Abstracts and Citations

Authors

  • Stephen H. Landy MD,

  • Robert G. Kaniecki MD,

  • Frederick R. Taylor MD


Headache and Stroke

Sacco S, Ornello R, Ripa P, Pistoia F, Carolei A. Migraine and hemorrhagic stroke: A meta-analysis. Stroke. 2013;44:3032-3038.

Background and Purpose: Several studies have assessed the possible increased risk of hemorrhagic stroke in migraineurs, drawing differing conclusions. No meta-analysis on the topic has been published to date.

Methods: Multiple electronic databases (MEDLINE, EMBASE, Science Citation Index, and the Cochrane Library) were systematically searched up to March 2013 for studies dealing with migraine and hemorrhagic stroke. We selected case control and cohort studies with a clear definition of the diagnostic criteria for migraine and hemorrhagic stroke using an adjusted model or a matching procedure that could control for potential confounders, and reporting effect estimates with 95% confidence intervals (CIs) or enough data to allow calculation of those numbers. Adjusted odds ratios and hazard ratios were used to estimate effect size.

Results: Of 11,264 records, we identified 8 studies (4 case control and 4 cohort studies) involving a total of 1600 hemorrhagic strokes, which were included in the meta-analysis. The overall pooled adjusted effect estimate of hemorrhagic stroke in subjects with any migraine versus control subjects was 1.48 (95% CI, 1.16–1.88; P = .002), with moderate statistical heterogeneity (I2 = 54.7%; P value for Q test = .031). The risk of hemorrhagic stroke in subjects with migraine with aura (1.62; 95% CI, 0.87-3.03; P = .129) was not significant. Compared with control subjects, the risk of hemorrhagic stroke was greater in females with any migraine (1.55; 95% CI, 1.16–2.07; P = .003) and in female migraineurs aged less than 45 years (1.57; 95% CI, 1.10–2.24; P = .012).

Conclusions: Available studies suggest that subjects with migraine have an increased risk of hemorrhagic stroke. Further studies are needed to address the hemorrhagic stroke risk according to migraine type, age, sex, and hemorrhagic stroke type.

Comments: We have previously commented on literature that migraine may be a risk factor for hemorrhagic stroke in women,[1, 2] and this is the first systematic review and meta-analysis evaluating the association. Hemorrhagic stroke in this research included both intracerebral hemorrhage and subarachnoid hemorrhage, and suggests that migraineurs have a 50% increased risk compared with non-migraineurs. The authors discuss several possible mechanisms, including endothelial dysfunction, comorbid vascular risk factors, chronic use of non-steroidal anti-inflammatory drugs and migraine mimics. An accompanying editorial states, “The meta-analysis by Sacco and colleagues add important data to the evidence that migraine is a marker for increased risk of stroke, including all major subtypes.”[3]

—Stephen H. Landy, MD

As I review these articles, the Winter Olympics are well underway and most of the eastern and southern USA is being slammed with winter weather much more extreme than that being streamed to us from Sochi. My contribution should stretch over several days, and my comments perhaps may make the most sense if read in the order written.

Although it has been 4 years since the last Winter Games, it has been nearly 3 years since we had the opportunity to review work on the relationships between migraine and stroke. The results of this meta-analysis should come as no surprise to those who have followed this topic. Although bland infarction and hemorrhagic stroke have several different risk factors, many are shared – and it appears migraine can now be confidently added to that list. As was true for bland infarction, the risk for hemorrhagic stroke appeared to be greatest among women, particularly those younger than 45 years of age. Unlike bland infarction, the risk does not seem to heighten in the presence of aura. I am not certain that this practically affects management in any way, but identification of the basis for the association may indeed teach us something important about migraine that might potentially impact patient care. I give this bronze medal for design. By the way, who poked Bob Costas in the eye?

—Robert G. Kaniecki, MD

Since at least the abstract coeditors appear agreed that migraine is a risk factor for stroke, has the time come for headache specialists to take responsibility for stroke risk management in their patients? Clearly, I think the time has come and past for participation in both primary and secondary management of risks. Regarding primary drug prevention, where does baby aspirin now fall into this schema? Daily, 3 days a week, only as secondary prevention? Perhaps the answer is that we need further stratification of risk by studies. Is the same true or even more necessary for complementary therapies, ie, fish oils and vitamin D? I suggest we make this a call to action for our patients, so if it's more studies, let's get to it.

—Frederick R. Taylor, MD

Katz BS, Fugate JE, Ameriso SF, Pujol-Lereis VA, Mandrekar J, Flemming KD, Kallmes DF, Rabinstein AA. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2014;71:68-73.

Importance: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches and evidence of vasoconstriction with subsequent resolution. The clinical course of RCVS is traditionally considered monophasic and benign. However, recurrent episodes of focal neurological symptoms have been described after initial presentation.

Objective: To define the frequency, timing, and consequences of clinical worsening in patients with diagnosis of RCVS.

Design, Setting, and Participants: Retrospective observational study of consecutive patients with RCVS at 2 referral institutions for neurological disease.

Main Outcome and Measure: Clinical worsening after diagnosis of RCVS. We defined clinical worsening as new permanent or transient neurological deficits (compared with presenting signs and symptoms) or new onset of seizures. We performed a logistic regression analysis to assess associations between patient characteristics and clinical worsening. Functional outcome was assessed at 1-3 months using the modified Rankin score.

