CHRONIC DAILY HEADACHE

II. ABSTRACT

Headache disorders are commonly encountered by physicians in the outpatient setting. Approximately 45 million Americans are affected by headache disorders, with tension-type headache being the most prevalent primary headache disorder in the population, while migraine is most prevalent in the physician’s office.¹ Distinguishing primary from secondary headache is an important first step in headache diagnosis. Clinical features of the different types of headache disorders vary based on headache duration, frequency, severity, location, and other features. Treatment of headache disorders includes lifestyle and risk-factor modification and pharmacotherapy. Pharmacologic treatment for headache disorders can be either abortive or prophylactic. However, many patients are treatment-resistant or undertreated. Certain headache disorders may be successfully treated with injections of botulinum neurotoxin type A. Results from two recent clinical trials of 1384 adult patients demonstrate that the botulinum neurotoxin type A onabotulinumtoxinA (Botox) is an effective and safe prophylactic treatment for chronic migraine. OnabotulinumtoxinA is approved in the United States and the United Kingdom for the preventive treatment of headaches in adults with chronic migraine. The use of botulinum neurotoxin in the treatment of chronic headache disorders is the focus of this module.

III. INTRODUCTION

Approximately 45 million Americans are affected by headache disorders.² Headache disorders are classified as primary or secondary (due to an underlying disorder) and episodic or chronic.

Figure 1. Differential diagnosis of headache disorders. Adapted from American Headache Society Chronic Education Program. 

 

The main focus of this review will be chronic daily headache (CDH), which encompasses a group of multiple headache diagnoses that affect approximately 4% of the general adult population.

Headache is one of the most common disorders encountered by physicians in the outpatient setting.³ Although most patients with CDH suffer from chronic tension-type headache (CTTH) or chronic migraine (CM), there are other primary and secondary headache disorders that can present similarly, and effective clinical management depends on proper differential diagnosis.

Migraine (from the Greek words hemi ([half]) and kranion ([skull]) is the most common neurologic condition evaluated by physicians.⁴ CM (headache on more than 15 days per month in patients with migraine) is difficult to treat and requires a multidisciplinary approach. However, CM remains largely underdiagnosed and undertreated.^{4, 5}

Results from two pivotal clinical trials demonstrate that the botulinum neurotoxin A (BoNT-A) onabotulinumtoxinA is a safe and effective prophylactic treatment for patients with CM, including those who overuse acute headache medications. BoNT-A has also been studied for the treatment of other headache disorders. The mechanisms by which BoNT-A prevents headache pain are probably more complex than simple muscle relaxation and may involve central effects of BoNT-A injection.

IV. CLASSIFICATION AND EPIDEMIOLOGY OF CRONIC DAILY HEADACHE

Based on multinational population studies, the prevalence of CDH is approximately 3% to 5%.⁶

Risk factors for CDH include comorbid pain disorders, stressful life events, obesity, habitual snoring, head or neck injury, and habitual caffeine consumption.⁶

There are four major types of primary CDH: CM, CTTH, new daily persistent headache (NDPH), and hemicrania continua (HC).

An important secondary condition, medication overuse headache, also exists.⁶

Table 1. Types of Primary Chronic Daily Headache of Long Duration¹⁹

Headache Disorder	Male:Female Ratio	Clinical Features
Chronic migraine	1:3	Migraine with or without aura ≥15 days per month for ≥3 months  (see Table 4 for diagnostic criteria)
Chronic tension-type  headache	1:1	Mild-to-moderate severity; no migrainous  symptoms; bilateral
New daily persistent  headache	More common in  women	Bilateral, persistent, moderately severe; may be preceded by  viral infection; may resemble migraine or tension-type  headache
Hemicrania continua	More common in  women	Daily, continuous, strictly unilateral, and constant exacerbations of  severe headache; cranial autonomic symptoms (miosis, ptosis,  eyelid edema, lacrimation, nasal congestion, or rhinorrhea; “ice-pick”  pain; responsive to indomethacin therapy by definition

Chronic Migraine

Of the 45 million Americans affected by headache disorders, an estimated 29.5 million suffer from migraine.⁷ CM affects approximately 2% of the adult population in Western countries, and as many as 6 to 8 million Americans.⁵ In the United States, the one-year prevalence rate of migraine is estimated to be 17.6% in women and 5.7% in men,⁸ and the cumulative lifetime incidence of migraine is 43% in women and 18% in men.⁹ Migraine may be associated with cardiovascular disease, asthma, obstructive sleep apnea, Raynaud’s phenomenon, systemic lupus erythematosus, restless legs syndrome, and non-headache pain disorders.⁶

Migraine often begins in childhood, where the prevalence is nearly equal among males and females. Females, however, begin to experience migraine more frequently than males at puberty, with a gender ratio of 3:1 (female to male).⁴ Data from epidemiologic studies support a link between migraine and female sex hormones, which is consistent with the observation that migraine attacks in women are more likely to occur in the perimenstrual period.¹⁰ Migraine typically improves in the last two trimesters of pregnancy; however, it may worsen postpartum. After menopause, incidence decreases in many, but not all, women. However, migraine may worsen in the perimenopausal period due to variations in estrogen levels.¹⁰

Chronic Tension-Type Headache

CTTH is the most prevalent primary headache disorder. A telephone survey of 13,345 subjects in the United States showed a 1-year prevalence of 2.2%, with prevalence higher in women and decreasing with higher education.¹¹ A prospective study of 549 subjects found an incidence of CTTH (≥15 headache days per month) or 14.2 per 1,000 person-years, with a female-to-male ratio of 3:1.¹² Risk factors for CTTH include poor self-related health and sleep, and difficulty with relaxation after work.⁶

