Diagnosis and treatment of headache

Major Recommendations and Clinical Highlights

• Headache is diagnosed by history and physical examination with limited need for imaging or laboratory tests.

• Warning signs of possible disorder other than primary headache are:
  • Subacute and/or progressive headaches which worsen over time (months)
  • A new or different headache
  • Any headache of maximum severity at onset
  • Headache of new onset after age 50
  • Persistent headache precipitated by a Valsalva maneuver
  • Evidence such as fever, hypertension, myalgias, weight loss, or scalp tenderness suggesting a systemic disorder
  • Presence of neurological signs that may suggest a secondary cause
  • Seizures
• Migraine-associated symptoms are often misdiagnosed as “sinus headache” by patients and clinicians. Most headaches characterized as “sinus headaches” are migraines.
• Early treatment of migraines with effective medications improves a variety of outcomes including duration, severity and associated disability.
• Drug treatment of acute headache should generally not exceed more than two days per week on a regular basis. More frequent treatment other than this may result in medication-overuse chronic daily headaches.
• Inability to work or carry out usual activities during a headache is an important issue for migraineurs.
• Prophylactic therapy should be considered for all patients.
• Migraines occurring in association with menses and not responsive to standard cyclic prophylaxis may respond to hormonal prophylaxis with use of estradiol patches, creams, or estrogen-containing contraceptives.
• Women who have migraines with aura have a substantially higher risk of stroke with the use of estrogen-containing [contraceptives] compared to those without migraines. Headaches occurring during perimenopause or after menopause may respond to hormonal therapy.
• Most prophylactic medications should be started in a low dose and titrated to a therapeutic dose to minimize side effects and maintained at target dose for 8–12 weeks to obtain maximum efficacy.

Special Circumstances

Adolescents

At this time the majority of the adolescent literature supports a strong placebo effect in this age group. Success of triptans and prophylactic medications in patients age 12-17 yield similar positive outcomes as in adult studies, but placebo administered in blinded, controlled studies has a similar effect. There has been a recent study that supports the use of almotriptan with statistically significant efficacy over placebo. As an acute treatment, almotriptan in the dose of 12.5 mg was effective in relieving pain and associated symptoms and was well tolerated [High Quality Evidence].

As a prophylactic treatment, topiramate 100 mg/day was effective in reduction of the number of migraine headaches a month [High Quality Evidence].

Psychological treatments, principally relaxation and cognitive behavioral therapies are effective treatments of childhood headache [Meta-analysis/Systematic Review].

Pregnancy and Breastfeeding

Special consideration should be given to medication selection and management during pregnancy and breastfeeding, considering the risks and benefits of selected drugs and their efficacy.

Information sourced from AHRQ

Diagnosis Algorithm Annotations

10. Patient Presents with Complaint of a HeadacheRecommendation
    • Clinicians should perform an appropriate prompt evaluation of the patient who presents with headache and initiate acute treatment.

    Migraine is the most common headache disorder seen by primary care providers [Low Quality Evidence].

    A patient may present for care of headaches during an attack or during a headache-free period. If a patient presents during a headache, appropriate evaluation (history, examination, appropriate testing) needs to be undertaken in a timely fashion. Once the diagnosis of primary headache is established, acute treatment is instituted. If the patient has a history of recurrent headaches, a plan for treatment (acute and prophylactic) needs to be established.

11. Critical First StepsRecommendation:
    • Clinicians should gather a detailed history, including a focused physical and neurological exam, of the patient who presents with headache.

    Minimal general physical examination is performed at the first consultation of patient presenting with a headache. Symptoms and signs with the use of criteria can diagnose headache. The International Classification of Headache Disorders, second edition (ICHD-II) system presently provides the gold standard. As empirical evidence and clinical experience accumulate, criteria for diagnosing headaches will be revised [Reference].

    Detailed History

    Inquire about functional disabilities at work, school, housework, or leisure activities during the past 3 months (informally or using well-validated disability questionnaire).

    Assessment of the headache characteristics requires determination of the following:

    Temporal profile:

    • Time from onset to peak
    • Usual time of onset (season, month, menstrual cycle, week, hour of day)
    • Frequency and duration
    • Stable or changing over past 6 months and lifetime

    Autonomic features:

    • Nasal stuffiness
    • Rhinorrhea
    • Tearing
    • Eyelid ptosis or edema

    Descriptive characteristics: pulsatile, throbbing, pressing, sharp, etc.

    Location: uni- or bilateral, changing sides

    Severity

    Precipitating features and factors that aggravate and/or relieve the headache

    Factors that relieve the headache

    History of other medical problems

    Pharmacological and non-pharmacological treatments which are effective or ineffective

    Aura (present in approximately 15% of migraine patients)

    Focused Physical Examination

    Vital signs (blood pressure, pulse, respirations, and temperature)

    Extracranial structure evaluation such as carotid arteries, sinuses, scalp arteries, cervical paraspinal muscles

    Examination of the neck in flexion versus lateral rotation for meningeal irritation. (Even a subtle limitation of neck flexion may be considered an abnormality.)

    Focused Neurological Examination

    A focused neurological examination may be capable of detecting most of the abnormal signs likely to occur in patients with headache due to acquired disease or a secondary headache.

    This exam should include at least the following evaluations:

    • Assessment of patient’s awareness and consciousness, presence of confusion, and memory impairment
    • Ophthalmological examination to include pupillary symmetry and reactivity, optic fundi, visual fields, and ocular motility
    • Cranial nerve examination to include corneal reflexes, facial sensation, and facial symmetry
    • Symmetry of muscle tone, strength (may be as subtle as arm or leg drift), or deep tendon reflexes
    • Sensation
    • Plantar response(s)
    • Gait, arm and leg coordination

12. Causes for Concern?Headache features beyond that of ICHD-II system criteria should raise concern of a more sinister underlying cause [Guideline].Causes for concern in the diagnosis of headaches may alter a diagnosis of migraine to a secondary diagnosis of headache, which can be more serious and/or life-threatening [Guideline, Low Quality Evidence].

    Causes for concern must be evaluated irrespective of the patient’s past history of headache. Warning signs of possible disorder other than primary headache are:

    • Subacute and/or progressive headaches which worsen over time (months)
    • A new or different headache or a statement by a headache patient that “this is the worst headache ever”
    • Any headache of maximum severity at onset
    • Headaches of new onset after the age of 50 years old
    • Persistent headache precipitated by a Valsalva maneuver such as cough, sneeze, bending, or with exertion (physical or sexual)
    • Evidence such as fever, hypertension, myalgias, weight loss, or scalp tenderness suggesting a systemic disorder
    • Neurological signs that may suggest a secondary cause. For example, meningismus, confusion, altered levels of consciousness, changes or impairment of memory, papilledema, visual field defect, cranial nerve asymmetry, extremity drifts or weaknesses, clear sensory deficits, reflex asymmetry, extensor plantar response, or gait disturbances.
    • Seizures

