CGRP Reveals Biochemical Link Between TMD and Headaches
By Ann McCulloch
We now better understand how associations of plasma calcitonin gene-related peptide (CGRP) with chronic temporomandibular disorder (TMD) or headaches are made.
Orofacial pain specialists continue to evaluate the relationship between the CGRP concentration in patients’ jaw and headache pain. We previously established that Temporomandibular joint (TMJ) pain and headaches are closely related. Knowing that temporomandibular disorders (TMDs) affect the muscles involved in chewing, the jaw joint, and associated structures, it is easier to establish where headaches, jaw and muscle sprain/strain may come from.
Table of Contents
- CGRP Reveals Biochemical Link Between TMD and Headaches
- What is Calcitonin Gene-Related Peptide (CGRP)?
- What is Peripheral Sensitization?
- What is Central Sensitization?
- How is CGRP Involved in Peripheral and Central Sensitization?
- How are TMJ Disorders and Headaches Biochemically Related?
- Next Steps in TMD and Headache Research
- Which Medications Help Decrease CGRP?
- Elements of a Multimodal Approach to Down-Regulate TMJ Pain
- Conclusion: Understanding CGRP’s Role Mediating TMD and Headaches
What is Calcitonin Gene-Related Peptide (CGRP)?
A key molecule known as calcitonin gene-related peptide (CGRP) appears to be at the root of the association between TMDs and headaches. It is a 37-amino acid neuropeptide and a potent vasodilator produced by neurons in people’s central and peripheral nervous systems. CGRP is implicated in the initiation of inflammation within the pain-sensing nerves.
In cases of TMD or headaches, these nerves become sensitized, transmitting erroneous pain signals and potentially leading to “central sensitization”, where the brain becomes increasingly responsive to pain signals even in the absence of injury. The truth behind the association between TMDs and headaches involves the intricate association between CGRP and central sensitization. This is exciting news as it may increase our understanding of these conditions and pave the way for more effective TMD treatment strategies.
Headaches can present in several ways, with tension headaches and migraines being among the most common manifestations. Researchers know that TMDs and headaches are connected, but they have not understood how until recently.
In the past month, a group of orofacial pain doctors uncovered a possible link that connects TMDs and headaches. These doctors published a paper entitled “Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches“, in the prestigious International Journal of Molecular Sciences. Here we break down these findings from the front lines of science so that you too can understand the link between TMDs and headaches.
The association between TMDs and headaches has been well established for many years. In science, an association means that two things are noted to happen together, but it doesn’t explain how.
Statistics that illustrate the TMD-headache association
- Nearly 55% of people with chronic headaches also display TMD symptoms (as opposed to around 15% of the general population. 
- In people with painful TMDs, more than 80% experience headaches. 
- In people with both TMDs and headaches, the more severe the TMD problem is, the more intense the headaches are. 
What factors contribute to pain amplification?
Chronic pain conditions such as headaches and TMD are characterized by two primary factors: peripheral and central sensitization. These mechanisms collectively contribute to the amplification of pain perception across a range of chronic pain conditions, including back pain, TMDs, and chronic headaches.
What is Peripheral Sensitization?
Following an injury to the head or jaw muscles, pain signals are transmitted through the trigeminal nerve, leading to heightened sensitivity and the release of molecules that exacerbate pain. As a result, even innocuous stimuli can induce pain (termed primary allodynia), and painful stimuli elicit heightened pain responses (referred to as primary hyperalgesia).
- Allodynia: Pain due to a stimulus that does not normally cause pain. The classic example is a light feather touching sunburned skin. 
- Hyperalgesia: Pain that is abnormally elevated or exaggerated compared to normal. An example is a pinprick on near infected skin. 
The following graph illustrates the relationship between these two phenomena :
What is Central Sensitization?
Central Sensitization is the persistent pain signaling of peripheral sensitization can lead to heightened sensitivity within the central parts of the brain, causing pain to intensify and persist. This starts to occur even in the absence of further injury. This phenomenon results in the perception of pain without an apparent cause.
You may ask, “So the pain is all in my head”? The simple answer is no. Clifford Woolf, who pioneered our understanding of central sensitization, put it this way:
[Central sensitization] does not mean that the pain is not real, just that it is not activated by noxious stimuli” .
How is CGRP Involved in Peripheral and Central Sensitization?
There is a pivotal role played by CGRP in both peripheral and central sensitization. This molecule is present within nerves throughout the body, including the head, where it amplifies pain signals, effectively acting as a messenger to increase pain perception. Consequently, CGRP can exacerbate pain both in its region of production and elsewhere, contributing to the development of chronic headaches and jaw pain.
How are migraines and CGRP related?
