I usually post in the RSD, aka Complex Regional Pain (CRPS) forum, but we were discussing whether folks with RSD tend to get a disproportionate amount of migraines, and I thought that perhaps I had come across something that might be of interest over here, although I personally haven't had a migraine in some time: I have my own issues. In any event, please consider this something of a free floating thread.

Thing is, there is at least one established link between migraines and CRPS-1 and that is a neuropeptide, calcitonin gene-related peptide (CGRP), which is the most potent of vasodilators (think edema) and plays a crucial role in the transmissions of pain signals. See, "Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS)," Birklein F, Schmelz M, Neuroscience Letters, 2008, 437:199-202, free full text at http://www.rsds.org/2/library/articl...in_Schmelz.pdf

This lines up nicely with a number of recent papers on migraines, including two with unusally readable abstracts by one author in particular. See, "Calcitonin gene-related peptide (CGRP) and migraine," Durham PL, Headache, 2006 June, 46 Suppl 1: S3-8, for which the abstract reads as follows:

The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. While clinical findings are consistent with such a role, the specific pathogenic mechanisms of CGRP in migraine have remained speculative until recently. Through advances in molecular neuroscience, the pathogenic mechanisms of CGRP in migraine have begun to be elucidated. This paper discusses the hypothesized role of CGRP in migraine and reviews recent findings on the molecular mechanisms of this neuropeptide in migraine pathophysiology. Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan. [Emphasis added.]

PMID: 16927957 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

And then there is Dr. Durham's earlier article, "Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug," Durham PL, Russo AF, J Neuroscience, 1999 May 1; 19(9):3423-9, free full text at http://www.jneurosci.org/cgi/content/full/19/9/3423 , the abstract of which follows:

We have investigated the regulation of calcitonin gene-related peptide (CGRP) release from trigeminal neurons by the serotonergic antimigraine drug sumatriptan. Serum levels of the neuropeptide CGRP are elevated during migraine. Treatment with the drug sumatriptan returns CGRP levels to normal coincident with the alleviation of headache. However, despite this clinical efficacy, the cellular target and mechanism of sumatriptan action are not well understood beyond the pharmacology of its recognition of the 5-HT1 class of serotonin receptors. We have used cultured trigeminal neurons to demonstrate that sumatriptan can directly repress CGRP secretion from sensory neurons. The stimulated secretion in response to depolarization or inflammatory agents was inhibited, but not the basal secretion rate. Unexpectedly, sumatriptan did not lower cAMP levels, in contrast to the classical role ascribed to the 5-HT1 receptors. Instead, activation of 5-HT1 receptors caused a slow and remarkably prolonged increase in intracellular calcium. The inhibition of CGRP secretion is attenuated by the phosphatase inhibitor okadaic acid, suggesting that sumatriptan action is mediated by calcium-recruited phosphatases. These results suggest that 5-HT1 agonists may block a deleterious feedback loop in migraine at the trigeminal neurons and provide a general mechanism by which this class of drugs can attenuate stimulated neuropeptide release.

Unfortunately, sumatriptan, marketed under the brand name Imitrex® is expressly contra-indicated for patients unable to tollerate vasospasm, which basically means anyone with CRPS. That, and not only is the drug linked with heart attacks and cerebral accidents of one sort or another, but, according to the FDA approved "Prescribing Information" page, "Chest discomfort and jaw or neck tightness have been reported following use of IMITREX Tablets and have also been reported infrequently following the administration of IMITREX® (sumatriptan) Nasal Spray." [Not good for the CRPS community, many of whom already have issues with spasms and/or dystonia.] http://us.gsk.com/products/assets/us..._injection.pdf

But some hope there may be, notwithstanding the general antipathy of the heath insurance industry to pick up the tab for treating pain if any sort with botulinum toxin type-A, another known mediator of CGRP. [For what may have been a "made to order" review of the literature, see, generally, "Efficacy of botulinum toxin type A for the prophylaxis of episodic migraine headaches: a meta-analysis of randomized, double-blind, placebo-controlled trials," Shuhendler AJ, et al, Pharmacotherapy, 2009 Jul;29(7):784-91 (botulinum toxin A for the prophylactic treatment of episodic migraine headaches was not significantly different from placebo, both from a clinical and statistical perspective).] But check note: "Future drugs for migraine," Farinelli I, De Filippis S, Coloprisco G, Missori S, Martelletti P., Intern Emerg Med. 2009 Jun 24. [Epub ahead of print] [Note to Headache forum members: you will probably catch the problem with this abstract, before I point it out below]