New Daily Persistent Headache

NDPH is a rare CDH of long duration characterized by the abrupt onset of persistent headache that generally develops over less than 3 days and does not remit.¹³ NDPH can affect all age groups,¹⁴ but the mean age of onset is 35 years of age.¹⁵ In women, the peak age of onset is in the second and third decades of life, and in men it is the fifth decade of life.¹⁴ The prevalence of NDPH in the general population is not known, although it has been estimated that approximately 11% of CDH patients suffer from NDPH.¹⁶

Hemicrania Continua

HC is a rare primary headache syndrome characterized by unilateral pain that responds to indomethacin. The frequency of HC in the general population is not known; however, more than 100 cases have been described worldwide since 1984. HC may have onset at any age, but peaks in the third decade of life.¹⁷ It is twice as common in women as in men.¹⁸

Medication-Overuse Headache

The prevalence of medication-overuse headache in the general population is approximately 1.5%, with a female-to-male ratio of 3.5:1.¹⁹ As many as 50% to 80% of patients treated in US tertiary headache centers suffer from medication-overuse headache.¹⁹ Opioids and butalbital-containing analgesics are associated with the greatest risk for development of medication-overuse headache.²⁰

V. CLINICAL FEATURES AND DIAGNOSIS

Chronic headache is defined by the presence of headache of any type occurring 15 or more days per month. Distinguishing primary versus secondary headache is an essential step in the diagnosis of headache (Figure 1). Causes of secondary chronic headache should be ruled out prior to establishing a diagnosis of primary headache disorder. The differential diagnosis of primary chronic headache disorders is based on symptomatology and described below.^{19, 21}

Table 2. Causes of Secondary Headache⁶³

Medication related	Medication-overuse headache  Medication-induced side effects
Posttraumatic	Headache attributable to head injury  Headache attributable to neck injury or whiplash
Disorders of intracranial  pressure	Increased intracranial pressure (primary or secondary tumor, idiopathic  intracranial hypertension, hydrocephalus)  Decreased intracranial pressure (post-lumbar puncture headache)
Structural	Headache attributable to cervical spine or head/neck myofascial pain  Headache attributable to temporomandibular joint/dental pathology
Cranial neuralgia	Trigeminal  Occipital
Vascular	Subdural hematoma  Giant cell arteritis  Ischemic or hemorrhagic stroke  Venous sinus thrombosis  Arterial dissection  Severe arterial hypertension
Infectious	Meningitis  Sinusitis
Metabolic	Obstructive sleep apnea, hypoxia, hypercarbia, carbon monoxide  Thyroid disease

 

Chronic Migraine

Criteria for CM diagnosis, as set forth by the 2nd International Headache Classification Committee, are listed in Table 3.²²

Table 3. Criteria for Chronic Migraine Diagnosis, 2nd International Headache Classification Committee²²

A. Headache (tension-type and/or migraine) on ≥15 days per month for ≥3 months

B. Occurring in a patient who has had ≥5 attacks fulfilling criteria for migraine without aura*

C. On ≥8 days per month for ≥3 months headache has fulfilled C1 and C2 (below), that is, has fulfilled criteria for pain and  associated symptoms of migraine without aura

1. Has at least two of a-d         a. Unilateral location         b. Pulsating quality         c. Moderate or severe pain intensity         d. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs) and at least             one of a or b                         a. Nausea and/or vomiting                         b. Photophobia and phonophobia

2. Treated and relieved by triptan(s) or ergot before the expected development of C1

D. No medication overuse and not attributed to another causative disorder

*Criteria for migraine without aura: (A) ≥5 attacks fulfilling criteria B-D; (B) attacks last 4-72 hours (untreated or unsuccessfully treated); (C) Headache has ≥2 of the following: 1. unilateral location; 2. pulsating quality; 3. moderate or severe pain intensity; 4. aggravation by or causing avoidance of routine physical activity; (D) During headache has ≥1 of the following: 1. nausea and/or vomiting; 2. photophobia and phonophobia; (E) Not attributed to another disorder.

CM patients suffer headaches on more than 15 days per month, and have had at least five attacks that met criteria for migrainous features (e.g., photophobia, phonophobia, nausea/vomiting). In some patients, environmental hypersensitivities persist even during headache-free periods.²³ Patients with CM are likely to have associated disability, depression, anxiety, and chronic pain^{.24, 25} Common migraine triggers are listed in Table 4.

 

Table 4.Common Migraine Triggers³⁷

Fasting  Alcoholic beverages  Caffeine withdrawal  Certain types of food, including chocolate, aged cheeses, processed meats, fermented  foods, aspartame, monosodium glutamate, citrus fruits, nuts  Stress or release from stress  Too much or too little sleep  Fatigue  Exposure to bright lights, loud noises, smoke, and strong scents  Change in the weather  Menstruation  Hormonal therapy  Acute head injury

Chronic Tension-Type Headache

CTTH is frequently called “the featureless headache” because it is predominantly characterized by head pain alone.²⁶ The diagnostic criteria for CTTH are as follows:

A. Headache ≥15 days/month ≥3 months and fulfilling B-D below
B. Headache lasts hours or may be continuous
C. Headache has ≥2 of
        1. Bilateral location
        2. Pressing/tightening (non-pulsating) quality
        3  Mild or moderate intensity
        4. Not aggravated by routine physical activity
D. Both of the following:
        1. ≤1 of photophobia, phonophobia, or mild nausea
        2. Neither moderate nor severe nausea nor vomiting
E. Not attributed to another disorder

 

New Daily Persistent Headache

Most patients with NDPH can recall the exact date it began.¹⁴ Clinically, NDPH is characterized by continuous head pain of moderate-to-severe intensity. International Headache Society criteria for NDPH include at least two of bilateral location, pressing or tightening in quality, mild-to-moderate intensity, and not being aggravated by routine physical activity, and no more than one of photophobia, phonophobia, and nausea, with neither moderate nor severe nausea nor vomiting. ²⁷

