Clinical Review & Education

JAMA Insights

Chronic Migraine in Adults

Migraine is the most common neurologic disease and the A suboptimal response to acute treatment is associated with a
second-most disabling condition worldwide. Diagnostic charac- 2.5-fold increased risk of progression to chronic migraine, al-
teristics of migraine include headaches lasting 4 to 72 hours though it is unclear if this is a causative relationship. In a meta-
accompanied by nausea or vomiting or by both photophobia analysis of 3 studies, patients with episodic migraine and depres-
and phonophobia, with at least sion were more likely to develop chronic migraine than those without
2 of the following pain charac- depression (RR, 1.58 [95% CI, 1.35-1.85]).2
Supplemental content teristics: unilateral, moderate
to severe, pulsating quality, Preventive Treatment for Chronic Migraine
CME at jamacmelookup.com and aggravated by or causing Preventive treatment should be offered to all patients with chronic
avoidance of physical activity. migraine.4 Goals of preventive treatment include decreasing the
Approximately 25% of people with migraine experience aura frequency, severity, and duration of headaches; reducing acute
(visual, sensory, or other neurologic symptoms, such as language medication use; lowering disability; and improving quality of life.
disturbance or motor weakness) before some or all migraine A 50% reduction in monthly headache days is considered a good
attacks. response to preventive treatment.4 Combinations of preventive
Migraine is categorized as episodic if patients have fewer than treatments may be used if migraine attacks do not improve with
15 days with headache per month. Chronic migraine is defined as trials of single agents.
headaches on 15 or more days per month, with 8 or more meeting Oral medications with good evidence for preventive treat-
the diagnostic criteria for migraine or considered to be a migraine ment of migraine are β-blockers (metoprolol, propranolol, and
by the patient and relieved by a triptan or ergot derivative. World- timolol), antiepileptics (sodium valproate and topiramate), the
wide, 12% of adults experience episodic migraine each year and angiotensin receptor blocker candesartan, and the calcitonin
1.4% to 2.2% meet the criteria for chronic migraine.1 Compared gene-related peptide (CGRP) receptor antagonists atogepant and
with episodic migraine, people with chronic migraine experience rimegepant4 (eTable in the Supplement).
longer and more severe headaches, have more disability, miss more Four monoclonal antibodies to the CGRP or its receptor (CGRP
work, have higher health care utilization, and report lower quality monoclonal antibodies), which are administered subcutaneously or
of life.1 Chronic migraine is associated with an increased likelihood intravenously every 1 to 3 months, are US Food and Drug Adminis-
of anxiety, depression, pain disorders, asthma, sleep disorders, tration (FDA) approved for episodic and chronic migraine. A meta-
obesity, metabolic disease, history of head and neck injury, adverse analysis including 8 randomized clinical trials (5838 patients)
childhood experiences, low educational attainment, and financial reported a 1.9- to 2.7-day reduction in monthly migraine days with
constraints.1 use of CGRP monoclonal antibodies vs placebo.5 Two oral small-
molecule CGRP receptor antagonists (gepants) are also FDA
Risk Factors for Progression From Episodic approved for migraine prevention. A randomized trial of 778 indi-
to Chronic Migraine viduals with chronic migraine reported a change from baseline in
Approximately 2.5% to 3% of individuals with episodic migraine mean (SE) monthly migraine days of −7.5 (0.4) with atogepant
progress to chronic migraine each year.1 Two longitudinal studies 30 mg twice daily, −6.9 (0.4) with atogepant 60 mg daily, and −5.1
found that patients with 10 or more headache days per month had (0.4) with placebo.6 Least-squares mean difference from placebo
increased risk of developing chronic migraine compared with those was −2.4 with atogepant 30 mg twice daily (95% CI, −3.5 to −1.3;
with lower baseline headache frequency (pooled risk ratio [RR], 5.95 adjusted P < .001) and −1.8 with atogepant 60 mg once daily
[95% CI, 4.75-7.46]).2 Another strong risk factor for progression to (95% CI, −2.9 to −0.8; adjusted P < .001).6 The most common
chronic migraine is medication overuse, defined as use of acetamino- adverse events were constipation (10%-10.9% in the atogepant
phen or nonsteroidal anti-inflammatory drugs (NSAIDs) on more than groups vs 3% in the placebo group) and nausea (8%-10% in the
15 days per month or use of opioids; ergotamines; triptans; combi- atogepant groups vs 4% in the placebo group), and 7% or greater
nation analgesics, such as butalbital; or multiple drug classes more weight reduction at any time postbaseline was higher with use of
than 10 days per month.3 As many as 65% of people with chronic atogepant (6% in both groups) vs placebo (2%).
migraine meet the International Classification of Headache Disor- Onabotulinum toxin A is FDA approved for patients with chronic
ders criteria for acute medication overuse. A meta-analysis of 5 stud- migraine. A meta-analysis including 23 studies (3912 patients)
ies found that medication overuse is associated with an 8.8-fold evaluating onabotulinum toxin A for prevention of chronic mi-
(95% CI, 2.88-27.00) greater risk of progression to chronic mi- graine reported a reduction of 3.1 migraine days per month (95% CI,
graine compared with those with episodic migraine without medi- −4.7 to −1.4) compared with placebo. Preliminary data suggest
cation overuse.2 Cessation of medication overuse likely reduces the that the combination of onabotulinum toxin A and a CGRP mono-
risk of progression from episodic to chronic migraine and may de- clonal antibody may reduce monthly headache days more than
crease the frequency of chronic migraines. either treatment alone in patients with chronic migraine.7

