Loo LS, Ailani J, Schim J, Baygani S, Hundemer HP, Port M, Krege JH.
Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials.
J Headache Pain. 2019 Jul 24;20(1):84. doi: 10.1186/s10194-019-1032-x. Epub 2019 Jul 24.
Abstract/Text
OBJECTIVE: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications.
BACKGROUND: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives.
METHODS: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes.
RESULTS: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications.
CONCLUSIONS: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications.
TRIAL REGISTRATION: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.
Sakai F, Takeshima T, Homma G, Tanji Y, Katagiri H, Komori M.
Phase 2 randomized placebo-controlled study of lasmiditan for the acute treatment of migraine in Japanese patients.
Headache. 2021 May;61(5):755-765. doi: 10.1111/head.14122. Epub 2021 May 15.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine.
BACKGROUND: Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine.
METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study in Japan (NCT03962738), which enrolled adults with migraine with or without aura. Participants were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg to be self-administered orally within 4 h of onset of a single moderate-to-severe migraine attack. Participants recorded their response to treatment prior to dosing and for 48 h postdose. The primary endpoint was headache pain freedom at 2 h postdose.
RESULTS: Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent-to-treat). At 2 h postdose, a significantly higher proportion of participants were headache pain-free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain-free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose-response relationship for pain freedom was achieved at 2 h by a Cochran-Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment-emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported.
CONCLUSIONS: Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies.
© 2021 Eli Lilly Japan K.K. The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Societ.
頭痛の診療ガイドライン作成委員会編：頭痛の診療ガイドライン2021．医学書院、2021.
McCrory DC, Gray RN.
Oral sumatriptan for acute migraine.
Cochrane Database Syst Rev. 2003;(3):CD002915. doi: 10.1002/14651858.CD002915.
Abstract/Text
BACKGROUND: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and, in some patients, neurological aura symptoms. Sumatriptan is one of a class of selective serotonin 5-hydroxytryptamine (5-HT1B/1D) agonists (triptans) thought to relieve migraine attacks by several mechanisms, including cranial vasoconstriction and peripheral and central neural inhibition.
OBJECTIVES: To describe and assess the evidence from randomized controlled trials (RCTs) concerning the efficacy and tolerability of oral sumatriptan for the treatment of a single acute attack of migraine in adults.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Cochrane Library, Issue 4, 2001), MEDLINE (1966 through November 2001), and reference lists of articles and books.
SELECTION CRITERIA: We included double-blind RCTs comparing oral sumatriptan (100 mg, 50 mg, 25 mg) with placebo, no intervention, other drug treatments, behavioral therapy, or physical therapy for the treatment of an acute attack of migraine in adults. Trials comparing different doses of sumatriptan or dosing regimens were also included. Outcomes considered were: 2-hour pain-free response, headache relief/headache intensity, and functional disability; headache recurrence; and adverse events.
DATA COLLECTION AND ANALYSIS: Data were abstracted by one reviewer and over-read by the other. The two reviewers independently assessed trial quality. Information on adverse events was collected from trial reports.
MAIN RESULTS: Twenty-five trials involving 16,200 participants were included. Methodological quality was generally good. Sixteen trials were placebo comparisons and showed that sumatriptan in doses of 100 mg (14 trials), 50 mg (five trials), and 25 mg (three trials) provided significantly better pain-free response (100 mg and 25 mg only), headache relief, and relief of disability at 2 hours. Numbers-needed-to-treat (NNTs) for pain-free response at 2 hours were 5.1 (3.9 to 7.1) for the 100-mg dose (n = 2221) and 7.5 (2.7 to 142) for the 25-mg dose (n = 131); there was no significant difference between the 50-mg dose and placebo for this outcome (n = 127). For headache relief at 2 hours, NNTs were 3.4 (3.0 to 4.0), 3.2 (2.4 to 5.1), and 3.4 (2.3 to 6.6) for sumatriptan 100 mg (n = 2940), 50 mg (n = 420), and 25 mg (n = 226), respectively. Precise estimates of the efficacy of the 50- and 25-mg doses relative to the 100-mg dose could not be obtained. Adverse events were more common with sumatriptan 100 mg than with placebo (risk difference [RD] = 0.14 [0.09 to 0.20]; number-needed-to-harm [NNH] = 7.1 [5.0 to 11.1]; n = 3172). RDs for the 50- and 25-mg vs. placebo comparisons were not statistically significant.
REVIEWER'S CONCLUSIONS: Oral sumatriptan has been shown to be an effective drug for the treatment of a single acute attack of migraine. It is well tolerated, though minor adverse events were not uncommon in the included trials. Other triptans were generally similar in efficacy and adverse events. Among non-triptan drugs, ergotamine + caffeine was significantly less effective than sumatriptan, and other drugs have been insufficiently studied to draw firm conclusions.
Oldman AD, Smith LA, McQuay HJ, Moore RA.
Rizatriptan for acute migraine.
Cochrane Database Syst Rev. 2001;(3):CD003221. doi: 10.1002/14651858.CD003221.
Abstract/Text
BACKGROUND: There are a number of different drug treatments for acute migraine, including currently four triptans, with several more likely to become available in the future. There is a need for evidence-based information to help determine the balance of benefit and harm for acute migraine treatment.
OBJECTIVES: To quantitatively assess the efficacy of a single dose of rizatriptan (Maxalt) for treating a single migraine attack using the outcomes of headache response and pain-free response at half-an-hour, one hour, two hours, and sustained relief over 24 hours. To express efficacy in terms of numbers-needed-to-treat (NNTs).
SEARCH STRATEGY: Trials were identified by searching MEDLINE (1966-July 2000), EMBASE (1980-June 2000), the Cochrane Library (Issue 3, 2000) and the Oxford Pain Relief Database (1950-1994). Date of last search: July 2000.
SELECTION CRITERIA: The inclusion criteria were randomised, placebo-controlled trials of rizatriptan for acute migraine; double-blind design; International Headache Society diagnostic criteria for migraine with or without aura; single migraine attack; single-dose treatment at standard doses; adult population; baseline pain of moderate or severe intensity using a four-point standardised rating scale; dichotomous or percentage data for at least one of the main efficacy outcomes; and full journal publication.
