Chronic migraine

INTRODUCTION — Chronic daily headache is a descriptive term that encompasses several different specific headache diagnoses characterized by frequent headaches. Primary chronic daily headache disorders with individual headaches of long duration (ie, four hours or more) include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache.

This topic will discuss chronic migraine. Other types of chronic daily headache are reviewed elsewhere. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)

PATHOPHYSIOLOGY — The pathophysiology of migraine centers on the trigeminovascular system. This is discussed in detail separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Pathophysiology'.)

Although the pathophysiology of the transformation from episodic to chronic migraine is not well understood, it is hypothesized that atypical pain processing, cortical hyperexcitability, neurogenic inflammation, and central sensitization are involved [1,2]. Furthermore, in patients with migraine, functional and structural alterations in the brain have been identified that correlate with longer disease duration and increased headache frequency [3,4]. However, it is not clear whether these alterations lead to chronic migraine. They may be simply markers of transformation or secondary effects from frequent migraine attacks.

EPIDEMIOLOGY — Chronic migraine affects approximately 2 percent of the world population [5]. It causes significant reductions in quality of life and is even more disabling than episodic migraine [6-9]. In addition, chronic migraine results in enormous expense to society. In the United States, the direct and indirect costs of migraine are estimated to be more than 20 billion dollars annually, and a significant proportion of this cost is attributable to chronic migraine [10].

Some patients with an episodic migraine pattern (<15 headache days a month) transition to a chronic migraine pattern (≥15 headache days a month), a transition that has been called "transformation" and "chronification" [11]. Among patients with episodic migraine, transformation to chronic migraine occurs in approximately 3 percent per year [12]. Those with more comorbidities, such as respiratory, cardiovascular, digestive, psychiatric, central nervous system, and pain disorders, have an increased likelihood for transformation to chronic migraine [13].

Nonmodifiable risk factors for the transformation from episodic to chronic migraine include the following [1,14-20]:

●Female sex

●Genetic makeup

●History of head or neck injury

●Low education level

●Low socioeconomic status

●Stressful life events (eg, divorce, job loss)

●Younger age

●Presence of cutaneous allodynia

●Comorbid pain disorders

Potentially modifiable risk factors for this transformation include [1,14-18,20-25]:

●Higher baseline headache frequency

●High frequency use or overuse of abortive headache medications

●Depression

●Habitual snoring

●High caffeine consumption

●Obesity

●Sleep disorders

●Low efficacy of acute migraine treatment

●Persistent, frequent nausea

●Asthma

A 2020 meta-analysis of 11 cohort studies found the strongest risk factors for transformation to chronic migraine were higher baseline headache frequency, depression, cutaneous allodynia, and medication overuse [25]. Further study is needed to determine if altering modifiable risk factors decreases the rate of transformation from episodic to chronic migraine.

Patients who develop chronic migraine may revert to episodic migraine, as discussed below. (See 'Prognosis' below.)

CLINICAL FEATURES

Headache — Many patients with chronic migraine have daily or near-daily mild-to-moderate intensity headaches and mild migrainous features with superimposed severe intensity headaches with more prominent migrainous features such as photophobia, phonophobia, osmophobia, nausea, vomiting, and cutaneous allodynia (ie, the perception of pain produced by innocuous stimulation of normal skin). (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Clinical features'.)

Comorbid conditions — In observational studies, patients with chronic migraine have a high frequency of comorbid psychiatric disorders, sleep disorders, respiratory disorders, fatigue, cardiovascular disorders, other types of pain, and gastrointestinal symptoms; migraine is also associated with a small increase in the absolute risk of ischemic stroke [26-35].

●In one study, psychiatric comorbidities among 152 patients with chronic migraine included major depression, dysthymia, panic disorder, and generalized anxiety disorder, observed in 57, 11, 30, and 8 percent, respectively [27].

●In another study of 63 patients with chronic migraine, two-thirds meet criteria for chronic fatigue syndrome [28].

●In a report of 101 patients with chronic migraine, the diagnostic criteria for fibromyalgia were fulfilled by 36 percent [29].

●In a sample of 1283 migraineurs who presented for evaluation to a tertiary headache clinic, patients with chronic migraine slept less than those with episodic migraine and were more likely to report difficulty falling and staying asleep [30]. In a study of 12,810 patients with migraine, those with chronic migraine (9 percent) were more likely to report poor sleep quality, snoring, and somnolence [36].

