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Management of acute and chronic migraine Gianluca Cand Jean Sc Purpose of reviewWe highlight the recent clinical trials for the management of acute and chronic migraine.
Recent findingsIn women with menstrual migraine, triptans seem to be well tolerated irrespective of whether or not patientsare taking oestrogen-containing contraceptives or have comorbidities that indicate increased cardiovascularrisk. The new acute drug, telcagepant, a calcitonin gene-related peptide (CGRP) antagonist, is safe forlong-term use (up to 18 months) in migraine patients with stable coronary artery disease in whom the useof triptans is not advisable. From the pooled analysis of the two Phase III Research Evaluating MigraineProphylaxis Therapy studies of onabotulinumtoxinA (BOTOX) in chronic migraineurs, it clearly emerged thatefficacy increases overtime (up to 56 weeks) and paralleled self-perceived improvement in quality of life.
Effectiveness was also observed in patients with severely disabling headaches, who met criteria for triptanabuse and were refractory to several prophylactic treatments. Finally, combination of preventivepharmacological agents with different action mechanisms may be the next frontier in therapeuticadvancements for treating migraine.
SummaryAlthough triptans are safe and well tolerated, CGRP antagonists may be an option for nonresponsivepatients or those in whom the use of triptans is not advisable. New drugs and combinations of oldtherapeutic options may help patients with severe forms of headache.
Keywordsacute, migraine, preventive, review, treatment Headaches are the most common pain syndrome in During the last two decades, the effectiveness of middle-aged adults. Among them, migraine head- 5-HT1B/1D agonists, triptans, in the treatment of ache has the highest prevalence and is the most attacks has been proved several times. Triptans are severe and disabling. It affects as many as 15% of able to act as vasoconstrictors via vascular 5-HT1B adults in North America and Western Europe, and receptors and to inhibit neurotransmitter release is probably one of the commonest reasons that on the peripheral as well as the central endings of patients visit their doctors, thus constituting a trigeminal nociceptors via 5-HT1B/1D receptors.
heavy social and individual burden. A rich and Sumatriptan, the first triptan, was followed by six varied symptomatology characterizes migraine, commercially available second-generation triptans especially migraine with aura. The latest clinical (zolmitriptan, naratriptan, rizatriptan, eletriptan, trial results in migraine treatment up to mid-2010 almotriptan, and frovatriptan), which, despite were comprehensively reviewed in a recent articlewe thus chose to focus this update on the mostrecent advances in the acute and prophylactic aDepartment of Neurophysiology of Vision and Neuro-ophthalmology, therapy of the most prevalent primary headache, G.B. Bietti Eye Foundation-IRCCS, Rome, Italy and bHeadache migraine, leaving aside other primary headaches.
Research Unit, Department of Neurology & GIGA Neurosciences,University of Lie ge, Lie ge, Belgium Correspondence to Dr Gianluca Coppola, Department of Neurophysi- TREATMENT OF THE MIGRAINE ATTACK ology of Vision and Neuro-ophthalmology, G.B. Bietti Eye Foundation-IRCCS, Via Livenza 3, 00198 Rome, Italy. Tel: +39 6 85356727; fax: +39 Novel information is coming out from studies of 6 84242333; e-mail: established antimigraine drugs, triptans, and of new nonpeptide calcitonin gene-related peptide receptor Curr Opin Support Palliat Care 2012, 6:177–182 antagonists, the so-called gepants.
1751-4258 ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins Pain: nonmalignant disease 69%), indicating that frovatriptan and zolmitriptan have equal efficacy in the treatment of menstrualmigraine. However, frovatriptan showed a lower risk
The new antimigraine drugs, the CGRP antagonists, will of headache recurrence over 24 h in comparison to be available in the near future. They will be the besthope for treating migraine patients who are zolmitriptan (15 versus 22%, respectively). The effi- nonresponders to triptans.
cacy of frovatriptan in the treatment of menstrualmigraine was confirmed in a new analysis of data
Available data in chronic headache patients suggest from five previously published studies Using that botulinum toxin effectiveness might increase when data from two phase III acute treatment trials injections were repeated over time, particularly inpatients irresponsive to several prophylactic treatments (n ¼ 496 women) and from three phase IIIb and who met criteria for drug abuse.
short-term preventive trials (n ¼ 1487 women)in menstrual migraine, MacGregor et al.

