Shift from high-frequency to low-frequency episodic migraine in patients treated with Galcanezumab: results from two global randomized clinical trials.

BACKGROUND: Patients with episodic migraine (EM) with a higher-frequency of migraine headache days (HFEM: 8-14 migraine headache days/month) have a greater disease burden and a higher risk of progressing to chronic migraine (CM) with associated acute treatment overuse versus those with low-frequency EM (LFEM: 4-7 migraine headache days/month). In this post hoc analysis, we assessed the proportions of patients who shifted from HFEM to LFEM and to very low-frequency EM (VLFEM: 0-3 migraine headache days/month) status following treatment with galcanezumab versus placebo. METHODS: EVOLVE-1 and EVOLVE-2 were double-blind, Phase 3 studies in patients with EM. Patients (18-65 years) were randomized (2:1:1) to subcutaneous monthly injections of placebo, galcanezumab 120 mg (240 mg loading dose) or 240 mg, for up to 6 months. Data were pooled and endpoints were change from baseline in number of migraine headache days/month and patients who shifted from HFEM to LFEM or VLFEM status. Impact of change in HFEM status on migraine headache days/month, quality of life and disability was also assessed. RESULTS: A total of 66% (1176/1773) patients from EVOLVE studies had HFEM status at baseline and were included in this analysis; placebo: 592, galcanezumab 120 mg: 294 and galcanezumab 240 mg: 290. At each month, both doses of galcanezumab resulted in a higher proportion of patients who shifted to 0-7 monthly headache days/month (VLFEM or LFEM status). Patients who shifted from HFEM at baseline to VLFEM status at Month 3, a relatively larger proportion of patients on galcanezumab 120 mg versus placebo remained at VLFEM status at Months 4-6; Months 4-5 for galcanezumab 240 mg versus placebo. Among the galcanezumab-treated patients who did-not-shift or shifted to LFEM or VLFEM status for ≥3 consecutive months until the end of the study, patients who shifted from HFEM to VLFEM status experienced the largest reduction in migraine headache days/month and the largest clinically meaningful improvements in daily functioning (MSQ-RFR) and disability (MIDAS). CONCLUSIONS: In patients with HFEM, treatment with galcanezumab (120 mg and 240 mg) significantly reduced migraine headache days/month, maintained remission status at subsequent months until the end of the study, and improved patients' quality of life versus placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: EVOLVE-1, NCT02614183 ; EVOLVE-2, NCT02614196 .

Long-Term Safety and Tolerability of OnabotulinumtoxinA Treatment in Patients with Chronic Migraine: Results of the COMPEL Study.

INTRODUCTION: OnabotulinumtoxinA is approved in the USA for the prevention of headache in adults with chronic migraine, a debilitating neurologic disease characterized by headaches occurring on ≥ 15 days per month for > 3 months and including migraine features on ≥ 8 days per month. OBJECTIVE: The COMPEL Study (NCT01516892), a 108-week, multi-center, open-label study, evaluated the long-term efficacy and safety of onabotulinumtoxinA in adults with chronic migraine. The objective of this subanalysis was to examine the safety and tolerability of onabotulinumtoxinA after each of nine treatment cycles. METHODS: OnabotulinumtoxinA 155 U was administered every 12 weeks. Safety and tolerability, overall and by treatment cycle, were assessed. Treatment-emergent adverse events reported between successive treatments were attributed to the preceding treatment. The safety population received one or more doses of onabotulinumtoxinA. The primary efficacy outcome was the reduction in headache days at week 108 compared with baseline. RESULTS: Of 716 patients enrolled, 373 patients (52.1%) completed the study and 343 (47.9%) withdrew; 481 patients (67.2%) received 60 weeks of treatment and 402 (56.1%) received 108 weeks of treatment. In total, 436 (60.9%) patients reported treatment-emergent adverse events; most were mild/moderate in severity. Thirty-two patients (4.5%) discontinued the study after experiencing treatment-emergent adverse events. The incidence of treatment-emergent adverse events typically decreased with repeated onabotulinumtoxinA treatment: first cycle, 24.2%; fourth cycle, 18.4%; ninth cycle, 12.2%. Neck pain (2.7%), eyelid ptosis (1.8%), musculoskeletal stiffness (1.4%), injection-site pain (1.3%), and headache (1.3%) were the most common treatment-emergent adverse events after the first cycle. Seventy-five patients (10.5%) reported serious treatment-emergent adverse events, 13 (1.8%) withdrew. Treatment-related adverse events were reported by 131 patients (18.3%), one was considered serious. OnabotulinumtoxinA significantly reduced headache day frequency by 10.7 (6.4) days per 28-day period (p < 0.0001) at week 108. CONCLUSIONS: OnabotulinumtoxinA treatment was well tolerated over 108 weeks; no new safety signals were identified. The overall incidence of treatment-emergent adverse events and the most common individual events decreased with repeated onabotulinumtoxinA administration. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT01516892.

