Current Treatment Options in Neurology

, Volume 15, Issue 1, pp 40–55

Current Concepts in Refractory Migraine

HEADACHE (JR COUCH, SECTION EDITOR)

DOI: 10.1007/s11940-012-0206-5

Cite this article as:
Schulman, E. & McGeeney, B.E. Curr Treat Options Neurol (2013) 15: 40. doi:10.1007/s11940-012-0206-5

Opinion statement

The Refractory or Intractable Migraine (RM) patient has long been a challenge to all healthcare providers (HCP). Headache specialists have recognized this sub group of patients who remain refractory to treatment. Despite this recognition, there are no formal criteria that characterize RM. This article will attempt to provide treatment approaches, some scientifically based and others that are empiric. A reasonable goal is to lessen disability. Combining the various modalities will improve the chances for successful treatment. The foundation of treatment is an emphasis on wellness. This includes optimizing mood, minimizing stress, practicing good sleep hygiene, and avoiding triggers. All comorbid factors should be addressed, including sleep and mood disorders, chronic neck pain, and obesity. Preventive treatment is necessary in the majority of patients, and a plan for “rescue” approaches is essential. Avoiding medication overuse, particularly narcotics, is advisable. Additional options for treatment include onabotulinumtoxinA, and more invasive modalities, such as neurostimulation. Adjunct treatment including supplements and relaxation may also be considered. Keeping a headache calendar is almost mandatory in management with attention to particular headache triggers, patterns and medication overuse (MOH). A trusting physician–patient relationship is also very important and will enhance compliance and foster communication. Patients often lapse from the management plan and the treating physician should be open minded about continuing care. RM is a long-term disease and requires close physician–patient interaction and cooperation for management of the problem. In those RM patients with multiple comorbidities, a multidisciplinary team should optimize management.

Keywords

Refractory Migraine Intractable Classification Definition Neurostimulation Supplements Sleep disorders Depression Anxiety Risk factors Abortive Prophylaxis Dopamine antagonists Opioids Anticonvulsants Nerve blocks Treatment 

Introduction

The diagnosis of RM is one of exclusion. Before treating the patient for RM, he or she should be carefully evaluated for unusual causes of headache. These include sphenoid sinusitis, pseudotumor cerebri, and venous sinus thrombosis, to name a few.

Few formal definitions for RM or intractable migraine have been proposed [1, 2, 3]. Some have included a rating scale to delineate the degree of intractability [4, 5]. The Refractory Headache Special Interest Section (RHSIS) of the American Headache Society (AHS) also published a commentary on the definition [6]. Despite these proposed definitions, none has been incorporated into the International Classification of Headache Disorders (ICHD). For this reason, no evidence-based treatments exist.

There are many challenges to a RM definition. Like with migraines, there are no biological markers, and criteria are largely based on satisfying treatment paradigms and optimizing comorbid factors. The authors are not endorsing any definition herein. For the purpose of this article the criteria crafted by RHSIS will be used [2] (Table 1).
Table 1

Proposed Criteria for Definition of Refractory Migraine and Refractory Chronic Migraine

Criteria

Definition

Primary diagnosis

A. ICHD-II migraine or chronic migraine

Refractory

B. Headaches cause significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy.

1. Failed adequate trials of preventive medicines, alone or in combination, from at least 2 of 4 drug classes:

a. Beta-blockers

b. Anticonvulsants

c. Tricyclics

d. Calcium channel blockers

2. Failed adequate trials of abortive medicines from the following classes, unless contraindicated:

a. Both a triptan and DHE intranasal or injectable formulation

b. Either nonsteroidal anti-inflammatory drugs or combination analgesics

Adequate trial

Period of time during which an appropriate dose of medicine is administered, typically at least 2 months at optimal or maximum-tolerated dose, unless terminated early due to adverse effects

Modifiers

With or without medication overuse, as defined by ICHD-II

With significant disability, as defined by MIDAS ≥ 11

DHE dihydroergotamine, ICHD International Classification of Headache Disorders, MIDAS Migraine Disability Assessment

RM is meant to be a subform of episodic migraine or chronic migraine (CM). This definition is operational in nature, addresses disability, and has worldwide applicability. It employs criteria addressing the use and effectiveness of acute and preventive medications, with modifiers for disability and medication overuse.