●Among 150 patients with chronic migraine complicated by probable medication overuse headache, the most common comorbidities were psychiatric and gastrointestinal, identified in 76 and 43 percent, respectively [31].

●Accumulating evidence supports an association between migraine, particularly migraine with aura, and ischemic stroke risk. However, the absolute increase in the risk of stroke is small. Migraine may also be associated with an increased risk for other forms of cardiovascular disease such as myocardial infarction. These relationships are discussed separately. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention".)

Recognition and treatment of these comorbidities can result in improved health, greater quality of life, and may potentially result in higher migraine treatment success rates.

DIAGNOSIS — The diagnosis of chronic migraine depends upon a consistent clinical history.

The diagnostic criteria for chronic migraine requires the presence of headache for 15 or more days per month for more than three months, with the features of migraine headache present on at least eight days per month (table 1) [37]. These criteria allow for the inclusion of migraine headaches that are treated early after the onset, prior to the development of typical migraine characteristics, when they may resemble tension-type headaches.

Chronic migraine (table 1) must be differentiated from other forms of chronic daily headache, such as chronic tension-type headache (table 2), hemicrania continua (table 3), new daily persistent headache (table 4), and secondary headaches. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)

MANAGEMENT — The treatment of chronic migraine should focus on prophylactic therapy while avoiding migraine triggers and limiting the use of acute headache medications that are associated with medication overuse headache [1,35]. Prophylactic interventions may include pharmacotherapy, behavioral therapy, physical therapy, and other strategies. Management often requires the simultaneous use of these different therapeutic modalities.

Identification and treatment of comorbid disorders is also important. (See 'Comorbid conditions' above.)

The use of acute headache medications should be limited to minimize the risk of medication overuse headache, but severe superimposed migraine attacks are treated in the same manner as episodic migraine attacks. (See "Acute treatment of migraine in adults" and "Preventive treatment of episodic migraine in adults".)

Patients and clinicians should have realistic treatment expectations with regard to chronic migraine. The overall goal is control of headaches as opposed to eradication. It is reasonable to expect reductions in headache frequency, severity, duration, and/or headache-related disability with a well-considered treatment plan.

Pharmacotherapy — Many prophylactic medications used for episodic migraine are also used for the prevention of chronic migraine based on efficacy for prevention of episodic migraine, tolerability, insurance coverage, and cost (table 5). Preventive medications for chronic migraine treatment are less well studied than they are for episodic migraine. In addition, some trials evaluating treatment of chronic migraine are limited by one or more methodologic problems, such as small size, concomitant use of other prophylactic medications, and/or lack of a specific headache diagnosis [38]. (See "Preventive treatment of episodic migraine in adults".)

First-line agents — We suggest starting with one of the first-line agents, based on individual patient factors. (See 'Choosing an agent' below.)

First-line prophylactic medications for chronic migraine include:

●Propranolol

●Amitriptyline

●Topiramate

●Valproic acid and its derivatives (for males and for females who do not have childbearing potential)

It is expected that up to 50 percent of patients treated with one of these medications will have at least a 50 percent reduction in the frequency of headaches after three months of treatment, given adequate doses. However, side effects are common and may limit the use of these prophylactic agents.

Topiramate has at least two randomized placebo-controlled trials supporting its use for chronic migraine prophylaxis [39-41]. There is lower-quality evidence for chronic migraine prophylaxis with valproic acid and derivatives, gabapentin, tizanidine, amitriptyline, atenolol, memantine, zonisamide, and pregabalin [42-50]. Nevertheless, some of these agents (eg, propranolol, amitriptyline) are considered first line for chronic migraine treatment based upon clinical experience and strong data supporting their benefit in episodic migraine.

Second- and third-line agents — We suggest the use of second-line agents for the prevention of chronic migraine for patients with a contraindication to or inadequate response (after at least eight weeks at a therapeutic dose) of two or more first-line drugs, in agreement with guidelines [51]. We use third-line agents when first-line and second-line agents have failed or are contraindicated.

In addition, alternative therapies may be used as adjunctive therapy when initial treatment provides partial but suboptimal benefit. These recommendations are based upon our clinical experience. Like first-line agents, the choice among the second- and third-line therapies depends upon individual patient factors. (See 'Choosing an agent' below.)