Results: We identified 59 patients (median age, 47 years; interquartile range, 32-54 years) with RCVS. Twenty patients (34%) experienced clinical worsening after a median of 2.5 days (range, several hours to 14 days). Eight of the 20 patients who worsened had permanent deficits, including 4 who died. We did not find an association between age, sex, smoking, migraine, acute or chronic hypertension, peripartum state, or use of serotonergic drugs with clinical worsening. Clinical worsening was associated with radiological infarction (P = .001) and worse functional outcome (P < .004). Functional outcome was favorable (modified Rankin score 0-2) in 51 patients (86.4%).

Conclusions and Relevance: Clinical worsening after diagnosis is common in patients with RCVS. Thus, RCVS is self-limited but not strictly monophasic. Most patients have a very favorable outcome, but clinical worsening may result in permanent deficits.

Comments: We have previously reported that “[p]atients with reversible cerebral vasoconstriction syndromes have a unique set of clinical imaging features with no significant differences between subjects.”[4, 5] This research suggests that clinical worsening after initial diagnosis occurs in approximately one third of patients, “Thus RCVS is self-limited but not strictly monophasic. The understanding that clinical worsening is common in RCVS is important so that if it occurs, clinicians do not unnecessarily revisit the diagnosis and pursue further unnecessary and invasive tests or therapies.”

—Stephen H. Landy, MD

I am not certain I understand the premise for this study or the definition of “monophasic” used by the authors. Reversible cerebral vasoconstriction syndrome (RCVS) manifests in a variety of ways, with a common presentation involving recurrent thunderclap headaches spread over the course of days or weeks. There may be an assortment of clinical findings, including stroke, and it is incredibly common for patients to describe fluctuating or intermittent symptoms and fluctuating or intermittent exam findings over that course of time. I would contend that the condition only may be termed “monophasic” if the phase included the entire period of time when the patient was either symptomatic or when cerebral vasoconstriction could be demonstrated. Since this almost universally extends beyond a period of 2.5 days, it is entirely predictable that some patients should exhibit clinical worsening over a median of 2.5 days (range several hours to 14 days). In fact, I am only surprised that only 34% exhibited clinical deterioration over this span. I also disagree with SHL in that such information helps clinicians avoid unnecessary testing when the deterioration is noted. Such patients are still likely to receive repeat neuroimaging studies to distinguish between ischemic and hemorrhagic events, and to perhaps best predict prognosis, which is clearly worse in the presence of identifiable radiological infarction. If I did not know better, I would diagnose Bob Costas with conjunctival RCVS. Has no one in Russia access to Visine for crying out loud?

—Robert G. Kaniecki, MD

I find the value in this paper in the following statement, “We did not find an association between age, sex, smoking, migraine, acute or chronic hypertension, peripartum state, or use of serotonergic drugs with clinical worsening” That is very reassuring, but I have concerns about external validity given only 59 patients and small subgroups. For instance, the 59 patients included only 7 male subjects, so are these statements truly applicable to men especially concerning smoking, hypertension, and serotonergic drugs. In addition, reportedly there were only 16 migraine subjects with 9 without worsening and 7 with worsening. Reassuring perhaps, but numbers are too low to be convincing. As for colleague comments, I find SHL's imaging comment “gutsy, bold and in a future health care environment probably cost effective” and RGK's “practical, expected and in the current American health care environment malpractice cost effective.”

—Frederick R. Taylor, MD

Trigeminal Neuralgia

Desouza DD, Hodaie M, Davis KD. Abnormal trigeminal nerve microstructure and brain white matter in idiopathic trigeminal neuralgia. Pain. 2014;155:37-44.

Idiopathic trigeminal neuralgia (TN) is classically associated with neurovascular compression (NVC) of the trigeminal nerve at the root entry zone (REZ), but NVC-induced structural alterations are not always apparent on conventional imaging. Previous studies report lower fractional anisotropy (FA) in the affected trigeminal nerves of TN patients using diffusion tensor imaging (DTI). However, it is not known if TN patients have trigeminal nerve abnormalities of mean, radial, or axial diffusivity (MD, RD, AD – metrics linked to neuroinflammation and edema) or brain white matter (WM) abnormalities. DTI scans in 18 right-sided TN patients and 18 healthy controls were retrospectively analyzed to extract FA, RD, AD, and MD from the trigeminal nerve REZ, and Tract-Based Spatial Statistics (TBSS) was used to assess brain WM. In patients, the affected trigeminal nerve had lower FA, and higher RD, AD, and MD was found bilaterally compared with controls. Group TBSS (P < .05, corrected) showed that patients had lower FA and increased RD, MD, and AD in brain WM connecting areas involved in the sensory and cognitive-affective dimensions of pain, attention, and motor functions, including the corpus callosum, cingulum, posterior corona radiata, and superior longitudinal fasciculus. These data indicate that TN patients have abnormal tissue microstructure in their affected trigeminal nerves, and as a possible consequence WM microstructural alterations in the brain. These findings suggest that trigeminal nerve structural abnormalities occur in TN, even if not apparent on gross imaging. Furthermore, MD and RD findings suggest that neuroinflammation and edema may contribute to TN pathophysiology.