Hemicrania Continua

HC is defined by the presence of unilateral continuous daily headache without side shift. The pain is generally moderate in intensity, but there may be exacerbations of severe pain. During exacerbations, there should be at least one ipsilateral cranial autonomic symptom, such as conjunctival injection, lacrimation, nasal blockage, rhinorrhea, ptosis, or miosis. Patients with HC experience a complete response to therapeutic doses of indomethacin.¹⁷

Medication Overuse Headache

Medication overuse is defined as the intake of simple analgesics (e.g, aspirin, acetaminophen, or ibuprofen) on more than 15 days per month, or the intake of combination analgesics, opioids, ergots, or triptans on more than 10 days per month.^{22, 28} Medication-overuse headache is a secondary chronic headache characterized by increased headache frequency over time, occurring within a predictable time frame after analgesic consumption and requiring escalating doses of analgesics.

VI. Pathophysiology and Pathogenesis

Chronic Migraine

Nociceptive peptide mediators, such as substance P, calcitonin gene-related peptide (CGRP) and neurokinin A, are released from perivascular nerve fibers in response to stimulation of the trigeminal nerve.²⁹ These mediators trigger the trigeminovascular system to transmit nociceptive information to the brainstem via the action of glutamate.^{29, 30} It has been hypothesized that patients with CM have persistent neuronal hyperexcitability that predisposes them to the pain associated with a migraine attack.³⁰ CGRP is involved in sensory neurotransmission and can be found in most sensory nerves, especially the trigeminovascular afferents in the meninges that are involved in migraine.^31-33 It is one of the most potent vasodilators known.³³ CGRP levels measured in the jugular venous system are elevated after migraine and cluster headache attacks, and are normalized by treatment with a triptan.³³ Epidemiological data suggest a link between migraine and female sex hormones, an observation supported by the known effects of estrogen on brain function, including pain perception.¹⁰ Migraine may worsen in the perimenopausal period as a result of fluctuations in estrogen levels.¹⁰

Chronic Tension-Type Headache

There is limited knowledge regarding the pathophysiology of CTTH. Psychological stress and weak coping mechanisms may initiate and propagate physiological pain via activation of second messengers in downstream substrates involved in pain. Peripheral mechanisms may predominant in episodic type tension headache, whereas central mechanisms appear to be involved in CTTH.³⁴ Research has demonstrated that patients with CTTH may have a general hypersensitivity to pain compared with control subjects³⁵ and that the supraspinal response to muscular pain (demonstrated by high-density electroencephalogram brain mapping) may be abnormal.³⁶

New Daily Persistent Headache

The pathogenesis of NDPH is unknown, but recent observations suggest a connection with cervical spine hypermobility and elevation of proinflammatory cytokines in the cerebrospinal fluid. Recognized triggers for NDPH include infection, stressful life events, and surgical procedures.²⁷

Hemicrania Continua

Functional imaging studies of patients with HC suggest a unique pattern of subcortical involvement. There is subcortical involvement contralateral to the pain in the posterior hypothalamic region, ipsilateral dorsal pons, and ipsilateral ventral midbrain. These observations, along with indomethacin’s particular effect, support the classification of HC as a unique entity.¹⁷

VII. TREATMENT

Effective management of CDH involves, first, ruling out secondary causes. Once the diagnosis of primary CDH is established, identify the specific CDH subtype so that appropriate treatment can be initiated.

Chronic Migraine

The three broad approaches for treating patients with episodic or chronic migraine are³⁷

        1) Lifestyle changes and nonpharmacologic measures, including avoidance of recognized triggers
        2) Prompt treatment of acute attacks
        3) Preventive antimigraine pharmacotherapy

Lifestyle modifications include sleep-pattern regulation, diet, exercise, weight loss, and reduction of caffeine intake. Nonpharmacologic adjunctive measures include physical therapy, acupuncture, biofeedback, relaxation therapy, and cognitive behavioral therapy.

Migraine headache is routinely managed with medications that abort headaches as they occur.³⁸ Drugs for abortive treatment of migraine include triptans and dihydroergotamine (DHE). Both triptans and DHE are 5-HT1B/1D receptor agonists. In addition to triptans and DHE, there are over-the-counter and prescription analgesics that are helpful to patients who experience milder attacks and for whom migraine-specific drugs are ineffective or contraindicated. These types of drugs include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, opioid analgesics, and combinations of these drugs. There is a new drug formulation that contains sumatriptan and naproxen in a single tablet. Alternatively, a physician may prescribe a triptan to be taken with an over-the-counter NSAID.³⁷ The acute treatment of menstrual migraine is similar to that of non-menstrual–related attacks, but the response to treatment may be less favorable.¹⁰

The use of prophylactic medications that reduce attack frequency is another approach to migraine management.

