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treatment would be expected to result in about one fewer treated patient being dead or dependent at hospital discharge. In reality, no diff erence was evident in the clinical outcomes at 7 days in the trial (21/53 dead or dependent in the MSU group vs 20/47 in the control group). Moreover, of those patients with ischaemic stroke in the MSU group who were treated with thrombolysis, three died over the next few days whereas there were no deaths in patients with ischaemic stroke in the control group. Although these numbers are too small to allow reliable interpretation, they highlight the need for larger trials with suffi cient power to establish the eff ect of the MSU intervention on clinical outcome.

An important intermediate step in showing the potential for improved clinical outcomes with an MSU service would be to study the CT brain scans from patients scanned early by the MSU and to consider the “tissue window”, estimated with the Alberta Stroke Program Early CT (ASPECT) score,2 as well as the “time window”. If the patients scanned early had high ASPECT scores, suggesting a signifi cant potential to benefi t from thrombolysis, then that would provide some reassurance that better clinical outcomes could be expected.

The generalisability of the trial fi ndings to potential MSU services elsewhere will depend very much on the setting. This trial was set in an urban area with a median distance from the patient to the hospital of 7 km and median alarm to arrival times of 8 min for the standard ambulance versus 12 min for the MSU. The MSU would potentially work less well in rural areas in which locally based ambulances might be able to get patients to hospital about as quickly as a hospital-situated MSU could get out to the patient. Nevertheless, this trial has shown convincingly that in at least some settings an MSU-based service is feasible and can substantially reduce delays to treatment.

*Peter M Rothwell, Alastair M BuchanNuffi eld Department of Clinical Neuroscience (PMR) and Nuffi eld Department of Medicine (AMB), Oxford University, John Radcliff e Hospital, Headington, Oxford, UKpeter.rothwell@clneuro.ox.ac.uk

We declare that we have no confl icts of interest.

1 Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; published online April 11. DOI:10.1016/S1474-4422(12)70057-1.

2 Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355: 1670–74.

Defi ning and refi ning 5-HT receptor targets for migraineThe triptans are well established as effective treatments for migraine, but the specific mechanisms responsible for their therapeutic effects remain unknown. Triptans selectively activate 5-HT1 receptors, in particular the 1B, 1D, and 1F receptor subtypes.1 There has been extensive discussion about which of these 5-HT1 receptor subtypes are responsible for the therapeutic and adverse effects of treatment with triptans and about the locations in and around the brain where these effects might occur. In this issue of The Lancet Neurology, Färkkilä and colleagues2 describe a clinical trial of an oral formulation of lasmiditan—a non-triptan selective 5-HT1F receptor agonist—as an acute treatment for migraine. This study, in combination with previous studies of the clinical pharmacology and efficacy of lasmiditan in migraine,3,4 confirms the potential of lasmiditan as a treatment for acute migraine and also provides new

insights into the mechanisms of 5-HT1 receptors in migraine.

Lasmiditan is chemically distinct from triptans and has different pharmacological properties. Unlike triptans, lasmiditan has higher selectivity for the 5-HT1F receptor than for the 5-HT1B and 5-HT1D receptors.4 Lasmiditan was active in two in-vivo models that have been used to investigate migraine—plasma protein extravasation evoked by stimulation of the trigeminal ganglion and activation of c-fos in the trigeminal nucleus caudalis evoked by similar stimulation.4 Although these assays do not predict efficacy of migraine treatment, they do suggest functional effects in vivo, which in the case of lasmiditan are probably mediated by the 5-HT1F receptor.4 A previous study of intravenous lasmiditan suggested that it was an effective treatment for migraine.3

Published OnlineMarch 28, 2012 DOI:10.1016/S1474-4422(12)70062-5

See Articles page 405

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The present study investigated multiple doses of an oral preparation (50, 100, 200, and 400 mg) of lasmiditan versus placebo as a treatment for acute migraine in 391 patients. The results show dose-dependent improvements in the primary endpoint of headache response at 2 h after lasmiditan treatment, which are comparable to results that have been reported for several different triptans.5 For the harder to achieve secondary endpoint of proportion of patients who are pain free at 2 h, the results were somewhat less impressive, with only the 200 mg and 400 mg doses showing statistically significant superiority versus placebo. There was also a dose-dependent incidence of side-effects with lasmiditan, with dizziness, vertigo, and fatigue the most common. Few patients reported chest, neck, or jaw tightness or heaviness, which are commonly reported with triptans.