DATA COLLECTION AND ANALYSIS: Main outcomes considered were i) headache response at two hours, ii) headache response at one hour, iii) pain-free response at two hours, iv) sustained relief over 24 hours, v) pain-free response at 24 hours and vi) adverse effects. Minor outcomes were headache response and pain-free response at half-an-hour and four hours, and pain-free response at one hour. Dichotomous or percentage data were extracted and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for each outcome.
MAIN RESULTS: Seven trials met our inclusion criteria, with 2626 patients given rizatriptan and 902 given placebo. Significant benefit of rizatriptan over placebo was shown for both doses of rizatriptan (5 mg and 10 mg) for all five main efficacy outcomes (ranging from one to 24 hours). A dose response was seen for the main outcomes. It was not possible to analyse adverse effects information in a meaningful way.
REVIEWER'S CONCLUSIONS: Rizatriptan 5 mg and 10 mg are effective in treating acute migraine, with a dose-related increase in efficacy.
Smith LA, Oldman AD, McQuay HJ, Moore RA.
Eletriptan for acute migraine.
Cochrane Database Syst Rev. 2001;(3):CD003224. doi: 10.1002/14651858.CD003224.
Abstract/Text
BACKGROUND: Eletriptan (Relpax) is a new triptan soon to be made available by prescription for the treatment of acute migraine. Currently five triptans are available by prescription and more are under development. In light of the many drugs for treating acute migraine, there is a need for evidence-based assessments to help determine the relative efficacy and harm of these treatments.
OBJECTIVES: To determine the efficacy of eletriptan for treating a single migraine attack using the outcomes of headache response and pain-free response at 0.5, 1, 2 and 4 hours, and sustained relief over 24 hours. To express efficacy in terms of number-needed-to-treat (NNT). To determine the adverse effects of a single dose of eletriptan and express this in terms of number-needed-to-harm (NNH). To allow for the comparison of the efficacy of eletriptan with other migraine treatments evaluated systematically in the same way.
SEARCH STRATEGY: Data from all Phase III randomised placebo-controlled trials were made available by the manufacturer, Pfizer Inc. To date, these trials comprise the only data on eletriptan relevant to this review in a published or unpublished form; thus, searches of electronic databases for further trials of eletriptan were not conducted.
SELECTION CRITERIA: Trials of eletriptan for acute migraine; randomised allocation to treatment groups, including a placebo group; double-blind design; International Headache Society diagnostic criteria for migraine with or without aura; single migraine attack; single-dose treatment at standard doses; adult population; baseline pain of moderate or severe intensity using a 4-point standardised rating scale (0 = no pain, 1 = mild pain, 2 = moderate pain and 3 = severe pain); and dichotomous or percentage data for at least one of the main efficacy outcomes.
DATA COLLECTION AND ANALYSIS: Trials were scored for quality and data extracted by two independent reviewers. Dichotomous or percentage data were extracted and pooled to calculate the relative benefit (RB) or relative risk (RR) and NNTs or NNHs for a number of outcomes for eletriptan 20 mg, 40 mg and 80 mg. The main outcomes considered were headache response at 1 and 2 hours, pain-free response at 2 hours, sustained relief over 24 hours and adverse effects. Minor outcomes considered were headache response at 0.5 and 4 hours, and pain-free response at 0.5, 1 and 4 hours.
MAIN RESULTS: Six trials met the inclusion criteria. Significant benefit of eletriptan over placebo was shown for eletriptan 20 mg, 40 mg and 80 mg for the primary efficacy outcomes of headache response and pain-free response at 2 hours. For headache response at 2 hours, the NNTs (with 95% confidence intervals) were 4.4 (3.4 to 6.2), 2.9 (2.6 to 3.3) and 2.6 (2.4 to 3.0) for eletriptan 20 mg, 40 mg and 80 mg, respectively. For pain-free response at 2 hours, the NNTs were 9.9 (6.9 to 18), 4.5 (4.0 to 5.1) and 3.7 (3.4 to 4.2), for eletriptan 20 mg, 40 and 80 mg, respectively. There was no significant difference in the incidence of major adverse effects between any dose of eletriptan and placebo. The incidence of minor adverse effects was significantly higher for all eletriptan doses than for placebo, with NNHs of 11 (95% confidence interval, 6.2 to 39), 7.0 (5.2 to 11) and 3.7 (3.1 to 4.5) for eletriptan 20 mg, 40 mg and 80 mg, respectively.
REVIEWER'S CONCLUSIONS: Eletriptan 20 mg, 40 mg and 80 mg are effective for the treatment of an acute migraine attack. Effectiveness is dose-related, with statistically significant differences between doses for pain-free response and 24-hour outcomes. Eletriptan compares well with other triptans available for outcomes measured up to 2 hours and provides meaningful relief for 24 hours. Taken as a single dose, eletriptan was well tolerated and caused no major harm. The incidence of minor harm was dose-dependent, with 80 mg giving significantly more adverse effects than 40 mg.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ.
Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials.
Lancet. 2001 Nov 17;358(9294):1668-75. doi: 10.1016/S0140-6736(01)06711-3.
Abstract/Text
BACKGROUND: The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice.
METHOD: We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials.
RESULTS: 53 clinical trials (12 unpublished) involving 24089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post dose); and 67% (63-70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12.5 mg almotriptan showed similar efficacy at 2 h but better other results; 2.5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2.5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy.
INTERPRETATION: At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success.
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 Oct;22(8):633-58. doi: 10.1046/j.1468-2982.2002.00404.x.
Abstract/Text
The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.
Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, Pilgrim AJ, Shevlin P.
Subcutaneous sumatriptan during the migraine aura. Sumatriptan Aura Study Group.
Neurology. 1994 Sep;44(9):1587-92. doi: 10.1212/wnl.44.9.1587.
