Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered® Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan.

OBJECTIVE: To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA® Xsail® (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults. BACKGROUND: AVP-825 is a delivery system that uses a patient's own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan powder administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for efficacy, safety, and tolerability endpoints. DESIGN/METHODS: COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sustained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occurring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs). RESULTS: A total of 185 patients completed both treatment periods, yielding 1,531 migraine attacks which were treated and assessed (765 AVP-825, 766 oral sumatriptan). Treatment with AVP-825 provided greater reduction in migraine pain intensity which was statistically significant vs oral sumatriptan in the first 30 minutes postdose regardless of whether attacks were treated when pain was mild (least squares mean SPID-30 = 3.90 vs 0.24, P = .0013) or moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07, P = .0002). At every time point from 15 to 90 minutes postdose, the proportion of attacks achieving total migraine freedom was greater and statistically significant after treatment with AVP-825 vs 100 mg oral sumatriptan. AVP-825 treatment resulted in greater odds of achieving pain freedom (odds ratio, OR = 1.29, P < .01) and meaningful pain relief (OR = 1.32, P < .0001), which were also statistically significant compared with oral sumatriptan. In addition, a greater proportion of attacks treated with AVP-825 vs oral sumatriptan was associated with sustained pain freedom, achieving statistical significance when assessed from 1 h postdose through 24 hours postdose (33.3% vs 27.9%; P < .05) and through 48 hours postdose (32.7% vs 27.4%; P < .05). For patients who treated multiple migraine attacks in both treatment periods, a greater proportion had consistent pain relief and pain freedom following treatment with AVP-825 compared to oral sumatriptan across multiple attacks, a difference that achieved statistical significance at 30 minutes postdose. Local TEAEs of abnormal taste and nasal discomfort were more common following AVP-825 treatment. Of the patients experiencing either of these TEAEs, about 90% described the intensity as mild, and only one discontinued treatment because of either of these two TEAEs. CONCLUSIONS: These results from the COMPASS study further demonstrate that treatment with AVP-825 provides earlier onset and more consistent across-episode improvement of pain and migraine-associated symptoms compared with oral sumatriptan, highlighting the clinical advantages of this newly approved intranasal delivery system for low-dose sumatriptan powder.

LASH: A Review of the Current Literature.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and explain our current understanding of a very rare disorder, long-lasting autonomic symptoms with associated hemicranias (LASH). RECENT FINDINGS: At present, there are four known cases in the literature of LASH. Its characteristics and reported response to indomethacin link it most closely to the trigeminal autonomic cephalalgias (TACs). Its pathophysiology and epidemiology remain unclear. Variance in the pain and autonomic symptom relationship in the existing TAC literature along with the reports of TAC sine headache suggests that LASH may represent a far end of the spectrum of TACs, with most similarities to paroxysmal hemicrania (PH) and hemicrania continua (HC).

The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis.

BACKGROUND: OnabotulinumtoxinA has been shown to reduce headache-days among patients with chronic migraine (CM). The objective of this analysis was to determine whether onabotulinumtoxinA has an impact on headache-day severity in patients with CM among those patients who were deemed non-responders based on reduction in the frequency of headache days alone. METHODS: Data from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trial program (a 24-week, 2-treatment cycle, double-blind, randomized, placebo-controlled, parallel-group phase, followed by a 32-week, 3-treatment cycle, open-label phase) were pooled for analysis. Patients kept a daily diary to record headache severity on a 4-point scale (from none to severe), and a 6-domain Headache Impact Test (HIT-6) was used to determine the clinical impact of headaches. Analysis was undertaken to assess whether the subset of patients that were headache-day frequency non-responders at week 24 (patients with <50% reduction in headache-day frequency) experienced a reduction in headache severity whilst receiving onabotulinumtoxinA. RESULTS: For headache-day frequency non-responders, significant reductions in the number of severe headache days, average daily headache severity, pooled percentage of severe headache days and headache severity score were observed at week 24 for patients who had received onabotulinumtoxinA compared with those who had received placebo. The between-group differences were reduced and non-significant at week 56. Similarly, headache-day frequency non-responders receiving onabotulinumtoxinA were found to have an improvement in the clinical impact of headaches using results from the HIT-6. CONCLUSIONS: These results suggest that even those patients with CM who are deemed non-responders based on analysis of headache frequency alone experience clinically meaningful relief from headache intensity following treatment with onabotulinumtoxinA.