Case report: successful epiradicular peripheral nerve stimulation of the C2 dorsal root ganglion for postherpetic neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is the most common complication following an acute varicella zoster virus infection. PHN often results in a chronic severe pain condition refractory to conservative pain management treatments. Peripheral nerve stimulation over the affected spinal nerve root may be an effective treatment option for patients with intractable PHN. OBJECTIVE: To describe a successful case of peripheral nerve stimulation of the second cervical dorsal root ganglion for the treatment of intractable PHN. CASE REPORT: An 80-year-old man with a 15-month history of severe PHN was referred to our clinic for pain management. His pain was localized to the left side in the distribution of the C2 dermatome. The patient's pain was unresponsive to comprehensive conventional treatments for PHN including physical therapy, membrane stabilizing medications, opioids, anti-inflammatories, cervical epidural steroid injections, cervical facet joint injections, and dorsal root ganglion blockade with pulsed radiofrequency. After failing to respond to conservative and interventional therapies, a peripheral nerve stimulator trial was conducted for a period of seven days. The lead was placed within the epidural space over the atlanto-axial joint under fluoroscopy to stimulate the left C2 nerve root. This trial resulted in a significant decrease of the patient's pain, and discontinuation of all pain medications. CONCLUSION: We describe a case of successful electrode placement at the C2 spinal level for the treatment of refractory PHN.

The Sinus, Allergy and Migraine Study (SAMS).

OBJECTIVE: The objective of this study is to classify (according to the current International Headache Society's criteria [ICHD-II]) the headache types that those with self-diagnosed sinus headache experience and to determine barriers to correct diagnosis. BACKGROUND: The American Migraine Study II estimates that 28 million Americans suffer from migraine headache. The majority of these patients remain undiagnosed and many are erroneously diagnosed as having sinus headache. Despite this common diagnosis, the concept of sinus headache remains an enigma with a relative paucity of information in the literature. METHODS: Advertising in the greater Phoenix, U.S. metropolitan area was used to recruit 100 willing and consecutive subjects to participate in this descriptive clinical study (The Sinus, Allergy and Migraine Study [SAMS]). All patients who believed they suffered from sinus headache and were over 18 years of age were enrolled without exclusion. A detailed history and exam was performed in each patient, and patients were given headache diagnoses based on the current International Headache Society's (IHS) criteria. RESULTS: Of the 100 subjects with self-diagnosed headache, IHS diagnoses mistaken as sinus headache included migraine with or without aura (52%), chronic migraine associated with medication overuse versus probable medication overuse headache (11%), probable migraine (23%), cluster headache (1%), hemicrania continua (1%), headache secondary to rhinosinusitis (3%), and headaches nonclassifiable (9%). Weather changes (83%), seasonal variation (73%), exposure to allergens (62%), and changes in altitude (38%) were frequent migraine triggers. Seventy-six percent of migraine subjects reported pain in the distribution of the second division of the trigeminal nerve (either unilateral or bilateral), and 62% experienced bilateral forehead and maxillary pain with their headaches. The most common associated features included nasal congestion (56%), eyelid edema (37%), rhinorrhea (25%), conjunctival injection (22%), lacrimation (19%), and ptosis (3%). The headaches nonclassifiable were characterized by a bilateral maxillary pressure of mild to moderate intensity associated with at least one cranial autonomic symptom. Features suggestive of migraine were absent in all 9 of these nonclassifiable cases. CONCLUSIONS: The majority of those with self-diagnosed sinus headache have migraine or probable migraine. In those patients with migraine, the most common reasons for misdiagnosis include headache triggers, pain location, and associated features ("guilt by provocation, location, and association") commonly attributed to sinus headache. The clinician must be aware of these unique presentations of migraine so that a correct diagnosis can be made and effective treatment instituted. A portion of patients with self-diagnosed sinus headache suffer from a headache type, which is unclassifiable by the current IHS criteria. These headaches are characterized by bilateral maxillary pressure, mild to moderate pain intensity, cranial autonomic symptoms, and the complete absence of migraine features.