Abstract/Text
This double-blind, placebo-controlled, multicenter, parallel-group study assessed whether subcutaneous sumatriptan administered during the migraine aura would prolong or modify the aura and prevent or delay development of the headache. One hundred seventy-one patients (88 receiving 6 mg sumatriptan, 83 receiving placebo) treated a single attack of migraine with typical aura at home, by self-injection. The median duration of aura following the first injection was 25 minutes for the sumatriptan group and 30 minutes for the placebo group (NS). The aura symptom profile was similar for the two treatment groups. The proportion of patients who developed a moderate or severe headache within 6 hours after dose administration was similar in the two groups--68% among those receiving sumatriptan and 75% among those receiving placebo (NS). Sumatriptan given during the aura did not prolong or alter the nature of the migraine aura and did not prevent or significantly delay headache development.
Dowson A.
Can oral 311C90, a novel 5-HT1D agonist, prevent migraine headache when taken during an aura?
Eur Neurol. 1996;36 Suppl 2:28-31. doi: 10.1159/000119101.
Abstract/Text
The purpose of this pilot study was to determine whether 20 mg oral 311C90 can prevent the development of migraine headache when taken during the aura phase of a migraine attack. The study also aimed to provide an initial safety profile for 311C90 when taken during the aura. Forty patients (31 females, 9 males) were entered into this outpatient, double-blind, placebo-controlled, 2-period crossover trial. They all almost invariably experienced a migraine headache after the aura phase. Patients treated two migraine attacks during the aura phase in a random order, one with 311C90 20 mg and the other with placebo. Efficacy assessments were recorded on standard diary cards completed by each patient. A primary response was defined as the complete absence of headache pain in the 24 hour period following administration of the first dose of study medication. Safety assessments included ECGs, laboratory tests and the recording of adverse experiences. Twenty patients completed the study by treating 2 attacks, 16 of these were fully adherent to the study protocol. Three of the 16 patients responded to 311C90 whereas all patients developed a migraine headache after taking placebo. Two patients who did not respond to 311C90 described the developing headache as being "non-migraine'. Adverse experiences reported were similar to those experienced by patients in previous studies when 311C90 was taken during a migraine headache. There were no reports of 311C90-related adverse effects on the aura. These preliminary results suggest that oral 311C90 may be of value in preventing a migraine headache and is safe when taken during the aura phase. This intriguing possibility therefore warrants further investigation possibly utilising formulations that would deliver meaningful plasma levels of drug more rapidly.
Olesen J, Diener HC, Schoenen J, Hettiarachchi J.
No effect of eletriptan administration during the aura phase of migraine.
Eur J Neurol. 2004 Oct;11(10):671-7. doi: 10.1111/j.1468-1331.2004.00914.x.
Abstract/Text
Migraine aura is a warning sign readily recognized by patients. From the onset of aura it takes 30-60 min before the headache phase starts. Administration of acute medication during aura should provide sufficient time to achieve therapeutic plasma levels, counteracting the headache. To test this hypothesis we evaluated the efficacy of eletriptan 80 mg taken during aura. Patients met International Headache Society diagnostic criteria for migraine with aura, with an attack frequency of at least one per month and with aura occurring in > 50% of recent attacks. Of 123 patients randomized, 87 (71%) were treated with a double-blind, one attack, during the aura phase before headache, dose of either eletriptan 80 mg (n = 43; 74% female; mean age, 40 years), or placebo (n = 44; 82% female; mean age, 40 years). The primary outcome measure was the proportion of patients not developing moderate-to-severe headache within 6 h post-dose. There was no significant difference in the proportion of patients developing moderate-to-severe headache on eletriptan (61%) versus placebo (46%). Eletriptan was well tolerated and did not prolong the aura phase. Typical transient triptan adverse events were observed; most were mild-to-moderate in intensity. This study confirms the findings of two studies showing that triptans are ineffective but safe when given during the migraine aura phrase.
Lange R, Schwarz JA, Hohn M.
Acetylsalicylic acid effervescent 1000 mg (Aspirin) in acute migraine attacks; a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.
Cephalalgia. 2000 Sep;20(7):663-7. doi: 10.1111/j.1468-2982.2000.00101.x.
Abstract/Text
In this multicentre, randomized, double-blind, single-dose study a total of 374 patients generally suffering from migraine attacks suitable for treatment with non-prescription drugs, received either oral acetylsalicylic acid effervescent 1000 mg (ASAE) or effervescent placebo for the treatment of an acute migraine attack. Of the 343 patients fulfilling the criteria for efficacy analysis 169 patients took acetylsalicylic acid and 174 placebo. Response rates (reduction of headache severity from severe or moderate to mild or no pain at 2 h after administration) were 55.0% for acetylsalicylic acid and 36.8% for placebo (P < 0.001). Twenty-nine percent of patients in the active treatment group were pain-free after 2 h compared with 16.7% in the placebo group (P = 0.007). No headache recurred within 24 h post-dose in 84.6% of patients in the active group and in 85.1% of patients in the placebo group. Effervescent placebo reduced nausea and vomiting to the same degree as the active drug. Adverse events of acetylsalicylic acid (8.3%) were generally mild or moderate and comparable to those of placebo (2.9%). This study shows that oral ASAE is safe and effective for the treatment of acute migraine attacks.
MacGregor EA, Dowson A, Davies PT.
Mouth-dispersible aspirin in the treatment of migraine: a placebo-controlled study.
Headache. 2002 Apr;42(4):249-55. doi: 10.1046/j.1526-4610.2002.02076.x.
Abstract/Text
OBJECTIVE: To compare the efficacy of mouth-dispersible aspirin 900 mg and placebo in the treatment of migraine.
BACKGROUND: Aspirin is widely accepted as an effective therapy for migraine. Previous studies have indicated that gastric stasis and delayed gastric emptying, which occur during migraine attacks, delay aspirin absorption. Mouth-dispersible formulations are considered to be more quickly absorbed than solid formulations and, therefore, may be more effective in treating migraine.
DESIGN: Randomized, double-blind, placebo-controlled, crossover study in four specialized migraine clinics in the United Kingdom.