Comments: This is the first study demonstrating that patients with classical trigeminal neuralgia (TN) have white matter (WM) abnormalities not only involving the trigeminal nerves but also in the brain. The most prominent WM brain abnormalities were found in the corpus callosum, cingulum, posterior corona radiata, and superior longitudinal fasciculus, all of which are intricately involved in the pain experience. These authors have also recently reported cortical and subcortical brain gray matter abnormalities in TN patients.[6] This may all originate peripherally from neurovascular compression of the trigeminal nerve at the root entry zone causing prolonged nociceptive activity leading to central sensitization, chronic pain, and neuroinflammation.[7, 8]

—Stephen H. Landy, MD

This abstract and paper are interesting in that there is documentation of abnormalities in the trigeminal nerves and central pain pathways with trigeminal neuralgia using diffusion tensor imaging techniques. The authors studied 18 patients with right-sided trigeminal neuralgia and 18 healthy controls, a reasonably decent “n” for comparative purposes. Weaknesses in the design include the retrospective nature of the trial and the use of healthy controls versus those with some other source of right-sided facial pain. Without the latter, we have no means of determining which findings are specific to trigeminal neuralgia. A curiosity in the results involved the absence of complete lateralization of trigeminal nerve abnormalities to the affected side: although the affected trigeminal nerve had lower FA, higher RD, AD, and MD were found bilaterally compared with controls. A weakness in the discussion involves linking radiological signs of “inflammation” to potential causation of the condition when these findings are quite possibly the result of having the condition. Given these flaws, this entry does not make it through the compulsory part of the program to the finals.

—Robert G. Kaniecki, MD

Triptan Concerns and Non-Triptans

Roberto G, Piccinni C, D'Alessandro R, Poluzzi E. Triptans and serious adverse vascular events: Data mining of the FDA adverse event reporting system database. Cephalalgia. 2014;34:5-13.

Aim: The aim of this article is to investigate the vascular safety profile of triptans through an analysis of the United States Food and Drug Administration Adverse Event Reporting System (FDA_AERS) database with a special focus on serious and unexpected adverse events.

Methods: A CASE/NON-CASE analysis was performed on the reports entered in the FDA_AERS from 2004 to 2010: CASES were reports with at least 1 event included in the MedDRA system organ classes “cardiac disorder” or “vascular disorders,” whereas NON-CASES were all the remaining reports. Co-reported cardiovascular drugs were used as a proxy of cardiovascular risk, and the adjusted reporting odds ratio (adj.ROR) with 95% confidence interval (95% CI) was calculated. Disproportionality signals were defined as adj.ROR value >1. Adverse events were considered unexpected if not mentioned on the relevant label.

Results: Among 2,131,688 reports, 7808 concerned triptans. CASES were 2593 among triptans and 665,940 for all other drugs. Unexpected disproportionality signals were found in the following high-level terms of the MedDRA hierarchy: “cerebrovascular and spinal necrosis and vascular insufficiency” (103 triptan cases), “aneurysms and dissections non-site specific” (15), “pregnancy-associated hypertension” (10), and “reproductive system necrosis and vascular insufficiency” (3).

Discussion: Our analysis revealed 3 main groups of unexpected associations between triptans and serious vascular events: ischemic cerebrovascular events, aneurysms and artery dissections, and pregnancy-related vascular events. A case-by-case assessment is needed to confirm or disprove their plausibility, and large-scale analytical studies should be planned for risk rate estimation. In the meantime, clinicians should pay special attention to migraine diagnosis and vascular risk assessment before prescribing a triptan, also promptly reporting any unexpected event to pharmacovigilance systems.

Comments: I am not convinced that this mining expedition extracted anything clinically valuable and I agree with the concluding statement from the editorial that accompanies the manuscript that “[a]t present, the preponderance of the evidence from post-marketing safety surveillance efforts does not suggest that clinical practice with regard to triptan prescribing should change.”[9]

—Stephen H. Landy, MD

Data mining. Gold or silver medals. Too easy. You were probably expecting me to go there. Wrong. This paper strikes me more as a fishing competition than an Olympic sport. This fishing competition also takes place at a lake stocked in advance with bass. What do you think most of the competitors catch that day? Crappies, catfish, old tires, or tree branches (that would be me)? Of course not – we expect them to catch bass. So what would we expect from a fishing expedition in the triptan adverse event reporting database at the FDA? Pneumonia, humeral fractures, ovarian cancer? Would you call with a patient who developed any of these conditions while using triptans? This database is obviously not randomly stocked with all types of fish. Of course, this lake is stocked with vascular events because those are precisely the types of events that clinicians are apt to link with triptan use and, when serious, spend the time completing reports to the FDA. Like many a fish story, there may be potential here for exaggeration of the results. A keeper or throwback? You decide.

—Robert G. Kaniecki, MD

So RGK, I must believe this study didn't qualify for competition let alone the Olympics. I know words matter and certainly don't always use words correctly in proper context or sentence structure. In this paper, I take issue with the use of “… three main groups of unexpected associations …” As so thoroughly delineated by RGK and suggested by SHL, these associations are unexpected only to these authors. Certainly cephalalgia can be said to have legitimated this work; have we also?

—Frederick R. Taylor, MD

Aslan G, Sade LE, Yetis B, Bozbas H, Eroglu S, Pirat B, Can U, Muderrisoglu H. Flow in the left anterior descending coronary artery in patients with migraine headache. Am J Cardiol. 2013;112:1540-1544.

