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Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment

Ashina, Hakan; Newman, Lawrence; Ashina, Sait
Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.
PMID: 28856479
ISSN: 1590-3478
CID: 2679742

Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines

Cohen, Joshua M; Dodick, David W; Yang, Ronghua; Newman, Lawrence C; Li, Thomas; Aycardi, Ernesto; Bigal, Marcelo E
BACKGROUND: Fremanezumab (formerly TEV-48125) is a monoclonal antibody directed against calcitonin-gene-related peptide (CGRP), a validated target for migraine preventive therapy. In two previous phase 2 studies, fremanezumab administered once every 28 days for 12 weeks was found to be effective and safe as a preventive treatment for patients suffering from episodic migraine (EM) and chronic migraine (CM). OBJECTIVE: To evaluate the efficacy and safety of fremanezumab as an add-on preventive therapy in individuals with EM and CM who are on stable doses of preventive migraine medications. METHODS: Two randomized placebo-controlled studies tested once-monthly subcutaneous injections of various dosing regimens of fremanezumab versus placebo in EM and CM. Headache information was captured daily using an electronic headache diary. For these post hoc analyses, data were pooled from patients who were on stable preventive medications and taking fremanezumab doses of 225 mg or 675/225 mg, or placebo. RESULTS: The sample consisted of 133 patients, (67 fremanezumab and 66 placebo). Total reduction in migraine days for the duration of the study was 12.4 for fremanezumab and 7.4 for placebo (P = .0321). There were also decreases in moderate/severe headache days (12.5 vs 7.1, P = .0058), and days using acute medication for headaches relative to placebo (11.6 vs 7.5, P = .0414). Treatment emergent adverse events were generally mild and transient, and no serious adverse events were considered to be treatment-related by the site investigators. CONCLUSIONS: The findings from these post hoc analyses suggest that fremanezumab is a safe and effective add-on treatment for migraine patients being concomitantly treated with other migraine preventive medications. Trials are registered at NCT02025556 and NCT02021773.
PMID: 28862758
ISSN: 1526-4610
CID: 2679592

Update on New Daily Persistent Headache

Nierenburg, Hida; Newman, Lawrence C
OPINION STATEMENT: New daily persistent headache (NDPH) is an uncommon and under-recognized primary headache disorder. Clinically, NDPH may resemble migraine or tension-type headache. Unlike migraine or tension-type headaches, however, a distinguishing feature of NDPH is that the majority of patients with NDPH can pinpoint the exact date of onset of symptoms. While cases can arise de novo, in multiple reports, a viral illness precedes the onset of headache. NDPH has two temporal profiles: a self-limited form that resolves spontaneously without treatment and a refractory, persistent form in which headaches continue unabated for years. Diagnosis is predicated on first eliminating secondary mimics via diagnostic imaging and hematological studies. Lumbar puncture should be considered in patients who are refractory to treatment to search for alterations in CSF pressure or for an infectious process. There have been no randomized clinical trials utilizing acute or preventive therapies for NDPH. In clinical practice, treatment is aimed at matching the predominant headache phenotype; nonetheless, most therapies are generally ineffective or only partially effective. Not surprisingly, medication overuse is very common among patients with this disorder and should be identified, although in most patients, eliminating medication overuse does not alter the course of the illness. There have been reports of successful treatment combining doxycycline 100 mg and montelukast 10 mg, dosed BID for 3 months. Anecdotally, in our practice, this combination has occasionally provided good results. Onabotulinum toxin injections are currently under investigation and may provide a potential new effective treatment regimen.
PMID: 27080086
ISSN: 1092-8480
CID: 2332972

Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study

Bigal, Marcelo E; Dodick, David W; Rapoport, Alan M; Silberstein, Stephen D; Ma, Yuju; Yang, Ronghua; Loupe, Pippa S; Burstein, Rami; Newman, Lawrence C; Lipton, Richard B
BACKGROUND: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at, number NCT02025556. FINDINGS: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively. INTERPRETATION: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. FUNDING: Teva Pharmaceuticals.
PMID: 26432182
ISSN: 1474-4465
CID: 2332982