METHODS: One hundred one patients diagnosed with migraine (according to the International Headache Society diagnostic criteria) participated in the study. Patients received either single doses of mouth-dispersible aspirin (3 x 300 mg) or placebo for moderate pain in the treatment of two migraine attacks. Rescue medication could be taken after 2 hours, if required. The primary efficacy parameter was response to therapy at 2 hours posttreatment. Other efficacy parameters were response to treatment, pain-free, and pain intensity at all other time points. Functional disability, nausea, vomiting, photophobia, phonophobia, symptom relief, patient and investigator global evaluation, use of rescue medication, headache recurrence, and palatability and convenience were also recorded.
RESULTS: Of 101 patients, 73 took both treatments. At 2 hours, 48% of patients taking mouth-dispersible aspirin responded, compared to only 19% taking placebo (P =.0005). Mouth-dispersible aspirin was significantly better than placebo for response to treatment (P<.05) and pain intensity difference (P<.01) at all time points from 30 minutes posttreatment; for pain-free (P<.05) and use of rescue medication (P<.01) from 3 hours posttreatment; for headache recurrence (P<.05); and for patients' and investigators' global evaluations of efficacy (P =.0001 in both cases).
CONCLUSIONS: Mouth-dispersible aspirin 900 mg is effective compared with placebo for the treatment of moderate migraine head pain, with relief seen from as early as 30 minutes after taking medication.
.
A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group.
Eur Neurol. 1992;32(3):177-84. doi: 10.1159/000116818.
Abstract/Text
In a double-blind, placebo-controlled study, the efficacy, safety and tolerability of 100 mg oral sumatriptan, given as a dispersible tablet, was compared with that of 900 mg oral aspirin plus 10 mg oral metoclopramide in the acute treatment of migraine. A total of 358 patients treated up to three migraine attacks within 3 months, recording clinical information on a diary card. In attack 1, headache relief after 2 h, defined as a reduction in severity from severe or moderate pain to mild or no pain, was recorded in 56% (74/133) of patients who took sumatriptan and 45% (62/138) of patients who took aspirin plus metoclopramide (p = 0.078). This analysis of the primary efficacy end point was not statistically significant. However, for attacks 2 and 3 (secondary end points), headache relief was achieved in 58 versus 36% of patients (p = 0.001) and 65 versus 34% of patients (p less than 0.001), respectively. Relief from nausea, vomiting, photophobia and phonophobia was similar in both treatment groups. Rescue medication was required by fewer patients treated with sumatriptan than by those who received aspirin plus metoclopramide (attack 1, 34 versus 56%, p less than 0.001; attack 2, 32 versus 51%, p = 0.001, and attack 3, 35 versus 54%, p = 0.001). Sumatriptan also produced a faster improvement and resolution of migraine attacks. Comparing the sumatriptan and aspirin plus metoclopramide treatment groups, complete resolution of the attack occurred within 6 h in 32 versus 19% (attack 1), 35 versus 23% (attack 2) and 32 versus 20% of patients (attack 3).(ABSTRACT TRUNCATED AT 250 WORDS)
Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G.
The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine.
Lancet. 1995 Oct 7;346(8980):923-6. doi: 10.1016/s0140-6736(95)91554-0.
Abstract/Text
Aspirin is commonly used to treat migraine attacks, although sumatriptan, a much more expensive treatment, is also effective. We compared a combination of lysine acetylsalicylate (equivalent to 900 mg aspirin) and 10 mg metoclopramide (LAS+MTC) with oral sumatriptan (100 mg) and placebo in 421 patients with migraine. LAS+MTC was as effective as sumatriptan with a decrease of headache from severe or moderate to mild or none of 57% and 53%, respectively, for the first migraine attack treated. Both treatments were better than placebo (success rate 24%, p < 0.0001). LAS+MTC was significantly more effective in the treatment of nausea than sumatriptan (p < 0.0001) and was better tolerated (adverse events in 18% and 28%, respectively, p < 0.05). LAS+MTC is as effective as sumatriptan in the treatment of migraine attacks. It is also much cheaper.
Geraud G, Compagnon A, Rossi A; COZAM Study Group.
Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomised, three-attack study.
Eur Neurol. 2002;47(2):88-98. doi: 10.1159/000047959.
Abstract/Text
This multicentre, randomised, double-blind study compared oral zolmitriptan 2.5 mg with a combination of oral acetylsalicylic acid 900 mg and metoclopramide 10 mg as acute anti-migraine therapy for 3 migraine attacks. In total, 666 patients took at least one dose of study medication (326 took zolmitriptan and 340 took acetylsalicylic acid plus metoclopramide). The percentage of patients with a 2-hour headache response after the first dose for all 3 attacks (the primary end point) was 33.4% with zolmitriptan and 32.9% with acetylsalicylic acid plus metoclopramide [odds ratio 1.06, 95% confidence interval (CI) 0.77-1.47; p = 0.7228]. For the majority of secondary end points, the two treatments demonstrated comparable efficacy. However, post hoc analysis showed that significantly more patients receiving zolmitriptan were free of pain 2 h after the first dose in all 3 attacks compared with patients receiving acetylsalicylic acid plus metoclopramide (10.7 vs. 5.3%; odds ratio 2.19, 95% CI 1.23-4.03; p = 0.0095). In addition, post hoc analysis showed that the overall 2-hour pain-free response rate was consistently higher with zolmitriptan (34.6%) than with acetylsalicylic acid plus metoclopramide (27.9%) (odds ratio 1.40, 95% CI 1.09-1.78; p = 0.007). Both treatments reduced migraine-associated nausea, vomiting, phonophobia and photophobia. There were no important inter-group differences with respect to the onset of meaningful migraine relief, the frequency of headache recurrence, the usage or efficacy of a second dose of medication or the use of escape medication. However, at the last attack, the proportion of patients who expressed overall satisfaction with the treatment was significantly higher in the zolmitriptan group, i.e. 83.7%, versus 75.0% with acetylsalicylic acid plus metoclopramide (p = 0.0346). Both agents were well tolerated. Adverse events were reported by 40.8% (133/326) of zolmitriptan-treated patients and 29.1% (99/340) of those treated with acetylsalicylic acid plus metoclopramide. The incidence of withdrawals due to adverse events was very low with both zolmitriptan (0.9%) and the combination regimen (1.5%); the latter percentage included 1 patient who withdrew from the study due to phlebitis, which was classified as a serious adverse event. This study showed that zolmitriptan is effective and well tolerated for the acute treatment of moderate to severe migraine. Zolmitriptan was at least as effective as acetylsalicylic acid plus metoclopramide in achieving a 2-hour headache response, but significantly more effective than the combination therapy for other end points, including the 2-hour pain-free response.