An otolaryngology, neurology, allergy, and primary care consensus on diagnosis and treatment of sinus headache.

While "sinus" headache is a widely accepted clinical diagnosis, many medical specialists consider it to be an uncommon cause of recurrent headaches. Unnecessary diagnostic studies, surgical interventions, and medical treatments are often the result of the inappropriate diagnosis of sinus headache. Both the International Headache Society and the American Academy of Otolaryngology-Head and Neck Surgery have attempted to characterize conditions leading to headaches of rhinogenic origin. However, they have done so from different perspectives and in isolation from the other specialty groups. An interdisciplinary ad hoc committee recently convened to discuss the role of sinus disease and the nose in the etiology of headache and to review recent epidemiologic studies suggesting that sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. Clinical trial data are presented which clearly indicate that the majority of sinus headaches can actually be classified as migraines. This committee reviewed scientific evidence available from multiple disciplines and concludes that considerable research and clinical study are needed to further understand and explain the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, there was a consensus from this group that greater diagnostic and therapeutic attention needs to be given to patients complaining of sinus headache that may indeed be due to the nose.

Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment.

Sinus headache is a widely accepted clinical diagnosis, although many medical specialists consider it an uncommon cause of recurrent headaches. The inappropriate diagnosis of sinus headache can lead to unnecessary diagnostic studies, surgical interventions, and medical treatments. Both the International Headache Society and the American Academy of Otolaryngology-Head and Neck Surgery have attempted to define conditions that lead to headaches of rhinogenic origin but have done so from different perspectives and in isolation of each other. An interdisciplinary ad hoc committee convened to discuss the role of sinus disease as a cause of headache and to review recent epidemiological studies that suggest sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. This committee reviewed available scientific evidence from multiple disciplines and concluded that considerable research and clinical study are required to further understand and delineate the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, this group agreed that greater diagnostic and therapeutic attention needs to be given to patients with sinus headaches.

Duration of migraine is a predictor for response to botulinum toxin type A.