Sumatriptan Iontophoretic Transdermal System Reduces Treatment-Emergent Nausea and Is Effective in Patients With and Without Nausea at Baseline - Results From a Randomized Controlled Trial

Bigal, Marcelo E; Lipton, Richard B; Newman, Lawrence C; Pierce, Mark W; Silberstein, Stephen D
OBJECTIVES: To test the hypothesis that sumatriptan iontophoretic transdermal system (TDS) is associated with lower rates of treatment-emergent nausea (TEN) relative to placebo, as well as to compare the efficacy of sumatriptan TDS in migraineurs with or without nausea at baseline. METHODS: Participants of a double-blind, randomized, parallel-group, single-attack, placebo-controlled study conducted at 38 sites in the United States were analyzed. Participants who treated their migraine attacks while nausea-free were identified. The primary endpoint was TEN over 24 hours post-treatment contrasting both treatment groups and it was assessed by regression analyses using generalized estimating equations. Secondary endpoint was headache response as a function of presence of nausea, assessed by generalized linear model. RESULTS: A total of 130 participants free of nausea at baseline were treated with sumatriptan TDS, while 109 participants free of nausea at baseline were treated with placebo TDS. The occurrence of TEN over 24 hours post-treatment was significantly lower with the sumatriptan TDS than with placebo (P = .0011). These differences were statistically significant at 1 hour (13.8% vs 9.2%, P < .01), 2 hours (13.8% vs 4.6% P < .001) and 3 hours (13.8% vs 8.5% P < .01). The efficacy of sumatriptan TDS was similar regardless of the presence or absence of nausea at baseline for all clinical parameters. CONCLUSION: Sumatriptan TDS is not associated with the emergence of nausea in migraineurs without nausea. It is equally effective in participants with or without nausea at the time of treatment.
PMID: 26178815
ISSN: 1526-4610
CID: 2333002

Trigeminal Autonomic Cephalalgias

Newman, Lawrence C
PURPOSE OF REVIEW: This article reviews the clinical features of and treatment options for the trigeminal autonomic cephalalgias (TACs). RECENT FINDINGS: The TACs are a group of primary headache disorders characterized by short-lasting episodes of severe unilateral headaches that are associated with ipsilateral cranial autonomic symptoms. The best known and most commonly seen TAC in clinical practice is cluster headache. The other syndromes within this group include paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks. Although these disorders share a similar phenotype, they are distinguished by differences in attack frequency and duration. Recognition of these clinical differences is paramount because treatment options vary; paroxysmal hemicrania and hemicrania continua demonstrate an absolute response to treatment with indomethacin, while the other syndromes respond to other agents. SUMMARY: Although much less common than other headache disorders seen in clinical practice, recognition of the TACs is especially important as they are among the most severe and disabling syndromes in headache medicine.
PMID: 26252590
ISSN: 1538-6899
CID: 2332992

Menstrual migraine: treatment options

Newman, L C; Yugrakh, M S
More than half of women with migraine note an association of headache attacks and their menstrual cycles. Headaches associated with menses are often more severe and disabling than headaches that occur other times of the month. First-line therapies include acute agents used for migraine in general; however, for many women, these therapies provide incomplete relief. In these situations, treatment options include short-term perimenstrual prevention employing nonsteroidal anti-inflammatory medications, triptans, or hormone-containing preparations. Should these options not suffice, or if menstrual cycles are irregular, continuous prevention using hormonal therapies or standard anti-migraine prophylaxis should be considered.
PMID: 24867838
ISSN: 1590-3478
CID: 2333282

Why triptan treatment can fail: focus on gastrointestinal manifestations of migraine