Copyright 2002 S. Karger AG, Basel
Ellis GL, Delaney J, DeHart DA, Owens A.
The efficacy of metoclopramide in the treatment of migraine headache.
Ann Emerg Med. 1993 Feb;22(2):191-5. doi: 10.1016/s0196-0644(05)80201-x.
Abstract/Text
STUDY OBJECTIVES: By evaluating the efficacy of metoclopramide alone and in combination with ibuprofen versus placebos, this study was designed to both evaluate the efficacy of metoclopramide and elucidate its mechanism of action in the treatment of migraine headache.
DESIGN: The study was conducted over a two-year period and was a randomized, double-blind, placebo-controlled study.
SETTING: An urban teaching hospital.
PARTICIPANTS: Patients enrolled were at least 18 years old and had recurring headaches with one or more of the following characteristics: unilateral, preceded by neurologic symptoms, significant nausea and vomiting, or mood changes and photophobia.
INTERVENTION: Ten milligrams of metoclopramide or an equal volume of IV normal saline was given and 600 mg of ibuprofen or identical-appearing placebo was given orally at time 0. Patients rated their pain and nausea at time 0, 30 minutes, and 60 minutes using visual-analog scales.
RESULTS: The differences in pain and nausea scores for the metoclopramide + placebos group versus the other three groups were tested using exact nonparametric (Mann-Whitney) statistical procedures. The metoclopramide + placebos group had significantly better relief of pain compared with the placebos + ibuprofen and placebos + placebos groups. The metoclopramide + placebos group had significantly better relief of nausea than the ibuprofen + placebos group; nausea scores for the placebos + placebos group could not be analyzed due to excessive variance from the other groups at baseline. The differences between the metoclopramide + placebos group and the metoclopramide + ibuprofen group were not statistically significant with regard to either pain or nausea.
CONCLUSION: Metoclopramide is efficacious in the treatment of both the pain and nausea of migraine headache. This is a direct action that is not dependent on the concomitant administration of another agent.
Jones EB, Gonzalez ER, Boggs JG, Grillo JA, Elswick RK Jr.
Safety and efficacy of rectal prochlorperazine for the treatment of migraine in the emergency department.
Ann Emerg Med. 1994 Aug;24(2):237-41. doi: 10.1016/s0196-0644(94)70135-0.
Abstract/Text
STUDY OBJECTIVE: To assess the safety and efficacy of rectal prochlorperazine in the treatment of acute migraines.
DESIGN: Randomized, double-blinded, placebo-controlled study.
SETTING: Emergency department of an inner-city university hospital.
PARTICIPANTS: ED patients with documented diagnosis of migraines.
INTERVENTIONS: Vital signs and level of alertness were monitored immediately before drug administration and 120 minutes after dosing. Pain intensity and adverse events were monitored immediately before drug administration and at 30, 60, and 120 minutes after dosing.
RESULTS: A positive outcome was defined as a pain score less than or equal to 5 on a 10-point scale or a 50% reduction in pain intensity from baseline at 120 minutes after dosing. All patients treated with prochlorperazine suppositories experienced a positive treatment outcome; only 50% of patients treated with placebo experienced a positive result at 120 minutes after dosing (P = .016). Pain intensity scores were significantly lower in the prochlorperazine group at 120 minutes (P = .018). There were no adverse reactions in either group, and there were no significant differences in vital signs or levels of alertness between groups. Patients who failed therapy were given rescue medication 120 minutes after dosing.
CONCLUSION: Prochlorperazine administered as a 25-mg rectal suppository provides excellent pain relief within 2 hours in patients with acute migraines.
Tfelt-Hansen P, Olesen J, Aebelholt-Krabbe A, Melgaard B, Veilis B.
A double blind study of metoclopramide in the treatment of migraine attacks.
J Neurol Neurosurg Psychiatry. 1980 Apr;43(4):369-71. doi: 10.1136/jnnp.43.4.369.
Abstract/Text
One hundred and fifty patients with migraine attacks attending the Copenhagen acute migraine clinic were treated either with metoclopramide 10 mg i.m. metoclopramide 20 mg as suppository or placebo in a double blind trial. All patients simultaneously or 30 minutes later received paracetamol 1 g and diazepam 5 mg orally. The nausea was relieved in 71% of the patients by placebo and bed rest, but metoclopramide was significantly (p = 0.04) more effective and relieved nausea in 86% of the patients. Metoclopramide did not by itself reduce the pain, but enhanced the effect of the analgesic or sedative medication. This effect, however, just failed to be statistically significant (p = 0.06).
Amery WK, Waelkens J.
Prevention of the last chance: an alternative pharmacologic treatment of migraine.
Headache. 1983 Jan;23(1):37-8. doi: 10.1111/j.1526-4610.1983.hed2101037.x.
Abstract/Text
Coppola M, Yealy DM, Leibold RA.
Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache.
Ann Emerg Med. 1995 Nov;26(5):541-6. doi: 10.1016/s0196-0644(95)70001-3.
Abstract/Text
STUDY OBJECTIVE: To determine the comparative efficacy of i.v. metoclopramide and prochlorperazine for the initial emergency department treatment of migraine headache.
DESIGN: Prospective, randomized, double-blind, placebo-controlled trial.
SETTING: Military community hospital ED with an annual census of 75,000.