Migraine is a common neurovascular disorder characterized by attacks of severe headache, autonomic, and neurologic symptoms. Migraine can affect many systems in the body, yet its effects on cardiovascular system are unclear. We hypothesized that migraine and coronary microvascular angina may be manifestations of a common systemic microvascular dysfunction and clinically associated. Forty patients with migraine and 35 healthy volunteers were included into the study. Using transthoracic Doppler echocardiography, coronary flow was visualized in the middle or distal part of the left anterior descending artery. Coronary diastolic peak flow velocities were measured with pulse wave Doppler at baseline and after dipyridamole infusion (0.56 mg/kg/4 minutes). Coronary flow reserve of <2 was considered normal. In addition, thorough 2-dimensional and Doppler echocardiographic examinations were also performed. Fifty-two women and 23 men were included. Coronary flow reserve was significantly lesser in the migraine group than in the control group (1.99 ± 0.3 vs 2.90 ± 0.5, P < .05). In addition, mitral annular velocities were lower, and the ratio of early mitral inflow velocity to early mitral annular velocity (E/E‘ lateral and E/E' septal) was higher in migraineurs than in the control group (P < .05 for all), indicating diastolic function abnormalities in the migraine group. In conclusion, these findings suggest that there is an association between coronary microvascular dysfunction and migraine independently of the metabolic state of the patients. A common pathophysiological pathway of impaired endothelial vasodilatation, vasomotor dysfunction, and increased systemic inflammatory factors may play a role in these 2 clinical conditions, and could be the underlying cause of subclinical systolic and diastolic left ventricular dysfunction in migraineurs.

Comments: I thought this is an interesting follow-up abstract demonstrating an association between coronary microvascular dysfunction and migraine. There are no surprises here, but considering the previous abstract's results, more food for thought.[10]

—Stephen H. Landy, MD

Coronary flow reserve. Mitral annular velocities. Ratio of early mitral inflow velocity to early mitral annular velocity. These are all terms probably foreign to most of us. SHL hit us with a bunch of diffusion tensor imaging technological terms a few abstracts ago, which some of us have at least seen, but with this cardiology terminology he has gone too far. At least with the double axel, triple lutz and quadruple salchow we have Scott Hamilton (whatever happened to Dick Button?) to explain the details. Like the velocity entering the death spiral. The explanation during the skating is also done over a background of some fine music. And SHL has no music. No explanation, no music. The authors state their findings suggest that common pathophysiological pathways of impaired endothelial vasodilatation, vasomotor dysfunction and/or increased systemic inflammatory factors may play a role in migraine and impaired cardiac systolic and diastolic dysfunction. Sounds good to me. Without explanation or music, I have little interest in digging deeper. I'm tired. Do you think Bob Costas is just tired? Naw, me either. FRT?

—Robert G. Kaniecki, MD

I'm lost in Siberia. In fact I'm so lost I am thinking this study is the unexpected association to the prior abstract and not the triptans.

—Frederick R. Taylor, MD

Depré M, Macleod C, Palcza J, Behm M, de Lepeleire I, Han T, Panebianco D, Smith W, Blanchard R, Chodakewitz J, Murphy M, de Hoon J. Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: Results from a randomized study in patients with migraine. Cephalalgia. 2013;33:1292-1301.

Objective: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period.

Methods: A double-blind, placebo-controlled, 4-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at 7 post-dose time points over a period of 6 hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times.

Results: The mean difference in time-weighted (0-2.5 hour) MAP (90% confidence interval) was 1.2 mmHg (−0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6 hour and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels.

Conclusion: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.

Comments: Considering the potential for serious vascular events secondary to triptans and migraine, it is generally agreed upon that antagonism of the CGRP receptor represents a viable, “vascular safe” migraine abortive treatment option since CGRP antagonists lack direct vasoconstrictor activity.[11, 12] As migraine patients sometimes combine medications for optimal relief, knowing that there is no change in BP when taking a CGRP antagonist alone or with a triptan is also reassuring from a vascular safety standpoint.

—Stephen H. Landy, MD

A Reeses Cup commercial just came on the television during the speed skating events. No foolin'. Peanut butter is great, sometimes with jelly. Chocolate is even better. Yet who would have thought peanut butter and chocolate would work so well together? I love all Reeses cups – regular cup, mini cup, big cup, giant cup (got one for my birthday). Even E.T. was a fan – but I think he liked the Reeses Pieces. It appears that mixing the use of triptans and CGRP antagonists – if the latter ever become commercially available – might prove to be a safe and effective alternative for patients who are refractory to monotherapy with either individual entity. Even better together I say. On a small scale, this paper addresses potential safety issues, with broader efficacy and tolerability measures yet to be determined. Since Merck headquarters is not all that far from Hershey, PA, it might not be a bad idea to partner with Hershey to develop a chocolate-flavored dissolvable CGRP-antagonist wafer. Now that you are all witnesses to this idea in print, someday I might be receiving some fat royalties – or getting my own commercial at the next Winter Games.

—Robert G. Kaniecki, MD

RGK, didn't you know “they” were on to that years ago. I even got asked to do one of those marketing surveys on this, didn't you? Or was I in Siberia then? While I like this sampling of combinations, I would have enjoyed the sample more if directly applicable to practice today. Can we assume a class effect for this effect; I suggest not wisely even while the following abstract might suggest to many otherwise.

—Frederick R. Taylor, MD

Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: A double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114-125.

Background: BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine.

Methods: In this randomized, double-blind, placebo-controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg), sumatriptan 100 mg (active comparator), and placebo. Patients were treated for a single migraine attack. The primary end-point was pain freedom at 2 hours post-dose.

Results: Of patients who took the study drug, 799 had 1 post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, P = .002), 150 mg (32.9%, P < .001), and 300 mg (29.7%, P = .002) groups and the sumatriptan group (35%, P < .001) had pain freedom at 2 hours post-dose vs placebo (15.3%). For the secondary end-point of sustained pain freedom from 2 to 24 hours post-dose, BMS-927711 doses (25-600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs.

