Headache & Pain

Updated 04.06.2021
Released 02.28.2001
Expires For CME 04.06.2024

Headache guidelines

Author: Michael J Marmura MD

Editor: Stephen D Silberstein MD

Introduction

Overview

This article updates the results from evidence-based reviews on the management of patients with migraine and cluster headache: specifically, acute, preventive, and nonpharmacologic treatments for migraine, as well as the role of neuroimaging in patients with headache. There have also been some important updates to treatment of cluster headache, and information from the most recent studies will be presented. The full papers for these treatment guidelines are published elsewhere (02; 04; 12; 13; 18; 25), and only the specific treatment recommendations are summarized below (10; 24; 11; 21; 23).

In June 1998, Duke University's Center for Clinical Health Policy Research, in collaboration with the American Academy of Neurology, completed 4 Technical Reviews on migraine sponsored by the Agency for Health Care Policy and Research: self-administered drug treatments for acute migraine (Gray et al 1999a); parenteral drug treatments for acute migraine (Gray et al 1999b); drug treatments for the prevention of migraine (Gray et al 1999c); and behavioral and physical treatments for migraine (Goslin et al 1999). The Education and Research Foundation of the American Academy of Neurology later funded additional reports on diagnostic testing for headache patients, an update on sumatriptan and other 5-HT1 agonists, and a report on butalbital-containing compounds for migraine and tension-type headache, using the same methodology that was used in the original Technical Reviews. A multidisciplinary panel of professional organizations (The US Headache Consortium) produced 4 treatment guidelines, each related to a distinct set of management decisions: diagnostic testing (primarily neuroimaging studies), pharmacological management of acute attacks, migraine-preventive drugs, and behavioral and physical treatments for migraine.

In 2012, the American Academy of Neurology updated and published new preventive treatment guidelines for migraine (10; 24). For pharmacologic therapy, the authors analyzed published studies from June 1999 to May 2009, using a structured review process to classify the evidence relative to the various medications available in the United States for migraine prevention. The author panel reviewed 284 abstracts, which ultimately yielded 30 Class I or Class II articles that are reviewed herein.

The original search identified 179 articles. A supplemental search (2007 to 2009) yielded 105 additional articles. Of the total 284 articles, 30 were pharmacologic and were classified as Class I or Class II and are reviewed herein. In addition, 15 were classified as Class I or Class II and identified as relating to nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments.

Studies were excluded if they included any of the following factors:

	• Assessed the efficacy of therapeutic agents for headache other than episodic migraine in adults
	• Assessed acute migraine treatment, migraine aura treatment/prevention, or nonpharmacologic treatments (eg, behavioral approaches)
	• Used quality of life measures, disability assessment, or nonstandardized outcomes as primary efficacy endpoints
	• Tested the efficacy of drugs not available in the United States

Since the guideline publication in 2000, the AAN revised its evidence classification criteria to include study completion rates. Studies with completion rates below 80% were downgraded; thus, several studies in the original guideline have been downgraded.

They found no new Class I or II studies published for acebutolol, atenolol, bisoprolol, carbamazepine, clonazepam, clonidine, clomipramine, fluvoxamine, guanfacine, nabumetone, nadolol, nicardipine, nifedipine, or protriptyline. Recommendations for these agents are based on the evidence reviewed in the original guideline (denoted with an asterisk in Table 1). Currently, no Class I or Class II studies exist for anticoagulants (limited Class III and IV studies were identified; Table 1 includes anticoagulants). Of the total 284 articles, 15 were classified as Class I or Class II and identified as relating to NSAIDs and complementary treatments; they are reviewed herein.

Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) effectively prevent migraine and have been approved in the past few years since the last publication of preventive guidelines. The 4 currently available treatments are erenumab, eptinezumab, fremanezumab, and galcanezumab, and all have demonstrated efficacy in both episodic and chronic migraine treatment (22).

In 2015, a study by Marmura and colleagues provided an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment (11). This assessment is an update to the American Academy Neurology Guidelines that were published in 2000, which summarized the available evidence related to the efficacy of acute migraine medications. The review was conducted by members of the Guidelines Section of the American Headache Society.

A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology Guidelines Development procedures followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence required at least 2 Class I studies, and level B evidence required 1 Class I or 2 Class II studies.

Future guidelines will address the use of novel treatments for acute migraine including new formulations, lasmiditan, rimagepant, and ubrogepant.

In 2016, the American Headache Society convened an expert panel of authors who defined a search strategy and performed a search of Medline, Embase, the Cochrane database, and clinical trial registries from inception through 2015. The authors provided evidence-based treatment recommendations for adults with acute migraine who require treatment with injectable medication in an emergency department. Identified articles were rated using the American Academy of Neurology’s risk of bias tool. They identified 68 unique randomized controlled trials utilizing 28 injectable medications. Of these, 19 were rated Class I (low risk of bias), 21 were rated Class II (higher risk of bias), and 28 were rated Class III (highest risk of bias). Metoclopramide, prochlorperazine, and sumatriptan each had multiple Class I studies supporting acute efficacy, as did dexamethasone for prevention of headache recurrence. All other medications had lower levels of evidence.

In 2016, a systematic review by Robbins and colleagues looked at the available evidence for the acute and prophylactic treatment of cluster headache (21). This was updated from the 2010 American Academy of Neurology (AAN) endorsed systematic review.

Since the publication of the 2010 AAN review, there are no new data from randomized, double-blind, controlled trials that contribute to determining the efficacy or safety of the following acute treatments: sumatriptan, zolmitriptan, oxygen, octreotide, dihydroergotamine, prednisone, cocaine/lidocaine, and somatostatin. Thus, the assessment of the data and recommendations regarding these treatments have been carried forward from the 2010 AAN assessment.

Medline, PubMed, and EMBASE databases were searched for double-blind, randomized controlled trials that investigated treatments of cluster headache in adults. To be included, studies must have been double-blind, randomized trials of any treatment versus placebo or sham versus another treatment studying adult participants (at least 18 years of age). Studies of episodic cluster headache, chronic cluster headache, or a combination were included. Studies were excluded if they were not double-blind, if there was no randomization, if a treatment or placebo/sham comparator was not used, and if children were studied. Research published between 1950 and April 15, 2015 was considered for inclusion.

