Background

The early years of synthetic production of corticosteroids dates to circa 1950. Corticosteroids early proven efficacy for different inflammatory musculoskeletal conditions (e.g., rheumatoid arthritis) were shortly followed by various clinical trials to study their efficacy to treat migraine attacks [1, 2]. Blumenthal (1952) [2] and Frohner (1953) [1] were the earliest to empirically test and demonstrate the clinical efficacy and utility of corticosteroids to manage migraine attacks among patients. Since those early days and to date, there have been 26 [3••, 4] heterogeneous clinical studies and four meta-analyses [5•, 6–8] examining the efficacy of corticosteroids in either aborting acute migraine attacks or recurrent headaches. Today, corticosteroids are known to be widely prescribed either as monotherapy or adjuvant therapy to other abortive medicines to treat for migraine attacks both within the outpatient and emergency clinical settings worldwide. In this article, we aim to provide careful examination and related updated discussions into the current evidence for corticosteroid administration, and offer type and dosage recommendations for treating in clinical practice to effectively abort migraine attacks.

Pain and Neurogenic Inflammation Interplay in Migraine Attacks

Present-day evidences indicate that migraine is a neurovascular inflammatory disorder, starting in the nervous system and secondarily affecting the vascular system [9–11]. Its head pain and accompanying sensory symptomatic phases are produced either peripherally or centrally; the former is triggered by abnormal activation of trigeminocervical neurons as primary afferents [12], while the latter is generated centrally at second-order neurons due to abnormal transition and regulation of orthodromically travelling peripheral signals [13–15]. That the trigeminal nucleus forms an inferior or caudal extension subserving not only facial and head but also nuchal sensory modulation explains the head and neck pain accompanying migraine attacks. Meningeal inflammatory symptoms are common during migraine presentation—which reminds the significance of sterile neural and meningeal inflammation occurring during these attacks.

Based on animal studies, trigeminocervical triggers emanating from peptidergic nociceptive afferents result in the release of neuropeptides onto second-order neurons of the trigeminal nucleus caudalis [11, 16, 17]. The very same peptidergic primary afferents are known to convey dual sensory-efferent functions whereby peptidergic peripheral terminals surrounding dural arterioles similarly release neuropeptides [17]. Neuropeptides are important in the neural regulation of arteriolar vasodilation, inflammatory cascades, and smooth muscular changes [11, 18]. At collateral neuronal branches, axon reflexes convert orthodomical action potentials to antidromic signals—thereby supplementing prejunctional trigeminovascular neuropeptide neuroregulation [11]. Vasodilatory neuropeptides released into dural vasculature include calcitonin gene-related peptide (CGRP), tachykinin peptides such as substance P (SP), and neurokinin A [19–21]. SP is known to stimulate histamine degranulation of dural mast cells and release of other pro-inflammatory molecules, i.e., nitric oxide (NO), prostaglandins (PGs particularly PGE2), leukotrienes (LT), serotonin (5-HT), histamine, proteolytic enzymes, and phospholipases from inflamed dura [21]. PGs and LTs, produced as a result of arachidonic acid metabolism are known to have algogenic (pain-inducing) properties through nociceptive afferent sensitization by lowering firing threshold [22].

Feedback mechanisms orchestrate between dural mast cells and trigeminal nociceptor terminals [23], where released histamine further stimulates discharge of vasoactive peptides, i.e., CGRP and SP [24]. Most of these inflammatory mediators can activate platelet aggregation around dural inflammation site; when activated, platelets secrete 5-HT which is another known nociceptive via actions specific to 5-HT3 receptor [19, 25, 26]. Neurally-induced inflammatory discharge of algogenic pro-inflammatory mediators, plasma protein extravasation, meningeal irritation, perivascular edema, and dural platelet aggregation are found to be important in animal models of trigeminal ganglion stimulation or animal dura mater inflammation [11, 27]. Neuronal changes are accompanied by pro-inflammatory and vascular changes [11, 27]. Among leaking proteins, bradykinin produces powerful algogenic responses on trigeminal nociceptor terminals [28]. This sequence of events related to complex inflammation-pain interplay is broadly termed sterile neurogenic inflammation (SNI) [11, 27]. In these animal models, SNI contributes to the development of hyperalgesia, pain prolongation, and peripheral sensitization of polymodal receptors [11, 13, 29]. SNI is theorized to be important in understanding perpetuated headache long after initial migraine triggers [11, 13]. However, SNI has not been translated to be relevant in the human condition of migraine [30, 31]. Among the vasoactive neuropeptides, CGRP has been inconsistently elevated in clinical studies [32]. Different clinical trials employing SNI inhibitors (e.g. SP or neurokinin receptor antagonists, neurosteroids such as ganaxolone) have been ineffective in both acute and preventive management of migraine [31, 33]. At this point, it would be interesting for future studies to explore for possible anti-nociceptive properties of corticosteroids.