Conclusions: BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Comments: BMS-927711 is the fifth CGRP receptor antagonist (“gepant”) and none have vasoconstricting properties, and all are efficacious and have placebo-like tolerability. As Dr. Bigal, a preeminent authority on CGRP antagonists states in an accompanying editorial, “What remains to be better described in future studies is the safety of the drug, especially in terms of liver toxicity, which, so far, has been the Achilles' heel of the class, to the point that other strategies (using monoclonal antibodies targeting CGRP) are now being tested for prevention. Antibodies, not being metabolized by the liver, are less likely to cause drug-mediated liver toxicity.”[13, 14]

—Stephen H. Landy, MD

CGRP-receptor antagonists. To date, most of the talk has revolved around potential. Finally, a competitor delivers in competition, although it is only the preliminary heats. As SHL mentions, BMS-927711 is the fifth CGRP receptor antagonist to come to clinical trials. These compounds possess intriguing merits that, over the past several years, have raised interest levels and expectations but in the end disappointed. Bode Miller, Flying Tomato. Hepatotoxicity, rather than poor efficacy, has indeed been the chief barrier to further development and potential market success. Now onto the final heat, and hopefully someday a gold medal (and the manufacturer surely hopes a lot of gold in the bank).

—Robert G. Kaniecki, MD

RGK as usual gives the perfect lead in. When I read antibodies in SHL, I thought about and had to look up the number of references to monoclonal antibodies and induced central nervous system disorders: that number was 110,000 in Google Scholar (granted it was sloppy and not refined or filtered). When RGK wrote about the bank I thought any company would be wise to create a second bank account for fatal disease in what we consider a non-fatal albeit disabling condition. Will antibody development be good for patients or better for the doctors who sell it to other doctors? Could we have the liver toxicity studies early rather than late and clear that air with BMS-927711. How about comparators to standard of care therapies and not placebo?

—Frederick R. Taylor, MD

Gomez-Mancilla B, Brand R, Jürgens TP, Göbel H, Sommer C, Straube A, Evers S, Sommer M, Campos V, Kalkman HO, Hariry S, Pezous N, Johns D, Diener HC, BGG492 Study Group. Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia. 2014;34:103-113.

Background: Glutamate is implicated in migraine pathophysiology; amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists represent a potential therapeutic approach because of their anti-excitatory actions.

Methods: This randomized, double-blind, proof-of-concept study assessed the efficacy of the AMPA receptor antagonist, BGG492 (250 mg), vs placebo and sumatriptan (100 mg), in 75 subjects with acute migraine attacks. Efficacy was measured using the patient migraine diary. Pharmacokinetic and safety data were collected.

Results: Improvement from severe/moderate to mild/no headache pain (primary response) was reported in 58%, 58%, and 54% of BGG492-treated subjects at 2, 3, and 4 hours post-dose (P = .2, .5, and .5 vs placebo), respectively, compared with 68%, 84%, and 92% sumatriptan-treated subjects, and 40%, 48%, and 44% in the placebo group. Percentages of subjects with ≥2-point improvement in pain score from baseline at 2 hours were 29%, 40%, and 16% for BGG492, sumatriptan, and placebo, respectively. Pain-free response at 2 hours was reported for 25%, 24%, and 16% of BGG492, sumatriptan, and placebo subjects, respectively. Adverse events were reported by 80%, 56%, and 60% of BGG492, sumatriptan, and placebo subjects, respectively.

Conclusions: Proof-of-concept criterion was not met (≥25% BGG492 subjects with a primary response vs placebo at 2 time points). BGG492 was comparable to sumatriptan in terms of pain-free response.

Comments: Continuing the comments on the need for alternative migraine abortive medication treatment options that lack vasoconstrictive properties, this research reports a non-triptan, non-gepant option. BGG492 is an AMPA receptor antagonist that blocks glutamate, potentially mitigating cortical spreading depression, trigeminovascular activation, and central sensitization.[15, 16] Unfortunately, it failed to meet the studies proof-of-concept criterion, and dizziness, the most common side effect, was reported by 12/25, 48%, with 2 of these subjects requiring hospitalization and “the investigator suspected a relationship between the events and the study drug.” Dr. Ramadan's accompanying editorial including an excellent review of “clinical trials of Glu modulation in migraine” concludes that “[t]o this end, both topiramate and botulinum toxin, two therapies with proven efficacy in migraine prevention and relatively good therapeutic indices, modulate central glutamatergic tone.[17, 18] Therefore, it is suggested conceptually at least and indirectly from preclinical experiments, that modulators of Glu receptors can prove more beneficial in migraine prevention than in the treatment of acute attacks.”

—Stephen H. Landy, MD

Yikes! Unbelievable. Now he's got it in both eyes. As SHL speaks of vasoconstriction, I still cannot believe Costas cannot scratch up some Visine. Or some dark Stevie Wonder sunglasses. For Pete's sake get this man off television – I need some Visine just watching this poor sap. Sorry for the digression – and back to our regular programming. Here in this abstract we find fresh face in the field that perhaps catches the spotlight, albeit briefly, before falling flat in competition. Perhaps not quite as fascinating as Eddie the Eagle was in his ski jumping exploits (remember him?), glutaminergic modulation through AMPA –receptor blockade possesses intriguing theoretical opportunities in migraine management. I found myself unexplainably glued to the article, hoping against hope, knowing full well after the opening abstract that ultimate success for BGG492 was indeed unlikely. Alas, it was not BGG492's day. I suspect we all hope that after more refinement of technique, 4 years from now the outcome may be different and we may be toasting the success of a new anti-migraine champion.

—Robert G. Kaniecki, MD

I agree with all of the above, including “coeditor” Nabih Ramandan's comments. There could be gold and more money in the bank for an agent required daily rather than once or twice a month. And gosh prevention would even be scientifically sound. And golly gee if not prevention, try try again.