In 2016, Rajapakse and Pringsheim reviewed Guidelines from the AAN/AHS, Canadian Headache Society, and the European Federation of Neurological Sciences (EFNS), as well as highlighted randomized control trial evidence for use of the following nutraceuticals: riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated fatty acids (OPFA) (17). This review will summarize their results.

Multiple noninvasive neuromodulation devices are approved for acute or preventive migraine treatment: noninvasive vagus nerve stimulation, single-transcranial magnetic stimulation, external trigeminal nerve stimulation, and remote electrical neuromodulation. Noninvasive vagus nerve stimulation is also approved for cluster headache treatment (20). Future guidelines will further evaluate their effectiveness.

Reviews have addressed the best practices of pediatric migraine management. Oskoui and colleagues evaluated pharmacologic and cognitive behavioral therapy for migraine prevention (14). The most proven treatment appears to be the combination of amitriptyline and cognitive behavioral therapy (16). The majority of studies of migraine prevention with oral drugs lack sufficient evidence. The panel noted topiramate treatment is probably likely to result in fewer migraine or headache days and children treated with propranolol are possibly more likely to have a greater than 50% reduction in headache days compared to placebo. Specific drugs with no significant evidence of effectiveness included divalproex, onabotulinumtoxinA, amitriptyline, nimodipine, and flunarizine. Many other commonly used migraine preventive treatments such as nortriptyline, metoprolol, and medical devices have not been evaluated as preventive treatment in children.

Clinical factors affect outcomes in trials for acute pediatric migraine treatment. Higher placebo response, more rapid onset and resolution, and nausea/vomiting complicate acute study designs for children (19). Medications with high confidence recommendations for pain-freedom at 2 hours include zolmitriptan nasal spray 5 mg and combinations of sumatriptan/naproxen. Sumatriptan nasal spray 20 mg and ibuprofen are probably effective and rizatriptan oral dissolvable tablets 5 and 10 mg are possibly effective. A large number of treatments are possibly effective based on single, lower-quality studies such as almotriptan 6.25 and 12.5 mg and acetaminophen (15).

Evans and colleagues evaluated the evidence for when to perform neuroimaging in patients with a diagnosis of migraine (03). Based on numerous large case series the authors concluded “there is no necessity to do neuroimaging in patients with headaches consistent with migraine.” This recommendation assumes a normal neurologic examination and no red flags present for other diseases. However, it is worthwhile to consider neuroimaging in those with prolonged or persistent aura, a change in clinical features, motor weakness, late-life migraine accompaniments, and posttraumatic headache, among other circumstances (03).

Description of the process

Seven organizations originally participated in The US Headache Consortium: the American Academy of Family Physicians, American Academy of Neurology, American Headache Society (formerly the American Association for the Study of Headache), American College of Emergency Physicians, American College of Physicians-American Society of Internal Medicine, American Osteopathic Association, and National Headache Foundation. Complete descriptions of the methodological details are described elsewhere (13).

Analysis of evidence. Evidence supporting the acute and preventive treatment were exclusively Class I studies; however, due to the lack of published Class I evidence, Class II and Class III studies were included for analysis of diagnostic testing and utility of neuroimaging in migraine. Clearly effective migraine treatments and techniques are available for the acute and preventive treatment of migraine. However, there are few studies on the relative efficacy of these agents or how to implement these treatments into successful treatment strategies.

Diagnosis of migraine. The International Headache Society classification of headache system is universally accepted and has become the basis for headache classification in the International Classification of Diseases (Headache Classification Committee of the International Health Society 1988). Migraine is a chronic condition with recurrent episodic attacks. Its characteristics vary among patients and often among attacks in a single patient. To diagnose migraine, it is necessary to exclude secondary headache causes and then determine whether the patient has any other coexisting primary headache (eg, tension-type headache). Testing is not recommended if the individual is not significantly more likely than the general population to have a significant abnormality. Testing should be avoided if it will not lead to a change in management. However, testing that normally may not be recommended as a population policy may make sense at an individual level. Exceptions can be considered for patients who are disabled by their fear of serious pathology or for patients about whom the provider is suspicious, even in the absence of known predictors of abnormalities on neuroimaging studies (red flags).

There was insufficient published clinical research to support evidence-based guidelines for any diagnostic testing other than neuroimaging. Previous reports that reviewed the evidence on the role of electroencephalography found that it is not indicated in the routine evaluation of headache (01).

Acute headache. The following symptoms significantly increased the odds of finding a significant abnormality on neuroimaging in patients with nonacute headache:

	• Rapidly increasing headache frequency
	• History of dizziness or lack of coordination
	• History of localized neurologic signs or a history such as subjective numbness or tingling
	• History of headache causing awakening from sleep (although this can occur with migraine and cluster headache)

The absence of these symptoms did not significantly lower the odds of finding a significant abnormality on neuroimaging

Nonacute headache. Consider neuroimaging in the following:

	• Patients with an unexplained abnormal finding on the neurologic examination (grade B)
	• Patients with atypical headache features or headaches that do not fulfill the strict definition of migraine or other primary headache disorder (or have some additional risk factor, such as immune deficiency), when a lower threshold for neuroimaging may be applied (grade C)
	• Neuroimaging is not usually warranted in patients with migraine and a normal neurologic examination (grade B).