For patients with chronic migraine that is refractory to adequate trials of first-line agents, several other drugs are potential alternatives, including the following:

●Second-line agents:

•OnabotulinumtoxinA

•Calcitonin gene-related peptide (CGRP) antagonists (erenumab, fremanezumab, galcanezumab, eptinezumab, atogepant)

•Occipital nerve block (ONB)

•Venlafaxine

•Verapamil

•Other beta blockers (atenolol, nadolol, metoprolol)

•Gabapentin

•Magnesium

•Riboflavin

•Candesartan

•Other tricyclic antidepressants (nortriptyline, protriptyline)

●Third-line agents:

•Feverfew

•Tizanidine

•Memantine

•Pregabalin

•Cyproheptadine

•Zonisamide

There is evidence from randomized placebo-controlled trials supporting the efficacy of onabotulinumtoxinA, CGRP antagonists, and occipital nerve blocks for chronic migraine. (See 'Botulinum toxin' below and 'CGRP antagonists' below and 'Occipital nerve block' below.)

The effectiveness of the remaining second-line medications for episodic and chronic migraine is uncertain, as most have been studied only on a limited basis. (See "Preventive treatment of episodic migraine in adults", section on 'Calcium channel blockers' and "Preventive treatment of episodic migraine in adults", section on 'Other agents'.)

Evidence of efficacy

Botulinum toxin — Initial randomized trials evaluating botulinum toxin injection for chronic migraine (≥15 headache days a month) or chronic daily headache yielded mixed results [52-54], but the findings from two relatively large 24-week multicenter randomized controlled trials (PREEMPT 1 AND PREEMPT 2) suggest that onabotulinumtoxinA is effective for the treatment of chronic migraine [55,56].

In PREEMT 1, a trial of 679 patients with chronic migraine, the reduction in headache episodes from baseline to week 24 was similar in treatment and placebo groups (-5.2 versus -5.3 days), but patients assigned to onabotulinumtoxinA had greater improvements in secondary outcome measures, including fewer headache days and fewer migraine days, than those assigned to placebo [55].

In PREEMT 2, a trial that included 705 patients with chronic migraine, patients assigned to onabotulinumtoxinA had a greater reduction in the number of monthly headache days than those assigned placebo (9 versus 7 days) [56]. Improvements in secondary outcome measures were also greater with onabotulinumtoxinA.

Pooled analyses of data from the PREEMPT 1 and PREEMPT 2 trials, which together enrolled 1384 adults, found differences favoring onabotulinumtoxinA for a decrease in the frequency of headache days relative to baseline (the same primary outcome as PREEMPT 2) and for nearly all secondary outcomes except the frequency of acute headache pain medication intake [57,58]. The rate of treatment discontinuation due to adverse events was low, but it was higher for onabotulinumtoxinA than for placebo (3.8 versus 1.2 percent). In addition, the placebo response was high in these trials, and the difference between onabotulinumtoxinA injection and placebo for many of the outcomes was modest, even if statistically significant [55-57]. A meta-analysis of observational data similarly found onabotulinumtoxinA was associated with reductions in the number of monthly headache days and other headache outcome measures when assessed at 24 and 52 weeks [59].

Overall, these and other data support the utility of botulinum toxin injection as moderately effective for the treatment of chronic migraine [60-62]. However, several factors have led us to consider it as second-line therapy. These factors include the following:

●Administration must be performed in a clinical setting, by an experienced clinician.

●Cost is high compared with many oral agents.

●Restrictive policies of some insurance companies limit reimbursement for onabotulinumtoxinA to patients who fail or are unable to tolerate other prophylactic medications.

In addition, some patients report a "wear-off" period days to weeks before the next onabotulinumtoxinA injections are due, a phenomenon that has not been well studied. During this period, patients often report an increase in headache frequency. In a prospective report of 24 patients, the wear-off phenomenon commenced around the eighth week post injection [63]. In a retrospective study of 143 patients, wear-off occurred in 63 percent, commonly two to four weeks before subsequent injections were due [64]. During this wear-off period, bridge therapy with craniocervical peripheral nerve blocks, intramuscular ketorolac, and other treatments can be used [64].