The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache.

The sphenopalatine ganglion (SPG) has attracted the interest of practitioners treating head and face pain for over a century because of its anatomical connections and role in the trigemino-autonomic reflex. In this review, we discuss the anatomy of the SPG, as well as what is known about its role in the pathophysiology of headache disorders, including cluster headache and migraine. We then address various therapies that target the SPG, including intranasal medication delivery, new SPG blocking catheter devices, neurostimulation, chemical neurolysis, and ablation procedures.

Occipital nerve block for the short-term preventive treatment of migraine: A randomized, double-blinded, placebo-controlled study.

BACKGROUND: Occipital nerve (ON) injections with corticosteroids and/or local anesthetics have been employed for the acute and preventive treatment of migraine for decades. However, to date there is no randomized, placebo-controlled evidence to support the use of occipital nerve block (ONB) for the prevention of migraine. OBJECTIVE: The objective of this article is to determine the efficacy of ONB with local anesthetic and corticosteroid for the preventive treatment of migraine. PARTICIPANTS AND METHODS: Patients between 18 and 75 years old with ICHD-II-defined episodic (> 1 attack per week) or chronic migraine (modified ICHD-II as patients with > 10 days with consumption of acute medications were permitted into the study) were randomized to receive either 2.5 ml 0.5% bupivacaine plus 0.5 ml (20 mg) methylprednisolone over the ipsilateral (unilateral headache) or bilateral (bilateral headache) ON or 2.75 ml normal saline plus 0.25 ml 1% lidocaine without epinephrine (placebo). Patients completed a one-month headache diary prior to and after the double-blind injection. The primary outcome measure was defined as a 50% or greater reduction in the frequency of days with moderate or severe migraine headache in the four-week post-injection compared to the four-week pre-injection baseline period. RESULTS: Thirty-four patients received active and 35 patients received placebo treatment. Because of missing data, the full analysis of 33 patients in the active and 30 patients in the placebo group was analyzed for efficacy. In the active and placebo groups respectively, the mean frequency of at least moderate (mean 9.8 versus 9.5) and severe (3.6 versus 4.3) migraine days and acute medication days (7.9 versus 10.0) were not substantially different at baseline. The percentage of patients with at least a 50% reduction in the frequency of moderate or severe headache days was 30% for both groups (10/30 vs nine of 30, Δ 0.00, 95% CI -0.22 to 0.23). CONCLUSIONS: Greater ONB does not reduce the frequency of moderate to severe migraine days in patients with episodic or chronic migraine compared to placebo.The study was registered with ClinicalTrial.gov (NCT00915473).

A Practical Approach to the Diagnosis of Spontaneous Intracranial Hypotension.

Spontaneous intracranial hypotension can be difficult to diagnose as there are a number of tests available and knowing how to appropriately choose amongst them is not always easy. In this article, we will review the available diagnostic options and provide a practical approach to the workup of a patient with suspected intracranial hypotension.

Identifying the factors underlying discontinuation of triptans.