The combination of two preventive pharmacological evaluated the safety and tolerability of frova- agents with different mechanisms of action may help to triptan compared with sumatriptan or placebo. The reduce the impact of adverse effects, improvingpatients' compliance.
authors showed that 27.3% of frovatriptan-treated,33.4% sumatriptan-treated, and placebo-treated patients in the acute treatment trialsexperienced generally mild-to-moderate adverse sharing similar characteristics with sumatriptan, events. No significant differences were observed differ in their dose-dependent efficacy, adverse- between groups with sustained pain-free status with effects profiles, onset of relieving effects, sustained no adverse events at 4 and 24 h or with a sustained pain-free duration, and rates of recurrences pain response with no adverse events at 2–24 h or at A latest pooled analysis systematically 4–24 h. In the short-term preventive trials, 57.8% (twice per day) and 63.4% (once daily) of frovatrip- tan-treated patients reported adverse events versus which compared the efficacy and safety of frova- 62.8% of placebo-treated patients. There were triptan with that of zolmitriptan rizatriptan similar proportions of adverse events reported by and almotriptan Despite the fact that the rates of patients with potential cardiovascular risks (around pain free, of pain relief episodes at 2 h, and of pain- 17% of women in each treatment group) or adverse free episodes at 48 h were not significantly different events related to the use of oestrogen-containing between frovatriptan (30, 55, and 22%, respectively) contraceptives (32.0% of women in the pooled and the compared triptans (34, 59, and 21%, analysis). However, patients in the short-term pre- respectively), frovatriptan showed a significantly ventive analysis were women and because patients lower rate of recurrent episodes at 48 h (27 versus with known cardiovascular disease were excluded, 40%), and this was also the case when recurrence more trials are needed to adequately investigate the was expressed as a cumulative hazard ratio over the safety of frovatriptan in the high-risk population.
Interestingly, when another triptan, sumatrip- occurred significantly less often with frovatriptan tan, was used in combination with naproxen (55 events, 5% of the attacks) than with the com- sodium to treat menstrual migraine, patients were pared triptans (78 events, 8% of the attacks), with significantly more satisfied than those randomized only three cardiovascular symptoms reported with to placebo at 24 h after dose, although they had frovatriptan compared with a total of 25 with the minimal adverse events compared triptans . Taken together, the authors To verify whether the presence of cutaneous suggest that these triptans have a similar immediate allodynia, that is, the perception of discomfort pain-relieving effect; frovatriptan seems to have the resulting from an ordinarily painless stimulus advantage in the long term, as it showed a lower risk involving the skin, can influence antimigraine treat- of recurrence as well as more sustained efficacy.
ment outcome, researchers treated a population of Many prospective, randomized, controlled trials the ‘Act when Mild' (AwM) study with almotriptan have proved that triptans are effective and prefera- 12.5 mg within 1 h from the onset of an attack, when ble for menstrual migraine treatment Allais et al.
the pain intensity is still mild Allodynia was first compared the head-to-head efficacy of fro- assessed by a specific questionnaire and the clinical vatriptan with that of zolmitriptan. Results showed outcome was investigated in the presence or absence similar proportions of pain relief episodes at 2 h (52 of allodynia. A total of 39% of the study's popu- and 53%, respectively, for frovatriptan and zolmi- lation experienced allodynia, which impaired the triptan) and 24 h (83 and 82%) and of pain-free efficacy of almotriptan only in patients experienc- episodes at 2 h (22 and 26%) and 24 h (74 and Volume 6
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June 2012 Management of acute and chronic migraine Coppola and Schoenen migraine attack duration, less patients achieving study, it was proved that telcagepant (two 300 mg pain-free status, and more requiring rescue medi- doses administered 2 h apart) was generally safe and cation. This was not the case when the migraine well tolerated in a small cohort of migraine patients pain was early to mild, which helps to explain the with stable coronary artery disease, as there were no improvement achieved with the early treatment consistent treatment-related changes in cardiovas- strategy in AwM study Interestingly, in a cular parameters Following a previous work which assessed the placebo-controlled, parallel group phase III study therapeutic efficacy of telcagepant over four con- that assessed the efficacy of a novel, orally inhaled secutive treated attacks Connor et al. con- firmed this result in a large trial of 1068 patients in LEVADEX; MAP Pharmaceuticals) for the acute which patients could treat up to eight attacks per treatment of migraine, the verum was superior to month for up to 18 months either with 280/300 mg placebo for pain relief and pain freedom at 2 h, and of telcagepant or 10 mg of rizatriptan. Both telcage- for 2–24 h sustained pain relief and pain freedom pant and rizatriptan were generally well tolerated.