—Frederick R. Taylor, MD

Ketorolac vs Metoclopramide

Friedman BW, Adewunmi V, Campbell C, Solorzano C, Esses D, Bijur PE, Gallagher EJ. A randomized trial of intravenous ketorolac vs intravenous metoclopramide plus diphenhydramine for tension-type and all nonmigraine, noncluster recurrent headaches. Ann Emerg Med. 2013;62:311-318.

Study Objective: We compare metoclopramide 20 mg intravenously, combined with diphenhydramine 25 mg intravenously, with ketorolac 30 mg intravenously in adults with tension-type headache and all nonmigraine, noncluster recurrent headaches.

Methods: In this emergency department (ED)-based randomized, double-blind study, we enrolled adults with nonmigraine, noncluster recurrent headaches. Patients with tension-type headache were a subgroup of special interest. Our primary outcome was a comparison of the improvement in pain score between baseline and 1 hour later, assessed on a 0-10 verbal scale. We defined a between-group difference of 2.0 as the minimum clinically significant difference. Secondary end-points included need for rescue medication in the ED, achieving headache freedom in the ED and sustaining it for 24 hours, and patient's desire to receive the same medication again.

Results: We included 120 patients in the analysis. The metoclopramide/diphenhydramine arm improved by a median of 5 (interquartile range [IQR] 3, 7) scale units, whereas the ketorolac arm improved by a median of 3 (IQR 2, 6) (95% confidence interval [CI] for difference 0-3). Metoclopramide + diphenhydramine was superior to ketorolac for all 3 secondary outcomes: the number needed to treat for not requiring ED rescue medication was 3 (95% CI 2 to 6); for sustained headache freedom 6 (95% CI 3 to 20), and for wish to receive the same medication again 7 (95% CI 4 to 65). Tension-type headache subgroup results were similar.

Conclusion: For adults who presented to an ED with tension-type headache or with nonmigraine, noncluster recurrent headache, intravenous metoclopramide + diphenhydramine provided more headache relief than intravenous ketorolac.

Comments: I included this abstract because headache not otherwise specified and tension-type headache are not uncommon emergency department headache presentations with treatment considerations. The authors acknowledge in the manuscript that some of the study patients may have suffered from migraine.[19, 20] Regardless, it is clinically relevant news that these emergent headache sufferers responded better to IV 20 mg metoclopramide combined with 25 mg diphenhydramine than to IV 30 mg ketorolac.

—Stephen H. Landy, MD

Two bitter rivals paired head to head in a classic competition. Ketorolac and metoclopramide. Mano-et-mano. Well, not precisely, since we see metoclopramide receives somewhat of an assist from diphenhydramine. Nonetheless, we have here a well-designed contest with 2 experienced competitors. Yet the contest is not conducted on a typical migraine course, but one involving primarily tension-type headache (diagnosed tension-type and other nonmigraine, noncluster headache. In essence, a shift from the downhill to the super-G. The outcome may have surprised many of you as it did me – that the metoclopramide + diphenhydramine group fared better on a number of outcome measures as compared with the ketorolac group. Pain-level reduction, need for rescue medication, and sustained pain freedom were all better achieved with the former. Such results may have been anticipated in a study involving migraineurs, but tension-type headache? The authors admit some with migraine may have indeed been introduced into the competition, which may have skewed the data. The results and discussion are interesting, but will practically not influence my patient care protocols. In our practice, we typically do not worry about the superiority of these 2 entities since our “headache cocktail” typically involves a combination of all 3 drugs.

—Robert G. Kaniecki, M.D.

I appreciate any trial that builds an evidence base for something other than a non-steroidal anti-inflammatory drug (NSAID) in nonmigraine noncluster acute therapy. While I think ketorolac can survive some handicapping, I wonder whether metoclopramide 20 mg instead of 10 mg was just more advantaged. And of course that was the rational of the investigators. But will the average ER doctor and associates use 20 mg given concerns with metoclopramide, especially given acathisia as the major reason for using diphenhydramine with the metoclopramide? What I found lacking in the abstract is any information about adverse events (AEs) and patient preference. Fortunately, data were not lacking in the paper with no serious or unexpected AEs reported and without differences for new symptom development. Furthermore, those who reported they would not want the same medication next time (no differences between groups) did so due to lack of efficacy and not AEs. The authors write, “Drowsiness at 1 hour was more common among patients who received the metoclopramide combination, although drowsiness sufficient to impair function was uncommon in both groups.” We know NSAIDs can cause drowsiness, and impairment was actually numerically more frequent.

—Frederick R. Taylor, MD

Migraine Chronification

Louter MA, Bosker JE, van Oosterhout WP, van Zwet EW, Zitman FG, Ferrari MD, Terwindt GM. Cutaneous allodynia as a predictor of migraine chronification. Brain. 2013;136:3489-3496.

Cutaneous allodynia is a common feature accompanying migraine attacks and is considered a clinical marker for central sensitization. In a longitudinal study, we wanted to investigate if allodynia in migraine patients is a predictor of increasing frequency of migraine days. We included 3029 well-defined, web-based migraine patients (86% female, mean age 42.8 ± 11.4 years, 61% migraine without aura). Questionnaires on migraine characteristics (including allodynia), depression, and demographic factors were applied. The number of migraine days was measured twice. Multivariate regression models were used, with correction for other factors that are involved in the relation between allodynia and the number of migraine attacks or migraine days, with specific focus on depression. Of all 2331 eligible migraine patients, 1624 (70%) had allodynia. Lifetime depression was an independent risk factor for allodynia (odds ratio 1.52, 95% confidence interval 1.26-1.84), as well as female gender, low age at onset, and high migraine attack frequency. Analysis of the longitudinal data (in migraineurs with a follow-up period of >6 months) showed that, apart from the known risk factors (low age at onset, high baseline number of migraine days, and depression), allodynia was an independent predictor for increase in the number of migraine days over a mean follow-up period of 93 ± 30 weeks (median 103 weeks, range 26-160 weeks). Cutaneous allodynia is a risk factor for migraine chronification and may warrant preventive treatment strategies.