13. Consider Secondary Headache DisorderThe presence of the symptoms or signs listed above suggests a secondary cause for the headache, and could be indicative of an underlying organic condition. Alternate diagnoses include subarachnoid hemorrhage, tumor, meningitis, encephalitis, temporal arteritis, idiopathic intracranial hypertension, and cerebral venous thrombosis, among others.Secondary Headaches
    • Subacute and/or progressive, worsening headaches over weeks to months:Headaches that worsen with time may be due to a progressive intracranial lesion such as tumor, subdural hematoma, or hydrocephalus. While the neurologic examination may reveal abnormalities that suggest a sinister process, this is not always the case. Accordingly, a history of a progressive headache is an indication for head imaging. For most processes, magnetic resonance imaging with and without gadolinium contrast will be more sensitive than a computed tomography head scan. Note: in patients who receive gadolinium contrast media used in magnetic resonance imaging (MRI), there is the potential for renal toxicity and the rare complication (3%-5% risk in patients with moderate to end-stage renal disease) of life-threatening nephrogenic systemic fibrosis. It is recommended that gadolinium use be avoided when possible in patients with advanced renal disease.
    • A new or different headache or a statement by a headache patient that “this is the worst headache of my life” – Primary headache disorders (mainly tension-type headache and migraine) are exceedingly common. A history of a primary headache disorder does not confer protection against a new, serious process that presents with headache. The acuteness of a headache will largely define the differential diagnosis. Headache that presents suddenly, “like a thunderclap,” can be characteristic of several serious intracranial processes, including subarachnoid hemorrhage, venous sinus thrombosis, bacterial meningitis, spontaneous cerebral spinal fluid leak, carotid dissection, and rarely, pituitary apoplexy and hypertensive encephalopathy. The first investigation is a computed tomography head scan without contrast. If there is no evidence of a subarachnoid hemorrhage, a lumbar puncture should be performed. If both studies are normal and the suspicion of subarachnoid hemorrhage is still high, MRI with and without gadolinium should be obtained. Neurological consultation is indicated and further tests for consideration include magnetic resonance angiogram and magnetic resonance venogram.If the headache is more subacute in onset, chronic meningitis may need to be considered along with a space occupying intracranial lesion or hydrocephalus. Again, neuroimaging should be performed. Whether a lumbar puncture is done will be guided by the index of suspicion regarding a meningeal process (e.g., meningitis).
    • Headache of sudden onset:This refers mainly to thunderclap headache (see above). It should be treated as an emergency since the possible presence of aneurysmal subarachnoid hemorrhage needs to be assessed as outlined above. Other secondary causes of headache will be found less commonly.
    • Headache precipitated by a Valsalva maneuver such as cough, sneeze, bending, or with exertion:Valsalva headaches, while often representing primary cough headache, can signal an intracranial abnormality, usually of the posterior fossa. The most commonly found lesion is a Chiari malformation although other posterior fossa lesions are sometimes found. Less commonly there are intracranial lesions located elsewhere. An MRI needs to be obtained to appropriately investigate for these possibilities. Exertional headache, such as with exercise or during sexual activity, may represent a benign process such as migraine. However, if the headache is severe or thunderclap in onset, investigations will be necessary as already outlined above.
    • Headaches of new onset after the age of 50 years:The large majority of individuals who are destined to develop a primary headache disorder do so prior to age 50 years. Of course, this is not universal, and migraine or other primary headache disorders may begin even at an advanced age. Nevertheless, care should be taken before a diagnosis of a primary headache disorder is assigned. Many patients who do have the onset of a new headache disorder after age 50 years will merit brain imaging. In addition, after the age of 50 years, a new headache disorder should evoke suspicion of possible giant cell arteritis. Obviously, symptoms of polymyalgia rheumatica, jaw claudication, scalp tenderness, or fever will increase the likelihood of this diagnosis. Findings of firm, nodular temporal arteries and decreased temporal pulses will increase the suspicion as will an elevated sedimentation rate.
    • Symptoms suggestive of a systemic disorder such as fever, myalgias, weight loss, or scalp tenderness or a known systemic disorder such as cancer or immune deficiency:Systemic disorders, while not incompatible with a coexistent primary headache disorder, should signal caution. Patients should be carefully evaluated. Obviously, the differential diagnosis will be long and the index of suspicion for any given process will largely depend on the clinical setting.
    • Presence of subtle neurological signs suggests a secondary cause for headache. For example, meningismus, confusion, altered level of consciousness, memory impairment, papilledema, visual field defect, cranial nerve abnormalities, pronator drift, extremity weakness, significant sensory deficits, reflex asymmetry, extensor plantar response, or gait disturbance when accompanying a headache should elicit caution:While neurological signs may be unrelated to a headache, previously undocumented neurological findings that are presumably new need to be carefully considered. Usually cranial imaging will be the initial study. Depending on the index of suspicion, lumbar puncture and blood studies may be indicated.
    • Seizures:While seizures can occasionally be a manifestation of a primary headache disorder such as migraine, this is the exception and not the rule; it is a diagnosis of exclusion. Other etiologies for seizures including space-occupying lesions, infection, stroke, and metabolic derangements will need to be considered. Again, MRI is the imaging procedure of choice unless there is an issue of acute head trauma, in which case a computed tomography (CT) head scan should be obtained initially.
    • Diagnosis to be included in secondary headache:
      • Subdural hematoma
      • Epidural hematoma
      • Tumor
      • Other metabolic disorders
      • Craniocervical arterial dissection
      • Giant cell arteritis
      • Acute hydrocephalus
      • Obstructive hydrocephalus
      • Cerebral spinal fluid leaks
      • Cerebral venous sinus thrombosis

      This list is not intended to be all-inclusive but rather to represent the most commonly seen diagnosis for secondary headache by the primary care clinician.

14. Meets Criteria for Primary Headache Disorder?The ICHD-II system for migraine has been studied in a community population sample without consideration of treatment. Findings suggest that the best criteria differentiating migraine from other headache types are the presence of nausea and/or vomiting in combination with two of the following three symptoms: photophobia, phonophobia, and osmophobia [Reference].The table “Modified Diagnostic Criteria” in the original guideline document has been modified from the ICDH-II system criteria and describes the differentiating criteria applicable for the diagnosis of migraine and other primary headache disorders.

15. Evaluate Type of Primary Headache. Initiate Patient Education and Lifestyle ManagementRecommendations:
    • Clinicians should provide patient education and lifestyle management options to patients with headache.
    • Clinicians should instruct patients with headache to maintain a diary to clarify the frequency, severity, triggers and treatment responses to their headaches.

    Migraine-associated symptoms are often misdiagnosed as “sinus headache” by patients and providers. This has led to the underdiagnosis and treatment of migraine.

    While education is of paramount importance in managing any condition, it is especially important in the ongoing management of headache. Patients may have to make lifestyle changes, are often required to make self-management choices in the treatment of individual headaches, and should maintain a diary to clarify the frequency, severity, triggers, and treatment responses.

    Refer to the original guideline document for detailed information regarding type of headache, lifestyle changes and self-management, and for mnemonic POUNDing for the screening of migraine headache.

19. Chronic Daily HeadacheChronic daily headache refers to the presence of a headache more than 15 days per month for greater than three months. Chronic daily headache can be divided into those headaches that occur nearly daily that last four hours or less and those that last more than four hours, which is more common. The shorter-duration daily headache contains less common disorders such as chronic cluster headache and other trigeminal autonomic cephalgias. Only daily headaches of long duration are considered in this guideline.Refer to the original guideline document for diagnostic criteria of the following types of chronic daily headache: medication-overuse headache, chronic tension-type headache, and hemicrania continua.

21. Specialty Consultation Indicated?Recommendation:
    • Clinicians may consider specialty consultation when the diagnosis or etiology cannot be confirmed, warning signals exist or quality of life is impaired.

    The decision to seek a specialty consultation will depend upon the practitioner’s familiarity and comfort with headache and its management. Specialty consultation may be considered when:

    • The diagnosis cannot be confirmed.
    • Etiology cannot be diagnosed or warning signals are present.
    • Headache attacks are occurring with a frequency or duration sufficient to impair the patient’s quality of life despite treatment or the patient has failed to respond to acute remedies or is in status migrainosus.

22. Perform Diagnostic Testing if IndicatedRecommendation:
    • Clinicians should use a detailed headache history, that includes duration of attacks and the exclusion of secondary causes, as the principal means to diagnose primary headache. Additional testing in patients without atypical symptoms or an abnormal neurologic examination is unlikely to be helpful.

    There are, as yet, no tests which confirm the diagnosis of primary headache. The diagnosis of primary headache is dependent on the clinician. The work group recommends careful consideration before proceeding with neuroimaging (CT or MRI). It is uncommon for neuroimaging to detect an abnormality in persistent headaches of longer duration versus new onset situations. Selective testing, including neuroimaging, or electroencephalogram, lumbar puncture, cerebrospinal fluid and blood studies, may be indicated to evaluate for secondary headache if causes of concern have been identified in the patient history or physical examination (see Annotation #12, “Causes for Concern?”). Diagnosis may be complicated if several headache types coexist in the same patient. The following symptoms significantly increased the odds of finding a significant abnormality on neuroimaging in patients with non-acute headache:

    • Rapidly increasing headache frequency
    • History of 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) [Guideline]

    Refer to the original guideline document for more information.

Migraine Treatment Algorithm Annotations

27. Patient Meets Criteria for MigraineMigraine is the most common headache disorder seen by primary care clinicians.It is expected that a patient with headache undergo a diagnostic work-up (see the Diagnosis Algorithm) establishing the diagnosis of migraine before initiating acute treatment.

28. Is Patient Experiencing a Typical Headache?Each individual headache must be evaluated in the context of the patient’s prior migraine headaches. The practitioner must always remain alert to the possibility of secondary causes for headache, particularly when there is a previously established history of a primary headache disorder such as migraine.Migraine headache does not preclude the presence of underlying pathology (arterial dissection, intracranial aneurysm, venous sinus thrombosis, ischemic or hemorrhagic stroke, temporal arteritis, etc.) that may also present with “vascular headaches.” If the history is scrutinized, ominous causes for headaches can often be identified and treated with the potential to avoid catastrophe.

30. Categorize According to Peak Severity Based on Functional Impairment, Duration of Symptoms, and Time to Peak ImpairmentRecommendations:
    • Clinicians should categorize headache according to peak severity, duration of symptoms and time to peak impairment.
    • Clinicians should treat according to severity.

    Accurate categorization and characterization by both providers and patients is important. The categorization of migraine influences choice of treatment method.

    Severity Levels

    Mild – Patient is aware of a headache but is able to continue daily routine with minimal alteration.

    Moderate – The headache inhibits daily activities but is not incapacitating.

    Severe – The headache is incapacitating.

    Status – A severe headache that has lasted more than 72 hours.