similarly in patients with and without allodynia Treatment groups showed similar overall incidence of adverse events, but fewer triptan-related adverse In the TEMPO study 79 patients treated at events (5% for telcagepant and 11.2% for rizatrip- least two migraine attacks within 1 h (early inter- tan) and drug-related adverse events (30.7% for vention) and were advised to continue to treat early, telcagepant and 46.3% for rizatriptan) were reported whereas 42 patients who had treated at least two for telcagepant versus rizatriptan. The most com- attacks 1 h after headache onset (late intervention) mon adverse events with telcagepant were dry were advised to switch from late to early dosing.
mouth, nausea, dizziness, and somnolence, and Spontaneous early intake achieved better control of each occurred in less than 10% of patients. Only migraine attacks than late intake; the switch from three adverse events (confusion, dissociation, and late to early intake following advice from the phys- euphoria), which all occurred in the telcagepant ician improved treatment efficacy. Overall analysis group but did not recur during subsequent attacks, confirmed that early intervention is associated with were identified as having potentially greater clinical significantly greater rates of pain-free state at 2 h significance for abuse liability. Overall, these find- (from 38.1% with late to 53.7% with early interven- ings suggest that CGRP receptor antagonists do not tion), headache relief at 2 h (from 66.7 to 80.5%), have potential for abuse liability. There were no and sustained pain-free state serious cardiovascular events during the trial, but These studies once again underline the need to having cardiovascular disease was in the exclusion educate migraine patients, so that they give up inadequate practices or unjustified prejudices about With the scope of verifying whether the same or triptan use.
different patients respond to triptans and telcage-pant, Ho et al. performed a post hoc analysis ofthe data from a large previously published study Calcitonin gene-related peptide antagonists which evaluated the efficacy and tolerability of Because triptans have major shortcomings such as telcagepant 150/300 mg, zolmitriptan 5 mg, and specific adverse events (the so-called ‘triptan symp- placebo They found that patients with a poor toms', i.e. burning, heat sensations, numbness, historical response to triptans or who never take tightness, tingling, etc.) and there is doubt about triptans had a substantially better response to telca- their cardiovascular safety, new better-tolerated and gepant 300 mg than to zolmitriptan. Conversely, efficacious drugs are needed. As calcitonin gene- patients who indicated a good historical response related peptide (CGRP) may play a role in the path- to triptans responded better to zolmitriptan than to ophysiology of migraine, possible use of selective telcagepant 150/300 mg This would suggest CGRP receptor antagonists as a novel treatment that patients who respond poorly to/did not take mechanism was tested. Olcegepant and, in particu- triptans might benefit from telcagepant, but these lar, telcagepant, oral CGRP receptor antagonists, are results should be validated in a placebo-controlled novel acute antimigraine drugs with efficacy that appears comparable to that of triptans but with The therapeutic efficacy and tolerability of fewer overall adverse side-effects telcagepant (280 mg) when co-administered with CGRP antagonists, which do not appear to cause ibuprofen (400 mg) or acetaminophen (1000 mg) vasoconstriction, may allow treatment of migraine was evaluated in a randomized, double-blinded, in patients with coronary disease. In a randomized, placebo-controlled trial Both in co-adminis- 1751-4258 ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins Pain: nonmalignant disease telcagepant resulted more effective than placebo headache days at the week 56 visit, suggesting that (percentages of patients with 2-h pain freedom the efficacy of onabotulinumtoxinA increases over 35.2, 38.3, and 10.9%, respectively), but was associ- time The proportion of patients who experi- ated with a higher percentage of adverse events.