Tools used in crafting the criteria included the results of the Internet survey, a review of the literature and collaborative discussions. RM, as defined, must significantly impair function or quality of life, despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy.

This definition does serve as a starting point and increases the visibility of the disorder. There are several limitations of the criteria. For example, “impairment in quality of life” is admittedly broad. While pain and the associated migraine symptoms contribute to impaired QOL, fewer social interactions and less “family time” also constitute an aspect of the patient’s disability. In addition, the optimal definition of RM is determined by the context of diagnosis and the consequences of assigning this label in that context. “Lack of response” to acute medicine is more descriptive than it is a definitive parameter. Is achieving a sustained pain-free state a reasonable endpoint? Finally, what constitutes sufficient “improvement” from the use of a preventive treatment? A possible operational definition might be a sufficient improvement after preventive treatment so that adding a different or additional preventive would not be necessary.

Epidemiology

Headaches in 370 consecutive patients attending a headache clinic in tertiary centers were classified using the criteria proposed by the RHSIS [2]; 5.1 % of the patients evaluated had refractory migraines. Of the 19 patients, 58 % were female, with a mean age of 43, while 63 % had MOH, and the mean MIDAS score was 96 [7].

Integral aspects of RM definition

The RHSIS definition includes criteria that should be incorporated into any sanctioned definition (Table 2). These include a trial of both preventive and abortive treatment, optimizing comorbid disorders, avoiding known triggers and patient compliance. Medication overuse and degree of disability should also be considered. A definition of RM can serve to enhance patient care and serve as a foundation for identifying an improved understanding of the entity (Table 3).
Table 2

Integral Aspects of RM definition

• Failure of preventive treatment in adequate doses

• Failure of abortive therapy

• Comorbidity optimally addressed

• Assessed degree of disability

• Consideration of medication overuse

(From Schulman [49]; by permission of Oxford University Press, Inc)

Table 3

An RM definition will allow

• Triaging of patients to appropriate level of care

• Identification of effective treatment

• Better characterization of the disorder and identification of unmet needs

• Selection of criteria for inclusion in studies of novel pharmacological approach

• Identification of risk factors for development of progression to RM

• Construction of a paradigm for the treating physician

• Improvement in the understanding of the pathophysiology of RM

(From Schulman [49]; by permission of Oxford University Press, Inc)

Many recommendations in the literature have focused on individual cases or on small groups of patients. Often the authors of these reports used their own criteria as to what constitutes refractory. Some suggested treatments are based on consensus. Others have been characterized as “best practices.” The treatment options included reflect personal experience or those that are effective for migraine, but not necessarily for RM.

Until a broadly accepted RM definition exists, evidence-based treatment recommendations for RM cannot be generated. Newer treatment options include onabotulinumtoxinA, neurostimulation, and nerve blocks. Suggestions for rescue treatment will be discussed. It is often helpful to collaborate with a psychologist or psychiatrist, and a physical therapist. Both mood and musculoskeletal components may contribute to the headache and each should be optimized.

A physician–patient relationship, based on mutual respect and trust, is essential for successful treatment. The patient should have input into the treatment plan and must take responsibility for his or her own care by remaining compliant. The physician should remain supportive, yet set patient “limits” and emphasize reasonable expectations.

Patient “wellness” includes good sleep hygiene and carefully screening for any underlying sleep disorders. Patients should avoid skipping meals and eat in a healthy manner. Exercising, while not shown to be effective in preventing migraine, can serve to relieve stress and provides important “me” time [8].