Comments: Migraine chronification is defined in this study as an “increase of the average number of migraine days per month.” This is the first longitudinal study demonstrating that allodynia is a risk factor for migraine chronification. Coupling this with the fact that allodynia may predict treatment response makes the absence or presence of allodynia, the clinical surrogate marker for central sensitization, all the more important.[21]

—Stephen H. Landy, MD

It seems there are not too many tough guys in the Winter Olympics. Can't think of one offhand. Cutaneous allodynia reminds me of a tough guy. Patients have long told us that cutaneous allodynia is a bad thing. When it comes to acute migraine management, we have learned that cutaneous allodynia, as a clinical marker for centralization, is a bad thing. Now this group shares with us data suggesting that cutaneous allodynia, when looking at an outcome of “chronification” of migraine over time, is a bad thing. If it was a childhood acquaintance, your parents would be telling you, “Nothing good will ever come from cutaneous allodynia.” If you met him in a dark alley you would want to walk away from cutaneous allodynia. Even Chuck Norris is afraid of cutaneous allodynia. Now we know why.

—Robert G. Kaniecki, MD

The definition of tough guy varies somewhat by media, but is mostly on the theme of “someone who bullies a weaker person.” RGK put it rather picturesquely, even audibly. And our patients feel it (as do some of us). And while we are not weak, we are bullied. So as providers we must remember to teach that treatment is a race against allodynia; a race against time as taught by Burstein.

—Frederick R. Taylor, MD

Migraine Health Resource Utilization

Sanderson JC, Devine EB, Lipton RB, Bloudek LM, Varon SF, Blumenfeld AM, Goadsby PJ, Buse DC, Sullivan SD. Headache-related health resource utilization in chronic and episodic migraine across six countries. J Neurol Neurosurg Psychiatry. 2013;84:1309-1317.

Objective: To describe headache-related health resource usage in chronic and episodic migraine across 6 countries.

Methods: A web-based questionnaire eliciting data on several topics, including health resource usage, was administered to panelists with migraine from the USA, Canada, UK, Germany, France, and Australia. Respondents were grouped into episodic and chronic migraine, based on reported headache phenotype and headache-day frequency. ORs were calculated, comparing usage in each country to that in the USA, controlling for chronic vs episodic migraine and other factors.

Results: Relative to the USA, the odds of visiting a provider for headache during the preceding 3 months were significantly higher in all countries, except Germany. Respondents in France were more likely to report having a provider they typically visited for headache-related care. The odds of visiting the emergency department for headache were significantly lower in France, the UK, and Germany, and hospitalization for headache was significantly more frequent in Canada and Australia. Respondents from all countries, except Canada, were more likely to report currently using a prescription-acute treatment, and those from France were more likely to report trying more than 3 acute treatments. Preventive treatment use did not differ significantly.

Conclusions: Headache-related resource usage differed significantly between the USA and other countries. US respondents were generally less likely to report recent provider visits and use of prescription-acute treatments. They were more likely to report emergency department visits than in European countries, but less likely to report hospitalization than in Canada and Australia.

Comments: Considering the ever-changing medical insurance requirements, evaluating headache-related health resource utilization seems quite timely. This research from the second International Burden of Migraine Study (IBMS II) describes and compares chronic and episodic migraine health resource utilization across 6 countries. It is interesting that USA respondents reported the lowest proportion of headache-related provider visits for chronic and episodic migraine, and the authors opined that “[m]any factors may limit healthcare access in the US, such as the lack of universal coverage or the presence of insurance deductibles for preventive services.” It is a sad scenario that as our ability to diagnose and treat episodic and chronic migraine improves, access to care in the USA seems significantly compromised.

—Stephen H. Landy, MD

I am not nearly as impressed with this paper as SHL seems to be. I have always found it difficult to assess the importance of studies that compare the “way we do things” here in the USA vs other countries. Our diets, our motor vehicles, our fashion choices (What exactly are the curlers from Norway wearing?), our tastes in music in humor (I still don't get Monty Python or Benny Hill), and our versions of football all vary tremendously from others around the globe. Our population dwarfs the other individual countries included in this study – UK, Canada, France, Germany, and Australia – potentially influencing results. Importantly, our healthcare delivery systems vary, absolutely influencing results. This paper describes the landscape, but I find its descriptions possess little meaning. Perhaps FRT, who has traveled to and for some time lived in some of these locations, has a more sophisticated take on it.

