Though the two major migraine subtypes commonly mentioned are migraine with or without aura, migraine can also be divided into episodic or chronic sub-forms depending on the number of headache days per month.¹ For a single patient, migraine can evolve from episodic to chronic, or conversely, revert from chronic to episodic and even complete remission of symptoms.¹ These transitions are thought to be associated with a wide range of proposed physiological and behavioral factors.¹

Four clinical trajectories in the course of episodic migraine

Episodic migraine (EM) and chronic migraine (CM) are primarily separated by the criterion for headache days per month—less than 15 days for EM, and greater than or equal to 15 days for CM.¹ It is estimated that 0.9% to 5.1% of the population meet the criteria for CM,² making its incidence significantly rarer than that of EM, which is approximately 11% to 15%.³ Nevertheless, evidence exists for CM being associated with greater disability,⁴ reduced quality of life, increased resource utilization, and increased comorbidities, presenting a serious challenge for both patients and clinicians.¹ Like EM, CM is more prevalent in women compared with men with migraine.¹ 

Generally, the evolution of EM to CM is referred to as “progression,” “chronification,” or “transformation”.¹ Research over the last decade has culminated in four partially overlapping clinical trajectories of the natural history of migraine—persistence, progression, partial remission (can include reversion of chronic to episodic migraine), and complete remission¹—supporting a transition model whereby various risk factors contribute to disease evolution.⁵ Because only a small subset (2% to 4%) of patients with EM progress to CM,¹ the identification of these risk factors is key to unfolding underlying mechanisms and implementing preventive measures.¹

Risk factors for chronification

Recently, a number of published cohort and case studies associated with risk factors for migraine progression were systematically reviewed, providing an overview of where current evidence stands in understanding chronification.¹

RISK FACTORS WITH relatively STRONG EVIDENCE

Higher headache day frequency

At least 4 cohort studies have confirmed previous data substantiating that high headache frequency, or number of headache days per month, is a significant risk factor for migraine progression.¹ In an American Migraine Prevalence and Prevention (AMPP) study, mean baseline headache days per month in patients with EM who progressed to CM was significantly higher than patients who did not (6.8 and 2.6, respectively).⁶ In another study, the odds ratio of developing CM was significantly higher in patients with EM who had 10 to 14 headache days per month compared to those who had 6 to 9 headache days (20.1 and 6.2, respectively).⁷ Intriguingly, however, recent data have shown that natural fluctuations occur in headache frequency due to chance alone—this may warrant some reconsideration of emphasizing headache days as a risk factor of migraine progression in rigid diagnostic criteria, and reexamine a wider range of disease characteristics instead.⁸

Depression

Migraine and depression are highly comorbid.¹ A large AMPP cohort study showed depression was a significant predictor of EM to CM progression and demonstrated a dose‑response relationship; as depression severity increased, the risk of progression increased.⁶ Depression remained a strong predictor even after adjusting for covariates such as sociodemographic and headache characteristics, and also often preceded migraine progression, potentially signifying a causal role.⁶ Notably, several studies presenting anxiety as a risk factor have also been published, suggesting a variety of psychiatric comorbidities may contribute to migraine progression.⁹

Acute and prophylactic medication use

At least 4 large, geographically diverse cohort studies have indicated that poor treatment optimization, often involving acute medication (with an emphasis on barbiturates and opioids) use or overuse, is a potential risk factor for migraine progression.¹ A dose-response relationship has been observed for barbiturates, whereby a greater number of days of medication use predicted a higher odds of progression to CM.¹⁰ In line with these data, ineffective acute treatment (poor treatment efficacy leading to longer periods of exposure to pain) has been associated with a dose‑dependent increase in the risk of transition from EM to CM in the AMPP study.¹¹

OTHER POSSIBLE RISK FACTORS with limited evidence

Persistent frequent nausea associated with migraine

Persistent and frequent nausea (PFN) is defined as the presence of nausea more than half of the time with migraine for 2 consecutive years.¹² The AMPP study has shown that PFN can approximately double the risk of progression from EM to CM.¹²

Cutaneous allodynia

Cutaneous allodynia is the perception of pain in response to typically non-painful stimuli to the skin, is associated with central sensitization of trigeminal neurons, and is a common feature experienced by migraineurs.¹ Data from the large cohort Leiden University Migraine Neuro-Analysis (LUMINA) study found that cutaneous allodynia is a significant and independent predictor of an increase in migraine days over time.¹³ Because allodynia is a physiological response, this could suggest important clues for understanding migraine progression.¹