CGRP antagonists — Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) ligand or its receptor are available for migraine prevention (table 6). Agents used for prevention of chronic migraine include eptinezumab, erenumab, fremanezumab, galcanezumab, and atogepant. However, given their high cost and insurance coverage stipulations, we consider these CGRP antagonists as second line, even though there is high-quality evidence for their efficacy (modest) and tolerability. (See 'Pharmacotherapy' above and "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

CGRP is a therapeutic target in migraine because of its role in mediating trigeminocervical pain transmission and the vasodilatory component of neurogenic inflammation. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Role of calcitonin gene-related peptide'.)

●Fremanezumab – A randomized controlled trial of 1130 adults with chronic migraine evaluated fremanezumab, which selectively binds to CGRP [65]. The trial randomly assigned subjects in a 1:1:1 ratio to subcutaneous injections of fremanezumab quarterly, fremanezumab monthly, or matching placebo. At 12 weeks, fremanezumab was modestly effective for reducing the average number of headache days per month (-4.3 days for the fremanezumab quarterly group, -4.6 days for fremanezumab monthly group, and -2.5 days for the placebo group). The corresponding absolute risk reduction (ARR) values for the fremanezumab quarterly and monthly groups were -1.8 and -2.1 days. Patients receiving placebo and newly enrolled patients were subsequently randomized to quarterly or monthly injections, and all patients were followed for another nine months. At 12 months, the reduction in baseline migraine burden was sustained with fremanezumab [66]. Subjects assigned to quarterly and monthly injections reported 7.2 and 8.0 fewer migraine days per month, respectively. Another trial of fremanezumab demonstrated its modest efficacy among individuals with chronic migraine for whom two to four classes of migraine preventive medication had failed within the prior 10 years [67]. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

●Erenumab – A randomized 12-week placebo-controlled trial of over 600 patients with chronic migraine evaluated subcutaneous erenumab, which inhibits the CGRP receptor [68]. Erenumab 70 mg and 140 mg given by subcutaneous injection every four weeks reduced monthly migraine days versus placebo (both doses -6.6 days, versus -4.2 days for placebo; ARR -2.4 days). Results from a one-year open-label extension phase suggested that long-term efficacy was sustained [69]. Other studies have reported that erenumab is associated with improvements in quality of life and reductions in headache-related disability and appears to be effective even when medication overuse is present and when prior migraine preventive medications have failed [70-72].

Erenumab appears to be effective for patients with chronic migraine with and without aura. In a secondary analysis of four clinical trials involving 667 patients with chronic migraine, erenumab 70 mg or 140 mg provided greater reductions in monthly migraine days by 12 weeks compared with placebo. The effectiveness of erenumab over placebo was also sustained when results, as assessed by the proportion of patients reporting at least a 50 percent reduction in the number of monthly migraine days by 12 weeks, were stratified among those with chronic migraine with (42 percent for 70 mg, 46 percent for 140 mg, 24 percent for placebo) and without aura (39 percent for 70 mg and 140 mg, 23 percent for placebo) [73]. Adverse effects were mild and similar between groups.

●Galcanezumab – Another controlled trial of 1113 adults with chronic migraine evaluated galcanezumab, which targets the CGRP ligand [74]. Participants were randomly assigned to monthly subcutaneous injections in a 1:1:2 ratio of galcanezumab 120 mg (with a 240 mg loading dose), galcanezumab 240 mg, or placebo. At three months, reductions in the mean number of monthly migraine headache days were greater for galcanezumab 120 mg and galcanezumab 240 mg compared with placebo (-4.8 and -4.2, versus -2.7 for placebo). The corresponding ARR values for the galcanezumab 120 mg and 240 mg groups were -2.1 and -1.5 days. Galcanezumab is also effective for patients who have not responded to prior preventive therapies [75,76]. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

●Eptinezumab – A randomized trial of over 1000 patients with chronic migraine evaluated intravenous eptinezumab, which targets the CGRP ligand, given at day 0 and week 12. At 12 weeks, the mean number of monthly migraine headache days was reduced with eptinezumab 100 mg (-7.7 days; ARR -2.1 days) and 300 mg (-8.2 days; ARR -2.6 days), compared with placebo (-5.6 days) [77]. At 24 weeks, the reduction in mean monthly migraine headache days was sustained with eptinezumab 100 mg (-8.2 days; ARR -2.0 days) and 300 mg (-8.8 days; ARR -2.6 days) compared with placebo (-6.2 days) [78].