No evidence-based recommendations are established for the following:

	• Presence or absence of neurologic symptoms (grade C)
	• Tension-type headache (grade C)
	• Relative sensitivity of MRI as compared with CT in the evaluation of migraine or other nonacute headache (grade C)

Treatment of migraine. Migraine varies in frequency, duration, and disability among sufferers and between attacks. It is appropriate to link the intensity of care with the level of disability and symptoms such as nausea and vomiting (stratified care) for the acute treatment of symptoms of an ongoing attack. It is not appropriate to continue ineffective or poorly tolerated medication in a sequential and arbitrary manner (step care). Consider preventive treatment (given on an ongoing basis whether or not an attack is present) for those patients whose migraine has a substantial impact on their lives and have not responded to acute care, or where the frequency of migraine attacks is such that the reliance on acute care medications would increase the potential for drug-induced (rebound) headache. The following are goals of preventive migraine treatment, both pharmacologic and nonpharmacologic:

	• Reduce attack frequency, severity, and disability
	• Reduce reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies
	• Improve quality of life
	• Avoid acute headache medication escalation
	• Educate and enable patients to manage their disease to enhance personal control of their migraine
	• Reduce headache-related distress and psychological symptoms

Behavioral and physical interventions are used for preventing migraine episodes rather than for alleviating symptoms once an attack has begun. Although these modalities may be effective as monotherapy, they are more commonly used in conjunction with pharmacological management.

Neuromodulation devices may have a role in both acute and preventive treatment of headache. Guidelines to date have not specified the exact role of how best to incorporate these devices into the treatment armamentarium.

General principles of management

	• Establish a diagnosis.
	• Educate migraine sufferers about their condition and its treatment. Discuss the rationale for a particular treatment, how to use it, and what adverse events are likely.
	• Establish realistic patient expectations by setting appropriate goals and discussing the expected benefits of therapy and how long it will take to achieve them. Empower the patients to be actively involved in their own management by encouraging patients to track their own progress through the use of diary cards, flow charts, headache calendars, and forms for tracking days of disability or missed work, school, or family activities. Treatment choice depends on the frequency and severity of attacks, the presence and degree of temporary disability, and associated symptoms such as nausea and vomiting.
	• Create a formal management plan and individualize management: consider the patient's response to, and tolerance for, specific medications. Consider comorbidity or coexisting conditions. Coexisting conditions (ie, heart disease, pregnancy, and uncontrolled hypertension) need to be ascertained as they may limit treatment choices.
	• Encourage the patient to factors associated with migraine including triggers and premonitory symptoms.

Acute treatment

Goals of acute migraine treatment

	• Treat attacks rapidly and consistently without recurrence, ideally leading to both pain freedom and relief of most bothersome nonheadache symptoms.
	• Restore the patient's ability to function.
	• Minimize the use of backup and rescue medications. (A rescue medication is used at home when other treatments fail and permits the patient to achieve relief without the discomfort and expense of a visit to the physician's office or emergency department.)
	• Optimize self-care and reduce subsequent use of resources.
	• Be cost-effective for overall management.
	• Have minimal or no adverse events.

To meet these goals

	• Use migraine-specific agents (triptans, dihydroergotamine, and ergotamine) in patients with moderate or severe migraine or whose mild-to-moderate headaches respond poorly to NSAIDs or combinations such as aspirin plus acetaminophen plus caffeine. Failure to use an effective treatment promptly may increase pain, disability, and the impact of the headache.
	• Select a nonoral route of administration for patients with migraine associated with severe nausea or vomiting. Antiemetics should not be restricted to patients who are vomiting or likely to vomit. Nausea itself is one of the most aversive and disabling symptoms of a migraine attack and should be treated appropriately.
	• Consider a self-administered rescue medication for patients with severe migraine that do not respond to (or fail) other treatments.
	• Guard against medication-overuse headache (“rebound headache” or “drug-induced headache”). Frequent use of acute medications (ergotamine [not dihydroergotamine], opiates, triptans, and simple and mixed analgesics containing butalbital, caffeine, or isometheptene) is generally thought to cause medication-overuse headache. Many experts limit acute therapy to 2 headache days per week on a regular basis. Patients with medication overuse should use preventive therapy.

Evidence-based recommendations for acute treatment of migraine

Specific medications

Triptans (serotonin 1B/1D receptor agonists)

	• Naratriptan, rizatriptan, sumatriptan, frovatriptan, almotriptan, eletriptan, zolmitriptan: triptans are effective and relatively safe for the acute treatment of migraine headaches and are an appropriate initial treatment choice in patients with moderate to severe migraine who have no contraindications for its use (grade A).
	• Initial treatment with any triptan is a reasonable choice when the headache is moderate to severe or in migraine of any severity when nonspecific medication has failed to provide adequate relief in the past (grade C).
	• Patients with nausea and vomiting may be given intranasal or subcutaneous sumatriptan (grade C).

Ergot alkaloids and derivatives

	• Ergotamine PO/PR (and caffeine combination) may be considered in the treatment of selected patients with moderate to severe migraine (grade B).
	• Dihydroergotamine nasal spray is safe and effective for the treatment of acute migraine attacks and should be considered for use in patients with moderate to severe migraine (grade A).
	• Dihydroergotamine SC/IV/IM and nasal spray may be given to patients with nausea and vomiting (grade C). Dihydroergotamine SC, IM, and nasal spray are reasonable initial treatment choices when the headache is moderate to severe, or in migraine of any severity when nonspecific medication has failed to provide adequate relief in the past (grade C).
	• Dihydroergotamine IM, SC may be considered in patients with moderate to severe migraine (grade B).
	• Dihydroergotamine IV plus antiemetics IV is an appropriate treatment choice for patients with severe migraine (grade B).

Nonspecific medications

Antiemetics

	• Oral antiemetics are an adjunct to treat nausea associated with migraine (grade C).
	• Metoclopramide IM/IV is an adjunct to control nausea (grade C) and may be considered as IV monotherapy for migraine pain relief (grade B).
	• Prochlorperazine IV, IM, and PR may be a therapeutic choice for migraine in the appropriate setting (grade B).
	• Prochlorperazine PR is an adjunct in the treatment of acute migraine with nausea and vomiting (grade B).
	• Chlorpromazine IV may be a therapeutic choice for migraine in the appropriate setting (grade B).
	• Serotonin receptor (5-HT3) antagonists are not effective as monotherapy for migraine pain relief (grade B), but may be considered as adjunct therapy to control nausea in selected patients with migraine attacks (grade C).

NSAIDs, nonopioid analgesics, and combination analgesics

• Acetaminophen, alone, is not recommended for migraine (grade A).

