Atenolol in Migraine Prophylaxis a Double-blind Cross-over Multicentre Study

SYNOPSIS
The prophylactic anti-migraine effect of atenolol was compared to placebo in a multicentre study on 63 patients with classical and/or common migraine. The study design was double-blind cross-over and patients were given atenolol 100 mg o.d. or matching placebo during a study treatment period of 24 weeks. The effect of atenolol was significantly better than that of placebo: integrated headache values were reduced in 70% of the patients (p = 0.004) and the proportion of days with headache was reduced in 59% of the patients (p = 0.010). Few side effects were reported with both atenolol and placebo. This study shows atenolol to be safe and effective in the prophylactic treatment of migraine.     

Comparative Trial of Tenormin (Atenolol) and Inderal (Propranolol) in Migraine

SYNOPSIS
Atenolol, 50 mg, b.i.d., and propranolol, 80 mg b.i.d., were given to 28 patients with a presumed diagnosis of migraine, in a placebo-controlled double-blind cross-over study, where each period lasted 6 weeks. In the total material, atenolol was significantly better than placebo in reducing attacks, whereas propranolol showed no definite such effect. In seven patients, the number of headache days was remarkably high (average: 22 headache days in 42 days), which may indicate that they have been inappropriately included in the material or have recorded interparoxysmal headache in addition to attacks. If these patients are excluded, the attack-reducing effects of both propranolol and atenolol are significant and of equal magnitude.     

Migraine Prophylaxis with Salmon Calcitonin: a Cross-over Double-blind, Placebo-controlled Study

SYNOPSIS
Ten women with histories of migraine attacks and with diagnosis of classic or common migraineconcluded a double-blind, placebo controlled, cross-over study to assess the effectiveness of syntheticsalmon calcitonin 100 MRC U. i.m. a day in preventing migraine attacks. After a two-month run-in phase thewomen were randomly allocated to one of the following two-month sequences: placebo-calcitonin orcalcitonin-placebo. The patients filled in every day a standard card with number, duration and severity ofattacks. The mean migraine frequency per month on calcitonin was 3.7±0.7 (s.e.m.) and on placebo 7.7±1.3(r<0.01). The ratio of total score of headache intensity to the number of days of observation on calcitoninwas 0.18±0.03 and on placebo was 0.30±0.04 (r<0.01). It is concluded that calcitonin is effective forprophylactic treatment of migraine and should be useful when other first-choice treatments arecontraindicated.     

CGRP may play a causative role in migraine

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.     

A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine

After four weeks of medication-free baseline observation, 29 patients with common migraine randomly received flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossed treatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizine significantly reduced the frequency of migraine attacks and the derived headache indices, but the duration and severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizine increased during the 16-week treatment period and during the last four weeks the number of migraine attacks reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was mild daytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent for common migraine.     

Naproxen sodium in the treatment of migraine

Seventy patients with classical or common migraine were treated during their attacks with either naproxen sodium or placebo in a randomised, double-blind parallel group study. The initial dose of naproxen sodium was 825 mg followed one hour later by a further 550 mg, if symptoms were the same or had improved. If the migraine symptoms had worsened, patients were offered an escape analgesic combination of 1000 mg paracetamol and 10 mg metoclopramide. Patients were assessed at monthly intervals for changes in the severity and duration of headache, premonitory symptoms (mainly visual disturbances) and photophobia, nausea and vomiting associated with migraine attacks that had occurred since the previous visit. Patients were studied for a maximum of ten attacks and significant improvement was observed in the severity and duration of headache when the patients were on naproxen sodium. Also the premonitory symptoms and photophobia improved significantly on naproxen sodium and significantly less rescue analgesics were required. Patients suffering from common migraine had less severe headaches and photophobia when taking naproxen sodium than when taking placebo and the headaches were shorter in duration and patients took less rescue analgesic. No significant difference was observed between the treatment groups in patients with classical migraine. Ten patients in the placebo group and six in the naproxen sodium group reported side-effects but these were possibly related to the use of rescue medication. Naproxen sodium proved safe and effective in common migraine attacks, but in this study efficacy was not established for classical migraine.     

PROPRANOLOL FOR MIGRAINE PROPHYLAXIS

SYNOPSIS
The preventive effect of propranolol on migraine attacks was compared to placebo in a double-blind cross-over trial. Thirty-two patients with serious and prolonged migraine participated in the 12-week study. The effect of propranolol was significantly better than that of placebo. The number of migraine attacks during the propranolol period was reduced in 22 patients (69%), and in 11 of these (34%) a reduction of more than 50% was seen. The intensity of headache was significantly reduced during the propranolol period. The intake of analgesics and preparations containing ergotamine was significantly reduced during the propranolol period also. No serious side effects were noted.     