●Atogepant – Atogepant is a small-molecule CGRP antagonist available by oral administration. A clinical trial evaluated 778 patients with chronic migraine who were randomized to atogepant or placebo [79]. The baseline frequency of migraine was a mean of 19 monthly migraine days. At 12-week follow-up, the mean reduction in baseline monthly migraine days was greater for patients assigned to atogepant 60 mg once daily or 30 mg twice daily than those assigned to placebo (-6.9 and -7.5 versus -5.1 days). In addition, the proportion of patients who achieved ≥50 percent reduction of monthly migraine days was also higher with atogepant 60 mg once daily and atogepant 30 mg twice daily (41 and 43 versus 26 percent). Treatment was well tolerated with the most common adverse effects being nausea and constipation. Atogepant was approved for use in patients with chronic migraine by the FDA in 2023 [80].

The CGRP monoclonal antibodies were generally well tolerated in these clinical trials. Injection site reactions and hypersensitivity reactions were the most commonly observed adverse effects. Constipation and hypertension, at times causing serious complications, have been observed with erenumab. Cases of angioedema and anaphylaxis have also been reported [81,82]. Potential adverse effects of the CGRP monoclonal antibodies related to pregnancy or breastfeeding are unknown and thus should be avoided.

CGRP antagonists may also provide additional benefit to patients with chronic migraine with a partial response to onabotulinumtoxinA [83]. In a retrospective study of 153 patients with chronic migraine treated with onabotulinumtoxinA, 73 percent (111 patients) reported a reduced headache burden after adding a CGRP antagonist [84]. There were no serious adverse events. In another retrospective study of 78 patients with chronic migraine, the addition of erenumab was associated with a reduction of approximately 7 monthly headache days at one month from a baseline of 23 mean monthly headache days on onabotulinumtoxinA alone [85]. These results were sustained at 60 and 90 days. Clinical trials are necessary to confirm results from these retrospective studies [83,85].

The use of CGRP antagonists for the prevention of episodic migraine is discussed separately. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

Occipital nerve block — Local injection of an anesthetic agent often used for occipital neuralgia has also been used for some headache disorders. ONB may modulate nociceptive activity in afferent pathways that converge on the trigeminal ganglion and reduce the likelihood of developing headache and migraine attacks. In a small trial of 44 patients with chronic migraine who received bilateral greater occipital nerve injections every four weeks for 12 weeks, those who received lidocaine 40 mg had a greater mean reduction in the number of migraine days at weeks 9 to 12 than patients who received placebo (least squares mean reduction -4.7 days, 95% CI -7.7 to -1.7) [86]. In addition, patients who received lidocaine injection were likelier to report ≥50 percent reduction in headache days (41 versus 9 percent). Adverse events were mild and transient and occurred at similar rates in treatment and placebo groups. Most common events were injection site bleeding and pain.

ONB may also have benefit as adjunctive therapy for patients treated with pharmacotherapy. In a clinical trial that assessed the effect of adding ONB to pharmacotherapy with topiramate, 125 patients with chronic migraine were randomized to receive topiramate titrated up to 50 mg twice daily as monotherapy, topiramate with bilateral ONB consisting of lidocaine 40 mg and methylprednisolone 80 mg followed by monthly ONB with lidocaine for two months, or topiramate with bilateral ONB consisting of lidocaine 40 mg for three months [87]. At three-month follow-up, the groups who received ONB both with and without initial glucocorticoid had greater reductions in monthly migraine days than those who received topiramate monotherapy (-9.6 and -10.1 versus -7.3 days). The responder rate, defined as achieving ≥50 percent reduction in mean monthly headache days, was also higher for patients who received additional ONB with or without glucocorticoid (71 and 62 versus 39 percent). The most common adverse events likely attributable to the ONBs included local site bleeding and swelling as well as alopecia in those receiving glucocorticoid.

Choosing an agent — The choice of specific prophylactic agent for either episodic or chronic migraine depends upon individual patient factors, including the presence of comorbid conditions such as medical disorders, psychiatric disorders, sleep disorders, fatigue, other types of pain, and gastrointestinal complaints (table 5). As an example, tricyclics or other antidepressants may be preferred for patients who are depressed or are prone to depression. On the other hand, beta blockers may be preferred for patients with hypertension. However, with some preventive agents, the doses used to treat migraine are insufficient to treat comorbid conditions. Thus, dosing may need to be adjusted if the intent is to treat a comorbid condition.