Adjuncts to treatment include riboflavin, coenzyme Q10, magnesium and butterbur. Other nonpharmacologic treatments include acupuncture, relaxation exercises and cognitive therapy. The section on ‘Treatment Pearls and Pitfalls’ reflect insights and observations while treating these challenging patients. Many are reflective; others come from our colleagues who have shared their valuable experience. Some serve to support the physician and sustain our wellbeing.

Risk factors for progression to chronic migraine (CM)

Risk factors for CM have been identified. The risk factors may not be operational in causing RM, but they should be modified if possible [9].

Attack frequency

  • There is an increased risk for progression in those who experience three or more headaches per month.

  • Prevention should be considered in those with frequent headaches.

  • Forty percent of migraineurs may benefit from prevention. Only 13 % of migraine sufferers receive prevention treatment [10].

  • Early use of preventive treatment may inhibit transformation from migraine to RM [11].

Address obesity

  • Associated with episodic and chronic migraine [12].

  • Studies suggest that weight loss is associated with a decline in migraine frequency [13].

  • Avoid, if possible, preventive medications that predispose to weight gain, such as divalproex and amitriptyline.

Stress is particularly important in RM

  • The most common trigger for migraine is emotional stress [14]. The stress associated with migraine itself may act as a trigger, and this bidirectional influence can lead to increased migraine frequency.

  • Biofeedback and cognitive based therapy (CBT) can be helpful in managing stress [15].

Medication overuse headache (MOH)

  • Most believe that medication overuse hinders improvement, although scientific evidence is lacking.

  • Medication overuse can occur with OTCs, combination analgesics, and triptans. Some prohibit the use of aspirin, acetaminophen, and ibuprofen.

  • Triptans should be limited to two days per week. There is general agreement that opioids worsen headache and should be prescribed only as a last resort, and in limited quantities.

  • Tapering of analgesics is usually done slowly, often over weeks, and usually one analgesic at a time, i.e., tapering drug A, then B, then C. Abrupt tapering of high doses of butalbital compounds can precipitate seizures. Preventive compounds are often ineffective in the face of overuse. Educating patients on MOH is paramount, as they need to understand that medication overuse will likely prevent improvement.

Sleep disorders can contribute to RM

  • Sleep and headache are intimately related. Over or under sleeping may cause headache and yet, often, sleep relieves headache. Headache upon awakening is common with obstructive sleep apnea [16, 17, 18, 19•, 20].

  • Screen for sleep disorders and if indicated, evaluate with a polysomnogram. Common sleep disorders associated with headache include obstructive sleep apnea (OSA), periodic leg movement disorder, insomnia, hypersomnia, and circadian rhythm disorders.

  • Insomnia is the most common sleep disorder associated with headache, and may reflect anxiety.

Caffeine excess

  • Caffeine is present in coffee, teas, soft drinks and chocolate. Caffeine is also present in many OTC analgesics and energy drinks.

  • The caffeine content in coffee can vary from 107 mg (brewed) to 330 mg (Starbucks Grande).

  • Caffeine withdrawal occurs with as little as one caffeinated beverage per day [21].

  • Patients with CM tended to use more caffeine.

Other aspects thought to be associated with RM

Look carefully for mood and personality disorders

  • Assess for such as depression, anxiety, bipolar disorder, along with the borderline, antisocial, histrionic and narcissistic personality disorders.

  • It is very helpful to include a tool that measures depression such as the Beck Depression Test or Zung Self-rating anxiety scale. All patients should be required to complete an inventory that can assist in identifying “masked” depression.

  • Ask specifically about anxiety, worrying, panic disorder, depression or bipolar disease.

  • In a gentle fashion, ask the accompanying family member whether the patients’ characterization of mood is correct. If possible, ask the patient about his or her mood when they are alone. Also routinely inquire about relationships and other stressors.