The Influence of Plasma Free Fatty Acids and Cholesterol on the Aggregation of Blood Platelets in Migraine Patients

SYNOPSIS
The Platelet Aggregate Ratio (PAR) was determined in 34 women with common migraine during headache-free intervals. Fourteen of them were studied also during migraine attacks.
The levels of FFA and total cholesterol in the blood were determined simultaneously to assess their influence on aggregation of blood platelets.
Plasma FFA levels rose significantly during headache (r<0.001). The levels of total blood cholesterol did not show a homogenous distribution. In 20 patients blood cholesterol was elevated; in the remaining 14 patients levels were within the standard range.
The migraineurs with high cholesterol showed a significantly lower PAR during headache-free intervals than did the control subjects (r<0.001). There was no significant difference between PAR in migraineurs with normal cholesterol and the controls. A significant fall of PAR during migraine attacks was observed only in migraineurs with high cholesterol (r<0.01). There was a significant correlation between the falling of PAR and the level of blood cholesterol (r<0.05). The same correlation was found between the falling of PAR and the rising of FFA during migraine attacks (r<0.05).
We suggest that FFA can raise the number of circulating platelet aggregates during migraine episodes. Total blood cholesterol is one of the factors which define migraine populations with respect to platelet aggregation.     

Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study

Aspirin 650 mg and metoclopramide 10 mg in an effervescent preparation (Migravess) were compared with effervescent aspirin 650 mg (Alka-Seltzer) and placebo for common migraine attacks with a double-blind cross-over design. One hundred and eighteen patients with common migraine were entered. Eighty-five patients completed all three forms of treatment, eleven completed two, and six completed one. Medicine was taken when patients were sure they had a migraine attack and not just interval headache. After each form of treatment, they mailed a report form to the investigators. Additional medication was allowed after 2 h and was taken for 79/95 placebo treated attacks, 63/92 Migravess treated attacks, and 51/86 aspirin treated attacks (p less than 0.01). Aspirin was significantly better than placebo for pain but not quite significant for nausea. Migravess was significantly better than placebo for pain and for nausea. There was no significant difference between aspirin and Migravess with regard to analgesic effectiveness (p = 0.33) or to antinausea effect (p = 0.18).     

Managing migraine headaches experienced by patients who self–report with menstrually related migraine: a prospective, placebo–controlled study with oral sumatriptan

The objective was to evaluate the efficacy and tolerability of oral sumatriptan (100 mg) in patients who self–reported with menstrually related migraine. A prospective, multicentre, randomised, double–blind, placebocontrolled, two–group crossover study was carried out in 20 UK primary and secondary care surgeries. Of 115 patients with a self–reported history of menstrually related migraine that entered the study, 93 patients completed it. Patients treated all migraine attacks for 2 months with sumatriptan (100 mg) and for 2 months with placebo. The primary endpoint was the proportion of patients reporting headache relief at 4 hours for the first treated attack. Only 11% of patients fulfilled the protocol definition of menstrually related migraine. Patients reported a variable pattern of migraine attacks occurring inside and outside the menstrual window. For the first attack, significantly more patients receiving sumatriptan than placebo reported headache relief for attacks occurring inside (67% vs. 33%, p=0.007) and outside (79% vs. 31%, p<0.001) the menstrual period. Sumatriptan was generally well tolerated. Oral sumatriptan (100 mg) is an effective and well tolerated acute treatment for patients who report menstrually related migraine.     

A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the treatment of migraine

(Headache 2011;51:1078‐1086) Background.— Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack. Some attacks require high‐end therapy, while other attacks have treatment needs that are less immediate. While triptans are considered the “gold standard” of migraine therapy, they do have limitations and many patients are seeking other therapeutic alternatives. In 2005, an open‐label study of feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase of the attack. Methods/Materials.— In this multi‐center pilot study, 60 patients treated 221 attacks of migraine with sublingual feverfew/ginger or placebo. All subjects met International Headache Society criteria for migraine with or without aura, experiencing 2‐6 attacks of migraine per month within the previous 3 months. Subjects had <15 headache days per month and were not experiencing medication overuse headache. Inclusion required that subjects were able to identify a period of mild headache in at least 75% of attacks. Subjects were required to be able to distinguish migraine from non‐migraine headache. Subjects were randomized 3:1 to receive either sublingual feverfew/ginger or a matching placebo and were instructed but not required to treat with study medication at the earliest recognition of migraine. Results.— Sixty subjects treated 208 evaluable attacks of migraine over a 1‐month period; 45 subjects treated 163 attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo preparation. Evaluable diaries were completed for 151 attacks of migraine in the population using feverfew/ginger and 57 attacks for those attacks treated with placebo. At 2 hours, 32% of subjects receiving active medication and 16% of subjects receiving placebo were pain‐free (P = .02). At 2 hours, 63% of subjects receiving feverfew/ginger found pain relief (pain‐free or mild headache) vs 39% for placebo (P = .002). Pain level differences on a 4‐point pain scale for those receiving feverfew/ginger vs placebo were ?0.24 vs ?0.04 respectively (P = .006). Feverfew/ginger was generally well tolerated with oral numbness and nausea being the most frequently occurring adverse event. Conclusion.— Sublingual feverfew/ginger appears safe and effective as a first‐line abortive treatment for a population of migraineurs who frequently experience mild headache prior to the onset of moderate to severe headache.     