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 Clinical Review & Education JAMA Insights

Acute Treatment of Chronic Migraine patients with chronic migraine and medication overuse headache
Medications for acute treatment of chronic migraine are similar to reported 50% or greater headache frequency reduction at 12 months
those for episodic migraine and include acetaminophen, NSAIDs, in 78.4% of patients randomized to 6 sessions of mindfulness and
5-HT1B and D receptor agonists (triptans), 5-HT1F receptor agonists usual care vs 48.3% with usual care alone.8 Two randomized con-
(ditans), and CGRP receptor antagonists (gepants) (eTable in the trolled trials evaluating cognitive behavioral therapy for insomnia
Supplement). showed a reduction in monthly headache days of 6.2 compared with
Patients should take medication for acute treatment of mi- the control group.9
graine as soon as they experience initial symptoms of a severe
migraine attack, as acute treatment is most effective when taken Neuromodulation
early. Other strategies to improve response to acute treatment in- Five noninvasive neuromodulation devices are FDA cleared for treat-
clude using the highest medication dose, changing medications ment of migraine.10 Neuromodulation can be useful for patients who
within the same class, changing to a different medication class, or prefer nonpharmacologic treatments for migraine, as adjunctive pre-
combining multiple classes of acute treatments (eg, combining a trip- ventive treatment in combination with medications, or as adjunc-
tan and an NSAID). Patients with frequent migraine attacks may be tive acute treatment in patients at risk for medication overuse due
advised not to take acute medications for treatment of milder head- to attack frequency.
aches to avoid medication overuse.4 Gepants used for acute treat-
ment of migraine have not been associated with medication over- Conclusions
use headache, so they may be useful in patients who need acute Migraine affects more than 1 billion people worldwide, with chronic
treatment frequently.4 migraine occurring in as many as 20 million people. Optimization of
acute and preventive migraine treatment reduces disability and
Behavioral Treatments improves quality of life in people with chronic migraine. Effective
Patients with chronic migraine may benefit from behavioral treat- therapeutic options for chronic migraine include new treatments
ments either alone or in combination with usual care. A study of 177 that target the CGRP pathway.

ARTICLE INFORMATION 2. Xu J, Kong F, Buse DC. Predictors of episodic treatment for preventive treatment in chronic
Author Affiliation: Department of Neurological migraine transformation to chronic migraine. migraine. Headache. 2022;62(1):106-108.
Sciences, University of Vermont Larner College of Cephalalgia. 2020;40(5):503-516. doi:10.1177/ 8. Grazzi L, D’Amico D, Guastafierro E, et al.
Medicine, Burlington. 0333102419883355 Efficacy of mindfulness added to treatment as usual
Corresponding Author: Rebecca Burch, MD, 3. Lipton RB, Buse DC, Nahas SJ, et al. Risk factors for in patients with chronic migraine and medication
Department of Neurological Sciences, University of migraine disease progression. J Neurol. 2023;270 overuse headache. J Headache Pain. 2023;24(1):86.
Vermont Larner College of Medicine, 1 S Prospect St, (12):5692-5710. doi:10.1007/s00415-023-11880-2 doi:10.1186/s10194-023-01630-0
Arnold 2, Burlington, VT 05452 (Rebecca.Burch@ 4. Ailani J, Burch RC, Robbins MS; Board of 9. Smitherman TA, Kuka AJ, Calhoun AH, et al.
uvmhealth.org). Directors of the American Headache Society. The Cognitive-behavioral therapy for insomnia to
Published Online: January 9, 2025. American Headache Society consensus statement. reduce chronic migraine. Headache. 2018;58(7):
doi:10.1001/jama.2024.26818 Headache. 2021;61(7):1021-1039. doi:10.1111/head. 1052-1059. doi:10.1111/head.13313
14153 10. Han X, Yu S. Non-pharmacological treatment
Conflict of Interest Disclosures: Dr Burch reported
receiving compensation from the American 5. Naghdi S, Underwood M, Madan J, et al. Clinical for chronic migraine. Curr Pain Headache Rep.
Academy of Neurology for serving as an associate effectiveness of pharmacological interventions for 2023;27(11):663-672.
editor of Neurology. managing chronic migraine in adults. J Headache Pain.
2023;24(1):164. doi:10.1186/s10194-023-01696-w
Note: Source references are available through
embedded hyperlinks in the article text online. 6. Pozo-Rosich P, Ailani J, Ashina M, et al.
Atogepant for the preventive treatment of chronic
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2019;37(4):631-649. doi:10.1016/j.ncl.2019.06.001 7. Ailani J, Blumenfeld AM. Combination CGRP
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