Guidelines for the use of preventive migraine therapy include the following³⁷
        1) More than 4 to 6 headache days per month
        2) Symptomatic medications are contraindicated or ineffective
        3) Acute medication required more than twice a week

Preventive therapy may also be appropriate for rare types of migraine including hemiplegic migraine, basilar migraine, migraine with prolonged aura, and migraine associated with cerebral infarction. In general, preventive medications take a minimum of 3-4 weeks and as long as 8-12 weeks to become effective.³⁷ They are rarely 100% effective in preventing migraine attacks; a 50% reduction in headache burden is considered a good result. If beneficial, the preventive treatment is usually given for 6-12 months, at which time the need for continuing the drug is reassessed. Commonly used preventive antimigraine medications are listed in Table 5. At this time there are six Food and Drug Administration (FDA)-approved prophylactic treatments for migraine: methysergide, propranolol, timolol, sodium divalproate, topiramate, and onabotulinumtoxinA (for chronic migraine only).⁴ Of these, methysergide is no longer manufactured in the United States and timolol is rarely used.⁴

Table 5. Commonly Used Preventive Antimigraine Medications and Their Side Effects³⁷

Medication	Side Effects
Amitriptyline and nortriptyline	Weight gain, dry mouth, sedation, constipation
Atenolol	Depression, fatigue, hypotension, bradycardia
Botulinum neurotoxin type A	Excessive weakness in facial or upper cervical muscle, ptosis
Divalproex sodium	Alopecia, weight gain, nausea, tremor
Gabapentin	Edema, sedation, fatigue, dizziness
Propranolol	Depression, fatigue, hypotension, bradycardia
Topiramate	Paresthesias, mental slowing, weight loss, kidney stones
Verapamil	Edema, constipation, hypotension

Many patients with episodic migraine and almost all patients with CM will require treatment with prophylactic agents,³⁹ but only 12% of patients with migraine frequency appropriate for preventive therapy are actually prescribed a prophylaxis.⁴⁰ Thus, there is a need for educating physicians on safe and effective pharmacologic preventive therapies for migraine.

Chronic Tension Type Headache

CTTH can also be treated with both prophylactic and abortive medications. Amitriptyline is the best-studied preventive drug, but nortriptyline, mirtazapine, tizanidine, and selective serotonin reuptake inhibitors are also used.⁴¹ Effective therapy should be continued for 3-6 months before attempting discontinuation.⁴² Common interventions for acute CTTH treatment are simple analgesics and NSAIDS, often taken by the patient without a prescription.

New Persistent Daily Headache

With NPDH, a search for secondary causes is mandatory, given that treatment attempts for NDPH are often less successful. If primary, it is recommended to classify the dominant headache phenotype (migraine or tension-type) and treat with preventatives.⁴³ In some cases NPDH is self-limited over several months and resolves without therapy, while in others it takes a more chronic refractory form that is unresponsive to typical headache treatment strategies and may persist for many years.²⁷

Hemicrania Continua

The treatment of HC is largely empirical due to the lack of understanding about its pathophysiology. Indomethacin defines the disorder and is the treatment of choice; the dose is variable.^{18, 44} Gabapentin, topiramate, and celecoxib are alternative treatments for patients who do not tolerate indomethacin or who have contraindications to its use.⁴⁴

VIII. ROLE OF BOTULINUM NEUROTOXIN

There are seven serotypes of botulinum neurotoxin (A, B, C, D, E, F, and G), but only serotypes A and B are available clinically. Three formulations of serotype A are commercially available: onabotulinumtoxinA (Botox^®), abobotulinumtoxinA (Dysport^®), and incobotulinumtoxinA (Xeomin^®); additionally, there is one formulation of serotype B, rimabotulinumtoxinB (Myobloc®/Neurobloc^®).

OnabotulinumtoxinA is FDA approved for the prophylaxis of headaches in adult patients with CM (≥15 days per month with headache lasting 4 hours a day

or longer other BoNT formulations are not interchangeable.

Clinical studies that have evaluated BoNT for the treatment of headache are described below.

a) Efficacy

Chronic Headache

Early studies evaluated the efficacy of onabotulinumtoxinA in for the treatment of chronic headache, and included patients with various subtypes of CDH. In one 11-month multicenter trial, Mathew et al⁴⁵ studied the efficacy of onabotulinumtoxinA in 355 patients. Another study was a randomized, placebo-controlled study of 702 patients, in which Silberstein et al⁴⁶ studied the efficacy and tolerability of onabotulinumtoxinA for chronic headache prevention using a fixed-site injection protocol. The results of these trials were inconclusive, largely due to issues concerning study design and patient population. However, they led to refinement of inclusion/exclusion criteria and study protocols, which were incorporated in the subsequent trials discussed below.

Chronic Migraine

OnabotulinumtoxinA has been studied as a migraine preventive in numerous clinical trials and in a variety of subpopulations with migraine. The largest and most recent clinical trials of patients with CM achieved statistically significant efficacy on numerous endpoints, including the primary endpoint of reduction of headache days.

Table 6. Recent Studies of OnabotulinumtoxinA in the Treatment of Chronic Migraine

Study	N	Injection Method	Duration (months)	Primary Endpoint	Treatment Groups	Results
PREEMPT 148	679	Fixed-site	8	Mean change in  frequency of headache  episodes from baseline	Placebo  155-195 U	Primary endpoint not  met; number of  headache days  reduced by 7.8 in  BoNT-A group vs 6.4 in  placebo (P =.006)
PREEMPT 249	705	Fixed-site	8	Reduction of number of  headache days	Placebo  155-195 U	6.7 days in the  placebo group vs 9.0  days for BoNT-A (P <  .001)
PREEMPT 1 and 2 pooled 64	1384	Fixed-site	8	Mean change from  baseline in frequency of  headache days at 24  weeks	Placebo  155–195 U	6.6 days in the  placebo group vs  8.4 days in the BoNT  group (P < .001)

 

In October 2010, the FDA approved onabotulinumtoxinA injection to prevent headaches in adult patients with CM.⁴⁷

Results from the two pivotal PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) trials demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for patients with CM, including those who overuse acute headache medications.²¹ PREEMPT is a multicenter, randomized, placebo-controlled trial of 1384 adult patients with CM.²¹ PREEMPT 1 and 2 used identical protocols, consisting of a 4-week baseline screening phase followed by a 24-week double-blind phase and then a 32-week open-label phase. Patients were randomized 1:1 to receive injections of onabotulinumtoxinA (155–195 U) or placebo every 12 weeks. All patients received injections using a standard approach (included anterior and posterior cranial injections, cervical paraspinal muscle injections, and trapezius injections). Patients were also eligible to receive additional injections using a follow-the-pain approach according to the injector’s discretion.