• NSAIDs (oral) and combination analgesics containing caffeine are a reasonable first-line treatment choice for mild to moderate migraine attacks or severe attacks that have been responsive in the past to similar NSAIDs or nonopioid analgesics (grade A). Ketorolac IM is an option that may be used in a physician-supervised setting, although conclusions regarding clinical efficacy cannot be made at this time (grade B).

Butalbital-containing analgesics

• Butalbital-containing analgesics: limit and carefully monitor their use based on overuse, medication-overuse headache, and withdrawal concerns (grade C).

Opiate analgesics

	• Butorphanol nasal spray is a treatment option for some patients with migraine (grade A). Butorphanol may be considered when other medications cannot be used or as a rescue medication when significant sedation would not jeopardize the patient (grade C). Butorphanol intramuscular is an option with less evidence (grade C). Butorphanol is widely used despite the established risk of overuse and dependence. Special attention should be given to these clinical concerns.
	• Opiates: parenteral opiates are used as rescue therapy for acute migraine when sedation side effects will not put the patient at risk and when the risk abuse has been addressed (grade C).
	• Consider parenteral and oral combination use in acute migraine when the risk of abuse has been addressed and sedation will not put the patient at risk (grade A).

Other medications

	• Isometheptene and isometheptene combination agents may be a reasonable choice for patients with mild-to-moderate headache (grade B).
	• Corticosteroids (dexamethasone or hydrocortisone) are a treatment choice for rescue therapy for patients with status migrainosus (grade C).
	• Lidocaine: evidence is insufficient at this time to establish a defined role for intranasal lidocaine or lidocaine IV in the management of acute migraine headache (grade U).

Table 1. Evidence Summary for Treatment of Acute Attacks of Migraine

Triptans
	Sumatriptan nasal spray
		• Quality of evidence: A
	Naratriptan
		• Quality of evidence: A
	Rizatriptan
		• Quality of evidence: A
	Sumatriptan
		• Quality of evidence: A
	Zolmitriptan
		• Quality of evidence: A
	Sumatriptan SC
		• Quality of evidence: A
	Almotriptan
		• Quality of evidence: A
	Eletriptan
		• Quality of evidence: A
	Frovatriptan
		• Quality of evidence: A
	Sumatriptan/naproxen
		• Quality of evidence: A
Ergot alkaloids and derivatives
	Dihydroergotamine SC/IM
		•Quality of evidence: B
	Dihydroergotamine IV
		• Quality of evidence: B
	Dihydroergotamine NS
		• Quality of evidence: A
Antiemetics
	Chlorpromazine IM/IV
		• Quality of evidence: B
	Metoclopramide IM
		• Quality of evidence: B
	Metoclopramide PR/IV
		• Quality of evidence: B
	Prochlorperazine PR/IM, IV
		• Quality of evidence: B
	Prochlorperazine IV
		• Quality of evidence: B
	Droperidol IV
		• Quality of evidence: B
NSAIDs and nonopioid analgesics
	Acetaminophen
		• Quality of evidence: A
	Ketorolac IM
		• Quality of evidence: B
NSAIDs-oral
	Aspirin
		• Quality of evidence: A
	Diclofenac
		• Quality of evidence: A
	Flurbiprofen
		• Quality of evidence: B
	Ibuprofen
		• Quality of evidence: A
	Naproxen
		• Quality of evidence: A
	Naproxen sodium
		• Quality of evidence: A
	Phenazone
		• Quality of evidence: C
Antiepileptics
	Valproate IV
		• Quality of evidence: C
Combination analgesics
	Acetaminophen, aspirin, caffeine
		• Quality of evidence: A
	Codeine/acetaminophen
		• Quality of evidence: B
	Tramadol/acetaminophen
		• Quality of evidence: B
Barbiturate hypnotics
	Butalbital/acetaminophen/caffeine/codeine 50/325/40/30 mg
		• Quality of evidence: C
	Butalbital/acetaminophen/ caffeine 50/325/40 mg
		• Quality of evidence: C
	Butalbital
		• Quality of evidence: C
Opiate analgesics
	Butorphanol nasal spray
		• Quality of evidence: A
	Opiates—oral combinations
		• Quality of evidence: A
	Opiates—parenteral butorphanol IM, meperidine IM/IV, methadone IM
		• Quality of evidence: C
	Tramadol IV
		• Quality of evidence: C
Other medications
	Corticosteroids IV plus antiemetics, dexamethasone, hydrocortisone
		• Quality of evidence: C
	Dexamethasone IV
		• Quality of evidence: C
	Isometheptene
		• Quality of evidence: B
	Lidocaine intranasal
		• Quality of evidence: C
	Lidocaine IV
		• Quality of evidence: U
	MgSO4 IV
		• Quality of evidence: B
Negative Studies
	Octreotide SC
		• Quality of evidence: B
	Chlorpromazine IM
		• Quality of evidence: C
	Granisetron IV
		• Quality of evidence: C
	Ketoralac Nasal Spray
		• Quality of evidence: C
	Acetaminophen IV
		• Quality of evidence: C
Legend: IM = intramuscular; IV = intravenous; PR = rectally; PO = orally; ? = not known

Table 2. Evidence Summary for Treatment of Acute Migraine Attacks in the Emergency Department

Should offer
	Level B
		• Metoclopramide / Prochlorperazine IV • Sumatriptan IV • Dexamethasone should be offered to prevent recurrence
Should avoid
	Level C
		• Morphine IV • Hydromorphone IV