enced a serious adverse event during the double- Combination therapy did not provide superior effi- blinded phase (onabotulinumtoxinA 4.8%, placebo cacy compared with telcagepant monotherapy 2.3%) or open-label phase (3.8%) was low. The pro- (31.2%) with regards to primary (pain freedom at portion of patients with a severe Headache Impact 2 h), secondary (pain relief at 2 h), tertiary (presence Test (HIT-6) score and higher values at the Migraine- of accompanying symptoms), and exploratory Specific Quality of Life Questionnaire (MSQ) notably (2–48 h sustained pain freedom) endpoints decreased from baseline in both the placebo andverum groups. However, significantly fewer patientswith severe HIT-6 scores and with less improvements ADVANCES IN PREVENTIVE MIGRAINE on the MSQ questionnaire were observed in the onabotulinumtoxinA-treated group at all weeks The criteria for chronic migraine have been revised during the double-blinded phase, including week in the new appendix of the second edition of the 24 This study suggests that prophylactic therapy International Classification of Headache Disorders with onabotulinumtoxinA is an option for this (ICHD-II) A vast proportion of chronic migraine highly disabled patient population.
disorder (headache present on 15 days/month) may OnabotulinumtoxinA also proved effective in develop or markedly worsen during greater than chronic refractory headache patients. Oterino 3 months of medication overuse (analgesics or trip- et al. treated 35 patients suffering from chronic tans or both). Chronic headache is a disabling health severely disabling headaches, who met criteria for problem that affects 2–5% of the general population triptan abuse. Patients were enrolled who had failed and causes considerable long-term morbidity and in at least one withdrawal attempt and had resulted disability Any progress in chronic migraine irresponsive to several prophylactic treatments.
management is thus very welcome.
After a number of onabotulinumtoxinA infiltrations The two Phase III Research Evaluating Migraine (ranging between 2 and 16), 32% of patients experi- Prophylaxis Therapy (PREEMPT) studies demon- enced at least a 50% reduction of headache days per strated the efficacy, safety, and tolerability of onabo- month and halved their monthly triptan consump- tulinumtoxinA (BOTOX) as headache prophylaxis in tion (from 22 to 11 oral triptans/month on average) adults suffering from chronic migraine Moreover, effective onabotulinumtoxinA although the real clinical benefit may not be consist- treatment substantially reduced the cost of acute ently relevant . The data of the entire 56-week migraine medications taken by patients with PREEMPT clinical programme were pooled to evalu- chronic migraine and triptan overuse ate the integrated summary of efficacy, safety, and With the scope of verifying whether prophylac- tolerability of onabotulinumtoxinA as headache pro- tic polytherapy is associated with improved out- phylaxis in adults suffering from chronic migraine comes as compared to maintaining monotherapy, and its impact on patients' quality of life researchers compared in a randomized pilot study The PREEMPT trials included 687 and 692 patients the effectiveness of long-term use of flunarizine and randomized to onabotulinumtoxinA or placebo topiramate alone and in combination for migraine (injection every 12 weeks) with a blinded follow-up prophylaxis in a Chinese population In this period of 24 weeks and a subsequent open-label phase study, 126 patients were randomized and 39 were of 32 weeks in which both groups received onabotu- treated with flunarizine alone (5 mg/day), 44 with topiramate alone (100 mg/day), and 43 with both Statistically significant reductions favouring drugs in combination. There was no significant onabotulinumtoxinA over placebo in the double- difference among the three groups in regards of blinded phase were observed at week 24 for the primary outcome variable of headache-day fre- migraine frequency. Among the three groups, the quency and for the secondary outcome change from combination therapy group decreased more signifi- baseline in mean migraine days, moderate/severe cantly in secondary endpoint mean monthly headache days, and total cumulative hours of head- migraine days and subjective perceived pain ache on headache days, with differences observed (measured on the visual analogue scale) than the throughout the open-label phase. However, almost flunarizine and topiramate group; no significant 70% of patients treated with onabotulinumtoxinA difference was found between the topiramate group throughout the entire study exhibited an at least and the flunarizine group. The combination of top- 50% decrease from baseline in migraine and iramate with flunarizine reduced the impact on Volume 6
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June 2012 Management of acute and chronic migraine Coppola and Schoenen body weight (flunarizine increases and topiramate seem to be well tolerated irrespective of whether decreases) of either drug taken alone However, or not patients are taking oestrogen-containing the major limitation of this study is the lack of a contraceptives. Furthermore, in women, triptans' placebo group, which may have an impact on treat- efficacy seems not to be influenced by the presence ment effectiveness. With the same scope of testing of comorbidities that may indicate increased cardio- the efficacy of combination of preventive drugs, vascular risk. Further studies should address the Krymchantowski et al. tested, in a randomized cardiovascular safety issue of triptans in men, who controlled trial, the effectiveness of 6 weeks' com- are known to have less favourable cardiovascular bination therapy of topiramate (TPM, 100 mg/day) risk factors. Data suggest that pain intensity is the and nortriptyline (30 mg/day) in a group of 44 epi- main driver of the response to triptans and not the sodic migraineurs versus placebo. Patients were presence or absence of cutaneous allodynia, an indi- selected from those who had less than 50% rect marker of central sensitization.