    There may be additional features that influence choice of treatment. For example, parenteral administration (subcutaneous, nasal) should strongly be considered for people whose time to peak disability is less than one hour, who awaken with headache, and for those with severe nausea and vomiting.

    Determining functional limitations during migraine episodes is the key to determining the severity and therefore the best treatment for a patient. Clinicians and patients should stratify treatment based on severity rather than using stepped care, though patients will often use stepped care within an attack. This algorithm uses a stratified-care model.

    Factors That May Trigger Migraine

    Certain influences can lead to a migraine attack. It is important to note that although a single trigger may provoke the onset of a migraine, a combination of factors is much more likely to set off an attack.

    Refer to the original guideline document for a detailed list of triggers, including environmental triggers, lifestyle habits, hormonal triggers, emotional triggers, and medications.

32. Mild TreatmentRecommendations:
    • Clinicians may manage mild migraines with over-the-counter medications.
    • Clinicians may use triptans for mild migraine pain levels.

    The guideline work group presumes most mild migraine headaches will be managed by self-care, which implies an emphasis on over-the-counter medications. However, since only 2% to 12% of initially mild migraine episodes remain mild (with the remainder progressing), treatments effective for mild headaches may be useful for only a short time. Studies on treatment of migraine headache at the mild level show that triptans are more effective in abolishing pain at this stage than if the headache is more severe. It is acceptable to use other symptomatic headache relief drugs as well as triptans for mild headache. However, current retrospective analyses of mild pain treatment studies reveal triptan response to two-hour pain freedom to be superior to any other comparator drug. Please see Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

    Use of non-steroidal anti-inflammatory drugs (NSAIDs) for acute treatment of headache for more than nine days per month or use of aspirin for more than 15 days is associated with an increased risk of chronic daily headache.

    Early treatment of migraines with effective medications improves a variety of outcomes including duration, severity and associated disability [Meta-analysis].

    Given a longer half-life of naratriptan, headache response is delayed with naratriptan when compared with other selective 5-hydroxy tryptamine (5-HT) receptor agonists. However, headache recurrence may be less frequent.

    Second doses of triptans have not been shown to relieve headache more if the first dose has been ineffective.

    Studies show that sumatriptan and naproxen sodium in combination may be more effective than either drug alone. However, there are no studies that demonstrate that sumatriptan 85 mg/naproxen sodium 500 mg is more effective than sumatriptan and naproxen sodium taken together. Therefore, a dose of sumatriptan 100 mg and a dose of naproxen sodium 550 mg taken at the same time is recommended.

33. Successful?Success for treatment of migraine is defined as complete pain relief and return to normal function within two hours of taking medication. In addition, patients should not have intolerable side effects and should find their medications reliable enough to plan daily activities despite migraine headache [Low Quality Evidence].Consider reasons for treatment failure and change treatment plan.

    Common reasons for migraine treatment failure are provided in the original guideline document.

36. Moderate TreatmentRecommendation:
    • Clinicians should avoid the use of opiates and barbiturates in the treatment of headache.

    Early treatment of migraines with effective medications improves a variety of outcomes including duration, severity, and associated disability [Meta-analysis].

    The use of opiates and barbiturates should be avoided. This guideline emphasizes the use of other agents over opiates and barbiturates, recognizing that many migraineurs are currently treated with drugs from the latter two classes. In general, opiates are characterized by having a short pain-relief window, release inflammatory neurochemicals, and increase vasodilation; none of these addresses the currently known treatment issues and pathophysiology of migraine.

    Meperidine should be avoided. The metabolite of meperidine, normeperidine, has a long half-life, produces less analgesic effect, and there is an increased risk of seizures that cannot be reversed by naloxone. The guideline developers have specifically excluded butorphanol because of its high potential for abuse and adverse side-effect profile.

    If an opiate must be used, meperidine should not be the opiate selected.

    See Appendix A, “Drug Treatment for Headache” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

43. Status (Greater Than 72 Hour Duration)Recommendation:
    • It is recommended that the patient be hydrated prior to neuroleptic administration with 250-500 mL of 5% dextrose with 0.45% sodium chloride intravenously and advised of the potential for orthostatic hypotension and acute extrapyramidal side effects. The patient should be observed in a medical setting as clinically appropriate after administration of a neuroleptic and should not drive for 24 hours.

44. Adjunctive TherapyRecommendation:
    • Clinicians may consider adjunctive therapy as a treatment option for headache.

    See Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document. As adjunctive therapy, any of the listed medications can be used singularly or in compatible combination. For intermittent, infrequent headache, caffeine should be added as first choice when not contraindicated. The use of caffeine in patients with chronic daily headache is to be discouraged. The prokinetic agent metoclopramide could be considered next. This guideline has no other preferences.

45. Patient Meets Criteria for Dihydroergotamine Mesylate (DHE)?DHE is effective in halting intractable migraine attacks or migraine status. DHE is also effective in halting the acute cycle of cluster headaches.DHE must not be given to patients with the following conditions:
    • Pregnancy and breastfeeding
    • History of ischemic heart disease
    • History of Prinzmetal’s angina
    • Severe peripheral vascular disease
    • Onset of chest pain following administration of test dose
    • Within 24 hours of receiving any triptan or ergot derivative
    • Elevated blood pressure
    • Patients with hemiplegic or basilar-type migraine (basilar-type migraine is defined as three of the following features: diplopia, dysarthria, tinnitus, vertigo, transient hearing loss or mental confusion) [Guideline]
    • Cerebrovascular disease

    Intravenous DHE is the method most frequently employed to terminate a truly intractable migraine attack or migraine status. The protocol outlined in the DHE algorithm is effective in eliminating an intractable migraine headache in up to 90% of patients within 48 hours. This method of administration has also been found to be effective in terminating an acute cycle of cluster headaches as well as chronic daily headaches with or without analgesic/ergotamine rebound.

47. Chlorpromazine, Intravenous Valproate Sodium, Intravenous Magnesium Sulfate or ProchlorperazineRecommendations:
    • Clinicians should treat patients with migraine >72 hours who do not meet criteria for DHE with chlorpromazine, intravenous valproate sodium, intravenous magnesium sulfate or prochlorperazine.
    • Clinicians should premedicate patients with diphenhydramine or benztropine who have migraine for >72 hours who do not meet criteria for DHE and who have a history of dystonic reaction.

    See Appendix A, “Drug Treatment for Headache” and Appendix B, “Drug Treatment for Adjunctive Therapy” in the original guideline document.

    If chlorpromazine, valproate sodium, or intravenous magnesium sulfate was used previously, one may not wish to repeat.

49. OpiatesThese are not drugs of first choice and headache practice recommends against the use of meperidine. Normeperidine, the active metabolite of meperidine, has a long half-life and is neuroexcitatory and neurotoxic. There is inconsistent absorption of opiates, at least with meperidine, when injected intramuscularly, and they are less effective than when given intravenously. Opiates release inflammatory neurochemicals and increase vasodilation that are mechanistically counterproductive to currently known migraine pathophysiology and can exacerbate headaches. Studies have been done using meperidine but the effects are likely due to class effect and other opiates are likely to be just as effective [High Quality Evidence]. However, it should be noted that there are no studies to support opiate effectiveness.See Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

51. DexamethasoneSee Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.Migraine Treatment – Annotations #32, 36, 39, 44, 47, 49, 51

    Adolescents

    At this time the majority of the adolescent literature supports a strong placebo effect in this age group. Success of triptans and prophylactic medications in patients age 12-17 yield similar positive outcomes as in adult studies, but placebo administered in blinded, controlled studies has a similar effect. There has been a recent study that supports the use of almotriptan with statistically significant efficacy over placebo. As an acute treatment, almotriptan in the dose of 12.5 mg was effective in relieving pain and associated symptoms and was well tolerated [High Quality Evidence].

    See Appendix A, “Drug Treatment for Headache,” in the original guideline document for more information.

Tension-Type Headache Algorithm Annotations

59. Patient Meets Criteria for Tension-Type Headache?Tension-type headache is one of the most common primary headaches. See Annotation #14 “Meets Criteria for Primary Headache Disorder?” for episodic (less than 15 days per month) and chronic tension-type headache (more than 15 days per month).It is important to evaluate the patient who comes to the office for tension-type headache for the possibility of migraine. While the ICHD-II system suggests migraine and tension-type headaches are distinct disorders, there is evidence to suggest that for the migraineur, tension-type headache is actually a low-intensity migraine [High Quality Evidence], [Low Quality Evidence].

62. Acute TreatmentRecommendation:
    • Clinicians may utilize over-the-counter analgesics or prescription NSAIDs for tension-type headache treatment.

    Analgesics offer a simple and immediate relief for tension-type headache. Medication overuse is potentially a concern that can lead to chronic daily headache. Use of drugs for acute treatment of headache for more than nine days per month is associated with an increased risk of chronic daily headache.

