Calcitonin Gene-Related Peptide is being looked at by some as the “Holy Grail” for Migraine prevention and relief.
The Trigeminal Nerve is where almost all headaches and migraines originate. There are both Somatosensory and Autonomic nerves that pass thru the Trigeminal Nervous System.
There are two currently used methods of Treating and preventing chronic daily headaches, tension headaches, migraines, and autonomic cephalgias that are not well known though both may be more successful than Botox injections. One is the use of Sphenopalatine Ganglion Blocks, sometimes called the “Miracle Block” because of the immediate relief they often provide on otherwise refractory headaches and migraines and particularly for cluster headaches. Neuromodulation of the Sphenopalatine Ganglion is also seriously being looked at as a cure or preventative for chronic headaches and migraines. See “TREATMENT OF REFRACTORY HEADACHES” (Abstract below).
Neuromuscular Dentistry has also shown to be extremely effective in treating and eliminating headaches and migraines especially in patients with TMJ issues, facial pains and trigeminally innervated pain. This huge success of Neuromuscular Dentistry may be do the the Neuromodulatory effects on the Sphenopalatine Ganglion by the Myomonitor which is used to relax muscles innervated by the trigeminal nerve and the facial nerve.
Both Neuromuscular Dentistry and Sphenopalatine Ganglion Blocks and Neuromodulation may all work in part due to effect on CGRP and CGRP receptors.
I have seen amazing results when combining Neuromuscular Dentistry and Self administered SPG Blocks. Frequency of blocks is very important initially and can be reduced over time. Patient testimonials on Neuromuscular dentistry and Sphenopalatine ganglion blocks can be found at: https://www.youtube.com/channel/UCk9Bfz6pklC7_UluWFHzLrg/videos
A 2012 paper “Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion — interaction with the sensory system.” (PubMed abstract below) talked about the role of CGRP in both Somatosensory trigeminal System and the Parasympathetic Pterygopalatine Ganglion.
According to the article “Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures.”
This study in Brain Research concluded that ” Our results suggest a possible sensory influence in the parasympathetic cranial ganglia. The sensory CGRP-containing fibers probably originate in the trigeminal ganglion, project to the SPG and act on CGRP receptors on SGCs.”
There are currently four drugs reaching phase 3 trials, Erenumab, Galcanezumab, Fremanezumab and Eptinezumab and all of them are somewhat effective at reducing the number of migraine days between 3-5 days per month. There is a high percentage of side effects including injection site pain and reaction, upper respiratory tract infections, abdominal pain, vomiting /nausea, urinary tract infection, fatigue, back pain, joint pain and runny or stuffy nose.
There is interesting material on the Harvard Health Blog on this subject. (excerpts below)
Brain Res. 2012 Jan 30;1435:29-39. doi: 10.1016/j.brainres.2011.11.058. Epub 2011 Dec 6.
Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion — interaction with the sensory system.
Csati A1, Tajti J, Tuka B, Edvinsson L, Warfvinge K.
Clinical studies have suggested a link between the sensory trigeminal system and the parasympathetic ganglia. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which plays an important role in vasodilatation and pain transmission in craniocervical structures. The present study was designed to examine if CGRP and CGRP receptor components are present in the human sphenopalatine ganglion (SPG) in order to reveal an interaction between the sensory and parasympathetic systems. Indirect immunofluorescence technique was used for immunohistochemical demonstration of CGRP, the calcitonin receptor-like receptor (CLR) and the receptor activity modifying protein 1 (RAMP1) in human and rat SPG. Cryostat sections were examined and images were obtained using a light- and epifluorescence microscope coupled to a camera to visualize co-labeling by superimposing the digital images. In addition, Western blot technique was used to demonstrate the existence of CGRP receptor components in rat SPG. CGRP immunoreactive fibers were frequently found intraganglionic in the SPG in the vicinity of neurons. CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers, but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial ganglia. The sensory CGRP-containing fibers probably originate in the trigeminal ganglion, project to the SPG and act on CGRP receptors on SGCs.
PMID: 22208649 DOI: 10.1016/j.brainres.2011.11.058
[Indexed for MEDLINE]
Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain.
- Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
- Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Kazan, Russian Federation.
- Open Laboratory of Neuropharmacology, Kazan Federal University, Kazan, Russian Federation.
- Laboratory of Neurobiology, Kazan Federal University, Kazan, Russian Federation.
Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown.
Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons.
Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors.
Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.
acetylcholine; acetylcholine receptor; mast cells; meninges; migraine; nicotine; sensory neurons
Treatment of the Patient with Refractory Headache.