These results have several interesting and important implications. First, they confi rm that selective activation of 5-HT1F receptors has therapeutic eff ects in patients with migrane. 5-HT1F receptors are not widely expressed in the vasculature, and activation of these receptors does not have vascular eff ects in vitro.4 Although the therapeutic eff ects of triptans and calcitonin gene-related peptide antagonists have, for some time, been hypothesised to be independent of their eff ects on the vasculature, this hypothesis has been diffi cult to prove. Other eff ective treatments for acute migraine, such as aspirin or non-steroidal anti-infl ammatory drugs, do not seem to work via vascular mechanisms; however, because these drugs have analgesic eff ects that are not specifi c for migraine, they might be working downstream from primary migraine mechanisms. The eff ects of lasmiditan in the study by Färkkilä and colleagues2 provide strong and direct evidence for a non-vascular mechanism for migraine-specifi c acute treatment.

An additional important implication of the study is that the sites of the anti-migraine eff ects of lasmiditan are central rather than peripheral. Because 5-HT1F receptors are expressed in the trigeminal ganglion, a peripheral site of action cannot be excluded.6 However, receptor subtypes 1B, 1D, and 1F are all expressed in the brain and have anti-nociceptive functions at multiple central sites that might play a part in migraine.1 CNS sites of action have been proposed for most treatments

for acute migraine, but with the triptans a central site of action has been controversial because they have limited ability to cross the blood-brain barrier.7 The CNS symptoms caused by lasmiditan provide strong evidence that lasmiditan is indeed reaching the brain and suggest that it is treating migraine within the brain.

Whether or not lasmiditan will be able to compete with triptans as an eff ective and well-tolerated migraine treatment remains an open question. Although triptans are generally safe and the potential for adverse cardiac events is low for most patients,8 there is a subset of patients with cardiac issues for whom triptans are contraindicated and for whom lasmiditan might represent a suitable alternative. For patients without cardiac issues, one interesting question is whether 5-HT1F receptor activation alone is as eff ective as activation of 1B, 1D, and 1F subtypes together. Regardless of the answer to these questions, further basic and clinical studies with lasmiditan will likely provide additional important information about where and how acute migraine treatments are working.

Andrew CharlesHeadache Research and Treatment Program, Department of Neurology, David Geff en School of Medicine at UCLA, Los Angeles, CA 90095, USAacharles@ucla.edu

AC has served as a consultant for AGA Medical, Amgen, Bristol Myers Squibb, Eli Lilly, eNeura, MAP Pharmaceutical, Monosol Rx, Pfi zer, and Zogenix, and has received research grant support from MAP Pharmaceutical.

1 Goadsby PJ. Serotonin receptor ligands: treatments of acute migraine and cluster headache. Handb Exp Pharmacol 2007; 177: 129–43.

2 Färkkilä M, Diener HC, Géraud G, et al. Effi cacy and tolerability of lasmiditan, an oral 5-HT1F receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 2012; published online March 28. DOI:10.1016/S1474-4422(12)70047-9

3 Ferrari MD, Farkkila M, Reuter U, et al. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan—a randomised proof-of-concept trial. Cephalalgia 2010; 30: 1170–78.

4 Nelson DL, Phebus LA, Johnson KW, et al. Preclinical pharmacological profi le of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia 2010; 30: 1159–69.

5 Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–58.

6 Classey JD, Bartsch T, Goadsby PJ. Distribution of 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor expression in rat trigeminal and dorsal root ganglia neurons: relevance to the selective anti-migraine eff ect of triptans. Brain Res 2010; 1361: 76–85.

7 Edvinsson L, Tfelt-Hansen P. The blood brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–58.

8 Dodick D, Lipton RB, Martin V, et al. Consensus statement: cardiovascular safety profi le of triptans (5-HT agonists) in the acute treatment of migraine. Headache 2004; 44: 414–25.