    See Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

    [High Quality Evidence], [Low Quality Evidence]

    Electromyography biofeedback has been found to have an effect on tension-type headaches. The goal is to help patients recognize muscle tension. Fifty-three studies have shown medium to large effect [Guideline].

66. Prophylactic TreatmentRecommendation:
    • Prophylactic treatment, including the use of tricyclic antidepressants, may be used for chronic tension-type headaches.

    Prophylactic therapy is reserved for patients with chronic tension-type headache (more than 15 headaches per month).

    Tricyclic antidepressants are effective in reducing the frequency and severity of tension-type headache.

    [High Quality Evidence], [Low Quality Evidence]

Cluster Headache Algorithm Annotations

71. Patient Meets Criteria for Cluster Headache?There is no more severe pain than that sustained by a cluster headache sufferer. This headache is often termed “suicide headache.” Cluster headache is characterized by repeated short-lasting but excruciating intense attacks of strictly unilateral peri-orbital pain associated with local autonomic symptoms or signs. The most striking feature of cluster headache is the unmistakable circadian and circannual periodicity. Many patients typically suffer daily (or nightly) from one or more attacks over a period of weeks or months [Low Quality Evidence], [High Quality Evidence].

75. Acute TreatmentRecommendations:
    • Clinicians should utilize inhaled oxygen for the treatment of cluster headaches at a rate of 7-15 L/min.
    • Clinicians should consider using subcutaneous sumatriptan or intranasal zolmitriptan as a first line option for the treatment of cluster headaches.

    Oxygen inhalation is highly effective when delivered at the beginning of an attack with a non-rebreathing facial mask (7-15 L/min). Most patients will obtain relief within 15 minutes. Acute drugs may be difficult to obtain in adequate quantity.

    Subcutaneous sumatriptan and intranasal zolmitriptan are the most effective self-administered medication for the relief of cluster headaches. Sumatriptan is not effective when used before the actual attack nor is it useful as a prophylactic medication [Systematic Review]. Intranasal sumatriptan can also be considered for acute treatment [Moderate Quality Evidence].

    DHE provides prompt and effective relief from cluster headaches in 15 minutes, but due to the rapid peak intensity and short duration of cluster headaches, DHE may be a less feasible option then sumatriptan.

    See Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

    [Low Quality Evidence], [High Quality Evidence]

76. Bridging TreatmentRecommendation:
    • Clinicians should initiate bridging treatment or transitional prophylaxis simultaneously with maintenance prophylactic treatment after acute treatment has suppressed the initial attack for cluster headaches.

    Bridging treatment allows for the rapid suppression of cluster attacks in the interim until the maintenance treatment reaches therapeutic levels.

    Options for bridging treatment are:

    • Corticosteroids
    • Occipital nerve block

    [Guideline], [Low Quality Evidence], [High Quality Evidence]

77. Maintenance ProphylaxisRecommendation:
    • Clinicians should initiate maintenance prophylaxis to provide sustained suppression of cluster headaches over the expected cluster period.

    Effective prevention cannot be overemphasized in these patients. Maintenance prophylaxis is critically important since cluster headache sufferers typically experience one or more daily (or nightly) attacks for a period of weeks or months. The goal of transitional therapy is to induce rapid suppression of attacks while maintenance prophylaxis is intended to provide sustained suppression over the expected cluster period.

    If the patient has intractable headache or is unresponsive to prophylactic treatment, consider referral to a headache specialist.

    See Appendix A, “Drug Treatment for Headache,” and Appendix B, “Drug Treatment for Adjunctive Therapy,” in the original guideline document.

    [Low Quality Evidence], [Reference], [High Quality Evidence]

Dihydroergotamine Mesylate (DHE) Algorithm Annotations

84. Intravenous Metoclopramide 10 mgMetoclopramide (10 mg) is given either by direct intravenous injection over 2-3 minutes, or infused intravenously in 50 mL of normal saline over 15 minutes. Each dose of metoclopramide should be administered 15 minutes prior to each DHE injection. Although uncommon, acute extrapyramidal side effects such as dystonia, akathisia, and oculogyric crisis may occur after administration of metoclopramide. Benztropine mesylate is effective in terminating this unusual adverse event, given as a 1-mg injection (intravenous or intramuscular). Often after five doses of metoclopramide, it may be given as needed every eight hours for nausea [High Quality Evidence].

85. Begin Continuous DHEBegin DHE 2 mg in 1,000 mL normal saline at 42 mL/hr. Limit the dose of DHE to no more than 2 mg/24 hours.Continue intravenous metoclopramide 10 mg IV every eight hours as needed for nausea.

    Side Effects

    • If significant nausea occurs at any time, reduce the rate of DHE to 21 to 30 mL/hr.
    • If diarrhea occurs, give diphenoxylate with atropine, one or two tablets, three times daily as needed.
    • If excessive anxiety, jitteriness (akathisia), or dystonic reaction occurs, give intravenous benztropine 1 mg.

    It may be continued up to seven days.

    This approach is an alternative to the intermittent dosing of DHE as outlined in the Raskin protocol, and some practitioners may prefer it rather than the intermittent DHE protocol. Continuous DHE, like the intermittent administration, can be continued for seven days, although 72 hours is more typical. Opioid analgesics should not be used with either protocol since these are likely to prolong the headache via analgesic rebound.

Menstrual-Associated Migraine Algorithm Annotations

87. Patient Meets Criteria for Menstrual Only or Menstrual-Associated MigraineRecommendation:
    • Clinicians should advise women who meet criteria for menstrual-associated migraine to keep a continuous daily record of headache occurrence, severity, duration and menstrual flow for at least two months.

    “Menstrual migraine,” a term misused by both patients and clinicians, lacks precise definition. The ICHD-II system has proposed that menstrual-only migraine be defined as attacks exclusively starting two days before and first two days of the menstrual cycle [Meta-analysis], [Guideline]. The woman should be free from attacks at all other times of the cycle.

    Many women who do not have attacks exclusively with menses are considered to have menstrual-associated migraines [Low Quality Evidence].

    The clinician and patient need to discuss diary documentation. The patient should keep a continuous daily record for at least two months to include the following:

    • Day/time of headache
    • Severity of headache
    • Duration
    • Onset of menstrual flow

91. Consider Cyclic ProphylaxisRecommendations:
    • Clinicians may consider non-hormonal cyclic prophylactic treatment with NSAIDs and triptans for patients with menstrual-associated migraine.
    • NSAIDsNSAIDs should be considered approaches of first choice in the prophylactic treatment of migraine associated with menses. Many clinicians consider triptans to be equally effective, but there are no comparative studies. [Conclusion Grade III: See Conclusion Grading Worksheet A — Annotation #91 (Non-Steroidal Anti-Inflammatory Drugs) in the original guideline document)].Naproxen sodium has been used as a preventive agent, although other NSAIDs may also be effective. Typically, the agent is initiated 2 to 3 days before anticipated onset of the headache and continued through the at-risk period.
    • TriptansThere are good placebo studies supporting the use of triptans (sumatriptan, naratriptan, frovatriptan and zolmitriptan) for cyclic prophylaxis [High Quality Evidence], [Low Quality Evidence].

94. Consider Hormone ProphylaxisRecommendations:
    • Clinicians may consider hormone prophylaxis treatment for patients with menstrual-associated migraines.
    • Transdermal EstradiolEstrogen levels decrease during the late luteal phase of the menstrual cycle, likely triggering migraine. Estrogen replacement prior to menstruation has been used to prevent migraine.Estradiol patches, 50-100 µg, are applied 48 hours prior to expected onset of migraine and used for one week.

      [Low Quality Evidence]

    • Estrogen-Containing ContraceptivesEstrogen-containing contraceptives have a variable effect on migraines, causing worsening of headaches in some patients, improvement of headaches in a small percentage of patients, and no change in migraines in other patients. The guideline developers are not aware of any population-based studies on this topic.[Low Quality Evidence]

      In a contraceptive containing drospirenone, an extended 168-day placebo-free oral contraceptive regimen showed a significant decrease in duration, severity of headaches, and loss of function due to headache compared with a standard 21/7 oral contraceptive cycle [Low Quality Evidence]. In 2011, the Food and Drug Administration concluded that drospirenone may be associated with a higher risk for blood clots than other progestin-containing pills (http://www.fda.gov/Drugs/DrugSafety/ucm273021.htm ).

    • Gonadotropin-Releasing Hormone (GnRH) Agonists with “Add Back” TherapyFor patients with severe menstrual migraine unrelieved by other therapies, suppression of the menstrual cycle with a gonadotropin-releasing hormone agonist and “add back” therapy may be effective.Tamoxifen, danazol and bromocriptine have shown limited efficacy in treatment of menstrual migraine.

      Whether oophorectomy is an effective treatment for refractory migraines is not settled at this time.

      [Low Quality Evidence]

Perimenopausal or Menopausal Migraine Algorithm Annotations

98. Perimenopausal or Menopausal with Active Migraine History and Is a Potential Candidate for Hormone TherapyRecommendation:
    • Clinicians should not prescribe hormone therapy for perimenopausal or menopausal migraine treatment in patients who are pregnant or have unexplained bleeding.