Migraine is a complex, neurovascular disorder in which genetic and environmental factors interact. At present, frontline therapies in the acute treatment of migraine include the use of non-steroidal anti-inflammatory drugs and triptans. Evidence indicates that calcitonin gene-related peptide (CGRP) plays a fundamental role in the mechanism of migraine. CGRP is a strong vasodilatatory neuropeptide that is released from activated trigeminal sensory nerves. The development of CGRP antagonists has also been driven by the fact that triptans are vasoconstrictive and cannot be safely used in patients with cardiovascular risk factors. Olcegepant (BIBN4096) is the first CGRP antagonist for the treatment of migraine that has been tested in clinical trials, but because of its poor oral bioavailability, only the intravenous formulation has been tested. The first oral non-peptide CGRP antagonist, telcagepant, has been shown recently to be highly effective in the treatment of migraine attacks. This development can be considered as the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are also of importance, since they support an interesting pathophysiological hypothesis of migraine. The pipeline of future compounds for the treatment of acute migraine headaches include TPRV1 antagonists, prostaglandin E receptor 4 (EP(4)) receptor antagonists, serotonin 5HT1(F) receptor agonists and nitric oxide synthase inhibitors. The immediate future of a preventative treatment for migraine headaches is well represented by botulinum toxin type-A, glutamate NMDA receptor antagonists, gap-junction blocker tonabersat and an angiotensin type 1 blocker candesartan.

PMID: 19551474 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

Sadly, [as you folks probably know all too well] the Phase IIa trial of telcagepant was terminated this spring, before the outative publication date of Future Drugs for Migraine:

. . . after the "identification of two patients with significant elevations in serum transaminases". A memo to study locations stated that telcagepant had preliminarily been reported to increase the hepatic liver enzyme alanine transaminase (AST) levels in "11 out of 660 randomized (double-blinded) study participants." All study participants were told to stop taking the medication. [Citations omitted but available through link.]

http://en.wikipedia.org/wiki/Telcagepant

And while olcegepant is still on track, as reflected in manufacturer's webpage, I wonder how well it, too, will be tollerated by CRPS patients:

Olcegepant is one of several CGRP antagonists in development as a potential treatment for acute migraine attacks. This new class of drugs is designed to block and/or reverse CGRP-mediated dilation of intracranial vessels induced by activation of the main sensory nerves in the brain. A highly potent CGRP antagonist, olcegepant has demonstrated the capacity to block release of CGRP in animal models.

PROOF OF CONCEPT DEMONSTRATED IN CLINICAL STUDIES

Building on the results from pre-clinical studies, early clinical trials have since shown that inhibition of CGRP is an effective approach to symptom relief in acute migraine. In a phase II, 126-patient study, intravenous administration of olcegepant 2.5mg proved significantly more effective than placebo in ameliorating symptoms associated with acute migraine. Among patients receiving olcegepant 2.5mg, the minimum effective dose, 66% of patients responded to treatment compared with 27% of placebo recipients (P=0.001).

Active treatment was also superior to placebo with respect to secondary efficacy endpoints that included: pain-free at two hours; rate of sustained response over 24 hours; rate of recurrent headache; incidence of nausea, photophobia, phonophobia, and functional capacity; and time to meaningful relief.

Olcegepant was generally well tolerated. Adverse events occurred in 25% of patients on olcegepant 2.5mg compared with 12% for those on placebo. Paresthesia, a burning or prickling sensation, was the most common adverse event to occur among olcegepant-treated patients. There were no serious adverse events. [Emphasis added.]

http://www.drugdevelopment-technolog...ts/olcegepant/

That said, Olcegepant may work out after all. If it doesn't we may be left in the short term back with our old friends, the glutamate NMDA receptor antagonists (Ketamine, Dextromethorphan, etc.) and Tonabersat (which looks really interesting and very much in the pipeline, and on account of which I would invite all to check out the manufacturer's webpage http://www.minsterpharma.com/tonabersat.asp). Finally, it's hard to get excited about using the "angiotensin type 1 blocker candesartan" (a drug used primarily to treat high blood pressure) in a [CRPS] patient population plagued by edema. So right now, I'm holding my breath for Tonabersat, and for me that would be "just" for off label use in CRPS. (And without doing a lot more work, I haven't a clue what role, if any, CGRP plays in its mechanism of action.)*

Mike

* "Tonabersat’s mode of action is understood to be its ability to influence the interactions between nerve cells and between nerve and glial cells. Abnormalities in these interactions are increasingly thought to underlie many neurological conditions, hence giving tonabersat considerable potential utility."