OBJECTIVE: To identify factors associated with triptan discontinuation among migraine patients. BACKGROUND: It is unclear why many migraine patients who are prescribed triptans discontinue this treatment. This study investigated correlates of triptan discontinuation with a focus on potentially modifiable factors to improve compliance. METHODS: This multicenter cross-sectional survey (n = 276) was performed at US tertiary care headache clinics. Headache fellows who were members of the American Headache Society Headache Fellows Research Consortium recruited episodic and chronic migraine patients who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years). Univariate analyses were first completed to compare current triptan users to past users for: migraine characteristics, other migraine treatments, triptan education, triptan efficacy, triptan side effects, type of prescribing provider, Migraine Disability Assessment (MIDAS) scores and Beck Depression Inventory (BDI) scores. Then, a multivariable logistic regression model was selected from all possible combinations of predictor variables to determine the factors that best correlated with triptan discontinuation. RESULTS: Compared with those still using triptans (n = 207), those who had discontinued use (n = 69) had higher rates of medication overuse (30 vs. 18%, P = .04) and were more likely to have ever used opioids for migraine treatment (57 vs. 38%, P = .006) as well as higher MIDAS (mean 63 vs. 37, P = .001) and BDI scores (mean 10.4 vs. 7.4, P = .009). Compared with discontinued users, current triptan users were more likely to have had their triptan prescribed by a specialist (neurologist, headache specialist, or pain specialist) (74 vs. 54%, P = .002) and were more likely to report headache resolution (53 vs. 14%, P < .001) or a reduction in pain intensity (71 vs. 28%, P < .001) most of the time from their triptan. On a 1-5 scale (1 = disagree, 5 = agree), triptan users felt they had more: control over their migraine attacks (2.9 vs. 2.1), confidence in their prescribing provider (4.5 vs. 4.0), and were more educated about triptan use (4.2 vs. 3.7) compared with triptan discontinuers (P < .001 for all comparisons). Although both current and prior users reported similar rates of side effects (48 vs. 43%, P = .44), of those who discontinued use, the main reasons were for lack of effect (44%) and side effects (29%). Our multivariable modeling revealed that the strongest correlate of triptan discontinuation was lack of efficacy (odds ratio = 17, 95% confidence interval [8.8, 33.0]). Other factors associated with discontinuation included MIDAS > 24 (2.6, [1.5, 4.6]), BDI >4 (2.5, [1.4, 4.5]), and a history of ever using opioids for migraine therapy (2.2, [1.3, 3.8]). Having a triptan prescribed by a specialist and using at least 1 other abortive medication with the triptan were associated with a decreased likelihood of triptan discontinuation (0.41, [0.2-0.7] and 0.44 [0.3, 0.8], respectively). CONCLUSIONS: As expected, discontinuation was most correlated with lack of efficacy, but other important factors associated with those who had discontinued use included greater migraine-related disability, depression, and the use of opioids for migraine attacks. Compared with patients who had discontinued triptans, current triptan users felt more: educated about their triptan, control over their migraine attacks, and confidence in their prescribing provider. Current triptan users had their triptan prescribed by a specialist and used other abortive medications with their triptan more often compared with patients who had discontinued triptans. Given the cross-sectional nature of this study, we cannot determine if these factors contributed to triptan discontinuation or reflect the impact of such discontinuation. Interventions that address modifiable risk factors for triptan discontinuation may decrease the likelihood of triptan discontinuation and thus improve overall migraine control. Because lack of efficacy was most strongly associated with triptan discontinuation, future research should determine why triptans are effective for some patients but not others.

Primary exertional headache: updates in the literature.

Primary exertional headache (PEH) has been recognized by the International Headache Society as a primary headache diagnosis since 1994. It is an uncommon, self-limited, and short-lasting disorder that is precipitated by exertion and is frequently comorbid with migraine. PEH shares a number of features with other headache disorders, including thunderclap headache, primary cough headache, and headache associated with sexual activity. Upon its initial occurrence, PEH requires a thorough neurologic evaluation and imaging studies to help eliminate possible underlying secondary causes, including subarachnoid hemorrhage and sentinel bleed. Although PEH is incompletely understood with regard to its epidemiology and pathophysiology, it is generally considered to be a benign disorder that is self-limited and responsive to trigger avoidance and indomethacin.

Cluster headache: diagnosis and treatment.