PARTICIPANTS: Seventy consenting adults from a convenience sample of patients presenting with migraine headache similar to that experienced in at least one prior episode. Exclusion criteria were pregnancy, fever, signs of meningismus, altered sensorium, drug or alcohol use, oxygen saturation less than 90%, recent trauma or seizure, "worst headache," abnormal blood pressure, recent (within 48 hours) use of metoclopramide or prochlorperazine, and allergy to metoclopramide or prochlorperazine.
INTERVENTIONS: In a random manner, each subject received a 2-mL i.v. injection of identical-appearing fluid containing metoclopramide (10 mg), prochlorperazine (10 mg), or saline solution (placebo). No other analgesics or medications were administered during the initial study period; rescue agents were administered by the choice of the treating physician after all data were collected.
MEASUREMENTS: Patients scored their nausea, pain, and sedation before receiving the 2-mL injections and at 30 minutes after injection. Ten-centimeter nonhatched visual analog scales were used for these measurements, with distance from the left end (zero) calculated for each use. Clinically important successful treatment was defined a priori as achievement of the following criteria: patient satisfaction and either a decrease of 50% or more in the 30-minute pain score (compared with the initial score) or an absolute pain score of 2.5 cm or less. Failure to achieve these criteria constituted treatment failure. Differences between groups were analyzed with the Kruskal-Wallis ANOVA and chi 2 tests. Data are reported as frequency percentages and median values, with a two-tailed P value of .05 or less considered significant.
RESULTS: Nausea, pain, and sedation scores were similar in all three groups before therapy. Thirty minutes after treatment, pain scores differed among those treated with prochlorperazine (1.1 cm), with metoclopramide (3.9 cm), and with placebo (6.1 cm, P = .003). Clinical success occurred more commonly after treatment with prochlorperazine (82%) than after metoclopramide (46%) or placebo (29%, P = .03). However, metoclopramide and placebo scores did not differ (P = .14). Nausea tended to be improved after prochlorperazine, compared with metoclopramide or placebo, at 30 minutes (P = .64). Four patients (6%) returned to the ED for relapse of migraine headache within 24 hours (three in the placebo group and one in the metoclopramide group).
CONCLUSION: i.v. prochlorperazine relieves the headache and tends to improve nausea better than metoclopramide in ED patients with acute migraine headache.
Cameron JD, Lane PL, Speechley M.
Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache.
Acad Emerg Med. 1995 Jul;2(7):597-602. doi: 10.1111/j.1553-2712.1995.tb03596.x.
Abstract/Text
OBJECTIVE: To compare the efficacy of IV chlorpromazine with that of IV metoclopramide in the treatment for acute migraine headache in the ED.
METHODS: A prospective randomized double-blind trial was undertaken at two university-affiliated urban EDs with a combined annual census of more than 85,000 patients. Included in the study were patients presenting to the ED with a diagnosis of migraine headache. The subjects were randomized to receive 0.1 mg/kg/dose IV of either chlorpromazine (CPZ) or metoclopramide (MC), up to a total of three doses.
RESULTS: Ninety-one patients completed the protocol; 44 received MC and 47 received CPZ. The demographics of the two groups were similar. Both drugs provided, for the majority of patients, adequate pain relief as measured on a visual analog scale (VAS) completed every 15 minutes from T = 0 minutes to T = 45 minutes. The average pain relief over 45 minutes (delta VAS) for CPZ was 4.87 cm, vs 4.34 cm for MC (p = 0.35). There also was no statistically significant difference in blood pressure (BP) changes (delta BP < 2 mm Hg for both systolic and diastolic BPs, p = 0.47 and 0.33) or numbers of patients reporting adverse effects (AEs) (CPZ: 16 of 35; MC: 13 of 29, p = 0.43). There was no severe AE with either study drug.
CONCLUSIONS: Metoclopramide and chlorpromazine administered IV are both effective in the management of acute migraine headache. They are associated with similar minor side-effect profiles.
Jones J, Pack S, Chun E.
Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache.
Am J Emerg Med. 1996 May;14(3):262-4. doi: 10.1016/S0735-6757(96)90171-0.
Abstract/Text
To compare the efficacy of intramuscular prochlorperazine and metoclopramide in the short-term treatment of migraine headache in the emergency department 86 eligible adult patients with moderate to severe migraine headache were evaluated prospectively at a university-affiliated community hospital. After randomization, each subject received a 2-mL intramuscular injection of sterile saline, prochlorperazine (10 mg), or metoclopramide (10 mg). No other analgesics were administered during the 60-minute study period; patient assessment of relief was followed using visual analog scales. Reduction in median headache scores was significantly better among those treated with prochlorperazine (67%) compared to metoclopramide (34%) or placebo (16%). Similarly, symptoms of nausea and vomiting were significantly relieved in the prochlorperazine group (chi 2 = 17.1, P < .001). However, rescue analgesic therapy was necessary in the majority of patients treated with prochlorperazine (16/28) and metoclopramide (23/29) after the 60-minute study period. Although intramuscular prochlorperazine appears to provides more effective relief than metoclopramide, these results do not recommend either drug as single-agent therapy for acute migraine headache.
MacGregor EA, Wilkinson M, Bancroft K.
Domperidone plus paracetamol in the treatment of migraine.
Cephalalgia. 1993 Apr;13(2):124-7. doi: 10.1046/j.1468-2982.1993.1302124.x.
Abstract/Text
This study was designed to evaluate the safety and efficacy of domperidone in combination with paracetamol in the treatment of migraine. Severity of headache, duration of migraine attack and overall efficacy of treatment were amongst the variables assessed in a randomized, double-blind, three-way cross-over comparison of 1 g paracetamol plus either domperidone 30 mg, domperidone 20 mg or placebo, taken at onset of headache. Forty-six patients attending the City of London Migraine Clinic completed the study. A significant difference was observed in the duration of the migraine attack: a median of 17.5 h with paracetamol alone was reduced to 12.0 h with the addition of domperidone 20 mg, and to 12.0 h with domperidone 30 mg. No significant adverse events were reported. A reduction in pain intensity and nausea was noted but this was not statistically significant. It was concluded that domperidone shortens the duration of a migraine attack and may help reduce headache and associated symptoms.
