Understanding Chronic Migraine: From Pathophysiology to Treatment Disparities

An expert roundtable of headache specialists helps outline chronic migraine as its own entity, disparities and barriers to treatment, and a need for better research and education.

Chronic migraine affects an estimated 1.4%-2.2% of people worldwide, with a preponderance of cases in women (1.7%-4.0%) compared to men (0.6%-0.7%). Each year, approximately 3% of individuals with episodic migraine progress to chronic migraine.1

In addition to female gender, other risk factors for this progression include high migraine frequency at baseline, medication overuse, stressful life events, and lower socioeconomic status.1 Higher rates of psychiatric disorders including depression and anxiety have also been noted in patients with chronic migraine and may represent risk factors for progression.1,2

As the bulk of migraine research to date has focused on episodic migraine, there is a dearth of evidence regarding the pathophysiology of chronic migraine. However, numerous potential mechanisms have been proposed, including “(d)ysfunction of the descending pain modulatory pathway, enhanced cortical hyperexcitability, central sensitization and structural brain changes,” according to an August 2021 review published in Frontiers in Pain Research.1 “Despite our limited understanding about the underlying pathogenesis of this condition, it is conceivable to infer that chronic migraineurs are in a constant premonitory phase which may perpetuate” these abnormalities, the researchers stated.

Given the range of treatment options currently available for chronic migraine, future research should examine the potential preventive and ameliorative effects of these therapies on the structural and functional abnormalities observed in this patient population.  

For an in-depth look on chronic migraine, including treatment strategies, relevant resources, and ongoing needs, we spoke with the following experts: Jessica Ailani, MD, FAHS, FAAN, FANA, associate professor of neurology at Georgetown University Medical Center and director of the Medstar Georgetown Headache Center in Washington, DC; Christopher B. Oakley, MD, assistant professor of neurology at Johns Hopkins University School of Medicine and co-director of the Johns Hopkins Headache Center in Baltimore, Maryland; and Rebecca Erwin Wells, MD, MPH, associate professor of neurology and associate director for clinical services at the Center for Integrative Medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina.

What are some of the key differences in the pathophysiology of chronic vs episodic migraine? 

Dr Ailani: The short answer is that chronic migraine is more likely to involve central and peripheral sensitization that is constant, making it more likely that in the time period between attacks, the brain is more sensitive to all external input including light, sound, and touch.   

Dr Oakley: There really isn’t a difference in the pathophysiology of chronic vs episodic migraine, as it is still migraine but on a more frequent basis. What may be different is that when there are more frequent headaches and migraines, the overall system becomes irritated and thus many chronic migraine patients will begin to notice more pain, inflammation, and irritation in their neck, shoulders, and upper back to go along with their frequent migraines.

What is also more problematic when looking at chronic vs episodic migraine patients is that chronic migraine patients may be more refractory to the treatments as they are more entrenched in their patterns, so more patience is needed when treatments are initiated to allow them to work. Additionally, these patients may need several treatments to gain control as compared to monotherapy with episodic migraine.

Dr Wells: According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), chronic migraine is defined by the presence of 15 or more headache days per month over the preceding 3 months, with at least 8 days per month meeting criteria for migraine.3

The headache frequency threshold of 15 days per month was determined by a committee and not based on a pathophysiological basis of disease. However, patients with chronic migraine have higher disability, lower quality of life, and more often have co-morbid diseases compared to those with episodic migraine.1

A debate has occurred over whether the 15-day threshold is appropriate, and recent research argues against it.4 

What are the main treatment options for chronic migraine, and what are the most notable emerging therapies?

Dr Ailani: When patients have chronic migraine, we begin to focus on prevention of attacks in addition to acute treatment that patients can take when a migraine occurs. There are several Food and Drug Administration (FDA)-approved treatments for chronic migraine: onabotulinumtoxinA, erenumab, galcanezumab, fremanezumab, and eptinezumab. The last 4 are considered calcitonin gene-related peptide (CGRP) monoclonal antibodies and represent emerging therapies targeting one of the causes of migraine – elevation of CGRP.1

For patients with chronic migraine, in addition to medication we will often discuss adding behavioral treatments to help reduce migraine disability. These treatments can include acupuncture, biofeedback, mindfulness-based stress reduction, cognitive behavioral therapy, and acceptance therapy.5

Dr Oakley: The basics still apply to chronic migraine just as they would for episodic migraine: lifestyle modifications, trigger avoidance, complementary and integrative therapies such as physical therapy, cognitive behavioral therapy, biofeedback, and acupuncture are offered and encouraged as part of the treatment plan. For prophylactic treatments, daily preventatives with nutraceuticals or medications are recommended and could include any and all of those that are used in episodic migraine prevention. 

What is different is that onabotulinumtoxinA is approved and recommended for chronic migraine prevention only, so this is a key option to consider for a chronic migraine patient, especially one who has tried and failed other daily prophylactic options. 

As for emerging therapies, the CGRP antibodies are the new wave of treatments and are the first treatments ever created specifically to combat headaches and migraines from a preventative perspective. There are now several available including several subcutaneous injectables and medications in pill form and an IV infusion form. These are used in episodic or chronic migraine patients, and similar to Botox, it is often necessary to try other traditional options first to get them covered through insurance.

Dr Wells: OnabotulinumtoxinA is FDA-approved for chronic migraine and is the only therapy that has indication specifically for chronic migraine.

The new CGRP preventive treatment options are indicated for migraine, including both episodic and chronic migraine.