  • If the patient presents with psychological concerns that you believe are beyond your comfort level, suggest a psychiatric or psychological referral. In cases where patients are suicidal or severely depressed, include psychiatric input as a condition for treatment. A psychiatric consultant can facilitate appropriate diagnosis, initiate psychiatric treatment, if indicated, and serve as a valued collaborator (Make certain the psychiatrist is interested in working with headache patients. Many psychiatrists are not.) Biofeedback and other relaxation techniques can be incorporated into treatment.

  • Consider using a multidisciplinary approach, especially if there is a concomitant mood disorder.

Routinely screen for abuse and maltreatment

  • All patients should be routinely screened for past or ongoing abuse.

  • Childhood emotional, sexual, or physical abuse is associated with an increase in headache frequency [22, 23, 24, 25].

  • Some have speculated that abuse is a risk factor for RM.

  • Prior or ongoing abuse is associated with comorbid mood disorders.

  • Abused patients should receive appropriate resources and referrals.

Educating the patient is pivotal

  • The patient should be educated about their disease and the importance of becoming a partner in their treatment.

  • Emphasize
    • Keeping a calendar. This is the only objective way to gauge improvement, or lack of it. Calendars are much more representative of headache frequency than patient perception. A calendar can display patterns (headaches only on weekends), if several headache days constitute one headache that is recurring or several distinct migraines, if perceived triggers are valid, or if triptans are taken early. There are now Smartphone applications with a headache calendar utility.

    • Realistic expectations: it is unlikely that the RM patient will become headache free. Although a 50 % decrease in headache frequency is a reasonable goal, any improvement in function is a benefit. There are no “quick fixes.” Improvement may take months. Be supportive and explain the rationale of the treatment plan. Sometimes when there are several reasonable options for the next step in treatment, the physician and patient may craft a decision together.

    • Avoiding MOH: the overuse of medications will undermine the treatment plan.

    • The need to see the “headache doctor” as the only physician who controls the dose and type of abortive or preventive medications for RM. Other physicians should not add or delete medications for headache unless these decisions are made in a collaborative fashion.

Treatment/management

Pharmacological treatment

  • The RM patient has often been on several prior acute and preventive medications. Before eliminating past treatments, be sure that they were taken in adequate doses for a reasonable period of time.

  • While the RM patient may be less responsive to treatment, pharmacological therapy is the mainstay of successful treatment.

  • The RM patient is often impaired by comorbid psychiatric conditions, including anxiety, panic disorder, major depression, bipolar disorder, dysthymia, and obsessive-compulsive disorder. These need to be addressed and it is advisable to liaise with a patient’s mental health professional.

  • Abortive treatment may include combining two separate agents. Appropriate goals include avoiding emergency room/urgent care evaluation and reducing emergency phone calls to the office. A plan for rescue therapy is essential [26•].

  • Acute and prophylactic pharmacological choices mean finding a balance between efficacy, tolerability, and side effects [27•].

  • The RM patient and practitioner should agree on a treatment plan, and the physician needs to set limits. Education can facilitate the process.

  • Medications used in RM lack evidence-based data, as there is no widely accepted definition for RM.

  • Patients should limit most acute therapy to 2–3 days a week at most. Those who do not accept the concept of medication overuse headache are more difficult to manage. Because of discomfort, the RM patient often overuses effective abortive medications. Anticipatory anxiety and obsessive behavioral traits can underlie medication overuse and may hinder improvement. Despite significant lifestyle disruption, most practitioners recommend slow tapering of analgesics.

Acute pharmacologic treatment

 

Nonsteroidal Anti-inflammatory Drugs

Usage

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly utilized class of medications for headache and may be useful in the RM population [28]. Parenteral anti-inflammatory agents are more effective than the oral or per rectum route. The intravenous/intramuscular route can be considered in an urgent care setting. A nasal spray option (ketorolac) is also available. NSAIDs are often used in combination rather than alone and are not for prolonged daily use. For instance, NSAIDs are often combined with an antiemetic/anxiolytic drugs such as promethazine or hydroxyzine for additional effect.