Table 3. Acute Therapies for Migraine

Group 1: proven pronounced statistical and clinical benefit (at least 2 double-blind, placebo-controlled studies + clinical impression of effect)
	• Acetaminophen, aspirin, plus caffeine PO • Acetaminophen/aspirin/caffeine • Almotriptan PO • Aspirin PO • Butorphanol NS • Dihydroergotamine NS • Ibuprofen PO • Naproxen sodium PO • Diclofenac, PO • Eletriptan PO • Frovatriptan PO • Naratriptan PO • Prochlorperazine IV • Rizatriptan PO • Sumatriptan NS, Oral, SC • Zolmitriptan NS, Oral • Sumatriptan/naproxen
	Group 2: moderate statistical and clinical benefit (1 double-blind, placebo-controlled study + clinical impression of effect)
	• Acetaminophen plus codeine PO • Butalbital, aspirin, caffeine, plus codeine PO • Butorphanol IM • Chlorpromazine IM, IV • Diclofenac K, PO • Ergotamine plus caffeine plus pentobarbital, plus Bellafoline PO • Ketorolac IM / IV • Lidocaine IN • Meperidine IM, IV • Methadone IM • Metoclopramide IV • Naproxen PO • Prochlorperazine IM, PR, IV • Acetaminophen/Codeine • Dihydroergotamine IV, IM, SC • Droperidol IV • Flurbiprofen • Isometheptene • Ketoprofen • MgSO4 IV
Group 3: statistically but not proven clinically, or clinically but not proven statistically effect (conflicting of inconsistent evidence)
	• Bultalbital/acetaminophen/caffeine PO • Bultalbital/acetaminophen/caffeine/codeine PO • Bultalbutal PO • Butalbital, aspirin, plus caffeine PO • Ergotamine PO • Ergotamine plus caffeine PO • Metoclopramide IM, PR • Butorphanol IM • Codeine PO • Dexamethasone IV • Ergotamine PO • Lidocaine Intranasal • Meperidine IM • Phenazone PO • Tramadol IV • Valproate IV
	Group 4: proven to be statistically or clinically ineffective (failed efficacy vs. placebo)
	• Acetaminophen IV • Chlorpromazine IM • Granisetron IV • Ketoralac NS • Lidocaine IV • Octreotide SC
	Group 5: clinical and statistical benefits unknown (insufficient evidence available)
	• Celecoxib • Dexamethasone IV • Hydrocortisone • Lidocaine IV
Legend: PO = oral; PR = rectal; IM = intramuscular; IV = intravenous

Table 4. Efficacy, Adverse Events, Level of Evidence and Recommendations for the Acute Therapy of Cluster Headache

Positive Evidence
	Sumatriptan (subcutaneous)
		•Level of evidence: 2 class I randomized, controlled trials. • Study population: episodic and chronic cluster headache • Efficacy: sumatriptan 6 mg is effective in improving headache response • Adverse effects: nonserious: injection site reactions, nausea and vomiting, dizziness, fatigue, paresthesias. • Recommendation: level A, established as effective
	Zolmitriptan (Nasal Spray)
		• Level of evidence: 2 class I randomized, controlled trials • Study population: episodic and chronic cluster headache • Efficacy: zolmitriptan 5 mg and 10 mg are effective in improving headache response • Adverse effects: nonserious: unpleasant taste, nasal cavity discomfort, somnolence, dizziness, nausea, throat/neck tightness • Recommendation: level A, established as effective
	Oxygen
		• Level of evidence: 2 class I randomized, controlled trials. • Study population: episodic and chronic cluster headache • Efficacy: 100% oxygen 6 to 12 L/min is effective in improving headache response • Adverse effects: not reported. • Recommendation: level A, established as effective
	Sumatriptan (nasal spray)
		• Level of evidence: 1 class I randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: Sumatriptan 20 mg is effective in improving headache response • Adverse effects: nonserious: bitter taste • Recommendation: level B: probably effective
	Zolmitriptan (oral)
		• Level of evidence: 1 class I randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: zolmitriptan 5 mg and 10 mg are effective in improving headache response • Adverse effects: nonserious: paresthesias, heaviness, asthenia, nausea, dizziness, chest pain •Recommendation: level B: probably effective
	Sphenopalatine ganglion stimulation
		• Level of evidence: 1 class I randomized, controlled trial • Study population: chronic cluster headache dissatisfied with current treatment • Efficacy: sphenopalatine ganglion stimulation is effective in improving headache response • Adverse effects: serious: lead revisions, device explants Nonserious: loss of sensation in the distribution of the maxillary nerve, infection, mild focal facial paresis, maxillary sinus puncture • Recommendation: level B: probably effective
	Cocaine/lidocaine (nasal spray)
		• Level of evidence: 1 class II randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: 10% cocaine hydrochloride and 10% lidocaine are effective in improving headache response • Adverse effects: nonserious: nasal congestion, unpleasant lidocaine taste • Recommendation: level C: possibly effective
	Octreotide (subcutaneous)
		• Level of evidence: 1 class II randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: octreotide 100 mg is effective in improving headache response • Adverse effects: nonserious: injection site reactions, diarrhea, abdominal bloating, nausea, dull back- ground headache, lethargy • Recommendation: level C: possibly effective
Insufficient evidence
	Dihydroergotamine (nasal spray)
		• Level of evidence: 1 class III randomized, controlled trial • Study population: episodic cluster headache (“typical periodic”) • Efficacy: insufficient evidence that dihydroergotamine 1 mg is effective in improving headache response • Adverse effects: not reported • Recommendation: level U: insufficient evidence to make recommendation
	Somatostatin
		• Level of evidence: 1 class III randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: insufficient evidence that somatostatin 25 mg is effective in improving • Adverse effects: nonserious: nausea without vomiting • Recommendation: level U: insufficient evidence to make recommendation
	Prednisone
		• Level of evidence: 1 class III randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: insufficient evidence that prednisone 30 mg is effective in improving headache response • Adverse effects: not reported • Recommendation: level U: insufficient evidence to make recommendation

Preventive treatment

The goals of migraine preventive therapy are to: (1) reduce attack frequency, severity, and duration; (2) improve responsiveness to treatment of acute attacks; and (3) improve function and reduce disability. One or more of the following helps guide management decisions on the use of preventive therapies:

	• Recurring migraines that, in the patients' opinion, significantly interfere with their daily routines, despite acute treatment
	• Frequent headaches
	• Contraindication to or failure or overuse of acute therapies
	• Adverse events with acute therapies
	• The cost of both acute and preventive therapies
	• Patient preference
	• Presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction (to prevent neurologic damage-as based on expert consensus)

These consensus-based principles of care will enhance the success of preventive treatment. Consider nonpharmacologic therapies and take patient preference into consideration.