    Menopause is the permanent cessation of menses.

    Perimenopause is the span of time from the reproductive to the post-reproductive interval.

    Hormone therapy may worsen, improve, or leave migraines unchanged.

    [Low Quality Evidence], [High Quality Evidence]

    Women with these conditions are not candidates for hormone therapy:

    • Pregnancy or unexplained bleeding: these are temporary but absolute contraindications to hormone therapy.
    • Past history of breast cancer or endometrial cancer: while usually considered contraindications to hormone therapy, short-term use for severe menopausal symptoms may be considered with proper precautions.

103. Hormone Therapy
     • Transdermal, transvaginal or oral estrogen
     • Progestin if indicated
     • Estrogen-containing contraceptives

     [Low Quality Evidence]

104. Successful?Successful is commonly defined as a 50% reduction in frequency in headache days and/or severity of headaches.

On Estrogen-Containing Contraceptives or Considering Estrogen-Containing Contraceptives with Migraine Algorithm Annotations

109. On Estrogen-Containing Contraceptives or Considering Estrogen-Containing Contraceptives with MigraineMigraine patients who do not have absolute contraindications to estrogen-containing contraceptives should consider that estrogen-containing contraceptives may have unpredictable effects on the severity and/or frequency of headaches. In addition, evidence exists that the risk of ischemic stroke increases for migraineurs taking estrogen-containing contraceptives [Guideline], [Low Quality Evidence].

111. Evaluate Vascular Risk FactorsRecommendation:
     

     • Clinicians should evaluate for vascular risk factors before prescribing estrogen containing contraceptives for treatment of migraine.

     • Risk factors for coronary artery disease
     • Prior thromboembolic disease
     • Migraine aura
     • Smoking

     Women who have migraine with an aura probably have significantly increased ischemic stroke risk if estrogen-containing contraceptives are used. This risk probably increases with age as baseline stroke rates increase, so that the increased risk may be acceptable to the younger patient (i.e., under age 30), but not to the older patient. It is probably too simplistic to say that no patient with migraine with aura should use estrogen-containing contraceptives. The decision should be individualized and should be made with the patient.

     It appears reasonable that women who have prolonged migraine auras (certainly those beyond 60 minutes), multiple aura symptoms, or less common aura symptoms (i.e., dysphasia, hemiparesis) should be strongly discouraged from using estrogen-containing contraceptives.

     Patients who develop a migraine aura for the first time while using estrogen-containing contraceptives, or whose previous typical migraine aura becomes more prolonged or complex, should discontinue estrogen-containing contraceptives.

     Use of oral contraceptives in patients with a history of migraine increases the risk of stroke [Conclusion Grade II: See Conclusion Grading Worksheet B – Annotation #111 (Risk of Stroke) in the original guideline document]

     Women with migraine aura who smoke and are hypertensive further increase their risk. Additional risk is also noted if they are taking estrogen-containing contraceptives.

Migraine Prophylactic Treatment Algorithm Annotations

122. Prophylactic TreatmentRecommendation:
     

     • Clinicians may prescribe prophylactic treatment for patients with migraine history after realistic goals and expectations have been established with the patient.

     • Criteria for Prophylactic Treatment
       • Three or more severe migraine attacks per month that fail to respond adequately to symptomatic therapy.
       • Less frequent but protracted attacks that impair the patient’s quality of life.
       • Patient is interested in prophylactic treatment.
     • Prophylactic TherapyPrior to instituting prophylactic therapy for migraine, it is imperative that realistic goals and expectations be established. Patients should have a clear understanding that the goals of preventative therapy are to:
       • Decrease migraine attack frequency by 50% or more
       • Decrease pain and disability with each individual attack
       • Enhance response to acute, specific, anti-migraine therapy

       One or more of these goals may be achieved.

     • MedicationsThe choice of prophylactic agent depends upon:
       • Side effect profile
       • Comorbid conditions
       • Medication interactions
       • Evidence-based efficacy
       • Patient preference (weight loss or gain)

       Patients should also understand that there is usually a latency of at least 3 to 6 weeks between the initiation of medication and recognizable efficacy. Often, an 8- to 12-week trial is necessary, allowing an adequate period for drug titration to a dosage likely to attain efficacy. It is also not uncommon for initial side effects to subside after continued therapy, and patients should be made aware of this so as to avoid premature discontinuation of a potentially effective medication.

       The choice of prophylactic medication should be individualized according to the side effect profile, the presence of comorbid conditions, and risk of medication interactions. For example, a tricyclic antidepressant may be especially useful with a migraineur with depression, while sodium valproate may be ideal for a patient with epilepsy.

       Reinforce education and lifestyle management. Refer to Annotation #15, “Evaluate Type of Primary Headache. Initiate Patient Education and Lifestyle Management.”

     • AdolescentsAs a prophylactic treatment topiramate 100 mg/day was effective in reduction of the number of migraine headaches a month [High Quality Evidence].

     Refer to the original guideline document for references pertaining to the medications used in prophylactic treatment (antiepileptics, beta-blockers, calcium channel blockers, tricyclics).

     Other Therapies

     The treatment therapies listed below are in alphabetical order and do not indicate work group preference or scientific support.

     • AcupunctureA systematic (Cochrane) review of acupuncture in migraine prophylaxis demonstrated that adding acupuncture to patients getting only acute treatment for headaches reduced the number of headaches patients had. When true and sham acupuncture were compared, they both reduced the number of headaches. There was no difference in benefit between true and sham acupuncture groups when results for all trials were pooled. Acupuncture demonstrated slightly better outcomes and fewer adverse effects than drugs shown to be helpful for prophylaxis [Systematic Review].
     • BiofeedbackVarious methods of biofeedback have been used as adjunctive therapy for migraine and tension-type headaches. A meta-analysis of 53 studies of biofeedback in combination with relaxation for tension-type headache demonstrated these to be more effective than headache monitoring, placebo or relaxation, especially in reducing headache frequency. Most of these studies were randomized controlled trials. Effects were most pronounced in adolescents [Meta-analysis].
     • Butterbur Root (Petasites hybridus)An extract from the plant Petasites hybridus is effective for migraine prevention. It should be used to reduce severity and frequency of migraine attacks [Guideline], [Moderate Quality Evidence], [High Quality Evidence].
     • Coenzyme Q10In one randomized placebo-controlled trial, coenzyme Q10 was superior to placebo for attack frequency, headache days and days with nausea [High Quality Evidence].
     • Cognitive Behavioral TherapyThis therapy is based on the premise that anxiety and distress aggravate an evolving migraine, and it has the potential for helping the patient recognize maladaptive responses that may trigger a headache [Guideline], [Low Quality Evidence].Psychological treatments, principally relaxation and cognitive behavioral therapies, are effective treatments of childhood headache [Meta-analysis/Systematic Review].
     • FeverfewThis herbal therapy is made from crushed chrysanthemum leaves. 250 µg of the active ingredient, parthenolide, is considered necessary for therapeutic effectiveness. Because these are herbal preparations, the quantity of active ingredient varies with the producer [Systematic Review], [High Quality Evidence].
     • MagnesiumDaily oral dosages of 400 to 600 mg of this salt have been shown to be of benefit to migraineurs in European studies [High Quality Evidence].
     • Onabotulinum ToxinOnabotulinum toxin has been approved by the Food and Drug Administration for the treatment of chronic migraine. Since this approach would be used by headache specialists or others trained specifically for use of this product, onabotulinum toxin is beyond the scope of this discussion.
     • Physical TherapyIndividuals unable to take medication or interested in other nonpharmacological headache management, may benefit from physical therapy including craniocervical exercises. Craniocervical exercises designed to correct postural faults by retraining and strengthening craniocervical flexion, cervico-thoracic extension, scapular retraction, thoracic extension and normalization of lumbar lordosis have been shown to significantly reduce tension-type and cervicogenic headaches over a prolonged time frame [High Quality Evidence].
     • Relaxation TrainingRelaxation training includes progressive muscular relaxation, breathing exercises, and directed imagery. The goal is to develop long-term skills rather than to treat individual events. Repetitive sessions and practice by the patient increase the success of these therapies in reducing headache frequency [High Quality Evidence].
     • RiboflavinA randomized, placebo-controlled study has found daily supplements of 400 mg moderately effective in reducing the frequency and severity of migraine [High Quality Evidence].

     Several additional treatment modalities are available. The modalities listed below lack sufficient scientific support to be recommended as therapies of proven value.