Regardless of the drug chosen, application of certain principles may improve the success rate of prophylactic migraine therapy and reduce complications:

●Start oral drugs at a low dose and increase gradually.

●Give the chosen medication an adequate trial:

•For oral medications, at least eight weeks at goal dose range [88]; the typical dosing of oral medications for migraine prophylaxis is reviewed in detail separately. (See "Preventive treatment of episodic migraine in adults".)

•For botulinum toxin, a minimum of three sets of injections separated by 12 weeks, since a substantial number of patients who do not respond to the first injection respond to the second or third one [89].

•For monoclonal antibodies targeting the CGRP ligand or its receptor, a minimum of three months for those administered monthly and six months after the start of quarterly treatments [88].

●Avoid overuse of acute headache medications.

●Avoid valproate for females of childbearing potential unless it is essential to management and alternative therapies are not appropriate.

●Address patient expectations and preferences.

These points are discussed in greater detail elsewhere. (See "Preventive treatment of episodic migraine in adults", section on 'Principles of preventive therapy'.)

Nonpharmacologic therapy — Nonpharmacologic forms of therapy may be useful for the treatment of chronic migraine. Modalities include behavioral therapy (eg, biofeedback, cognitive-behavioral therapy, stress management, relaxation therapy), physical therapy (eg, exercise, heat, cold packs), and neurostimulation. In addition, therapeutic lifestyle changes (eg, good sleep hygiene, routine meal schedules, regular exercise) and avoidance of migraine triggers are often advocated for patients with chronic migraine [35]. However, there is a paucity of high-quality studies examining the role of nonpharmacologic interventions specifically for chronic migraine.

Avoidance of migraine triggers — Patients with chronic migraine are more likely to have headaches triggered by stress, not eating, odors, neck pain, smoke, sleeping late, and exercise than patients with episodic migraine [90]. These are discussed in detail separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Precipitating and exacerbating factors'.)

Avoidance of specific migraine triggers may reduce the frequency of headaches in patients with chronic migraine. Of course, patients with continuous headaches are less likely to be able to determine specific migraine triggers than those who have episodic headaches.

Behavioral and physical therapy — In agreement with guidelines for migraine headache (mainly based upon studies of episodic migraine) from the American Academy of Neurology (AAN) published in 2000 [91], we suggest the use of behavioral therapy for migraine prevention. Options include relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, or cognitive-behavioral therapy. The choice among these interventions should be individualized according to factors that include clinician familiarity, local availability and expertise, and patient preference.

In our clinical experience, physical therapy may be useful for the treatment of chronic migraine in patients who have constant muscle tension or in those who report onset of muscle tension preceding migraine headaches. Of note, the AAN guidelines concluded that evidence-based recommendations could not be made regarding the use of hypnosis, acupuncture, transcutaneous electrical nerve stimulation, chiropractic or osteopathic cervical manipulation, occlusal adjustment, or hyperbaric oxygen [91].

Both behavioral therapy and physical therapy may be combined with each other and/or with preventive drug therapy [92].

Neurostimulation

●Transcranial magnetic stimulation – Limited observational evidence suggests that single-pulse transcranial magnetic stimulation (sTMS) may be effective for migraine prevention, as reviewed separately [93]. (See "Preventive treatment of episodic migraine in adults", section on 'Neuromodulation'.)

●Transcutaneous supraorbital nerve stimulation – There is evidence from at least one small randomized-controlled trial that supraorbital transcutaneous electrical nerve stimulator is beneficial for migraine prevention, as reviewed elsewhere [94] (see "Preventive treatment of episodic migraine in adults", section on 'Neuromodulation'). Evidence from a small open-label study suggests benefit for some patients with chronic migraine as well [95].

●Occipital nerve stimulation – There are inconsistent data from small randomized trials regarding the benefit of occipital nerve stimulation for the treatment of chronic migraine [96,97]. In the largest trial, there was no significant difference at 12 weeks for the primary endpoint, the percentage of patients who had a ≥50 percent reduction in mean daily pain score in the active compared with the control group [97]. However, there were statistically significant if modest improvements with active stimulation for a number of secondary endpoints, including the percentage of patients with a ≥30 percent reduction in mean daily pain score, and reduction in the mean number of headache days and migraine-related disability. The findings from these reports are limited by concerns about blinding in the control (sham treatment) groups, given that active treatment causes paresthesia, and relatively high rates of complications, including lead migration in 14 to 24 percent of subjects [96-99].