PURPOSE OF REVIEW:
To review recent studies outlining the management of refractory primary headache patients, including emerging therapies such as neuromodulation. This includes both noninvasive and invasive neuromodulation techniques. Recent studies on the management of medication overuse headache were also reviewed.
There is no consensus as yet on the definitions of refractory chronic migraine and chronic cluster headache although there is broad agreement on some aspects of these terms. The importance of identifying medication overuse headache and dealing effectively with it has been highlighted in several studies although there is still not consensus on how best to achieve the cessation of medication overuse. Some recommend the use of preventative medication together with medication cessation, while others do not. Recent studies on neuromodulation have used both noninvasive vagal nerve stimulation as well invasive techniques. Recent studies using noninvasive vagal nerve stimulation for chronic migraine have been disappointing although the data in chronic cluster headache are more encouraging. Similarly, recent studies on occipital nerve stimulation have again been more positive in chronic cluster headache and generally negative in chronic migraine. In recent years, new forms of neuromodulation have emerged and long-term follow-up data from previous invasive neuromodulation techniques have become available. The sphenopalatine ganglion has been increasingly targeted by various interventions in several different headache types. Sphenopalatine ganglion stimulation is yielding encouraging data for the treatment of chronic cluster headache. New studies and long-term follow-up data from previous studies have provided further evidence for the benefit of deep brain stimulation for refractory chronic cluster headache although the exact target location is still debated. Data from phase 3 trials using CGRP monoclonal antibodies in chronic migraine and chronic cluster headache, if positive, may herald a long overdue, new and effective treatment for our refractory headache patients.
Chronic cluster headache; Chronic migraine; Medication overuse headache; Neuromodulation; Refractory headache
Excerpted from Harvard Health Blog
What does “targeted” therapy mean?
Calcitonin gene-related peptide (CGRP) is a molecule that is synthesized in neurons (nerve cells in the brain and spinal cord). It has been implicated in different pain processes, including migraine, and functions as a vasodilator — that is, it relaxes blood vessels. Once scientists identified this target molecule, they began trying to develop ways to stop it from being activated at the start of migraines, as a kind of abortive treatment. An agonist makes a molecule work more efficiently, and an antagonist blocks or reduces the molecule’s effect. The CGRP antagonist did work to decrease migraine pain based on certain measures, but there were some serious side effects including liver toxicity.
Back to the drawing board.
Monoclonal antibodies: Cutting-edge translational science
You have likely seen ads for monoclonal antibody (mAb) cancer and autoimmune therapies. There are lots of different types of mAbs, and while some harness a person’s own immune system to block replication of cancer cells, others stop a reaction in the body by binding to a target molecule or receptor and inhibiting it, thus preventing the reaction from continuing. The CGRP mAbs have this effect, and because they have a long duration of action (called a half-life), they can be administered much less frequently than typical migraine medications that are taken daily (with the exception of botulinum toxin, which is injected every 90 days). These new migraine medications are injected under the skin monthly, and have thus far demonstrated a statistically significant decrease in days of migraine. Four different drug companies are developing these new molecules, with two versions already sent to the FDA for approval.
This information is excerpted from Business Insider
Allergan just got one step closer to approval for its migraine drug — and it’s part of a wave of new treatments for the condition that affects 38 million Americans
- Amgen, erenumab— Amgen filed erenumab with the FDA in May. In data released in June, Amgen said its drug was able to reduce the number of migraine days per month by 6.6 days in patients who received the treatment, compared to a 4.2-day reduction in the placebo group. Before the trial, patients had about 18 migraine days.
- Lilly, galcanezumab — Lilly presented phase 3 data in June. The company found in two studies that patients on the drug had between a 3.6 and 4-day reduction in migraine days per month (to be eligible, patients had to have between 4 and 14 migraine days per month). That’s compared to the 2.15 and 1.85 day reduction that was observed in the placebo groups. Lilly filed galcanezumab with the FDA in December.
- Teva, fremanezumab— On June 7, the company came out with data from its late-stage trial. On average, the trial participants had 9.1 migraine days. Those who got the medication had on average 3.7 fewer migraine days per month, compared to 2.2-day reduction in the placebo group. Teva filed with the FDA in October.
- Alder Biopharmaceuticals, eptinezumab— Alder’s drug, which would be administered on a quarterly basis, succeeded in phase 3 trials, the company said in January. The company plans to submit to the FDA in the second half of 2018.
The new class of drugs aims to reduce the number of days per month people have migraines. With the exception of Allergan’s oral version, the drugs are injected typically on a monthly basis. If approved, the drugs are expected to cost $8,500 per year.