treatment 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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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 prospect 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. Triptans 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 nociceptors not activated?
  • 2
    Trigeminocervical complex activation initiated by glutamate and SSS stimulation can be blocked by microiontophoretic application of olcegepant onto neurons of this region, demonstrating a non-presynaptic site of action for CGRP, ie, central.41
  • 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 telcagepant 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 µM. 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 headache attacks, also suggesting cluster as a potential target.68 Goadsby and Edvinsson also showed increase in CGRP in paroxysmal 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

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References

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 antagonists terminate migraine with efficacy similar to triptans. Both olcegepant, a potent IV CGRP antagonist, and oral telcagepant are effective, safe, and well tolerated in phase I and II studies. At the time of writing, telcagepant is in phase III trials, but 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.

References

  1. Top of page
  2. Abstract
  3. PATHOPHYSIOLOGY OF MIGRAINE AND CGRP
  4. PRECLINICAL WORK ON CGRP
  5. CONTROVERSY ON CGRP IN THE EXTERNAL JUGULAR DURING MIGRAINE
  6. FURTHER EVIDENCE FOR CGRP IN ANIMAL MODELS AND MIGRAINE
  7. LOCATION OF CGRP RECEPTORS AND CLINICAL EFFECTS
  8. RELIEF OF MIGRAINE
  9. THE CGRP RECEPTOR ANTAGONISTS
  10. CLINICAL IMPLICATIONS FOR A CGRP RECEPTOR ANTAGONIST
  11. CONCLUSIONS
  12. Acknowledgments
  13. References