Migraine Recurrence among Common Abortive Medications

Migraine patients receiving acute treatments measure the efficacy and outcome of the intervention as optimal when the headache is completely gone, does not recur and there are no adverse events. Headache recurrence is a common experience following discharge of migraine patients from both emergency and outpatient clinical settings. Here, we briefly describe migraine recurrence among the common acute care medications of triptans and discuss situations where corticosteroids can be helpful options.

Headache recurrence following oral triptan administration for migraine ascendingly averages 17 % for frovatriptan 2.5 mg [34], 20 % for naratriptan 2.5 mg [35], 26 % for eletriptan 40 mg [35], 28 % for zolmitriptan 5 mg [35], 31 % for sumatriptan 100 mg [35], 31 % for zolmitriptan 2.5 mg [35], 33 % for almotriptan 12.5 mg [35], and to 38 % for rizatriptan 10 mg [35] while 37 % for placebo [35]. When contraindications preclude the use of triptans or ergots (i.e., ergotamine tartrate or dihydroergotamine) or when such therapies fail, parenteral dexamethasone may provide another reasonable option for the office or ED treatment of resistant, severe, or prolonged episodic migraine [36]. Doctors often add a nonsteroidal anti-inflammatory to a triptan in patients with repeated bouts of recurrence following treatment. Another way to attempt to decrease recurrence is to ensure that the patient is taking the optimal dose and route of administration of the triptan they are using. Triptans come in a number of different forms and doses; the correct dose typically is the highest allowable dose. It is a common practice for physicians to decrease the dose only if patients have adverse effects, rather than increase the dose if they have recurrence. The goal is to treat with the highest dose initially; patients are much more likely to continue the medication than if there is no efficacy. When there are adverse effects, a patient can decrease the dose; if there is no effect, a patient would be much more reluctant to try the drug again at a higher dosage. In those patients who continue to have recurrence, one option is to add an NSAID and another is, the use of a longer-acting triptan, e.g., frovatriptan, although there is no proof that it might prevent the recurrence. Another consideration in the ED is the use of IV, SC, or IM dihydroergotamine, but this is contraindicated within 24 h of triptan use. One author (AMR) will use DHE after 4-5 half lives of the triptan have past. For sumatriptan that is 8-10 hours and for zolmitriptan it is 12-15 hours. When patients come to the ED having failed their triptan in appropriate doses, many ER physicians repeat the triptan by injection, use pain medication or start an IV for hydration or give dopamine antagonists. The last option would seem to work the best, but giving corticosteroids in this setting would be safe, easy and probably produce the desired result.

Guidelines and Recommendations for Systemic Corticosteroids Administration in Migraine