Newman, Lawrence C
BACKGROUND: Results of randomized, double-blind, controlled studies establish the efficacy of triptans in the acute treatment of migraine, but triptan benefits demonstrated in clinical trials have not consistently been realized in clinical practice. This paper explores the contribution of gastrointestinal manifestations of migraine--namely nausea (with or without vomiting) and gastroparesis--to triptan treatment failure. SYNTHESIS: Migraine-related nausea and vomiting and migraine-associated gastroparesis appear to be prevalent and highly impactful and have been characterized as being among the greatest challenges affecting migraine care today. These gastrointestinal signs and symptoms have not been satisfactorily taken into account in the management of migraine, which is dominated by the use of oral therapies. Oral triptans are not the optimal therapy in the presence of migraine-related nausea because nausea predicts poor response to oral triptans and because nausea can cause patients to delay oral treatment, which can further compromise therapeutic efficacy. Oral triptans are not the optimal therapy in the presence of migraine-associated gastroparesis because these agents rely on gastric motility and gastrointestinal absorption and may be ineffective or slowly or inconsistently effective in the presence of gastroparesis. Health care providers need to work with their patients to address the still-all-too-frequent problem of treatment failure in migraine. First, health care providers need to have greater appreciation of the importance of nausea, vomiting, and gastroparesis as factors affecting migraine prognosis and treatment success. Second, health care providers need to systematically assess migraine patients for gastrointestinal signs and symptoms. Finally, patients and health care providers need to be willing to practice customized migraine care, in which patients tailor the treatment and formulation to the characteristics and context of the individual migraine episode.
PMID: 23721285
ISSN: 1526-4610
CID: 2333012

Migraine and vestibular symptoms--identifying clinical features that predict "vestibular migraine"

Cohen, Joshua M; Bigal, Marcelo E; Newman, Lawrence C
BACKGROUND: Migraine and symptoms that may suggest a vestibular disorder (referred to herein broadly as vestibular symptoms-VS) often co-exist. In part due to a lack of standardized diagnostic criteria, this relationship remains unknown to many physicians. OBJECTIVE: To determine common clinical features that may be associated with "vestibular migraine" (VM). METHODS: We retrospectively reviewed charts of patients diagnosed with VM at a headache center. In this group we recorded certain demographic and clinical features related to their disorder, including the most common triggers of the VS and the specific characteristics of the symptoms that suggested VM. RESULTS: Our sample consisted of 147 patients (68% women, mean age = 45 years, 39% with aura). Migraine onset preceded the onset of VS by a mean of 8 years. A total of 62 patients (42%) had gradual onset of VS, while in 48 (33%) symptoms began suddenly. The most commonly reported symptoms that led to the diagnosis of VM were: unsteadiness (134; 91%), balance disturbance (120; 82%), "light-headedness" (113; 77%), and vertigo (84; 57%). VS and headache occurred concomitantly in 48% of patients. A total of 67 (47%) patients had VS that were chronic from onset, 29 (21%) had episodic symptoms, and in 46 (32%) the VS had evolved from episodic to chronic (with an average duration of 7.04 years required for this evolution to occur). CONCLUSIONS: Vestibular migraine is a heterogeneous condition with varying symptomatology. As with migraine itself, symptomatic expression varies along a spectrum that extends from episodic to chronic. As the histories of many of the patients we evaluated would not meet current International Classification of Headache Disorders criteria, we suggest that new criteria which account for the heterogeneity and natural history of the disorder may be required to adequately diagnose and treat those who suffer from VM.
PMID: 21649658
ISSN: 1526-4610
CID: 2333022

Hemicrania continua: a second case in which the remitting form evolved from the chronic form [Case Report]

Yablon, Lisa A; Newman, Lawrence C
We report the case of a woman with a 15-year history of chronic hemicrania continua, which over time evolved to remitting hemicrania continua. This is the second reported case in the literature documenting this transition.
PMID: 21044282
ISSN: 1526-4610
CID: 2333032