In a pooled analysis of PREEMPT 1 and 2, the primary endpoint was mean change from baseline in frequency of headache days at 24 weeks.²¹ OnabotulinumtoxinA was statistically significantly more effective than placebo in reducing the mean frequency of headache days at each visit in the double-blind phase starting at the first post-treatment study visit (week 4) and including the week 24 primary endpoint.

Figure 2. Mean change from baseline in frequency of headache days in the pooled analysis of the PREEMPT 1 and 2 trials. 

Headache days at baseline: 19.9 ± 0.1 BoNT-A group versus 19.8 ± 0.1 placebo group, P=.498. Data are the mean ± standard error. Reprinted from Dodick et al.²¹  Permisson pending.

OnabotulinumtoxinA was also superior to placebo for reducing the number of headache days. Patients receiving onabotulinumtoxinA had a reduction of 8.4 days compared with the reduction of 6.6 days in patients receiving placebo injections (P<.001). There were also statistically significant benefits of onabotulinumtoxinA compared with placebo for several secondary endpoints, including frequency of migraine episodes, frequency of migraine days, frequency of headache days with moderate or severe pain, total number of hours with headache, and the proportion of patients with severe (≥60 points) Headache Impact Test-6 (HIT-6) scores. The amount of migraine-abortive medication use did not differ between the two groups. Adverse events were more common in the patients receiving onabotulinumtoxinA (62%) compared with those receiving placebo (52%). Most adverse events were mild to moderate in severity and the discontinuation rate due to adverse events was low (3.8% and 1.2% in the onabotulinumtoxinA and placebo groups, respectively). It should be noted that the reductions in headache days compared with placebo in the PREEMPT trial are similar to that seen in pivotal trials of topiramate and divalproate sodium.⁴

The primary endpoint for PREEMPT 1, change in headache episode frequency from the 4-week baseline period to the last 4 weeks of the double-blind phase (weeks 21-24 after the initial injections), was not reached. Results from this trial suggest superiority of onabotulinumtoxinA compared with placebo for several secondary outcomes.⁴⁸ There was no significant difference in the reduction of headache episodes between the onabotulinumtoxinA group and the placebo group (P=.344). There were also no significant between-group differences in reduction of migraine/probable migraine episodes and the use of migraine-abortive medications. However, the onabotulinumtoxinA group had significant reductions in number of headache days compared with placebo (−7.8 in onabotulinumtoxinA group vs −6.4 in placebo group, P=.006), number of migraine/probable migraine days, reduction in HIT-6 score, and improvements in quality of life. Adverse events occurred in 60% and 47% of patients in the onabotulinumtoxinA and placebo groups, respectively.⁴⁸

The PREEMPT 2 trial met the primary endpoint: onabotulinumtoxinA was superior to placebo for reduction in number of headache days during weeks 21 to 24 of the double-blind treatment phase compared with the 4-week baseline phase.⁴⁹ Frequency of headache days in the onabotulinumtoxinA group was reduced by 9.0 days, compared with 6.7 days in the placebo group (P<.001). Moreover, onabotulinumtoxinA was superior to placebo for secondary outcomes, including frequency of headache episodes, number of migraine/probable migraine days, cumulative hours of headache on headache days, number of moderate-to-severe headache days, and number of patients remaining in the severely affected category on the HIT-6. Adverse events occurred in 65% and 56% of patients in the onabotulinumtoxinA and placebo groups, respectively.⁴⁹

A subgroup analysis of pooled data from PREEMPT 1 and PREEMPT 2 examined the efficacy of onabotulinumtoxinA for the prophylactic treatment of CM in patients overusing acute headache medications.⁵⁰ Of 1384 total patients, 906 (66%) overused acute headache medications. Overuse of acute headache medications was defined as using acute headache medications ≥2 times per week with intake ≥15 days for simple analgesics and/or intake ≥10 days for other medications during the 4-week baseline phase. Patients overusing acute headache medications who received onabotulinumtoxinA had reduced frequency of headache days and headache episodes superior to that observed in patients receiving placebo. The mean change in headache episodes at week 24 was −5.4 in the onabotulinumtoxinA group compared with −5.1 in the placebo group (P=.028). The reduction in number of headache days was 8.2 days for the onabotulinumtoxinA group compared with 6.2 days for the placebo group (P<.001). The amount of acute headache medication intake following injections was not significantly different between groups. These results suggest that the overuse of acute headache medications does not impede the efficacy of chronic migraine onabotulinumtoxinA therapy.⁵⁰

A 32-week open-label phase followed the 24-week placebo-controlled phase of the PREEMPT trials.⁵⁰ During the open-label phase, all patients received three treatments with onabotulinumtoxinA (weeks 24, 36, and 48). Improvements from onabotulinumtoxinA treatment during the open-label phase were seen both in patients who received onabotulinumtoxinA during the initial 24 weeks (the 5-cycle onabotulinumtoxinA group) and those who had initially received placebo (the placebo/3-cycle onabotulinumtoxinA group). However, the 5-cycle onabotulinumtoxinA group continued to have superior benefit during the open-label phase compared with the placebo/3-cycle onabotulinumtoxinA group. At week 56, the 5-cycle onabotulinumtoxinA group had a reduction of headache days by 11.7 compared with 10.8 days in the placebo/3-cycle onabotulinumtoxinA group (P=.019) .

Figure 3. PREEMPT pooled analysis (primary): mean change from baseline in frequency of headache days. Reprinted from Aurora, et al.⁵⁰ Permission pending.