OBJECTIVE: To identify the clinical characteristics and/or injection parameters that predict a favorable response to botulinum toxin type A in patients with episodic and chronic migraine. BACKGROUND: There is emerging scientific and clinical evidence to support the utility of botulinum toxin type A (BoNT-A) in the prophylaxis of episodic and chronic migraine headache. However, the patient characteristics and injection strategies that predict a favorable treatment response are unknown. METHODS: We conducted a prospective, open-label study on 74 patients from our clinic receiving BoNT-A for episodic or chronic migraine. For all patients, migraine-related disability (Migraine Disability Assesment [MIDAS]), headache frequency, and average headache intensity were obtained at baseline and at 3 months post-BoNT-A. Information regarding demographic characteristics and injection parameters was also collected. RESULTS: Sixty-one patients met the study criteria and were available for 3-month follow-up. At the 3-month follow-up visit, the mean MIDAS scores of the 61 qualified study patients had decreased from 102 at baseline to 49 (52% decrease, P<.001). The mean number of headache days was reduced from 60 to 39 (P<.001), and the mean headache intensity decreased from 7.6 at baseline to 5.9 (P<.001). Frequency of migraine attacks, presence of analgesic overuse, total BoNT-A dose, and presence of underlying muscle tenderness were not predictive of treatment response. Age and duration of migraine were the only clinical factors significantly predictive of treatment response. Age likely was a predictor only as a consequence of duration of illness as subjects with migraine duration greater than 30 years were significantly less likely to respond to treatment with BoNT-A. CONCLUSION: BoNT-A may be effective in decreasing headache frequency, headache intensity, and headache-related disability in episodic and chronic migraine patients. Duration of illness emerged as a predictor of treatment response. Randomized controlled studies should evaluate headache-related disability as a primary endpoint in patients with episodic and chronic headache.

Migraine in special populations. Treatment strategies for children and adolescents, pregnant women, and the elderly.

Although migraine is a common occurrence in children and adolescents, its diagnosis and treatment present unique challenges. Migraine management in pregnant women and the elderly can also be difficult and requires selection of appropriate and safe medications for patients in these special circumstances. In this article, Drs Gladstone, Eross, and Dodick provide pearls for both abortive and prophylactic treatments for migraine in these populations.

Clinical, anatomical, and physiologic relationship between sleep and headache.

The intimate relationship between sleep and headache has been recognized for centuries, yet the relationship remains clinically and nosologically complex. Headaches associated with nocturnal sleep have often been perceived as either the cause or result of disrupted sleep. An understanding of the anatomy and physiology of both conditions allows for a clearer understanding of this complex relationship and a more rational clinical and therapeutic approach. Recent biochemical and functional imaging studies in patients with primary headache disorders has lead to the identification of potential central generators which are also important for the regulation of normal sleep architecture. Medical conditions (e.g. obstructive sleep apnea, depression) that may disrupt sleep and lead to nocturnal or morning headache can often be identified on clinical evaluation or by polysomnography. In contrast, primary headache disorders which often occur during nocturnal sleep or upon awakening, such as migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache, can readily be diagnosed through clinical evaluation and managed with appropriate medication. These disorders, when not associated with co-morbid mood disorders or medications/analgesics overuse, seldom lead to significant sleep disruption. Identifying and classifying the specific headache disorder in patients with both headache and sleep disturbances can facilitate an appropriate diagnostic evaluation. Patients with poorly defined nocturnal or awakening headaches should undergo polysomnography to exclude a treatable sleep disturbance, especially in the absence of an underlying psychological disorder or analgesic overuse syndrome. In patients with a well defined primary headache disorder, unless there are compelling historical or examination findings suggestive of a primary sleep disturbance, a formal sleep evaluation is seldom necessary.

Chronic daily headache: a rational approach to a challenging problem.

Chronic daily headache (CDH) is a significant public health problem with 3 to 5% of the population worldwide experiencing daily or near-daily headaches. Patients with CDH can be particularly challenging, and clinicians require a systematic approach to help guide investigations and management. The revised 2004 International Headache Society Classification Criteria introduces formalized criteria for several CDH disorders including chronic migraine and medication overuse headache as well as new daily persistent headache, hemicrania continua, hypnic headache, and SUNCT syndrome. Medication overuse is common in patients with CDH who present to physicians. Familiarity and comfort with drug-withdrawal and detoxification strategies is therefore essential. Patients with chronic migraine and chronic cluster experience significant disability and diminished quality of life. The ability to manage these patients effectively is a rewarding clinical experience.