     • Cervical ManipulationPrevious studies suggested potentially high levels of risk associated with improper application of this modality. Although some studies report few complications, the scientific evidence of significant benefit is not convincing. There is well-documented evidence of cerebral infarction and death from cervical manipulation [Low Quality Evidence], [High Quality Evidence]. A systematic review demonstrates that numerous deaths have been associated with high-velocity, short-lever thrusts of the upper spine with rotation [Meta-analysis].
     • Transcutaneous Electrical Stimulation UnitsTranscutaneous electrical stimulation units for migraine or muscle contraction headache have not been found to be more beneficial than placebo when evaluated in a controlled study [High Quality Evidence].

124. Continue Treatment for 6-12 Months, Then ReassessRecommendation:
     • After 6 to 12 months, a gradual taper of prophylactic migraine treatment is recommended unless headaches become more frequent or more severe.

125. Try Different First-Line Medication or Different Drug of Different ClassRecommendation:
     • Monotherapy is recommended with dose increasing until patient receives benefit, maximum recommended dose is reached, or unacceptable side effects occur. If failure with one medication, try another from the same class.

128. Try Combination of Beta-Blockers and TricyclicsA beta-blocker and a tricyclic antidepressant may be more effective and produce fewer side effects in combination than a single drug at a higher dose from either class.

“It’s out, it’s published, you should start using it immediately because it’s much better than the second edition,” Jes Olesen, MD, PhD, professor of neurology, University of Copenhagen, Glostrup Hospital, Denmark, told delegates to the 2013 International Headache Congress (IHC).

Dr. Olesen, who chaired the working group on migraine, encouraged delegates to start citing this new classification system and to participate in field testing, which will take place during the next few years, before publication of the final version.

If physicians note any mistakes or have comments, they should contact the chairperson of the relevant chapter, said Dr. Olesen, who anticipates that only minor modifications will be necessary.

The ICHD-III beta version is available at the International Headache Society Web site.

Chronic Migraine

One of the biggest changes in the current edition, which has been in the works for 3 years, is the addition of chronic migraines that occur on at least 15 days of the month for more than 3 months.

In the past, patients with these headaches were all diagnosed with migraine, whether they had 1 attack a year, 1 a month, 1 a week, or 1 a day, but there has been growing interest in considering the most severe end of the migraine spectrum as a separate entity, said Dr. Olesen.

Separating out chronic migraine is “parallel” to how tension type headache is treated in the classification system, he said. “Even in the first and second editions we had chronic tension type headache, which are tension type headaches on 15 days a month or more.”

In fact, many patients have tension headaches on a daily basis and are debilitated by it, he said. “So it’s important to single out that severe end of the spectrum; and for some reason we didn’t do it for migraine, but we’re doing it now.”

In addition to the frequency of attacks, there are a number of other criteria that have to be met before a diagnosis of chronic migraine should be given.

Other migraine classifications include the following: migraine with aura, migraine without aura, complications of migraine, probable migraine, and episodic syndromes that may be associated with migraine.

Migraine with aura is subdivided into migraine with typical aura; typical aura with headache; typical aura without headache; migraine with brainstem aura; hemiplegic migraine; several types of familial hemiplegic migraine; sporadic hemiplegic migraine, and retinal migraine.

For a diagnosis of migraine with aura, the following criteria must be met:

• One or more visual; sensory; speech; motor; brainstem; or retinal symptoms;
• At least 2 of these 4 criteria: (1) at least 1 aura symptom spreading gradually over 5 or more minutes and/or 2 or more symptoms occurring in succession; (2) each aura symptom lasts 5 to 60 minutes; (3) at least 1 aura symptom is unilateral; (4) the aura is accompanied or followed shortly by headache.

Although in the main body of the text, it is specified that a patient needs 2 of 4 criteria for migraine with aura, in the Appendix, they need to have 3 of 6 criteria; field testing will reveal which approach is better, said Dr. Olesen.

As in earlier editions, the new classification system distinguishes primary headaches, which are diseases in their own right, from secondary headaches, which are caused by something else.

Other Primary Headaches

For primary headaches other than migraine, some diagnostic entities have been rearranged and renamed. There are 4 subgroups: (1) physical exertion (primary cough headache; primary exercise headache; primary headache associated with sexual activity; primary thunderclap headache; (2) headaches associated with direct physical stimuli (cold-stimulus headache; external pressure headache); (3) epicranial headaches (primary stabbing headache; nummular headache; epicrania fugax (in the Appendix); and (4) other (hypnic headache; new daily persistent headache).

Some changes in the primary headache section include the following:

• Under headaches associated with sexual activity, the subtypes of preorgasmic and orgasmic headache have been eliminated.
• For thunderclap headaches, the headache must last at least 5 minutes, but the criterion of not recurring regularly during subsequent weeks or months has been discarded.
• Hypnic headaches no longer have to first occur after age 50 years.
• A number of pain characteristics under the new daily persistent headaches section have been eliminated.

New daily persistent headache is the only headache category in which onset should be “distinct and clearly remembered,” noted Shuu Jiun Wang, MD, professor and chairman, Faculty of Medicine, National Yang-Ming University School of Medicine, and deputy head, the Neurological Institute, Taipei Veterans General Hospital, Taiwan, who chaired the working group on other primary headaches.

As for Epicrania fugax, now included in the Appendix, this could be a possible new headache entity, said Dr. Wang. It consists of brief stabbing head pain that stems from a particular area of the head and rapidly radiates forward or backward in a wide linear or zigzag movement.

Secondary Headaches

The criteria in the secondary headache section have been presented in a new format. One change here is that it is not required that the causative agent be removed before a diagnosis. There are also no longer “probable secondary” headaches.

The main categories of secondary headache include the following: posttraumatic headache; headaches due to vascular disorders; headaches due to nonvascular disorders (such as tumors); headaches due to medications, toxins and other substances; medication overuse headaches; headaches due to infections; headaches due to metabolic (homeostatic) disturbances; headaches due to cranial, cervical, EENT, and dental disorders; and headaches due to psychiatric disease.

The Appendix lists headaches associated with various psychiatric disorders, including depressive disorder, separation anxiety, panic disorder, and social anxiety disorder. Also in the Appendix is the novel headache attributed to travel in space as well as headache due to airplane travel during landing.

Another addition in the Appendix is vestibular migraine. Among the criteria for this diagnosis are having vestibular symptoms of moderate or severe intensity lasting between 5 minutes and 72 hours, photophobia, and visual aura.

Dr. Olesen said he was “sceptical” about including vestibular migraine in the new classification system, but he supports having it in the Appendix. “The way it’s defined, it sort of overlaps with other entities, in particular, migraine with brainstem aura, but we will see how it works out. At least it can get more rigorous studies.”

The diagnostic criteria in the expanded Appendix can be field tested and used for research, but they are not meant for clinical use, added Dr. Olesen.

Classification Rule

An important “rule” with the new classification system is still “to put a diagnosis on every single distinct kind of headache the patient has,” said Dr. Olesen. “So some people need 2 headache diagnoses, and even 3 headache diagnoses.”

For example, a patient can have a diagnosis of both cluster headache and tension type headache. A patient with chronic migraine and medication overuse headache will also have 2 diagnoses.

Asked by a delegate why menstruation-related migraine is still in the Appendix and not in the main body, Dr. Olesen said that this type of migraine “is very important but not suitable” for the main classification body, partly because it does not apply to men and partly because subdividing migraine could create “a mess.”

“People have suggested dividing migraine into whether it’s refractory or nonrefractory; people have suggested subdividing it on whether its associated with sensitization and not associated with sensitization; people have suggested various other ways of subdividing migraine, but it becomes too confusing.

The first edition of the International Classification of Headache Disorders was published in 1988, and the second in 2004.

Information on field testing is available on the International Headache Society Web site or the World Health Organization (WHO) Web site. WHO is field testing the International Classification of Diseases, 11th Edition (ICD-11), and for its headache section, it will also test the ICHD-III. The 2 are identical except for the degree of detail, said Dr. Olesen.

Field testing should continue for 3 years, with the final version of the updated edition ready by 2016, said Dr. Olesen.

2013 International Headache Congress (IHC). Special HIS Session. Presented June 27, 2013.

The results are significant in terms of understanding the neurobiology of migraine and could have future implications for drug treatment, said study author Peter James Goadsby, MD, PhD, professor, neurology, and director, Headache Program, University of California at San Francisco, and president, International Headache Society.

“This is an important step in solidifying our ideas that migraine is fundamentally a disorder of the brain, not a disorder of structures outside the brain,” said Dr. Goadsby. “We were able to address the question that people have wondered about for many, many years, that is, what is the degree to which pain is driving the initial symptomatology — and we got clear answers to that.”

Dr. Goadsby and his colleagues won the Harold G. Wolff Lecture Award for this research during the 2013 International Headache Congress (IHC).

Subtle Symptoms

Premonitory symptoms of migraine can include yawning, neck discomfort, nausea, thirst, photophobia, phonophobia, craving sweet or savory foods, and mood swings. It’s not clear what proportion of patients with migraine experience these early symptoms, which are often quite subtle, Dr. Goadsby said. Estimates vary widely, from about a third to 80%.