Standard dosage

Naproxen 500 mg PO, Celecoxib 200 mg PO, Ibuprofen 200–800 mg PO;

Indomethacin 25–50 mg PO or PR, Flurbiprofen 100 mg PO;

Ketorolac 15 mg–30 mg IV, 30–60 mg IM, 15.75–31.5 mg nasal spray

Contraindications

Peptic ulcer disease and anticoagulation. No significant drug interactions.

Main side effects

Gastrointestinal intolerance and propensity to bleeding. Chronic use may be associated with hypertension and kidney disease. In patients with peptic ulcer disease, celecoxib can be considered. Most NSAIDs carry a small increased risk of cardiovascular events.

Cost

Inexpensive

Triptans

Usage

Seven triptans are available in the US, all being selective 5-hydroxytryptamine 1B/1D agonists [29]. All are available as tablets, with two options for nasal spray and one for subcutaneous administration (sumatriptan). Each triptan is unique, and if a patient fails to find relief with one triptan, this does not predict he will fail with another. At least three triptans should be tried before labeling a patient a triptan nonresponder. Not all patients respond to triptans. The subcutaneous option should be considered before regarding a patient as nonresponsive to triptans and in the RM population all triptans should be used at the maximum milligram dose tolerated. Some practitioners combine a triptan with an NSAID (as in Treximet), or an antiemetic when the triptan alone is only moderately effective.

Standard dosage

Single dose, may be repeated in 2 hours. Not for continuous daily use.

Sumatriptan 4–6 mg SC, 50–100 mg PO, 20 mg NS

Zolmitriptan 5 mg PO, 5 mg NS

Rizatriptan 10 mg PO

Eletriptan 40 mg PO

Frovatriptan 2.5 mg PO

Naratriptan 2.5 mg PO

Almotriptan 12.5 mg PO

Main side effects

Chest or neck discomfort and dizziness (most prominent with the subcutaneous formula) and, less commonly, some drowsiness.

Drug interactions

Avoid monoamine oxidase A inhibitors and ergotamines. Reduce dose of rizatriptan in conjunction with propranolol. The concern for serotonin syndrome when used with SSRIs has not been borne out in clinical practice but remains a point of note.

Cost

Moderate

Dihydroergotamine and ergotamine

Usage

Dihydroergotamine (DHE) is used as an abortive and for short term (1–5 days) q 8 hourly use to abort an exacerbation of headache [30]. DHE can be given intravenously (IV), subcutaneously (SC) or via nasal spray. This class can be very useful in patients who do not respond to triptans and in treating a headache crisis [31]. Some patients can be taught to administer SC DHE with oversight to ensure there is no overuse.

Standard dosage

Dihydroergotamine nasal spray 0.5 mg/spray, 4 sprays;

Dihydroergotamine 0.5–1 mg SC; or IV q 8 h for up to 5 days

Ergotamine 1 mg/caffeine 100 mg 1–2 PO

Ergotamine 2 mg/caffeine 100 mg PR (compounded)

Contraindications

Cardiovascular disease, uncontrolled hypertension, pregnancy and not within 24 hours of a triptan.

Main drug interactions

Ergotamine levels may be significantly increased when used in conjunction with potent cytochrome P450 3A4 inhibitors such as macrolide antibiotics (clarithromycin), ketocomazole and protease inhibitors.

Main side effects

Nausea, leg cramps, peripheral vasoconstriction

Special points

Ergotamines are more vasoconstrictive than triptans and are best avoided in the older population. DHE exhibits less peripheral vasoconstriction and less nausea than ergotamine.

Cost

Expensive

Dopamine Antagonists

Usage

Dopamine antagonists are not only effective as anti-emetics and but are often used as abortive therapy. They are a good option when triptans are contraindicated [32]. They are most effective when given parenterally or rectally, but oral options work quite well in alleviating migraine pain. Inpatient management with parenteral dopamine antagonists like chlorpromazine is very useful in alleviating headache exacerbations [33].