Headache days at baseline:19.9 ± 0.1 onabotulinumtoxinA group vs 19.8 ± 0.1 placebo group, P = .498. 95% confidence intervals at: week 24: O/O -8.90, -7.92; P/O -7.07, -6.08; week 56: O/O -12.17, -11.20; P/O -11.32, -10.31. Data are presented as mean ± standard error. O/O = onabotulinumtoxinA/onabotulinumtoxinA; P/O = placebo/onabotulinumtoxinA.

The 5-cycle onabotulinumtoxinA group also had greater reductions in headache episodes at week 28 (P=.036) and at week 52 (P=.044). Seventy-three percent of patients completed the open-label phase. There were no new safety or tolerability concerns. These analyses suggest that onabotulinumtoxinA therapy maintains its efficacy and is safe when injected at 12-week intervals for up to 5 cycles. Furthermore, the superior efficacy noted in the 5-cycle onabotulinumtoxinA group compared with the placebo/3-cycle onabotulinumtoxinA group suggests that there is continued improvement with long-term onabotulinumtoxinA therapy in patients with CM.⁵⁰

Chronic Tension-Type Headache

Four randomized, placebo-controlled studies investigated onabotulinumtoxinA therapy for CTTH; none of the studies showed any significant benefit of onabotulinumtoxinA.^{51, 52} Perhaps patients with CTTH who have pericranial muscle tenderness are more likely to respond to onabotulinumtoxinA therapy.⁴⁵

b) Other Headache Disorders

Episodic Headache

Episode headaches occur at a frequency of less than 15 days per month. Most studies have not demonstrated that treatment with BoNT-A is superior to placebo for the prophylactic treatment of episodic migraine.^53-55 In a large, placebo-controlled study, Aurora et al examined the effect of onabotulinumtoxinA, injected in a follow-the-pain approach at doses of 110 U to 260 U, on 369 patients with episodic migraine.⁵⁶ There were no significant between-group differences in the primary efficacy endpoint (change from baseline in migraine-attack frequency). However, in the subgroup of patients who had 12-15 headache days per month at baseline, those who received onabotulinumtoxinA did significantly better than those who received placebo (a mean decrease of 4.0 vs 1.9 headache episodes per month, respectively). The results of this study suggest that onabotulinumtoxinA may be effective for episodic migraine patients who experience frequent headache attacks.⁵⁶ Blumenfeld et al studied the efficacy and tolerability of onabotulinumtoxinA and divalproex sodium daily in the prophylactic treatment of chronic and episodic migraine in a randomized comparative study. There were significant and comparable reductions in the number of headache days per month and in Migraine Disability Assessment (MIDAS) scores compared with baseline for both groups. However, onabotulinumtoxinA was better tolerated than divalproex sodium.⁵⁷

Cluster Headache

Cluster headache is a type of trigeminal autonomic cephalalgia, a primary headache disorder characterized by unilateral head pain that occurs in association with ipsilateral cranial autonomic features.⁵⁸ BoNT is not well studied as a treatment for cluster headache.⁵⁹ The largest clinical trial to date on the use of BoNT-A in patients with cluster headache is an open-label study of three patients with episodic cluster headache and nine patients with chronic cluster headache.⁶⁰ A positive result was defined as ≥50% reduction of pain intensity and/or attack frequency. Patients received an injection of 50 U onabotulinumtoxinA as an add-on preventive medication. A standard injection protocol was used and the muscles ipsilateral to the headache site were injected as follows: temporalis (10 U), frontalis (10 U), splenium capitis (10 U), and trapezius (20 U). Patients were followed for 90 days. A total of 25% of patients experienced a reduction of cluster-attack frequency of 50% within the first week after injection, an effect that lasted for 2 to 3 months. However, this benefit was observed only in patients with chronic cluster headache.⁶⁰

c) Safety

Clinical trials involving more than 2000 headache patients have demonstrated that onabotulinumtoxinA injections as preventive treatment of headache have been safe and well tolerated, with a notable lack of the systemic effects of other headache medications. Minor side effects can be minimized by modifying injection technique.⁶¹

In the PREEMPT pivotal efficacy trials, the discontinuation rate was 12% in the onabotulinumtoxinA-treated group and 10% in the placebo-treated group. Discontinuations due to an adverse event were 4% in the onabotulinumtoxinA group and 1% in the placebo group. The most frequent adverse events leading to discontinuation in the onabotulinumtoxinA group were neck pain, headache, worsening migraine, muscular weakness, and eyelid ptosis.⁴⁷,⁴⁹ The most frequently reported adverse reactions following injection of onabotulinumtoxinA for CM appear in Table 7.

Table 7. Treatment-Related Adverse Effects (AEs) Reported by ≥2% of Patients in the PREEMPT Clinical Trials²¹

Treatment-Related AEs	OnabotulinumtoxinA (n=687) (%)	Placebo (n=692) (%)
Total	29.4	12.7
Neck pain	6.7	2.2
Muscular weakness	5.5	0.3
Eyelid ptosis	3.3	0.3
Injection-site pain	3.2	2.0
Headache	2.9	1.6
Myalgia	2.6	0.3
Musculoskeletal stiffness	2.3	0.7
Musculoskeletal pain	2.2	0.7

d) Potential Predictors of Response to Botulinum Neurotoxin Therapy

Patients with imploding or ocular migraine headache may be more likely to respond to BoNT-A therapy than patients with exploding headache pain. Jakubowski et al³⁹ reported a study that explored neurologic markers that might distinguish migraine patients who benefit from onabotulinumtoxinA treatment (100 U divided into 21 injections sites across pericranial and neck muscles). Responders to onabotulinumtoxinA treatment and nonresponders were compared prospectively (n=27) and retrospectively (n=36) for a variety of neurologic symptoms associated with their migraines.³⁹ Data were pooled from all 63 patients. Among these patients, 94% who described their migraine headaches as imploding were responders (n=27); if the headache location was ocular, 100% were responders (n=5). In contrast, 81% of patients who described their headaches as exploding were nonresponders (n=32). There was a 90% decrease in headache frequency in the group with imploding headache and 96% in the ocular headache group, but no change in the group with exploding headache.³⁹ The prevalence of aura, photophobia, phonophobia, nausea, and throbbing was similar between responders and nonresponders.