Obesity

Obesity was significantly associated with chronification of migraine in at least one analysis, although this study examined wider chronic daily headaches (CDH), expanding the patient criteria beyond just those with CM.¹⁴ Nevertheless, the magnitude of the cohort study and high odds ratio reported makes obesity one of the major lifestyle-related risk factors of interest.¹

Other possible risk factors

Some evidence exists for asthma and sleep disturbances (notably snoring and insomnia) being risk factors for migraine progression, as well as caffeine consumption, major stressful life events, and non-cephalic pain.¹ Genetic and epigenetic factors have also been investigated, albeit with minimal evidence so far.¹ In terms of sociodemographic factors, association between onset of CDH and age, gender, marital status, educational level, and race has not produced statistically significant results.¹⁴

Current hypotheses for migraine progression

In light of the combined data from some of the largest cohort and case studies, an integrative hypothesis of migraine progression has been proposed whereby a combination of risk factors contribute to persistent activation of the trigeminovascular pathway.¹ Cutaneous allodynia may be a symptom of an increased trigeminal response, reflecting physiological progression.¹ Whether cutaneous allodynia is more likely a risk factor or a symptom is still unclear. However, its potential utility as a biomarker for progression would be a valuable tool for clinicians and patients.¹

The path to remission

Few studies have examined interventions to modify risk factors and monitor subsequent remission of CM in a well-controlled fashion, making reversion and remission understudied areas.¹ At least one study has reported that weight loss resulted in reduction of migraine days after bariatric surgery.¹⁵ Behavioral sleep modification has also been shown to support reversion of CM to EM.¹⁶ Lastly, botulinum toxin treatment, approved in some regions for the treatment of CM, has demonstrated reductions in headache frequency and related disability in patients with CM.¹⁷ Further large-scale, blinded studies are necessary to test whether other risk factors can be addressed to achieve migraine reversion or remission.¹

Diagnostic criteria for migraine may need to be re-examined

The International Classification of Headache Disorders criteria, which define EM and CM today, evolve over time as increasing data become available.¹⁸ Recently, increasing evidence suggests that high-frequency cases of EM (8–14 headache days per month) and CM are more similar than different on many features including sociodemographics, migraine-related disability, and comorbidities.¹ If this concept becomes further corroborated, a multilevel or continuous spectrum for migraine, rather than a dichotomous classification, could become more widely adopted.¹

Migraine progression likely occurs due to a combination of genetic, epigenetic, social, behavioral, and environmental risk factors.¹ Future work should build more robust data on these risk factors and include more longitudinal studies to account for the natural fluctuations of headache, in order to achieve a more refined understanding of disease evolution.¹

References

1. Buse DC, Greisman JD, Baigi K, Lipton RB. Migraine Progression: A Systematic Review. Headache 2019;59(3):306–38. 
2. Natoli JL, Manack A, Dean B, et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia 2010;30(5):599–609. 
3. Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci 2017;372:307–15.
4. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 2003;43(4):336–42.
5. Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology 2008;71(11):848–55. 
6. Ashina S, Serrano D, Lipton RB, et al. Depression and risk of transformation of episodic to chronic migraine. J Headache Pain 2012;13(8):615–24. 
7. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62(5):788–90.
8. Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache Pain 2017;18(1):101.
9. Smitherman TA, Rains JC, Penzien DB. Psychiatric comorbidities and migraine chronification. Curr Pain Headache Rep 2009;13(4):326–31.
10. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48(8):1157–68.
11. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology 2015;84(7):688–95.
12. Reed ML, Fanning KM, Serrano D, Buse DC, Lipton RB. Persistent frequent nausea is associated with progression to chronic migraine: AMPP study results. Headache 2015;55(1):76–87.
13. Louter MA, Bosker JE, van Oosterhout WPJ, et al. Cutaneous allodynia as a predictor of migraine chronification. Brain 2013;136(11):3489–96. 
14. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003;106(1–2):81–9.
15. Bond DS, Vithiananthan S, Nash JM, Thomas JG, Wing RR. Improvement of migraine headaches in severely obese patients after bariatric surgery. Neurology 2011;76(13):1135–8.
16. Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache 2007;47(8):1178–83.
17. Boudreau GP, Grosberg BM, McAllister PJ, Lipton RB, Buse DC. Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: An open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety. Int J Gen Med 2015;8:79–86. 
18. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1–211. 

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