I. Medication use.
	A. Initiate therapy with medications that have the highest level of evidence-based efficacy.
	B. Initiate therapy with the lowest effective dose of the drug. Increase it slowly until clinical benefits are achieved in the absence of, or until limited by, adverse events.
	C. Give each drug an adequate trial. It may take as long as 2 to 3 months to achieve clinical benefit, and 6 months to achieve maximal benefit, after achieving a dose of established clinical efficacy.
	D. Avoid medications that increase headache frequency or severity (eg, overuse of acute headache medications).
II. Evaluation.
	A. Monitor the patient's headache and headache medication consumption through a headache diary.
	B. Monitor the disability/impact associated with headache (eg, HIT-6, MIDAS).
	C. Re-evaluate therapy. After 6 to 12 months of excellent control of headache frequency and severity, discussion with the patient regarding tapering or discontinuing treatment is reasonable.
III. Patient education.
	A. Maximize compliance. Discuss with the patient the rationale for a particular treatment, when and how to use it, and the potential adverse events.
	B. Address patient expectations. Discuss with the patient the expected benefits of therapy and how long it will take to achieve them.
	C. Create a formal management plan.
IV. Coexisting conditions. Some (comorbid or coexisting) conditions are more common in persons with migraine (eg, stroke, myocardial infarction, Raynaud phenomenon, epilepsy, affective and anxiety disorders). These conditions present both treatment opportunities and limitations:
	A. Select the best drug to treat each disorder. (Therapeutic independence may be required; avoid picking a less-effective drug in order to treat both disorders with a single medication).
	B. Establish that the treatments being used for migraine are not contraindicated for the coexistent disease.
	C. Establish that the treatments being used for coexistent conditions do not exacerbate migraine.
	D. Beware of all drug interactions.
	E. Direct special attention to women who are pregnant or want to become pregnant. Preventive medications may have teratogenic effects. If treatment is absolutely necessary, select a treatment with the lowest risk of adverse effects to the fetus.
IV. Nonpharmacologic treatment. Many migraine patients try nonpharmacologic treatment to manage their headaches before they begin drug therapy or concurrently with drug therapy. Behavioral treatments are classified into 3 broad categories: relaxation training, biofeedback therapy, and cognitive-behavioral training (stress-management training). Physical treatment includes acupuncture, cervical manipulation, and mobilization therapy. They are treatment options for headache sufferers who have one or more of the following characteristics:
	A. Patient preference for nonpharmacologic interventions
	B. Poor tolerance to specific pharmacologic treatments
	C. Medical contraindications for specific pharmacologic treatments
	D. Insufficient or no response to pharmacological treatment
	E. Pregnancy, planned pregnancy, or nursing
	F. History of long-term, frequent, or excessive use of analgesic or acute medications that can aggravate headache problems (or lead to decreased responsiveness to other pharmacotherapies)
	G. Significant stress or deficient stress-coping skills

Cognitive and behavioral treatment recommendations

	• Relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy may be considered as treatment options for prevention of migraine (grade A). Specific recommendations regarding which of these to use for specific patients cannot be made.
	• Behavioral therapy may be combined with preventive drug therapy to achieve additional clinical improvement for migraine relief (grade B).
	• Evidenced-based treatment recommendations regarding the use of hypnosis, acupuncture, transcutaneous electrical nerve stimulation, chiropractic or osteopathic cervical manipulation, occlusal adjustment, and hyperbaric oxygen, as preventive or acute therapy for migraine are not yet possible.

Pharmacological preventive therapy

Individual medications have been put into treatment groups based on their established clinical efficacy, significant adverse events, and safety profile:

A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least 2 consistent Class I studies.)*

B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or 2 consistent Class II studies.)

C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least 1 Class II study or 2 consistent Class III studies.)

U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

Table 5. Clinical Considerations for Migraine

Coexisting factors	Clinical application comment
Anorexia	Caution should be taken in using topiramate in thin or anorexic patients as it may exacerbate weight loss.
Asthma	Propranolol and other similar agents may have adverse effects on patients with asthma.
Bipolar disorder	Patients with bipolar depression might benefit from valproic acid, assuming that they do not have underlying liver disease, thrombocytopenia, and are not women with childbearing potential.
Cardiac arrhythmias, heart block, bradycardia	Caution should be taken in using tricyclics in patients with cardiac arrhythmia, or verapamil in patients with a heart block. Propranolol and other beta blockers may be avoided in patients with bradycardia.
Cognitive impairment	Topiramate may be avoided in subjects with cognitive concerns.
Depression	Use of propranolol or other beta blockers may exacerbate depression.
Epilepsy	Topiramate, valproic acid, and gabapentin may be preferred options in migraineurs with coexisting epilepsy.
Hypotension and hypertension	Use of beta blockers, ACEI/ARB, and calcium channel blockers are a concern in patients with hypotension, which is not at all uncommon in young women with migraine. ACEI, beta blockers, and calcium channel blockers are particularly attractive with coexistent hypertension.
Obesity	Caution should be taken in using valproic acid, tricyclic antidepressants, cyproheptadine, and gabapentin as it may contribute to additional weight gain.
Other--glaucoma, renal stones	Topiramate may be avoided in migraineurs with renal stones. (NOT REGULAR GLAUCOMA)
Pregnancy	Valproic acid and ACEI should be avoided if the patient is attempting to become or is pregnant. This is of particular concern in light of the majority of migraineurs tending to be younger women of childbearing potential.
Serotonin syndrome	There is no scientific evidence despite FDA warning that the addition of SSRIs, such as fluoxetine, or an SSNRI, such as venlafaxine, may exacerbate triptan effects leading to serotonin syndrome.
Stroke	ACEI and ARB might offer benefits in terms of secondary stroke prevention for patients with migraine.
Legend: ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; SSRI = selective serotonin re-uptake inhibitor; SSNRI = serotonin-norepinephrine reuptake inhibitor