—Robert G. Kaniecki, MD

The gate has been opened so widely that I can't but ski, skate, or jump through. Agreed that Americans are a breed apart from all other countries and from ancestors where the comparison is appropriate. Lack of gun control despite 90% of the population surveyed in favor of some reasonable measures jumps to mind. The findings in this study are expected and not a one out of line with every other condition for which I have read data. Despite the facts that our healthcare patchwork (it really fails the definition of system as it lacks a set of organized principles) arguably has on average the best trained professionals in the world, spends between 1.6 and 2.5 times more of our gross doomestic product than anyone else, and has worse outcomes on every measure measurable than the 36 countries better than us, that includes all the worlds other democracies. Since RGK mentioned it, I will report that I have received medical care in 3 of the comparison countries and never paid a cent, never saw a bill to ponder over or question why a charge was so outlandish. And in each instance, I was more satisfied with my care there than I ever have been here at home. The multitude of barriers to care in this patchwork called care, some of which have been mentioned, cause visit avoidance leading to further chronification and sicker patients, which leads to increased costs at all levels. Of those aged 19-64, 46% are either uninsured (16%) or underinsured (30%), creating these difficulties in America the Great. The underinsured (defined at risk of costs exceeding 10% of income) suffer from increasingly high deductibles with ever narrower network of providers, creating problems for access and worse outcomes. Far too many headache specialists have tried to remove themselves from these everyday realities by creating cash practices, but all of us should care about access to the providers we want in a timely manner to reduce risk of more serious disease and at a price we can afford. The lack of all of this might be more tolerably suffered if the money spent were on care delivered with outcomes that bettered the world, but they are not. Those cash practices while contributing to the problem are also the result, to avoid the administrative costs that amount to about 30+% of our expenditures, including the $48 million we paid CEO Hemsley of United Health Group in 2013.

—Frederick R. Taylor, MD

Migraine Prophylaxis-Placebo

Meissner K, Fässler M, Räcker G, Kleijnen J, Hróbjartsson A, Schneider A, Antes G, Linde K. Differential effectiveness of placebo treatments: A systematic review of migraine prophylaxis. JAMA Intern Med. 2013;173:1941-1951.

Importance: When analyzing results of randomized clinical trials, the treatment with the greatest specific effect compared with its placebo control is considered to be the most effective one. Although systematic variations of improvements in placebo control groups would have important implications for the interpretation of placebo-controlled trials, the knowledge base on the subject is weak.

Objective: To investigate whether different types of placebo treatments are associated with different responses using the studies of migraine prophylaxis for this analysis.

Design, Setting, and Participants: We searched relevant sources through February 2012 and contacted the authors to identify randomized clinical trials on the prophylaxis of migraine with an observation period of at least 8 weeks after randomization that compared an experimental treatment with a placebo control group. We calculated pooled random-effects estimates according to the type of placebo for the proportions of treatment response. We performed meta-regression analyses to identify sources of heterogeneity. In a network meta-analysis, direct and indirect comparisons within and across trials were combined. Additional analyses were performed for continuous outcomes.

Exposure: Active migraine treatment and the placebo control conditions.

Main Outcomes and Measures: Proportion of treatment responders, defined as having an attack frequency reduction of at least 50%. Other available outcomes in order of preference included a reduction of 50% or greater in migraine days, the number of headache days, or headache score or a significant improvement as assessed by patients or their physicians.

Results: Of the 102 eligible trials, 23 could not be included in the meta-analyses owing to insufficient data. Sham acupuncture (proportion of responders, 0.38 [95% CI, 0.30-0.47]) and sham surgery (0.58 [0.37-0.77]) were associated with a more pronounced reduction of migraine frequency than oral pharmacological placebos (0.22 [0.17-0.28]) and were the only significant predictors of response in placebo groups in multivariable analyses (P = .005 and P = .001, respectively). Network meta-analysis confirmed that more patients reported response in sham acupuncture groups than in oral pharmacological placebo groups (odds ratio, 1.88 [95% CI, 1.30-2.72]). Corresponding analyses for continuous outcomes showed similar findings.

Conclusions and Relevance: Sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos. Clinicians who treat patients with migraine should be aware that a relevant part of the overall effect they observe in practice might be due to nonspecific effects and that the size of such effects might differ between treatment modalities.

Comments: Last but not least, this abstract uncovers what most of us already suspected or knew that “sham acupuncture and sham surgery are associated with higher responder ratios than oral pharmacological placebos.” It is interesting that “[o]ral placebos for herbs, vitamins, or homeopathic drugs; injected placebos for pharmacological drugs; a sham electromagnetic devise; and sham cognitive-behavioral treatment were associated with effects similar to oral pharmacological placebos.” I thought this abstract especially apropos considering the American Headache Society's “Choosing Wisely” task force recently opined, “don't recommend surgical deactivation of migraine trigger points outside of a clinical trial.”[22] The manuscript includes an excellent review of the importance and limitations of placebo controls, and also includes an eloquent discussion of the abstract's conclusions.

—Stephen H. Landy, MD

No surprises here. No upsets in this game. The results for most of us would seem entirely predictable. No “miracle on ice” with the classic Al Michael's call, “Do you believe in miracles … Yes!” The more invasive or extensive the placebo, the higher we find the placebo rate. Knives and needles impress patients more than pills and potions. My guess suppositories are inserted (still paying attention?) somewhere in between – at least in the USA. The relatively surprising observation that pharmacological injection fared similarly to pharmacological pill placebos may be partly explained by the design where only migraine prevention strategies were analyzed in this paper – perhaps the frequency of administration (preventive injections are likely administered at a lower frequency than would be seen in acute migraine trials) may influence such findings.

By the way, NBC must have heard my cries and mercifully they seem to have taken Mr. Costas to the Moscow Eye Hospital. Or at least perhaps to the Sunglass Hut at the airport. Also, as I come to my close, the USA just beat Russia in a thrilling ice hockey game. My work here is done. I will now turn things over to FRT.

—Robert G. Kaniecki, MD

I'm sorry, I think he's AWOL from competition. Probably failed a drug test or overslept?

—Frederick R. Taylor, MD