In the past, this symptomatology has not received much medical attention, said Dr. Goadsby. Physicians might not ask about premonitory symptoms because this information doesn’t influence their diagnosis.

In years gone by, people used to think of migraine as a disorder of the blood vessels. In more recent times, the view has been that migraine is a reaction to pain stimuli. “I think our new research suggests that this is just not true,” said Dr. Goadsby.

Using nitroglycerin, a well-documented trigger for migraine, researchers induced premonitory symptoms in patients who have migraine without aura. Instead of waiting for headache onset to begin scanning the patients’ brains, as has been done in the past, researchers did the scanning during the premonitory phase. Eight patients had at least 1 premonitory scan without pain.

“Before this, all the imaging of migraine has been during the headache and the question has risen as to the degree to which what’s happening in the brain is just a response to pain, or is something more fundamental, a part of the process of the migraine,” said Dr. Goadsby. “By studying the premonitory symptoms, you get rid of that question because these patients don’t have any pain.”

Neuronal Activation

Researchers used H₂ ¹⁵O (radioactive water) to measure regional cerebral blood flow as a surrogate marker for neuronal activation.

They found that compared with baseline scans, there was activation in several key areas, including the hypothalamus, an area involved in low-level regulation of sleep, appetite, mood, and fluids. “It seems likely that the hypothalamus is pivotal in the onset of migraine,” commented Dr. Goadsby.

Other structures that were activated included the midbrain, around the periaqueductal grey, which has been shown to be active during a migraine attack, and an area in the pons that past migraine imaging has also shown to be active.

“This shows you the areas of the brain that are involved at the earliest in the attack,” said Dr. Goadsby.

Scans of the 8 patients plus another 2 patients experiencing photophobia symptoms, again before they felt any pain, showed activation in the visual cortex. “This suggests that the photophobia experience can be dissected away from the pain experience,” said Dr. Goadsby.

Similarly, scans of patients experiencing nausea had activation of an area of the medulla that includes nausea and vomiting centers. “So it’s entirely plausible that those areas are activated by the migraine process and that’s why nausea and vomiting are so common in migraine; it’s not simply a response to the pain,” said Dr. Goadsby.

“It was thought that nausea and pain were highly linked, but that doesn’t seem to necessarily be the case,” he added.

Dr. Goadsby hopes the research will “shift thinking” to consider migraine as a brain disorder, but he stressed that this should not lessen the importance of the pain that migraine patients suffer.

The research could have ramifications for treatment in that the most obvious target would be the brain, but developing targeted therapies that don’t have adverse effects could be challenging.

“From a big picture treatment perspective, this says to me that we probably won’t get away with developing drugs that don’t get into the brain to have substantial effects on migraine prevention,” said Dr. Goadsby.

He noted that to date, the best proven migraine prevention therapies are anticonvulsant drugs, tricyclic antidepressants, and the β-blocker propranolol, all of which affect the brain. This, he said, is consistent with the theory that migraine is a disorder of the brain.

Original Article

Methods.— A cross-sectional, questionnaire-based study was conducted with a cohort of 978 U.S. soldiers who screened positive for a deployment-related concussion upon returning from Iraq or Afghanistan. All soldiers underwent a clinical evaluation at the Madigan Traumatic Brain Injury Program that included a history, physical examination, 13-item self-administered headache questionnaire, and a battery of cognitive and psychological assessments. Soldiers with CDH, defined as headaches occurring on 15 or more days per month for the previous 3 months, were compared to soldiers with episodic headaches occurring less than 15 days per month.

Results.— One hundred ninety-six of 978 soldiers (20%) with a history of deployment-related concussion met criteria for CDH and 761 (78%) had episodic headache. Soldiers with CDH had a median of 27 headache days per month, and 46/196 (23%) reported headaches occurring every day. One hundred seven out of 196 (55%) soldiers with CDH had onset of headaches within 1 week of head trauma and thereby met the time criterion for posttraumatic headache (PTHA) compared to 253/761 (33%) soldiers with episodic headache. Ninety-seven out of 196 (49%) soldiers with CDH used abortive medications to treat headache on 15 or more days per month for the previous 3 months. One hundred thirty out of 196 (66%) soldiers with CDH had headaches meeting criteria for migraine compared to 49% of soldiers with episodic headache. The number of concussions, blast exposures, and concussions with loss of consciousness was not significantly different between soldiers with and without CDH. Cognitive performance was also similar for soldiers with and without CDH. Soldiers with CDH had significantly higher average scores on the posttraumatic stress disorder (PTSD) checklist compared to soldiers with episodic headaches. Forty-one percent of soldiers with CDH screened positive for PTSD compared to only 18% of soldiers with episodic headache.

Conclusions.— The prevalence of CDH in returning U.S. soldiers after a deployment-related concussion is 20%, or 4− to 5-fold higher than that seen in the general U.S. population. CDH following a concussion usually resembles chronic migraine and is associated with onset of headaches within the first week after concussion. The mechanism and number of concussions are not specifically associated with CDH as compared to episodic headache. In contrast, PTSD symptoms are strongly associated with CDH, suggesting that traumatic stress may be an important mediator of headache chronification. These findings justify future studies examining strategies to prevent and treat CDH in military service members following a concussive injury.

Introduction

Over 160,000 U.S. military service members have been diagnosed with traumatic brain injury since 2000.^[1] Concussions occur in 15–23% of U.S. service members deployed in support of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF).^[2–4] Headache is one of the most common symptoms after a concussion and may persist for months to years after injury. The prevalence of headaches in returning U.S. military service members who had a concussion while deployed to Iraq or Afghanistan ranges from 22% to 97%.^[2,3,5]

Chronic daily headache (CDH), defined as 15 or more headache days per month, is one of the most disabling headache syndromes with a prevalence of 4–5% in the general population.^[6,7] A number of primary headache disorders may manifest as CDH. Chronic migraine is one of the most common and most disabling forms of CDH among primary headache disorders. Secondary headache disorders can also manifest as CDH. Head trauma has been suggested as an important risk factor in the development of chronic daily headache in civilians. It has been estimated that 15% of cases of CDH in the general population are attributable to head or neck trauma.^[8]

Little is known about CDH in military populations. Given the association between head trauma and CDH in civilians, we hypothesized that CDH would be highly prevalent among service members who had a concussion while serving in Iraq or Afghanistan. We previously reported the prevalence, characteristics, and impact of headaches in a large cohort of returning U.S. soldiers who had a concussion while deployed to Iraq or Afghanistan.^[5] The aim of the current study was to determine the prevalence and characteristics of, and factors associated with, CDH in this same cohort of U.S. soldiers who had a deployment-related concussion.

Methods

This study was approved by the Madigan Army Medical Center Institutional Review Board. A cross-sectional, questionnaire-based study was conducted with a cohort of 978 U.S. soldiers who screened positive for a deployment-related concussion upon returning from Iraq or Afghanistan. The details of the screening process and a description of the headaches in this same cohort have been previously reported.^[5] All soldiers underwent a clinical evaluation at the Madigan Traumatic Brain Injury Program that included a history, physical examination, 13-item self-administered headache questionnaire, and a battery of cognitive and psychological assessments as described previously. Information about head trauma was obtained by interviewing the soldier and reviewing theater medical records. The Madigan Redeployment Evaluation of Concussion (MREC) test, scored from 0 to 30 with below 25 defined as abnormal, was used to assess cognitive function. The MREC, which is similar to the Military Acute Concussion Evaluation (http://www.dvbic.org/images/pdfs/providers/MACE-Information-Paper-V3.aspx), is a neurocognitive screening instrument intended for evaluating soldiers with a deployment-related concussion after returning stateside. Posttraumatic stress disorder (PTSD) symptoms were assessed using the PTSD symptom checklist, military version (PCL). A global measure of acute traumatic brain injury (TBI) symptoms at the time of the injury was obtained using the 2-plus-10 questionnaire.^[5] The 2-plus-10 questionnaire consists of an initial 2-question followed by a 10-question screen if the soldier answers yes to either of the first 2 questions. This questionnaire is scored in a standardized manner from 0 to 39; the score from the 2-plus-10 questionnaire will herein be called the TBI Score.^[5] Data from soldiers with CDH, defined as headaches occurring 15 or more days per month for the previous 3 months, were compared to soldiers with episodic headaches who had less than 15 headache days per month.

Fisher’s exact test was used to test for differences in proportions, and unpaired t-test was used to test for differences in ordinal variables with a normal distribution. Correlation coefficients were calculated to test the relationship between individual variables where appropriate. P values less than .05 were considered significant.