New understanding of the role of CGRP in migraines has revolutionized the treatment of these types of headaches. CGRP induces vasodilation and inflammation in blood vessels, leading to increased blood flow and swelling within the head, ultimately exacerbating pain. As a result, many migraine treatments target CGRP, either by inducing blood vessel constriction or directly inhibiting CGRP-mediated inflammation.
How does CGRP connect TMDs and headaches?
The key insight from our featured article is that TMDs and headaches are related through CGRP-mediated trigeminal ganglionitis. CGRP-induced cross-excitation of sensory nerves in the trigeminal ganglion allows pain in one branch of the trigeminal nerve to instigate pain in other branches of the trigeminal nerve. When sustained, central sensitization to take place and a pattern of chronic pain develops.
How are TMJ Disorders and Headaches Biochemically Related?
The intricate relationship between migraines and TMD becomes evident through their shared association with the trigeminal nerve. When jaw muscles sustain injury, facial nerves relay signals to the brain through the trigeminal nerve, and CGRP contributes to the amplification of these pain signals. Animal experiments provide insights into this link, revealing how injuries to the jaw can potentially exacerbate headaches through CGRP-mediated mechanisms.
This convergence of migraines and TMD underscores the significance of CGRP. Injuries affecting one area, such as the jaw, can sensitize nerves in the trigeminal ganglion, leading to pain throughout the entire head, neck, and jaw region. In this way, jaw pain can directly affect the frequency and severity of headaches. This perspective positions CGRP release in the trigeminal ganglion as a critical factor influencing the co-occurrence of migraines and TMD.
Investigations into anti-CGRP therapy for TMD have primarily been conducted on animal models. Interestingly, emerging evidence suggests a potential connection between CGRP dysregulation and the co-occurrence of headaches, migraines, and TMD. This intriguing molecule appears to serve as a bridge linking these conditions.
Does CGRP activate the trigeminal nerve?
The release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Trigeminal nerve fibers that contain CGRP innervate the synovial membrane, articular disc, periostium, and joint capsule of the temporomandibular.
What is the trigeminal nerve?
The trigeminal nerve is responsible for carrying sensory information from various parts of the face and head to the brain. The “tri-“ prefix in trigeminal refers to the three main branches of the nerve:
- Ophthalmic Branch (V1): This branch supplies sensation to the forehead, the top of the head, and the front part of the scalp. Importantly, it also supplies the meninges, which is the lining of the brain. This is where migraine pain comes from.
- Maxillary Branch (V2): This branch provides sensory information from the upper jaw, upper teeth, cheeks, and parts of the nasal cavity.
- Mandibular Branch (V3): This branch is responsible for sensations from the lower jaw, lower teeth, and the front of the tongue. It also controls the muscles involved in chewing. This is classically where TMJ pain comes from.
The association between TMDs and headaches is immediately apparent by virtue of sharing the same cranial nerve.
What is the trigeminal ganglion?
A ganglion is a cluster of nerve cell bodies that serves as a sensory relay station. The trigeminal ganglion contains the cell bodies of sensory neurons, which receive and process various sensory signals from the skin, mucous membranes, and other structures of the face, including touch, temperature, and pain sensations. These sensory neurons have long projections called axons that extend from the trigeminal ganglion to different areas of the face and head.
The three main branches of the trigeminal nerve described above all originate from the trigeminal ganglion. Each branch carries sensory information from specific regions of the face to the ganglion, where it’s then relayed to the brain for further processing and interpretation.
What is trigeminal ganglionitis?
Ganglionitis means inflammation of the ganglion. We typically understand inflammation to be associated with infection, but there are many cases where inflammation is “sterile”. This means that it is not associated with any bacteria or virus, but rather is caused by substances produced by the body. Trigeminal ganglionitis is when there is diffuse inflammation of the trigeminal ganglion. This diffuse inflammation can affect all 3 branches of the trigeminal nerve.
CGRP is one of the more prominent molecules that can cause trigeminal ganglionitis. New research shows that when CGRP is released in the trigeminal ganglion in response to peripheral pain or inflammation, it acts not only on the nerves involved, but also on the surrounding nerves. This is described as “cross excitation”.
Next Steps in TMD and Headache Research
Ongoing research aims to elucidate whether CGRP-targeted treatments can alleviate TMD-related pain. These studies seek to determine whether such interventions can effectively reduce pain in individuals suffering from TMD. Notably, medications designed to modulate CGRP activity, initially approved for migraine treatment, are being explored for their potential efficacy in TMD management.
Synthesizing this wealth of information, CGRP emerges as a central protagonist in both headaches and TMD. Its involvement underscores the intricate interplay between these conditions, wherein TMDs and headaches can instigate and influence one another, driven in part by CGRP-mediated processes.
The National Institute of Health (NIH) is leading further CGRP research.
[NIH Study]To assess associations of plasma calcitonin gene-related peptide (CGRP) with chronic temporomandibular disorder (TMD) myalgia/arthralgia or frequent/chronic migraine, alone and in combination, and to evaluate relations between the CGRP concentration and clinical, psychological, and somatosensory characteristics of participants.