A recently completed pooled analysis of a 65-year systematic review has shown that corticosteroid administration can be effective in controlling both recurrent and acute migraine headaches; a slightly higher efficacy (in 78.6 % of the studies) was shown for controlling recurrent headaches, compared to controlling acute migraine headache (in 61.2 % of the studies) [3••]. The numbers needed to treat (NNT) was found to be 3 for 24-h and 10 for 72-h effective headache recurrence management [3••]. The different forms and dosages used within the studies reviewed in this recent systematic review include the following: parenteral dexamethasone in 56 % (median 10 mg), parenteral methylprednisolone in 4 % (500 mg), oral dexamethasone in 8 % (4 mg), oral dexamethasone in 4 % (8 mg), oral prednisolone (100 mg) 5-day-taper dose in 4 %, oral prednisolone (60-40-20 mg) 6-day-taper dose in 12 %, oral prednisolone (150 mg) in 4 %, oral dexamethasone (12-8-4 mg) 3-day taper in 4 %, and oral cortisone (50 mg) in 4 %—all these methods have shown either observable superior or non-inferior efficacy as compared to other abortive medications [3••]. As there exists positive clinical scientific evidence for effective oral dosing of corticosteroids (36 % of the clinical studies in this 65-year systematic review used oral doses successfully) [3••], it makes sense to consider using lower dose, oral corticosteroids, as they work well. Recommendations for systemic corticosteroid administration in managing migraine in emergency situations vary greatly as they do in the outpatient setting [36]. One author (AMR) uses 4 mg of dexamethasone orally (which may be repeated in 3 h for non-efficacy) for prolonged headache, lasting greater than 48 hour, status migrainosus, non-responsive headache and to avoid recurrence. Patients appear to go into a refractory period and say they feel great for several days and do not have to worry about migraine for a while.

Some independent guidelines such as the Agency for Healthcare Research and Quality (AHRQ) recommend corticosteroids only as a last resort for status migranosus and to be included only in an effort to smoothen transfer of care to specialty referral centers [3••, 36], while others, e.g., Canadian guidelines [37], relegate dexamethasone to a fourth-line treatment for resistant migraines [37, 38]. We certainly do not agree that this safe, inexpensive medication, with strong clinical evidence for efficacy in the most difficult migraineurs, should be relegated to fourth line or last resort. The cohort of patients for whom the efficacy of corticosteroids was high includes those presenting with status migrainosus, severe and resistant or refractory migraines, higher baseline disability, and previous history of recurrent headaches [3••]. In lower- and middle-resource settings where migraine burden is currently on the rise [39], corticosteroids offer not only effective treatment option but also being relatively available and affordable as compared to triptans or other parenteral forms of migraine medications [3••].

Approach to the Repetitive Emergency Visitor and Difficult-to-Treat Patient

At this juncture, it is essential to recognize the challenge presented by the common phenotype of the frequent emergency department visitor with migraine. Such patients usually have compulsive preoccupation with symptoms and express decompensated emotions besides other psychological and medical comorbidity [37, 40]. Some of them are opiate seekers or are simply convinced that their severe headaches has to be treated with opiates. Therefore, it is important to identify these difficult-to-treat patients who have developed such preconceived notions and may have comorbidities which overshadow their migraine. Corticosteroids may be useful in breaking their recidivism or “medication-seeking behavior” cycles.When it does not work, these patients need to be referred to headache specialists and behavioral psychologists and occasionally addiction specialists.

So we all need to conduct a careful assessment of each new patient headache type, patient expectation management, consideration of opiate and barbiturate use and dependency, medical and psychological comorbidities, previous misdiagnosis, mistreatment and undertreatment, and overmedication leading to medication overuse headache. Corticosteroids have also been shown to be efficacious as a bridge therapy for managing medication overuse headache. Expert recommendations for intermittent corticosteroids therapy include short tapering doses of up to six times per year. The recent systematic review did not reveal major adverse events; the lowest number needed to harm was 30 patients among the studies included [3••]. Treatment resistant and chronic migraineurs are often managed in a multimodal fashion where multiple disciplinary experts attend the patient’s problems from different angles, both on an inpatient and outpatient basis; corticosteroids are one of the main options for effective management of these patients.

Conclusion

Corticosteroids are among the oldest medicines used to treat migraine attacks. The cohort of patients for whom the efficacy of corticosteroids was high in our review includes those presenting with status migrainosus, severe and resistant or refractory migraines, higher baseline disability, and previous history of recurrent headaches. Various types of steroids and dosing protocols have been used both as mono- and adjunctive-therapies. Both oral and parenteral dosing have shown to be efficacious in aborting migraines, preventing recurrence and when other acute care medications have failed. Corticosteroid administration can smoothen transfer of care to a specialist setting; they should not be administered more than six times within 1 year. Adverse effects of short-tapers or single doses are mild and tolerable. Corticosteroids can be especially useful in the management of migraineurs who frequent the emergency room, and any patient in the outpatient setting whose migraine attack will not break or has not responded to appropriate migraine specific medications like triptans.