.
Guidelines and recommendations for the treatment of migraine. Italian Society for the Study of Headache (SISC).
Funct Neurol. 1993 Nov-Dec;8(6):441-6.
Abstract/Text
Pryse-Phillips WE, Dodick DW, Edmeads JG, Gawel MJ, Nelson RF, Purdy RA, Robinson G, Stirling D, Worthington I.
Guidelines for the diagnosis and management of migraine in clinical practice. Canadian Headache Society.
CMAJ. 1997 May 1;156(9):1273-87.
Abstract/Text
OBJECTIVE: To provide physicians and allied health care professionals with guidelines for the diagnosis and management of migraine in clinical practice.
OPTIONS: The full range and quality of diagnostic and therapeutic methods available for the management of migraine.
OUTCOMES: Improvement in the diagnosis and treatment of migraine, which will lead to a reduction in suffering, increased productivity and decreased economic burden. EVIDENCE AND VALUES: The creation of the guidelines followed a needs assessment by members of the Canadian Headache Society and included a statement of objectives; development of guidelines by multidisciplinary working groups using information from literature reviews and other resources; comparison of alternative clinical pathways and description of how published data were analysed; definition of the level of evidence for data in each case; evaluation and revision of the guidelines at a consensus conference held in Ottawa on Oct. 27-29, 1995; redrafting and insertion of tables showing key variables and data from various studies and tables of data with recommendations; and reassessment by all conference participants.
BENEFITS, HARMS AND COSTS: Accuracy in diagnosis is a major factor in improving therapeutic effectiveness. Improvement in the precise diagnosis of migraine, coupled with a rational plan for the treatment of acute attacks and for prophylactic therapy, is likely to lead to substantial benefits in both human and economic terms.
RECOMMENDATIONS: The diagnosis of migraine can be improved by using modified criteria of the International Headache Society as well as a semistructured patient interview technique. Appropriate treatment of symptoms should take into account the severity of the migraine attack, since most patients will have attacks of differing severity and can learn to use medication appropriate for each attack. When headaches are frequent or particularly severe, prophylactic therapy should be considered. Both the avoidance of migraine trigger factors and the application of nonpharmacological therapies play important roles in overall migraine management and will be addressed at a later date.
VALIDATION: The guidelines are based on consensus of Canadian experts in neurology, emergency medicine, psychiatry, psychology, family medicine and pharmacology, and consumers. Previous guidelines did not exist. Field testing of the guidelines is in progress.
.
Guidelines for the management of headache. Danish Neurological Society and the Danish Headache Society.
Cephalalgia. 1998 Jan;18(1):9-22.
Abstract/Text
Silberstein SD.
Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2000 Sep 26;55(6):754-62. doi: 10.1212/wnl.55.6.754.
Abstract/Text
Silberstein SD, Dodick D, Freitag F, Pearlman SH, Hahn SR, Scher AI, Lipton RB.
Pharmacological approaches to managing migraine and associated comorbidities--clinical considerations for monotherapy versus polytherapy.
Headache. 2007 Apr;47(4):585-99. doi: 10.1111/j.1526-4610.2007.00760.x.
Abstract/Text
Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than would be found as a coincidental association in the general population. Conditions that are frequently comorbid with migraine include depression, anxiety, stroke, epilepsy, sleep disorders, and other pain disorders. In addition, many common illnesses occur concomitantly (at the same time) with migraine and influence the treatment choice. Migraine management, and especially migraine prevention, can be challenging when patients have comorbid or concomitant illnesses. The objectives of this initiative are to review the literature on managing patients who have migraine and common comorbidities, present additional clinical approaches for care of these difficult patients, and evaluate the areas in which research is needed to establish evidence-based guidelines for the management of migraine with associated comorbid conditions.
Snow V, Weiss K, Wall EM, Mottur-Pilson C; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine.
Pharmacologic management of acute attacks of migraine and prevention of migraine headache.
Ann Intern Med. 2002 Nov 19;137(10):840-9. doi: 10.7326/0003-4819-137-10-200211190-00014.
Abstract/Text
Géraud G, Lantéri-Minet M, Lucas C, Valade D; French Society for the Study of Migraine Headache (SFEMC).
French guidelines for the diagnosis and management of migraine in adults and children.
Clin Ther. 2004 Aug;26(8):1305-18. doi: 10.1016/s0149-2918(04)80161-9.
Abstract/Text
BACKGROUND: The French Recommendations for Clinical Practice: Diagnosis and Therapy of Migraine are guidelines concerning the overall management of patients with migraine, including diagnostic and therapeutic strategies and assessment of disability.
OBJECTIVE: This article summarizes the guidelines as they apply to adults and children, and proposes future direction for steps toward optimal treatment of migraine in patients in France.
METHODS: The recommendations were categorized into 3 levels of proof (A-C) according to the National Agency for Accreditation and Evaluation in Health (ANAES) methodology and were based on a professional consensus reached among members of the Working Group and the Guidelines Review Group of the ANAES.
RESULTS: The International Headache Society diagnostic criteria for migraine should be used in routine clinical practice. Recommended agents for the treatment of migraine in adults include nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) monotherapy or in combination with metoclopramide, acetaminophen monotherapy, triptans, ergotamine tartrate, and dihydroergotamine mesylate. Patients should use the medication as early as possible after the onset of migraine headache. For migraine prophylaxis in adults, the following can be used: propranolol, metoprolol, oxetorone, or amitriptyline as first-line treatment, and pizotifen, flunarizine, valproate sodium, or topiramate as second-line treatment. Migraine in children can be distinguished from that in adults by shorter duration (2-48 hours in children aged <15 years), more frequent bilateral localization, frequent predominant gastrointestinal disturbances, and frequent pallor hailing the onset of the attack. The following drugs are recommended in children and adolescents: ibuprofen in children aged >6 months, diclofenac in children weighing >16 kg, naproxen in children aged >6 years or weighing >25 kg, ASA alone or in combination with metoclopramide, acetaminophen alone or in combination with metoclopramide, and ergotamine tartrate in children aged >10 years.