Results

Nine hundred fifty-seven of 978 soldiers with a deployment-related concussion reported headaches in the preceding 3 months. One hundred ninety-six soldiers (20%) reported 15 or more headache days per month for the previous 3 months and thereby met criteria for CDH (Table 1). Soldiers with CDH had a median of 26.7 headache days per month, and the headache syndrome had been present for a median of 11.5 months. Forty-six (23%) of the soldiers with CDH reported headaches on 90 of the previous 90 days. One hundred seven (55%) soldiers with CDH had headaches that began within 1 week of head trauma and thereby met the time criterion for posttraumatic headache (PTHA). In comparison, 33% of episodic headaches had onset within 1 week of a concussion (P < .0001). Soldiers with CDH used abortive headache medications an average of 15.1 days per month compared to 3.3 days per month for soldiers with episodic headache (P < .0001). Ninety-seven (49%) soldiers with CDH used abortive headache medications on 15 or more days per month for the previous 3 months (P < .05).

Discussion

This study examined CDH in a large cohort of returning U.S. Army soldiers who had a deployment-related concussion. We found that 20% of soldiers with a history of concussion had headaches manifesting as CDH. When one considers prevalence rates of CDH of 4–5% in the general population,^[6,7] the prevalence of CDH in soldiers after a deployment-related concussion is 4− to 5-fold higher. The high prevalence of CDH in soldiers after concussion is consistent with previous studies suggesting a role for mild head trauma in the development of CDH. In a U.S. population sample, 20% of males with CDH reported a preceding head or neck injury.^[8] We previously reported that one third of soldiers with a history of head or neck trauma referred to a military headache clinic had CDH.^[9]

Head trauma can trigger new headaches and/or can exacerbate preexisting primary headaches. When new headaches develop within 1 week after head trauma, they are classified as posttraumatic headaches according to ICHD-2.^[10] Compared to episodic headache, we found that CDH was significantly associated with headache onset within a week of the concussive event. Soldiers with CDH were 1.7-fold more likely to have headaches meeting ICHD-2 criteria for PTHA compared to soldiers with episodic headaches. This finding further supports trauma as a triggering event in the development of CDH. Given the increased propensity of posttraumatic headaches to manifest as CDH, interventions administered early after injury that prevent headache chronification may be beneficial. It may be more effective to prevent the development of CDH early after injury than to treat established CDH.

Migraine was the headache phenotype in 66% of soldiers with CDH in our study, with an additional 28% having multiple features of migraine. Migraine headaches were significantly more common in soldiers with CDH compared to those with episodic headache. In a headache clinic-based population, migraine was the headache phenotype in over 90% of soldiers with posttraumatic headache, over half of whom had CDH.^[11] In comparison, the prevalence of chronic migraine is 2% in the general U.S. population and 4% in Army soldiers post-deployment.^[12,13] These findings support a strong association between concussion and chronic migraine in U.S. service members. Chronic migraine should be regarded as the predominant headache syndrome among soldiers with posttraumatic CDH.

Topiramate and botulinum toxin are the only treatments that have been shown to be effective for chronic migraine in the general population.^[14] It remains to be determined if these treatments are also effective for posttraumatic chronic migraine. In an uncontrolled observational study, topiramate was associated with headache improvement in soldiers with chronic PTHA, many of whom had posttraumatic chronic migraine.^[11] Identifying effective therapies for posttraumatic chronic migraine is an important goal of future research.

Exposure to an explosive blast was the mechanism of concussive injury in over 80% of soldiers in our study, similar to findings reported by other studies of service members deployed to Iraq or Afghanistan.^[2–4,15] The potential mechanisms of blast-induced neurotrauma are complex and may include primary effects from the blast wave, secondary effects caused by fragments or debris, tertiary effects of rapid acceleration and deceleration, flash burns, and effects of inhalation of toxic gases.^[16,17] We found no differences in blast exposures between soldiers with CDH compared to those with episodic headaches. Likewise, in a clinic-based population, headache frequency was found to be similar between soldiers with blast-related concussion and non-blast causes of concussion. Wilk et al recently reported that blast mechanism was associated with persistence of headaches and tinnitus at 3 to 6 months in soldiers with concussion and loss of consciousness.^[18] The available information suggests that while blast injury increases the likelihood of developing chronic headaches that persist beyond 3 months after injury, it does not appear to affect the frequency of headaches as compared to other mechanisms of concussion.

An important question is whether the severity of head trauma or repetitive head injuries increases the risk of CDH. Couch et al found an association between multiple head and neck traumas and CDH in the general population.^[8] We did not find significant differences in the total number of concussions or the number of concussions resulting in loss of consciousness between soldiers with CDH and episodic headaches. Soldiers with CDH did report more symptoms immediately after the concussion, as measured by the TBI score, suggesting that they may have experienced a more acutely symptomatic injury and perhaps, by extension, a potentially more severe concussion. This is a tenuous assertion that requires validation by prospective studies because of the high likelihood of recall bias.

Psychological trauma and posttraumatic stress may be significant mediators of headache chronicity after head trauma. In support of this, we found that soldiers with CDH had more symptoms of PTSD and were more than twice as likely to screen positive for PTSD compared to soldiers with episodic headaches. Indeed, 41% of soldiers with CDH had a positive screen for PTSD. Additionally, PCL scores were significantly correlated to the number of headache days and blast exposures. Studies in civilian and military populations have demonstrated an association between PTSD and an increased frequency of headache.^[19,20] Bryan et al, using regression modeling, found a statistically significant association between PTSD symptoms and headache severity in veterans of the wars in Iraq and Afghanistan.^[21]

The extent to which symptoms of the post-concussive syndrome after mild head injury can be attributed to PTSD or depression in returning U.S. service members remains a topic of significant debate.^[22,23] In a pivotal study by Hoge et al, after controlling for PTSD and depression, headache was the only symptom significantly associated with mild concussion in 2525 U.S. Army infantry soldiers screened 3–4 months after return from a 1 year deployment to Iraq.^[2] Thus, while posttraumatic stress may magnify the frequency and severity of headaches, it does not appear to be the proximate cause of headaches in this population. The observed high prevalence of PTSD in our study cohort, particularly among soldiers with CDH, reinforces the importance of screening soldiers and veterans for PTSD and, when positive, referring them for behavioral health evaluation and treatment.

Another important factor that can contribute to headache chronification is overuse of acute analgesic medications resulting in medication overuse headache (MOH). Medication overuse has been implicated in transforming episodic migraine to chronic migraine.^[24] Medication overuse is defined as use of abortive headache medication on 15 or more days per month for 3 or more months.^[10] Nearly half (49%) of soldiers with CDH in our study met criteria for possible MOH. The majority, 80% or more, of soldiers in this cohort used nonsteroidal anti-inflammatory agents and acetaminophen as abortive headache medications.^[5] We may have underestimated possible MOH in the proportion of soldiers using prescription medications such as triptans or narcotics (less than 10% of soldiers in this cohort)^[5] or combination analgesics such as acetaminophen–aspirin–caffeine (6% of soldiers in this cohort)^[5] given the lower threshold of medication days per month associated with MOH with use of these medications. A diagnosis of definite MOH requires resolution of headaches following cessation of the overused analgesics medication(s). Thus, it is not possible to determine precisely the proportion of subjects in our study who had definite MOH. Avoiding medication overuse in the first place and identifying and addressing MOH when it develops are strategies that may decrease the development of CDH in soldiers following a concussion.

This study has many limitations related to the questionnaire-based, cross-sectional design. Headache frequency was retrospectively reported by soldiers and was not prospectively recorded in a headache log. It is possible that recall errors in reporting headache frequency resulted in misclassification of some soldiers with regard to having CDH or episodic headache. Likewise, reporting of blast exposures and acute symptoms of concussion that may have occurred many months ago are subject to recall error. Screening for preexisting headaches was not performed, potentially contributing to misattribution and making an analysis of incident headaches vs worsening of previous headache syndromes impossible. While all soldiers met screening criteria for a deployment-related concussion, concussion severity was not determined, thereby limiting any conclusions regarding concussion severity and headache chronicity drawn from this study. Theater records were used to validate some of these events but were not available in all cases. Soldiers in the study were evaluated at a TBI clinic, and this type of setting may have inclined them to over-report symptoms. Finally, this study may not be representative of all U.S. service-members with a deployment-related concussion as it was conducted at a single U.S. Army installation over a 6-month period.

Conclusions

The prevalence of CDH in U.S. soldiers after a deployment-related concussion is 20%, or 4− to 5-fold higher than that seen in the general population. CDH in soldiers with concussion usually has multiple features of migraine and frequently resembles chronic migraine. Onset of headaches within 1 week of a concussion is associated with the development of CDH as compared to episodic headache. Overuse of headache abortive medications, raising the possibility of MOH, occurs in half of soldiers with CDH. Blast exposure and multiple concussions are common in this population, but these factors are not specifically associated with CDH as compared to episodic headache. PTSD symptoms are strongly associated with CDH suggesting that traumatic stress may be a significant mediator of headache chronicity. These findings justify future studies examining strategies to prevent and treat CDH in military service members.

Study supported by
The Comprehensive National Neuroscience Program at the Uniformed Services University of the Health Sciences by a grant from the Congressionally Directed Medical Research Program.

Disclaimer
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.