Painful temporomandibular disorder (TMD) often co-exists with migraine. For example, TMD prevalence was 5 times higher in people with severe headache and migraine than in people without the headache (15.6% and 2.6%, respectively). Likewise, migraine is highly prevalent in TMD patients: in our recent study, migraine occurred in 52% of patients with chronic myogenous TMD. Currently, both disorders are defined solely by clinical criteria which, in the absence of specific biomarkers, limit the capacity for screening, diagnosis, determining prognosis, and predicting response to therapy. – Evaluation of Plasma Calcitonin Gene-Related Peptide as a Biomarker for Painful Temporomandibular Disorder and Migraine, by Inna E Tchivileva, July 11, 2023
Which Medications Help Decrease CGRP?
Direct reduction of CGRP can be achieved through prescription medications as well as nutraceuticals.
Table 1: FDA-Approved CGRP-Inhibiting Medications
|Drug Class||Route of Administration||Examples|
|Monoclonal Antibodies||Injection||Eptinezumab (Vyepti)
|Gepants (small molecule drugs)||Oral||Ubrogepant (Ubrelvy)
Of course, there are side effects to these medications and they are quite expensive. 
Supplements that decrease CGRP
Over the years, many have found that supplements help with migraine headaches. In recent years, these supplements have been studied in rigorous scientific trials. In turns out for many of the effective supplements, the mechanism of action appears to be that they decrease CGRP levels.
Here are some of the more studied CGRP supplements:
Selected CGRP-Reducing supplements 
- Curcumin (turmeric).
- Grape seed Extract.
- Cocoa extract.
Non-pharmacologic CGRP reduction
Strategies that address CGRP-mediated inflammation resulting from these injuries in their early stages may prevent the onset of chronic pain. Varied approaches, encompassing pharmaceutical interventions, dietary adjustments, oral devices, stress management, and exercise regimens, seek to mitigate the risk of central sensitization and prolonged pain. A multimodal approach to decreasing inflammation in the acute period after an injury holds promise in this regard.
Elements of a Multimodal Approach to Down-Regulate TMJ Pain
- Oral appliances.
- Physical Therapy.
- Cognitive behavioral therapy.
Observing a connection between two conditions in science demands a clear mechanism that explains the connection. That’s why the new research by Sangalli and colleagues is so exciting. It marks a significant breakthrough in elucidating the biochemical link between TMDs and headaches.
Conclusion: Understanding CGRP’s Role Mediating TMD and Headaches
We now understand that CGRP plays a pivotal role in mediating the relationship between these conditions, and its primary site of action is identified as the trigeminal ganglion. This revelation sheds light on the intricate connections within the nervous system and offers promising insights for targeted interventions and TMJ treatments.
Ann McCulloch, MBA is co-founder and president of Orofacial Therapeutics, this site, and oversees the company’s expanding portfolio of resources and tools for jaw and headache pain diagnosis and treatment. Her chronic jaw pain issues continue to inspire her to investigate the needs and challenges of patients suffering from orofacial pain.
 I. E. Tchivileva, et al. “Temporal change in headache and its contribution to risk of developing first-onset TMD in the OPPERA study,” Jan. 2017, https://pubmed.ncbi.nlm.nih.gov/27984525/
 H. A. van der Meer, et al. “The Association Between Headaches and Temporomandibular Disorders is Confounded by Bruxism and Somatic Symptoms,” Sep. 2017, https://pubmed.ncbi.nlm.nih.gov/28002094/
 L. L. Florencio et al., “Association Between Severity of Temporomandibular Disorders and the Frequency of Headache Attacks in Women With Migraine: A Cross-Sectional Study,” May 2017, https://pubmed.ncbi.nlm.nih.gov/28390711/
 Y. He and P. Y. Kim, “Allodynia,” Aug 2023, http://www.ncbi.nlm.nih.gov/books/NBK537129/
 Mary M. Volcheck, MSN, RN quotes C. J. Woolf, “Central sensitization, chronic pain, and other symptoms: Better understanding, better management,” April 2023, https://www.ccjm.org/content/90/4/245
 L. Sangalli, B. Eli, S. Mehrotra, S. Sabagh, and J. Fricton, “Calcitonin Gene-Related Peptide-Mediated Trigeminal Ganglionitis: The Biomolecular Link between Temporomandibular Disorders and Chronic Headaches,” Jul. 2023, https://www.mdpi.com/1422-0067/24/15/12200
 J. C. Ray et al., “Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects,” Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/33495299/
 M. Fila, et al. “Nutrition and Calcitonin Gene Related Peptide (CGRP) in Migraine,” Jan. 2023, https://www.mdpi.com/2072-6643/15/2/289