Standard dosage

Promethazine 25–50 mg PO, 25 mg PR

Prochlorperazine 5–10 mg IV/IM/PO, 25 mg PR

Metoclopramide 5–10 mg IV/IM/PO, 20 mg PR

Chlorpromazine 25–50 mg PO, 10–50 mg IV

Main side effects

There is considerable variability of side effects between the different agents but sedation, akathisia (easily missed by the unvigilant health care provider) and dystonia are notable. Frequent use can be associated with tardive dyskinesia but the risk with intermittent dopamine antagonists is unknown. Hyperprolactinemia, dry mouth, hypotension, weight gain and QTc prolongation are also possible. Intravenous promethazine is a vesicant, with the potential for much tissue injury if administered incorrectly.

Special points

Generally promethazine can be given to those who have had dyskinesias with other dopamine antagonists.

Cost

Inexpensive

Steroids

Usage

Not used as first-line agents, but can be valuable in treating exacerbations [34]. Can be used in combination with other abortive agents and ideally, use should be infrequent. Steroids are a good alternative for those in whom triptans are contraindicated.

Standard dosage

Dexamethasone 4–8 mg PO/IV

Prednisone taper from 60 mg to zero over 1 week

Medrol Dosepak

Main side effects

Very well tolerated in short courses. Insomnia and anxiety and emotional lability are possible.

Special points

Cumulative risk for osteoporosis and a small and undefined risk for osteonecrosis.

Cost

Inexpensive

Opioids

Usage

Use of opioids is controversial due to concerns for rebound, abuse/addiction and sensitization that have not been fully characterized [35]. Refractory migraine patients are at particular risk for overuse and utilization opens the door to long-term daily use. Most headache experts believe that long-term use is not associated with any increased function or material decrease in pain due to significant tolerance and even a hyperalgesic response. RM is poorly suited for chronic opioids. Careful retrospective review on the use of daily opioids has yielded disappointing results, with little literature support. If used for rescue, strict limits are recommended. Some states have prescription monitoring programs making it easier for prescribers to identify patients receiving pain medications from other unknown prescribers. Because some opioids are safer during pregnancy they can be used sparingly in this period [36].

Standard dosage

Oxycodone 5–10 mg PO

Morphine 2 mg IV, 10 mg PO

Hydrocodone/acetaminophen 5/325 mg PO

Methadone 5 mg PO

Hydromorphone 3 mg PR

Main drug interactions

Generally devoid of significant drug interactions.

Main side effects

Sedation, nausea, withdrawal potential with continued use. Usage is a particular concern in those with an addiction background.

Cost

Inexpensive

Prophylactic pharmacologic treatment

Anticonvulsants

Anticonvulsants are used for prophylaxis, with topiramate and valproate having FDA approval for migraine [27•, 37, 38]. There is very little evidence to support the use of other anticonvulsants for migraine treatment, but gabapentin and to a lesser extent pregabalin and zonisamide are used in prophylaxis. Anticonvulsants have no acute use, with the possible exception of intravenous valproic acid.
Standard dosage

These are target doses for initiating therapy. Some patients may require higher doses, or may accommodate to an effective dose with headache recurrence. In these cases, higher doses may be needed. The patient should start with a low dose and escalate gradually to one of the three endpoints: (1) effective preventative antimigraine control is achieved, (2) a side effect or toxic effect occurs that will not allow the dose to be raised further, or (3) an absolute maximum dose based on the pharmacology of the drug is reached. Lower doses may be effective. In practice, one should “start low and go slow.” The final dose is based on efficacy and tolerability. There is no clear dose–response curve for these agents and no “standard dose” will fit every patient. Each patient must be managed individually. The doses referenced are meant to serve as guidelines.