Three types of neuromodulation are cleared for use as monotherapy or adjunctive therapy for preventive migraine treatment: external trigeminal nerve stimulation, noninvasive vagus nerve stimulation, and single pulse transcranial magnetic stimulation.6-8

Biobehavioral treatment approaches such as mindfulness and acceptance and commitment therapy are also very important for migraine treatment, with emerging evidence of benefit.5,9

What are some of the disparities or barriers affecting access to migraine treatment, and what are specialists doing to improve the standard of care?

Dr Wells: Limited access to headache specialists and financial limitations contribute to disparities in care. I am the co-chair of the American Headache Society Diversity, Equity, and Inclusion Taskforce, and we are working to determine systematic ways that we as a field can improve such disparities.

In addition, the Underserved Populations in Headache Medicine Special Interest Section of the American Headache Society has recently published 2 articles on this very topic.11,12

Dr Ailani: One of the main barriers to care in migraine is a lack of education about migraine as a disease process amongst the general public. There is also a need for better understanding among health care providers about how to diagnose and manage migraine.

The American Academy of Neurology and the American Headache Society (AHS) have created guidelines on the preventive and acute treatment of migraine, and AHS has created consensus statements to help health care providers understand how to integrate new treatments into practice.10 AHS also has multiple programs available to health care providers to increase awareness of migraine and to improve their understanding of how to treat the disease. Some of these programs are free to non-members and are available virtually. Examples include Next Generation Migraine Therapies and First Contact – Headache in Primary Care.

The National Headache Foundation has free webinars to educate healthcare providers on headache, and the Diamond Headache Foundation also has free CME for healthcare providers on headache disorders.

Dr Oakley: There are a variety of issues that affect access to migraine treatment, with one of the biggest being a lack of providers who focus on headache. This makes wait times very long, and accessibility is a major issue. Through training programs as well as collaborating with primary care providers, the numbers are increasing so that patients won’t have to wait as long to see a specialist before their migraines can be addressed. 

Through ongoing outreach and education, as well as programs for the community such as Miles for Migraine and other patient resources through the AHS and the American Migraine Foundation, patients can more directly access resources and options in a timelier manner. Additionally, through Headache on the Hill, patients and providers alike –including headache specialists – are working with Congress to advocate for headache patients across the board.

What are other remaining needs in this area in terms of research or education?

Dr Ailani: We need a continued pipeline of new treatments for migraine, especially for those with chronic migraine – which is about 3.2 million people in the US.13 Targeted treatment to the cause of migraine seems to be better tolerated by patients and continues to allow this disease to be recognized as its own entity.

Dr Oakley: There are great needs for ongoing research. While we have come a long way, we are not there yet in terms of our complete understanding regarding headaches and migraines, nor in our treatments. Despite recent advancements, we are still in need of more options and better treatments moving forward. 

Education is another area that, while improving, still has a long way to go to help the countless migraine patients out there given the discrepancy in supply and demand in terms of headache providers.

Dr Wells: We are working to understand the risk factors for migraine chronification and how to prevent patients from transitioning from episodic to chronic migraine.

Additionally, migraine awareness is critical to decreasing the stigma associated with migraine.


1. Mungoven TJ, Henderson LA, Meylakh N. Chronic migraine pathophysiology and treatment: a review of current perspectives. Front Pain Res.Published online August 25, 2021. doi:10.3389/fpain.2021.705276

2. Buse DC, Silberstein SD, Manack AN, et al. Psychiatric comorbidities of episodic and chronic migraine. J Neurol. Published online November 7, 2012. doi:10.1007/s00415-012-6725-x

3. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. Published online January 25, 2018. doi:10.1177/0333102417738202

4. Ishii R, Schwedt TJ, Dumkrieger G, et al. Chronic versus episodic migraine: The 15-day threshold does not adequately reflect substantial differences in disability across the full spectrum of headache frequency. Headache. 2021;61(7):992-1003. doi:10.1111/head.14154

5. Wells RE, Beuthin J, Granetzke L. Complementary and integrative medicine for episodic migraine: an update of evidence from the last 3 years. Curr Pain Headache Rep. Published online June 3, 2021. doi:10.1007/s11916-019-0750-8

6. Stanak M, Wolf S, Jagoš H, et al. The impact of external trigeminal nerve stimulator (e-TNS) on prevention and acute treatment of episodic and chronic migraine: A systematic review. J Neurol Sci. May 15, 2020. doi:10.1016/j.jns.2020.116725

7. Diener HC, Goadsby PJ, Ashina M, et al. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. Published online September 15, 2019. doi:10.1177/0333102419876920

8. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia. Published online March 4, 2019. doi:10.1177/0333102418762525

9. Wells RE, O’Connell N, Pierce CR, et al. Effectiveness of mindfulness meditation vs headache education for adults with migraine: a randomized clinical trial. JAMA Intern Med. Published online December 14, 2020. doi:10.1001/jamainternmed.2020.7090

10. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. Published online June 23, 2021. doi:10.1111/head.14153

11. Charleston L 4th, Royce J, Monteith TS, et al. Migraine care challenges and strategies in US uninsured and underinsured adults: a narrative review, part 1. Headache. Published online March 8, 2018. doi:10.1111/head.13286

12. Charleston L 4th, Royce J, Monteith TS, et al. Migraine care challenges and strategies in US uninsured and underinsured adults: a narrative review, part 2. Published online May 21, 2018. Headache. 2018. doi:10.1111/head.13321

13. Carod-Artal FJ. Tackling chronic migraine: current perspectives. J Pain Res. Published online April 8, 2014. doi:10.2147/JPR.S61819