Cluster headache is a rare yet exquisitely painful primary headache disorder occurring in either episodic or chronic patterns. The unique feature of cluster headache is the distinctive circadian and circannual periodicity in the episodic forms. The attacks are stereotypic--they are of extreme intensity and short duration, occur unilaterally, and are associated with robust signs and symptoms of autonomic dysfunction. Although the pathophysiology of cluster headache remains to be fully understood, there have been a number of recent seminal observations. To exclude structural mimics, patients presenting with symptoms suggestive of cluster headache warrant at least a brain magnetic resonance imaging (MRI) scan in their work-up. The medical treatment of cluster headache includes acute, transitional, and maintenance prophylaxis. Agents used for acute therapy include inhalation of oxygen, triptans, such as sumatriptan, and dihydroergotamine. Transitional prophylaxis refers to the short-term use of fast-acting agents. This typically involves either corticosteroids or an occipital nerve block. The mainstay of prophylactic therapy is verapamil. Yet, other medications, including lithium, divalproex sodium, topiramate, methysergide, gabapentin, and even indomethacin, may be useful when the headache fails to respond to verapamil. For medically refractory patients, surgical interventions, occipital nerve stimulation, and deep brain stimulation remain an option. As the sophistication of functional neuroimaging increases, better insight into the pathophysiological mechanisms that underlie cluster headache is expected.

Establishing a diagnosis of benign paroxysmal positional vertigo through the dix-hallpike and side-lying maneuvers: a critically appraised topic.

BACKGROUND: Many patients consult neurologists because of vertigo. Benign paroxysmal positional vertigo (BBPV) is one of the most common types of vertigo. Although the clinical presentation of this common condition is straightforward, the diagnosis and diagnostic maneuvers can be challenging. OBJECTIVES: How useful is the Dix-Hallpike test in establishing the diagnosis of BPPV? How useful is an alternative positional test, such as the side-lying maneuver, in the diagnosis of BPPV? METHODS: We addressed the question through development of a structured critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content expert in the field of otolaryngology. Participants started with a clinical scenario and structured questions, devised search strategies, located and compiled the best evidence, performed critical appraisals, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. RESULTS: A single study comparing the Dix-Hallpike and side-lying tests was identified. For the Dix-Hallpike test, the estimated sensitivity was 79% [95% confidence interval (CI) 65-94], specificity was 75% (33-100), positive likelihood ratio (LR) was 3.17 (95% CI 0.58-17.50), negative LR was 0.28 (95% CI 0.11-0.69). For the side-lying test, the estimated sensitivity was 90% (95% CI 79-100), specificity was 75% (33-100), positive LR was 3.59 (95% CI 0.65-19.67), negative LR was 0.14 (95% CI 0.04-0.46). The study employed very weak methodology, and therefore the results had limited validity. CONCLUSIONS: The Dix-Hallpike test is the standard from which the diagnosis of posterior semicircular canal BPPV is made. Hence evaluations of its diagnostic test properties and utility are challenging. For patients unable to move into the Dix-Hallpike test positions, alternative tests such as the side-lying test can be attempted. These modifications, however, are rarely necessary.

Sex and Gender Differences in Migraine-Evaluating Knowledge Gaps.

Migraine is a common chronic neurological disease that disproportionately affects women. Migraine has significant negative effects on physical, emotional, and social aspects of health, and can be costly for patients, employers, and society as a whole. Growing evidence supports the roles of sex and gender in migraine risk, pathophysiology, presentation, diagnosis, treatment, and management. However, sex and gender differences in migraine have received limited attention, which can impede advancements in migraine detection, treatment, care, and education. The Society for Women's Health Research convened an interdisciplinary expert panel of researchers, clinicians, and advocates for a roundtable meeting to review the current research on sex and gender differences in migraine. This review summarizes discussions from the roundtable and prioritizes areas of need that warrant further attention in migraine research, care, and education. Examining sex and gender differences in migraine and addressing knowledge gaps will decrease the health and economic burden of migraine for both women and men.

Caffeine for the prevention and treatment of postdural puncture headache: debunking the myth.