Topiramate 50–300 mg daily PO

Valproate 500 mg twice daily PO

Gabapentin 300–900 mg TID PO

Zonisamide 200–400 mg daily PO

Pregabalin 150 mg twice daily PO

Main side effects

The side effect profile varies considerably with the agent used. Topiramate causes acral and face dose-dependent paresthesias, kidney stones, dysguesia and at times cognitive dysfunction. Valproate can cause drowsiness/dizziness. Both topiramate and valproate are class D in pregnancy, with valproate having a black box warning as a teratogen, hence these agents should be avoided in pregnancy. Some practitioners insist that patients use two forms of birth control while on valproate. The main side effect with gabapentin is drowsiness. As a class, anticonvulsants may be associated with depression.

Tricyclic antidepressants

Usage

Tricyclic antidepressants (TCAs), which are older agents, continue to be very useful in headache management including RM [29]. Extreme caution is advised in older people because of sedation, hypotension and cardiac arrhythmias.

Target doses

Very low doses of TCAs may be effective and one should begin with low doses.

Blood levels of tricyclics are used to monitor compliance and avoid toxicity in higher doses.

Amitriptyline 10–150 mg daily PO

Nortriptyline 25–150 mg daily PO

Imipramine 25–200 mg daily PO

Doxepin 25–300 mg daily PO

Main side effects

Burden of side effects is wide and frequent, causing variable amounts of drowsiness, dizziness with possible cognitive dysfunction, hypotension and anticholinergic features such as urinary retention, dry mouth and tachycardia.

Cost

Inexpensive

SNRI antidepressants

Usage

Commonly used for comorbid psychiatric disorders, serotonin–norepinephrine reuptake inhibitors (SNRIs) are likely have beneficial effects on headache as well [39].

Standard dosage

Venlafaxine 75–300 mg daily PO

Buloxetine 60–90 mg daily PO

Milnacipran 12.5–100 mg BID PO

Cost

Moderate

Other non-prescription agents

A variety of alternatives to prescription medication are available, with recently updated guidelines [40]. Petasites, an extract from the butterbur plant, have the most evidence behind them [41]. Riboflavin has probable efficacy, as does magnesium. Magnesium comes in different forms, which can have different absorption characteristics and can cause diarrhea. Coenzyme Q 10 and MIG 99 (feverfew) may also be useful.
Standard dosage

Petasites 50–75 mg BID PO

Riboflavin 400 mg daily PO

Magnesium 400–600 mg daily PO

Interventional procedures

  • Unlike some pharmacological therapies, local procedures in general have not been subject to blinded placebo controlled trials (with the exception of botulinum toxin) so study outcomes are vulnerable to expectations, conditioning and the natural history of this waxing and waning disorder.

  • Peripheral nerve blocks should be considered in the RM patient, especially those with very poor medication response [42•]. The hope is that temporary relief with local analgesics will coax secondary mechanisms and achieve long-term benefit [43].

  • Some patients respond to regular blocks. Such procedures are generally very safe.

  • Some plastic surgeons claim good results from facial surgery options but this lacks a biological rationale and the expert headache community is skeptical.

Common peripheral nerve blocks

  • Greater and lesser occipital nerve block

  • Auriculotemporal nerve block

  • Supraorbital and supratrochlear nerve block

Special points of nerve blocks

Lidocaine or bupivacaine are used most commonly, either with or without steroids. The addition of steroids such as methylprednisolone is without clear benefit but has advocates.

  • Peripheral nerve blocks may be administered singly or in combination, both for acute treatment and as part of regular therapy every few weeks.

Main side effects

Well tolerated. Steroid use may result in local depigmentation and alopecia.

Botulinum toxin injections

Usage

Botulinum toxin type A is a protein that inhibits the release of acetylcholine from presynaptic nerve endings and inhibits the release of calcitonin gene-related peptide and substance P. Use in episodic migraine is not supported by multiple clinical trials. However onabotulinumtoxinA is approved for chronic migraine, albeit with very modest clinical outcomes. Two phase 3 clinical trials support the efficacy of onabotulinumtoxinA for chronic migraine, including for patients overusing acute headache medications [44, 45]. The biological effects of botulinum toxin are reversible, and successful treatment is usually repeated at 3-month intervals.