Table 6. Pharmacologic Preventive Therapies for Migraine

RECOMMENDATIONS
Level A. The following medications are established as effective and should be offered for migraine prevention:
	• Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate • Beta blockers: metoprolol, propranolol, timolol • Triptans: frovatriptan for short-term menstrual-associated migraine prevention
Level B. The following medications are probably effective and should be considered for migraine prevention:
	• Antidepressants: amitriptyline, venlafaxine • Beta blockers: atenolol, nadolol • Triptans: naratriptan, zolmitriptan for short-term menstrual-associated migraine prevention
Level C. The following medications are possibly effective and may be considered for migraine prevention:
	• Alpha agonists: clonidine, guanfacine • Angiotensin receptor blockers: candesartan, lisinopril • Antiepileptic drugs: carbamazepine • Beta blockers: nebivolol, pindolol
Level U. Evidence is conflicting or inadequate to support or refute the use of the following medications for migraine prevention:
	• Anticoagulants: acenocoumarol, warfarin, picotamide • Antidepressants
		-- SSRI/SSNRI: fluoxetine, fluvoxamine -- Tricyclics: protriptyline

	• Beta blockers: bisoprolol • Calcium channel blockers: cyclandelate, nicardipine, nifedipine, nimodipine, verapamil • Acetazolamide • Gabapentin
Level A negative. The following medications are established as ineffective and should not be offered for migraine prevention:
	• Lamotrigine
Level B negative. The following medications are probably ineffective and should not be considered for migraine prevention:
	• Clomipramine
Level C negative. The following medications are possibly ineffective and may not be considered for migraine prevention:
	• Acebutolol • Clonazepam • Nabumetone • Oxcarbazepine • Telmisartan

Table 7. NSAIDs and Other Complementary Treatments

RECOMMENDATIONS
Level A. The following therapy is established as effective and should be offered for migraine prevention:
	• Petasites (Butterbur)
Level B. The following therapies are probably effective and should be considered for migraine prevention:
	• NSAIDS: fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium • Herbal therapies, vitamins, and minerals: riboflavin, magnesium, MIG-99 (feverfew) • Histamines: histamine SC
Level C. The following therapies are possibly effective and may be considered for migraine prevention:
	• NSAIDs: flurbiprofen, mefenamic acid • Herbal therapies, vitamins, and minerals: CoQ10, estrogen • Antihistamines: cyproheptadine
Level U. Evidence is inadequate or conflicting to support or refute the use of the following therapies for migraine prevention:
	• NSAIDs: aspirin, indomethacin • Herbal therapies, vitamins, and minerals: omega-3 • Other: hyperbaric oxygen therapy (HBO)
Level B negative. The following therapy is probably ineffective and should not be considered for migraine prevention:
	• Leukotriene receptor antagonists: montelukast

Table 8. Nutraceutical Preventive Therapies for Migraine

	Riboflavin (vitamin B2)
		• CHS guidelines: strong recommendation, daily dose of 300 mg, as 100 mg TID • AAN/AHS: Level C recommendation • EFNS: Level C recommendation
	Coenzyme Q10
		• CHS guidelines: strong recommendation, daily dose of 300 mg, as 100 mg TID • AAN/AHS: Level C recommendation • EFNS: Level C recommendation
	Magnesium
		• CHS guidelines: strong recommendation, recommend 600 mg daily • AAN/AHS: Level B recommendation • EFNS: Level C recommendation
	Butterbur (Petasites hybridus)
		• CHS guidelines: Strong recommendation, at dose of 75 mg twice daily. Only commercially prepared products. • AAN/AHS: Level A recommendation • EFNS: Level B recommendation
	Feverfew (Tanacetum parthenium)
		•CHS guidelines: strong recommendation against offering feverfew (no better than placebo for migraine prophylaxis) • AAN/AHS: Level B recommendation • EFNS: Level C
	Omega-3 polyunsaturated fatty acids
		• CHS guidelines: none • AAN/AHS: Level U indication • EFNS: none
Legend: CHS = Canadian headache society; AAN/AHS = American Headache Society/American Academy of Neurology; EFNS = European Federation of Neurological Sciences