●Noninvasive vagus nerve stimulation – A noninvasive vagus nerve stimulation (nVNS) device is approved by the US FDA for migraine prevention in adult patients. However, the efficacy of nVNS for migraine prevention is not established. In two randomized controlled trials, the mean reduction in the number of headache days per month was greater for patients assigned to nVNS compared with sham stimulation, but the difference was modest and did not reach statistical significance [100,101].

PROGNOSIS — Chronic migraine may revert to episodic migraine over time in 26 to 70 percent of patients [102,103].

●The largest study, conducted by mailed questionnaire, followed 383 respondents with chronic migraine [103]. After two years, chronic migraine had remitted to either low-frequency episodic migraine (≤9 headache days/month), other episodic headache, or no headache in 26 percent. Predictors of remission were lower baseline headache frequency and absence of cutaneous allodynia.

●Another report evaluated 136 patients with chronic migraine who presented to a specialty headache clinic and were followed for one year [102]. Reversion to episodic migraine from transformed migraine was observed in 95 patients (70 percent). Predictors of reversion included complete withdrawal of overused medications, compliance with prophylactic medication regimens, and regular physical exercise.

Some patients have a pattern of moving in and out of a chronic migraine state over time [1,20,104].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Migraines in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Migraines in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Chronic migraine occurs when patients with an episodic migraine pattern transition to a pattern of ≥15 headache days a month. Many patients with chronic migraine have daily or near-daily headaches of mild to moderate severity. Superimposed on this baseline are exacerbations of pain with more prominent migrainous features. (See 'Clinical features' above.)

Patients with chronic migraine have a high frequency of comorbid psychiatric disorders, sleep disorders, fatigue, respiratory disorders, other types of pain, gastrointestinal complaints, cerebrovascular disease, and cardiovascular disease. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of chronic migraine depends upon a consistent clinical history (table 1). Chronic migraine also must be differentiated from other forms of long-duration primary chronic daily headache, including chronic tension-type headache (table 2), hemicrania continua (table 3), and new daily persistent headache (table 4). (See 'Diagnosis' above.)

●Management – The management of chronic migraine should focus on prophylactic therapy and avoidance of acute headache medication overuse. Prophylactic interventions may include pharmacotherapy, behavioral therapy, physical therapy, lifestyle modification (good sleep hygiene, routine meal schedules, regular exercise), neuromodulation, and avoidance of migraine triggers. Management often requires the simultaneous use of these different therapeutic modalities. (See 'Management' above.)

•Pharmacotherapy – The choice among migraine prophylactic agents depends upon individual patient factors and comorbid conditions (table 5). (See 'Pharmacotherapy' above and 'Choosing an agent' above.)

-For patients with chronic migraine who desire pharmacologic treatment, we suggest a trial with one of the first-line prophylactic migraine medications (Grade 2C). First-line prophylactic agents are propranolol, amitriptyline, and topiramate; valproic acid and its derivatives are also first line for those who do not have childbearing potential. (See 'First-line agents' above.)

-For patients with chronic migraine who have failed treatment with at least two first-line agents, options include onabotulinumtoxinA injections, a CGRP antagonist (eg, erenumab, fremanezumab, galcanezumab, eptinezumab, or atogepant), verapamil, other beta blockers, venlafaxine, gabapentin, magnesium, riboflavin, candesartan, other tricyclic antidepressants, or occipital nerve blocks (ONBs). While comparative efficacy studies are lacking, botulinum toxin, CGRP antagonists, and ONBs have the most evidence of efficacy in placebo-controlled studies in these patients.

-Third-line agents for those who fail treatment with first- and second-line agents include feverfew, tizanidine, memantine, pregabalin, cyproheptadine, and zonisamide. (See 'Second- and third-line agents' above.)

•Nonpharmacologic options – For patients with chronic migraine who desire nonpharmacologic therapy, we suggest behavioral therapy (Grade 2C). Options include relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, or cognitive-behavioral therapy. As with medications, the choice among these interventions should be individualized. (See 'Behavioral and physical therapy' above.)