Standard Procedure

For chronic migraine 155 units of botulinum toxin are injected into frontal, temporal and occipital regions every 3 months. Some practitioners may increase the unit dose targeting areas where the patient experiences most pain and use 100 units.

Complications

Excellent tolerability with occasional facial weakness proximate to injection sites. Long-term effects are unknown.

Cost

High

Occipital nerve stimulation

Usage

For the various chronic refractory primary headache disorders [46]. Published trials suggest a possible benefit in patients with chronic daily headache and chronic migraine. Studies are ongoing in an attempt to further define a benefit. As with all interventions, lack of proper blinding impairs assessment of true efficacy.

Main side effects

Local infection and discomfort. Well tolerated and eminently removable for those not responding.

Transcranial magnetic stimulation

This procedure involves a hand-held device about the size of a hairdryer to deliver magnetic pulses when placed close to the back of the head [47]. Its repeated use in RM patients has not been studied.

Suggestions for rescue therapy

  • Consider a short course of steroids

  • Utilize an infusion unit where IV medications including metoclopramide, DHE and ketorolac can be given. If patients are given abortive migraine medications for a reasonable period and there is no improvement, the diagnosis should be reconsidered.

  • Opioids may be considered, but for no more than three days. Limited quantities should be dispensed. The overuse of opioids can contribute to the genesis of RM.

  • Hospitalization is an option, but unless there is a designated team who has an understanding of the disease, a medication protocol, and an adequate support staff, this may be a negative experience.

Pearls and pitfalls in the RM treatment

  • “Don’t rest until you test” [48•]. The diagnosis of RM is based on ruling out the presence of pathologies which can cause headaches.

  • Recognize the problem patient early [48•]. Identify the angry patient, those who disagree with a treatment plan, and those whose level of pain is incongruous with their appearance or social functioning. Patients with personality disorders are particularly challenging.

  • Always consider MOH. This may be iatrogenic or as a result of self-treatment [48•].

  • Becoming pain free may be unrealistic. Lessening disability is a reasonable goal. Sometimes patients forget the degree of disability they experienced. Referring to the first assessment may help them appreciate their improvement. Initiating a preventive or utilizing onabotulinumtoxinA should not be a promise that they will be free of headaches.

  • Be a cheerleader, always have another plan. If you give up, so will your patient. However, if the patient is becoming frustrated, encourage a second opinion from a trusted headache expert. Patients appreciate your openness. This gives them implicit “permission” to leave or seek a new assessment. Emphasize that you are not discharging the patient and that they are free to return if they wish. Sometimes a fresh perspective can provide diagnostic possibilities previously not considered.

  • Set strict limits. The physician is in charge, not the patient. Compliance is imperative. If you think your patient is using multiple physicians, call their pharmacy to obtain medication history. If this is the case, gently confront the patient and inform them that these actions will not be tolerated and are grounds for discharge.

Acknowledgment

The authors wish to thank Kate Ciavarelli for providing editorial assistance in preparing the manuscript.

Disclosure

Dr. McGeeney has served as a consultant for and received honoraria from Merck & Co., Allergan, MAP Pharmaceuticals, Zogenix, and NuPathe; has received payment for the development of educational presentations (including service on speakers’ bureaus) from Merck & Co., Eli Lilly and Company, Ortho-McNeill, and Pfizer; and holds stock in Pfizer.

Conflicts of Interest

Dr. Schulman has served as a consultant to NuPathe and Zogenix. He is the speakers bureau of Merck and Impax. He has received research funding from NuPathe and has received royalties from Oxford University Press.

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Lankenau Medical Center and Lankenau Institute for Medical ResearchWynnewoodUSA
  2. 2.NeurologyBoston University School of MedicineBostonUSA

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