Table 9. Pharmacologic Preventive Therapies for Cluster Headache

Positive evidence
	Suboccipital steroid injection
		•Level of evidence: 2 class I randomized, controlled trials • Study population: episodic and chronic cluster headache • Efficacy: suboccipital single injection or injection series with corticosteroids is effective in reducing attack frequency • Adverse effects: nonserious: transient injection site pain, headache • Recommendation: Level A, established as effective
	Civamide (Nasal Spray)
		• Level of evidence: 1 class I randomized, controlled trials • Study population: episodic cluster headache • Efficacy: 100 mL of 0.025% civamide in each nostril daily is effective in reducing attack frequency • Adverse effects: Nonserious: nasal burning, lacrimation, pharyngitis, rhinorrhea • Recommendation: Level B: probably effective
	Lithium
		• Level of evidence: 2 class II randomized, controlled trials (1 positive, 1 negative) • Study population: episodic and chronic cluster headache • Efficacy: lithium 900 mg is effective in reducing attack frequency • Adverse effects: nonserious: polyuria • Recommendation: Level C: possibly effective
	Verapamil
		• Level of evidence: 1 class II and 1 class III randomized, controlled trials • Study population: episodic and chronic cluster headache • Efficacy: verapamil 360 mg daily is effective in reducing attack frequency • Adverse effects: nonserious: constipation, reduced blood pressure, reduced heart rate • Recommendation: Level C: possibly effective
	Warfarin
		• Level of evidence: 1 class II randomized, controlled trial • Study population: refractory chronic cluster headache • Efficacy: Warfarin daily with International Normalized Ratio goal of 1.5 to 1.9 is effective in reducing attack frequency • Adverse effects: Nonserious: epistaxis, skin bruising
	Melatonin
		• Level of evidence: 1 class II randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: melatonin 10 mg every evening is effective in reducing attack frequency • Adverse effects: not reported •Recommendation: Level C: possibly effective
Insufficient evidence
	Frovatriptan
		• Level of evidence: 1 class III randomized, controlled trial • Study population: episodic cluster headache • Efficacy: insufficient evidence frovatriptan 5 mg daily is effective in reducing attack frequency • Adverse effects: not reported •Recommendation: Level U: insufficient evidence to make recommendation
	Capsaicin (Intranasal)
		• Level of evidence: 1 class III randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: insufficient evidence that capsaicin 0.025% cream applied twice daily is effective in reducing attack frequency • Adverse effects: not reported •Recommendation: Level U: insufficient evidence to make recommendation
	Nitrate tolerance
		• Level of evidence: 1 class III randomized, controlled trial • Study population: chronic cluster headache • Efficacy: insufficient evidence that nitrate tolerance with 5-isosorbide mononitrate 30 mg 3 times daily is effective in reducing attack frequency • Adverse effects: nonserious: hypotension, headache • Recommendation: Level U: insufficient evidence to make recommendation
	Prednisone
		• Level of evidence: 1 class III randomized, controlled trial • Study population: not specified • Efficacy: insufficient evidence that prednisone 20 mg every other day is effective in reducing attack frequency • Adverse effects: not reported • Recommendation: Level U: insufficient evidence to make recommendation
Negative evidence
	Sodium Valproate
		• Level of evidence: 1 class I randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: sodium valproate 1000 to 2000 mg daily is not effective in reducing attack frequency • Adverse effects: nonserious: nausea and vomiting, somnolence • Recommendation: Level B: probably ineffective
	Sumatriptan
		• Level of evidence: 1 class I randomized, controlled trial • Study population: episodic and chronic cluster headache • Efficacy: sumatriptan 100 mg 3 times daily is not effective in reducing attack frequency • Adverse effects: nonserious: nausea, vomiting, headache, malaise • Recommendation: Level B: probably ineffective
	Deep brain stimulation
		• Level of evidence: 1 class I randomized, controlled trial • Study population: refractory chronic cluster headache • Efficacy: unilateral hypothalamic deep brain stimulation is not effective in reducing attack frequency • Adverse effects: serious: subcutaneous infection, preoperative loss of consciousness with hemiparesis after test stimulation, severe micturition syncope; nonserious: transient diplopia, change in hunger, change in libido • Recommendation: Level B: probably ineffective
	Cimetidine/chlorpheniramine
		• Level of evidence: 2 class II and 1 class III randomized, controlled trials • Study population: not specified • Efficacy: Cimetidine 800 to 2000 mg and chlorpheniramine 16 to 20 mg are not effective in reducing attack frequency • Adverse effects: serious: prolonged rash; nonserious: transient, erythematous skin rash • Recommendation: Level C: possibly ineffective
	Misoprostol
		• Level of evidence: 1 class II randomized controlled trial • Study population: Refractory chronic cluster headache • Efficacy: misoprostol 300 mg daily is not effective in reducing attack frequency • Adverse effects: not reported • Recommendation: Level C: possibly ineffective
	Oxygen (hyperbaric)
		• Level of evidence: 1 class II randomized controlled trial • Study population: episodic and chronic cluster headache • Efficacy: 100% hyperbaric oxygen is not effective in reducing attack frequency • Adverse effects: not reported • Recommendation: Level C: possibly ineffective
	Candesartan
		• Level of evidence: 1 class II randomized controlled trial • Study population: Episodic cluster headache • Efficacy: candesartan 32 mg daily is not effective in reducing attack frequency • Adverse effects: nonserious: orthostatic reactions, dizziness, tiredness • Recommendation: Level C: possibly ineffective

Clinical context

Evidence to support pharmacologic treatment strategies for migraine prevention indicates which treatments might be effective, but is insufficient to establish how to choose an optimal therapy. Consequently, although Level A recommendations can be made for pharmacologic migraine prevention, similar evidence is unavailable to help the practitioner choose one therapy over another. Treatment regimens, therefore, need to be designed case by case, which may include complex or even nontraditional approaches. Moreover, decision making must remain with the physician and the patient to determine the optimal therapy, accounting for efficacy, adverse events, coexisting/comorbid conditions, and personal considerations. Often, trial and error is needed. Studies assessing the efficacy of NSAIDs and complementary treatments for migraine prevention are limited and should be considered relative to other available pharmacologic therapies.

Newer guidelines focus on evidence-based treatment, with a reduced focus on expert opinion. Older studies using smaller numbers of subjects with less rigorous study design may not be considered Class I studies, leading to a lower evidence-based score such as seen with opioids in migraine.

Evidence is also unavailable for making broad-range comparisons among multiple agents within a single class; such evidence would provide a more comprehensive understanding of relative efficacy and tolerability profiles across a broader range of therapeutic agents. Studies are needed that specifically evaluate when preventive therapy is warranted and how medications should be titrated. Table 1 lists some specific consensus-based clinical circumstances wherein considering preventive therapy would be reasonable. A shortcoming of migraine prevention clinical studies is the relatively brief treatment duration (often only 12 to 16 weeks). Long-term assessment of the efficacy and safety of migraine preventive treatments is needed. Additionally, overall cost is a consideration when prescribing medications; cost may influence compliance, especially long-term.

It seems reasonable that a clinician be mindful of comorbid and coexistent conditions in patients with migraine, to maximize potential treatment efficacy and minimize adverse events risk. Table 3 identifies which therapies to consider or avoid when common migraine coexisting conditions are present. Because migraine is frequent in women of childbearing age, the potential for adverse fetal effects related to migraine prevention strategies is particularly concerning.

References

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Table 1. Evidence Summary for Treatment of Acute Attacks of Migraine

Table 2. Evidence Summary for Treatment of Acute Migraine Attacks in the Emergency Department

Table 3. Acute Therapies for Migraine

Table 4. Efficacy, Adverse Events, Level of Evidence and Recommendations for the Acute Therapy of Cluster Headache

Preventive treatment

Cognitive and behavioral treatment recommendations

Pharmacological preventive therapy

Table 5. Clinical Considerations for Migraine

Table 6. Pharmacologic Preventive Therapies for Migraine

Table 7. NSAIDs and Other Complementary Treatments

Table 8. Nutraceutical Preventive Therapies for Migraine

Table 9. Pharmacologic Preventive Therapies for Cluster Headache

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