In an open-label study of 82 adult patients with chronic headache, 71 patients with CM and 11 patients with CTTH were treated with 100 U onabotulinumtoxinA. Patients received at least two sets of injections at intervals of 12-15 weeks. Injections were given by fixed-site, fixed dose, and follow-the-pain approaches.⁶² In the CM group, 76% of patients were responders to onabotulinumtoxinA, of which 69% (37/54) had headaches that were predominantly unilateral in location. The remaining 32% (17/54) of patients had headaches that were predominantly bilateral in location (both P<.01 vs CM nonresponders). Of the 24% (17/71) of CM nonresponders, 77% (13/17) reported predominantly bilateral headache. In the remaining 24% (4/17) of nonresponders, the headache was unilateral. In the chronic migraine responders group, 82% (44/54) had clinically detectable scalp allodynia and 61% (33/54) had pericranial muscle tenderness (both P<.01 vs chronic migraine nonresponders). The proportion of CM nonresponders with scalp allodynia and pericranial muscle tenderness was 12% (2/17) and 18% (3/17), respectively. In the CTTH group, all patients (100%, 11/11) had bilateral headache. Among these patients, 36% (4/11) were responders to onabotulinumtoxinA.⁶² The results of this study suggest that headaches predominantly unilateral in location, with scalp allodynia and pericranial muscle tenderness, may be predictors of response to onabotulinumtoxinA therapy in patients with CM.  

e) Mechanism of Action

The mechanisms by which BoNT-A may alleviate headache pain are not fully understood, but they are more complex than simple muscle relaxation resulting from the inhibition of acetylcholine release at the neuromuscular junction. Initially, the antinociceptive effect of BoNT in headache was thought to be a result of relief of muscle spasms.⁵² Direct and indirect evidence suggests that distinct antinociceptive effects of BoNT-A contribute to its observed efficacy in alleviating headache pain. BoNT-A inhibits release of substance P, CGRP, and glutamate.³⁰ There are at least three possible mechanisms by which BoNT-A may affect central circuits: 1) BoNT-A–mediated blockade of gamma motor endings with reduction of spindle afferent input from the injected muscle; 2) plastic changes following BoNT-A–mediated blockade of neuromuscular transmission; and 3) retrograde transport and transcytosis of BoNT-A following uptake at the neuromuscular junction. The reader is referred to the Mechanism of Action Module for further discussion on this topic.

IX. SUMMARY

Chronic daily headache is a common and complicated clinical disorder. Differentiating primary from secondary conditions is the first step in diagnosis. There are several types of primary CDH, and it is important to recognize the signs and symptoms of the various subtypes. Patients with chronic migraine may benefit from appropriate prophylactic therapy, and botulinum neurotoxin should be considered as a potential treatment.

REFERENCES

1. Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004;44(9): 856-64.

2. National Headache Foundation. Fact Sheet. http://www.health-exchange.net/pdfdb/headfactEng.pdf.

3. Samton J, Mauskop A. Treatment of headaches with botulinum toxin. Expert Rev Neurother 2006;6(3): 313-22.

4. Cady RK. OnabotulinumtoxinA (botulinum toxin type-A) in the prevention of migraine. Expert Opin Biol Ther 2010;10(2): 289-98.

5. Lipton R. Chronic migraine epidemiology, classification, and differential diagnosis. AHS Symposium: Decoding chronic migraine: Translating clinical trial data into optimal outcomes with novel therapies 2010.

6. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol 2010;30(2): 107-19.

7. Lipton R, Bigal M, Hamelsky S, Scher A. Headache: Epidemiology and Impact. In: Silberstein S, Lipton R, Dodick D, editors. Wolff”s Headache and Other Head Pain, 8th ed. New York: Oxford University Press, 2008:45-61.

8. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 1992;267(1): 64-9.

9. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB. Cumulative lifetime migraine incidence in women and men. Cephalalgia 2008;28(11): 1170-8.

10. Ashkenazi A, Silberstein SD. Hormone-related headache: pathophysiology and treatment. CNS Drugs 2006;20(2): 125-41.

11. Schwartz BS, Stewart WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998;279(5): 381-3.

12. Lyngberg AC, Rasmussen BK, Jorgensen T, Jensen R. Incidence of primary headache: a Danish epidemiologic follow-up study. Am J Epidemiol 2005;161(11): 1066-73.

13. Evans RW, Seifert TD. The challenge of new daily persistent headache. Headache 2011;51(1): 145-54.

14. Li D, Rozen TD. The clinical characteristics of new daily persistent headache. Cephalalgia 2002;22(1): 66-9.

15. Takase Y, Nakano M, Tatsumi C, Matsuyama T. Clinical features, effectiveness of drug-based treatment, and prognosis of new daily persistent headache (NDPH): 30 cases in Japan. Cephalalgia 2004;24(11): 955-9.

16. Bigal ME, Sheftell FD, Rapoport AM, Lipton RB, Tepper SJ. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002;22(6): 432-8.

17. Cittadini E, Goadsby PJ. Update on hemicrania continua. Curr Pain Headache Rep 2011;15(1): 51-6.

18. Peres MF, Silberstein SD, Nahmias S, et al. Hemicrania continua is not that rare. Neurology 2001;57(6): 948-51.

19. Dodick D, Freitag F. Evidence-based understanding of medication-overuse headache: clinical implications. Headache 2006;46 Suppl 4: S202-11.