CONCLUSIONS: These guidelines are intended to help general practitioners to manage migraine patients according to the rules of evidence-based medicine.
Silberstein SD, Winner PK, Chmiel JJ.
Migraine preventive medication reduces resource utilization.
Headache. 2003 Mar;43(3):171-8. doi: 10.1046/j.1526-4610.2003.03040.x.
Abstract/Text
OBJECTIVE: To determine if long-term resource utilization is reduced by adding a preventive medication to a migraine management regimen that already includes acute medication.
BACKGROUND: In 2000, new evidence-based guidelines for the treatment of migraine were released by the US Headache Consortium and the American Academy of Neurology. Although these guidelines emphasize the role of preventive medication in achieving significant clinical improvement, little yet is known concerning the impact of such management on medical and pharmaceutical resources. Methods.-Resource utilization information in a large claims database was analyzed retrospectively.
RESULTS: Adding a preventive medication to migraine management reduced the use of other migraine medications, as well as visits to physician offices and emergency departments. In addition, both acute and preventive medications were associated with lower utilization of computed tomography and magnetic resonance imaging scans.
CONCLUSION: Migraine preventive drug therapy is effective in reducing resource consumption when added to therapy consisting only of an acute medication.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS.
Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.
Lancet Neurol. 2014 Sep;13(9):885-92. doi: 10.1016/S1474-4422(14)70128-0. Epub 2014 Aug 10.
Abstract/Text
BACKGROUND: Migraine remains poorly treated, with few effective preventive drugs available. We assessed the safety and efficacy of LY2951742, a fully humanised monoclonal antibody to calcitonin gene-related peptide, for migraine prevention.
METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 proof-of-concept study at 35 centres in the USA. Patients aged 18-65 years with four to 14 migraine headache days per month were randomly assigned (1:1) to LY2951742 or placebo by a computerised randomisation scheme. LY2951742 (150 mg) or placebo were given as a subcutaneous injection once every 2 weeks for 12 weeks. The primary endpoint was the mean change in number of migraine headache days per 28-day period assessed at 9-12 weeks. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Patients and treating investigators were masked to treatment allocation. Analyses were by intention to treat. A mixed-effects model of repeated measures was used, including patient baseline value, treatment, visit, and treatment-by-visit interaction as fixed effects, and patients as random effects. Safety measures were analysed according to the treatment received. This study has been completed and is registered with ClinicalTrials.gov, NCT01625988.
FINDINGS: Between July 31, 2012, and Sept 18, 2013, 218 patients were randomly assigned to LY2951742 (n=108, but one patient withdrew before treatment) or placebo (n=110). The mean change from baseline to week 12 in the number of migraine headache days was -4·2 (SD 3·1; 62·5% decrease) in the LY2951742 group compared with -3·0 (SD 3·0; 42·3% decrease) in the placebo group (least-squares mean difference -1·2, 90% CI -1·9 to -0·6; p=0·0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs seven [6%] of 110), upper respiratory tract infections (18 [17%] vs ten [9%]), and abdominal pain (six [6%] vs three [3%]). There were two serious adverse events reported in the treatment arm and four in the placebo arm, none of which were deemed to be related to the study drug.
INTERPRETATION: These results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of calcitonin gene-related peptide in the pathogenesis of migraine. Further controlled studies are needed to assess the safety and efficacy of monoclonal calcitonin gene-related peptide antibodies for the preventive treatment of migraine.
FUNDING: Arteaus Therapeutics.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR.
Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial.
JAMA Neurol. 2018 Sep 1;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212.
Abstract/Text
IMPORTANCE: Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients.
OBJECTIVE: To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura.
DESIGN, SETTING, AND PARTICIPANTS: The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population.
INTERVENTIONS: Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg.
MAIN OUTCOMES AND MEASURES: The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported.
RESULTS: Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups.
CONCLUSIONS AND RELEVANCE: Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02614183.
Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E.
Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial.
JAMA. 2018 May 15;319(19):1999-2008. doi: 10.1001/jama.2018.4853.
Abstract/Text
IMPORTANCE: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine.
OBJECTIVE: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose.
DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12.
PARTICIPANTS: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded.
INTERVENTIONS: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8).
MAIN OUTCOMES AND MEASURES: The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose.
RESULTS: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2).
CONCLUSIONS AND RELEVANCE: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02629861.
Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, Tepper SJ, Aycardi E, Loupe PS, Ma Y, Goadsby PJ.
TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points.
Neurology. 2016 Jul 5;87(1):41-8. doi: 10.1212/WNL.0000000000002801. Epub 2016 Jun 8.
Abstract/Text
OBJECTIVE: To evaluate the onset of efficacy of TEV-48125, a monoclonal antibody against calcitonin gene-related peptide, recently shown to be effective for the preventive treatment of chronic migraine (CM) and high-frequency episodic migraine.
METHODS: A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg vs placebo. Headache information was captured daily using an electronic headache diary. The primary endpoint was change from baseline in the number of headache hours in month 3. Herein, we assess the efficacy of each dose at earlier time points.
RESULTS: The sample consisted of 261 patients. For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively). For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057). For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005).
CONCLUSIONS: TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CM, TEV-48125 significantly decreases the number of headache hours within 3 to 7 days of injection.
© 2016 American Academy of Neurology.
Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA.
A Controlled Trial of Erenumab for Episodic Migraine.
N Engl J Med. 2017 Nov 30;377(22):2123-2132. doi: 10.1056/NEJMoa1705848.
Abstract/Text
BACKGROUND: We tested erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, for the prevention of episodic migraine.
METHODS: We randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of migraine days per month. Secondary end points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning).
RESULTS: A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P<0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P<0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo.
CONCLUSIONS: Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE ClinicalTrials.gov number, NCT02456740 .).
日本頭痛学会：CGRP関連新規片頭痛治療薬ガイドライン（暫定版）. Available from: https://www.jhsnet.net/guideline_CGRP.html