OBJECTIVE: Is caffeine effective in preventing and treating postdural puncture headache (PDPH)? METHODS: The question was addressed with a structured evidence-based clinical neurologic practice review via videoconferencing between 3 academic institutions. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarians, and clinical content experts. A critically appraised topic format was employed, starting with a clinical scenario and structured question. Participant groups at each of the 3 institutions independently devised search strategies, located and compiled the best evidence, performed critical appraisals, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. RESULTS: Three directly relevant randomized controlled trial articles were selected as the best available evidence for the clinical questions. Two investigated caffeine [oral and intravenous (IV)] as PDPH prophylaxis and 1 (oral) as PDPH treatment. One additional quasirandomized trial (IV) and 1 open-label trial (IV) of caffeine for PDPH treatment were located by reviewing bibliographies. Articles describing the pharmacological basis for caffeine therapy were also identified. No valid pharmacological rationale for caffeine as an antinociceptive agent for PDPH exists. The clinical trials are few in number, small in sample size, methodologically weak or flawed, and either demonstrate no effectiveness, contradictory and conflicting results, or invalid answers. CONCLUSIONS: The wide endorsement for caffeine to prevent and treat PDPH found in textbooks and review articles appears to be unwarranted and insufficiently supported by the available pharmacological and clinical evidence.

ACE and ARB Agents in the Prophylactic Therapy of Migraine-How Effective Are They?

OPINION STATEMENT: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are antihypertensive agents that can be considered for migraine preventative therapy. Although the exact mechanisms by which ACE inhibitors and ARBs may work for migraine prophylaxis are unknown, there are several plausible hypotheses as to why modulating the activity of the renin angiotensin system could result in migraine prevention. Clinical trials of ACE inhibitors and ARBs provide evidence that they are effective and generally well tolerated when used for migraine prophylaxis. Based upon biologic plausibility, the quality of evidence for efficacy from clinical trials, and recommendations in published guidelines, we consider ACE inhibitors and ARBs as second- or third-line options for migraine prophylaxis.

Sensitivity of MRI of the spine compared with CT myelography in orthostatic headache with CSF leak.

OBJECTIVE: To investigate the sensitivity of MRI of the spine compared with CT myelography (CTM) in detecting CSF leaks. METHODS: Between July 1998 and October 2010, 12 patients with orthostatic headache and a CTM-confirmed spinal CSF leak underwent an MRI of the spine with and without contrast. Using CTM as the gold standard, we retrospectively investigated the sensitivity of spinal MRI in detecting a CSF leak. RESULTS: Eleven of 12 patients with a CSF leak documented by CTM also had extradural fluid collections on spinal MRI (sensitivity 91.7%). Six patients with extradural fluid collections on spinal MRI also had spinal dural enhancement. CONCLUSION: When compared with the gold standard of CTM, MRI of the spine appears to be a sensitive and less invasive imaging modality for detecting a spinal CSF leak, suggesting that MRI of the spine should be the imaging modality of first choice for the detection of spinal CSF leaks.

Risk of development of medication overuse headache with nonsteroidal anti-inflammatory drug therapy for migraine: a critically appraised topic.

BACKGROUND: The development of medication overuse headache (MOH) is associated with frequent use of analgesics, especially opiates, for treatment of primary headache disorders, particularly migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat migraine. OBJECTIVE: To critically evaluate evidence estimating the risk of MOH associated with NSAID therapy in patients with migraine. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and headache neurology content experts. RESULTS: The 1-year incidence of MOH was 2.5%. In patients with low (0 to 4 d monthly) to moderate (5 to 9 d monthly) baseline headache frequency, NSAIDs were not associated with progression to MOH and may be protective (odds ratio=0.31; 95% confidence interval, 0.27-0.34). However, in patients with a high baseline headache frequency (10 to 14 d monthly), NSAIDs are associated with progression to MOH (odds ratio=1.93; 95% confidence interval, 1.82-2.06). CONCLUSIONS: Acute NSAID therapy is associated with progression to MOH in migraineurs with a high baseline migraine frequency but may be protective in patients with low baseline headache frequency. However, a causal role for NSAIDs in progression from episodic to chronic headache has not been established.