20. Smith TR, Stoneman J. Medication overuse headache from antimigraine therapy: clinical features, pathogenesis and management. Drugs 2004;64(22): 2503-14.

21. Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 2010;50(6): 921-36.

22. International Headache Society. The International Classification of Headache Disorders 2nd ed (ICHD-II). http://www.ihs-classification.org/en/0_downloads/

23. Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007;47(2): 170-80.

24. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry 2010;81(4): 428-32.

25. Lipton RB, Chu MK. Conceptualizing the relationship between chronic migraine and episodic migraine. Expert Rev Neurother 2009;9(10): 1451-4.

26. Fumal A. Chronic tension-type headache. In: Goadsby P, Dodick D, editors. Chronic Daily Headache for Clinicians. Hamilton, Ontario: BC Decker Inc, 2005:57-64.

27. Rozen TD. New daily persistent headache. Handb Clin Neurol 2010;97: 489-94.

28. Diener HC, Holle D, Dodick D. Treatment of chronic migraine. Curr Pain Headache Rep 2011;15(1): 64-9.

29. Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43(6 Suppl 3): S16-20.

30. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management.Headache 2003;43 Suppl 1: S9-15.

31. Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003;8(6): 446-9.

32. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993;33(1): 48-56.

33. Rapoport AM. New acute treatments for headache. Neurol Sci 2010;31 Suppl 1: S129-32.

34. Chen Y. Advances in the pathophysiology of tension-type headache: from stress to central sensitization. Curr Pain Headache Rep 2009;13(6): 484-94.

35. Bendtsen L. Central sensitization in tension-type headache--possible pathophysiological mechanisms. Cephalalgia 2000;20(5): 486-508.

36. Buchgreitz L, Egsgaard LL, Jensen R, Arendt-Nielsen L, Bendtsen L. Abnormal pain processing in chronic tension-type headache: a high-density EEG brain mapping study. Brain 2008;131(Pt 12): 3232-8.

37. Silberstein S, Freitag F, Bigal M. Migraine Treatment. In: Silberstein S, Lipton R, Dodick D, editors. Wolff”s Headache and Other Head Pain, 8th ed. New York: Oxford University Press, 2008:177-292.

38. Jakubowski M, McAllister PJ, Bajwa ZH, Ward TN, Smith P, Burstein R. Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A. Pain 2006;125(3): 286-95.

39. Rossi P, Faroni J, Tassorelli C, Nappi G. Diagnostic delay and suboptimal management in a referral population with hemicrania continua. Headache 2009;49(2): 227-34.

40. Diamond S, Bigal ME, Silberstein S, Loder E, Reed M, Lipton RB. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study. Headache 2007;47(3): 355-63.

41. Bigal ME, Rapoport AM, Hargreaves R. Advances in the pharmacologic treatment of tension-type headache. Curr Pain Headache Rep 2008;12(6): 442-6.

42. Lenaerts ME. Pharmacoprophylaxis of tension-type headache. Curr Pain Headache Rep 2005;9(6): 442-7.

43. Goadsby PJ, Boes C. Chronic daily headache. J Neurol Neurosurg Psychiatry 2002;72 Suppl 2: ii2-ii5.

44. Rossi P, Tassorelli C, Allena M, Ferrante E, Lisotto C, Nappi G. Focus on therapy: hemicrania continua and new daily persistent headache. J Headache Pain 2010;11(3): 259-65.

45. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache 2005;45(4): 293-307.

46. Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2005;80(9): 1126-37.

47. U.S. Food and Drug Administration. FDA News Release: FDA approves Botox to treat chronnic migraine. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm 2010.

48. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010;30(7): 793-803.

49. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010;30(7): 804-14.

50. Aurora S, Winner P, Freeman M, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56 Week PREEMPT clinical program. Headache 2011; 51(9);1358-73.

51. Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70(19): 1707-14.

52. Evidente VG, Adler CH. An update on the neurologic applications of botulinum toxins. Curr Neurol Neurosci Rep 2010;10(5): 338-44.

53. Saper JR, Mathew NT, Loder EW, DeGryse R, VanDenburgh AM. A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine. Pain Med 2007;8(6): 478-85.

54. Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia 2007;27(6): 492-503.

55. Elkind AH, O'Carroll P, Blumenfeld A, DeGryse R, Dimitrova R. A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis. J Pain 2006;7(10): 688-96.

56. Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache 2007;47(4): 486-99.

57. Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache 2008;48(2): 210-20.

58. Cittadini E, Matharu MS. Symptomatic trigeminal autonomic cephalalgias. Neurologist 2009;15(6): 305-12.

59. Ailani J, Young WB. The role of nerve blocks and botulinum toxin injections in the management of cluster headaches. Curr Pain Headache Rep 2009;13(2): 164-7.

60. Sostak P, Krause P, Forderreuther S, Reinisch V, Straube A. Botulinum toxin type-A therapy in cluster headache: an open study. J Headache Pain 2007;8(4): 236-41.

61. Barrientos N, Chana P. Botulinum toxin type A in prophylactic treatment of migraine headaches: a preliminary study. J Headache Pain;4: 146-51.

62. Mathew NT, Kailasam J, Meadors L. Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache. Headache 2008;48(2): 194-200.

63. Halker RB, Hastriter EV, Dodick DW. Chronic daily headache: an evidence-based and systematic approach to a challenging problem. Neurology 2011;76(7 Suppl 2): S37-43.

64. Dodick D, Aurora S, Turkel C, et al. Botulinum neurotoxin type A for treatment of chronic migraine: Double-blind, randomized, placebo-controlled PREEMPT trials (abstract). Headache currents: 14th International Headache Congress, Philadelphia, PA 2009.