reduction in headache frequency after a previous The new acute drug, telcagepant, a CGRP- 8-week, open-label trial with TPM or nortriptyline antagonist, may be the best hope for treating alone. At the sixth week, differences between migraine patients who are nonresponders to trip- switching to combination therapy and continuing tans. It was proved to be safe in the long-term (up to monotherapy were significant. In fact, overall, 18 months) and was generally well tolerated in a almost 80% of patients randomized to receive both small cohort of migraine patients with stable cor- medications combined achieved the primary end- onary artery disease, in whom the use of triptans is point (reduction of headache frequency by at least not advisable.
50%), while less than 50% of patients randomized to Some progress was made with regards to the receive placebo in addition to nortriptyline or TPM pharmacological preventive treatment of episodic achieved this endpoint. In another small study, the and chronic migraine.
same group of researchers published an open-label When the data from the two PREEMPT studies study in which they tested combined lower-than- of onabotulinumtoxinA (BOTOX) as headache reported therapeutic doses of topiramate (75 mg/ prophylaxis in adults suffering from chronic day) and sodium divalproate (DVS, 500 mg/day) in migraine were pooled, the stable safety and toler- a group of patients previously treated with a full ability of the injections clearly emerged. Moreover, dosage of one of the two drugs alone (topiramate the efficacy increases overtime (up to 56 weeks) and 100 mg or sodium valproate 1000 mg) and, despite a in parallel with self-perceived improvement in therapeutic gain, had reported intolerable side- quality of life. Efficacy of onabotulinumtoxinA effects 6 weeks after starting the drug. Of the 38 was also observed in patients with severely dis- patients (22 from the TPM group and 16 from the abling headaches, who met criteria for triptan DVS group) who completed the study after the abuse and resulted irresponsive to several prophy- initiation of combination therapy, 17 from the lactic treatments (called ‘refractory'). Future trials original TPM monotherapy group (77.3% of those may help to identify subgroups of patients who who could not tolerate TPM 100 mg/day) and 10 will better respond to botulinum toxin and to from the original DVS monotherapy group (62.5% clarify the role of analgesic-overuse withdrawal in of those who could not tolerate DVS 1000 mg/day) improving response to preventive treatment with reported a decrease in side-effects and persistence of the improvement in headache initially exhibited Finally, as multiple pathogenic mechanisms are Small sample size and lack of placebo are the likely to be involved in perpetuating the recurrence major study biases.
of the migraine attacks, the combination of pharma-cological agents with different mechanisms ofaction may be the next frontier in therapeutic advancements for treating migraine.
In the past 2 decades, triptans, 5HT1B/1D agonists,have proven efficacious in the treatment of acute migraine attack. New studies have once again under- lined the small, but sometimes useful, differencesbetween various triptans which, despite sharingalmost the same immediate efficacy in aborting Conflicts of interest the attacks (including those related to the menses), This study was supported by the research convention include some that showed a significantly lower rate 3.4.650.09 from the National Fund for Scientific of recurrent episodes and drug-related adverse Research – Belgium to J.S. and by research grants from events. In women with menstrual migraine, triptans the Faculty of Medicine-University of Lie ge.
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Volume 6
Number 2
June 2012

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