Propranolol in the treatment of acute migraine attacks

The efficacy of the beta-adrenoceptor antagonist propranolol in the acute treatment of patients in attacks of either classical (migraine with aura) or common migraine (migraine without aura) headache was assessed in a double-blind placebo-controlled crossover trial with fixed doses. The trial was carried out on 25 patients. The treatment period was set at eight weeks, with the provision of shortening or lengthening it if necessary with a maximum period of seventeen weeks. A minimum of three migraine attacks were treated during each treatment period. Patients were assessed according to: the mean duration and mean severity per treatment period of migraine attacks. The secondary efficacy assessment was made on the basis of the percentage of attacks requiring escape medication per treatment period. The study, based on the t-distribution statistical model with a confidence level of 95%, showed that propranolol had no significant effect in aborting acute attacks of migraine when compared with placebo.     

Efficacy of topical Rose (Rosa damascena Mill.) oil for migraine headache: A randomized double-blinded placebo-controlled cross-over trial

AimTo evaluate the effect of topical formulation of Rosa damascena Mill. (R. damascena) oil on migraine headache, applying syndrome diffrentiation model.Methods and materialsForty patients with migraine headache were randomly assigned to 2 groups of this double-blind, placebo-controlled cross-over trial. The patients were treated for the first 2 consecutive migraine headache attacks by topical R. damascena oil or placebo. Then, after one week of washout period, cross-over was done. Pain intensity of the patients' migraine headache was recorded at the beginnig and ten-sequence time schadule of attacks up to 24 h. In addition, photophobia, phonophobia, and nausea and/or vomitting (N/V) of the patients were recorded as secondary outcomes. Finally, gathered data were analysed in a syndrome differentiation manner to assess the effect of R. damascena oil on Hot- and Cold-type migraine headache.ResultsMean pain intensity of the patients' migraine headache in the different time-points after R. damascena oil or placebo use, was not significantly different. Additionally, regarding mean scores of N/V, photophobia, and phonophobia severity of the patients, no significant differences between the two groups were observed. Finally, applying syndrome differentiation model, the mean score of migraine headache pain intensity turned out to be significantly lower in patients with “hot” type migraine syndrome at in 30, 45, 60, 90, and 120 min after R. damascena oil application compared to “cold” types (P values: 0.001, 0.001, <0.001, <0.001, and 0.02; respectively).ConclusionIt seems that syndrome differentiation can help in selection of patients who may benefit from the topical R. damascena oil in short-term relief of pain intensity in migraine headache. Further studies of longer follow-up and larger study population, however, are necessitated for more scientifically rigorous judgment on efficacy of R. damascena oil for patients with migraine headache.     

Early treatment of migraine with rizatriptan: a placebo-controlled study

OBJECTIVE: To evaluate the efficacy of rizatriptan when administered early during a migraine attack. BACKGROUND: Several studies indicate that triptans are more efficacious when administered early during a migraine attack, when the pain is still mild. METHODS: One hundred and twelve rizatriptan-na?ve patients aged 20 to 64 years with a history of migraine with or without aura that progressively worsened when left untreated were instructed to treat a total of three migraine attacks with either rizatriptan 10 mg or placebo as early as possible during each attack. Seventy-four patients (68 women and 6 men) were assigned to use the active drug and 38 (35 women and 3 men) to placebo. The primary efficacy endpoint was pain-free response at 2 hours after administration of the study drug. Secondary efficacy measures were pain-free response at 1 hour and sustained pain-free response lasting between 2 and 24 hours. RESULTS: A total of 216 attacks were treated in the rizatriptan group and 109 in the placebo group. Pain-free response at 2 hours after early treatment was noted in 151 (70%) of attacks in the rizatriptan group and in 24 (22%) in the placebo group (P < .01). Pain-free response at 1 hour occurred in 97 (45%) and 9 (8%) attacks, respectively (P < .01). When the attacks were categorized by headache severity at the time of treatment, the pain-free response at 2 hours was higher for mild attacks than for moderate or severe attacks (P < .01). Sustained pain-free response after treatment was significantly higher for attacks treated with rizatriptan (60%) than for those treated with placebo (17%) (P < .001). Adverse events were observed in 62 patients in the rizatriptan group and 15 in the placebo group. Only 1 patient taking rizatriptan discontinued the study because of adverse events, and no serious adverse events were reported. CONCLUSIONS: Rizatriptan is significantly more likely than placebo to produce a pain-free response within 2 hours when the drug is administered early in the migraine attack, when pain is mild rather than moderate or severe.     

Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks

Glyceryl trinitrate, an exogenous nitric oxide (NO) donor, and histamine, which causes NO formation in vascular endothelium, have been shown to trigger migraine attacks. However, it remains uncertain whether NO is involved in the subsequent phase of migraine attacks. To answer this question we studied the effect of L-NGmethylarginine hydrochloride (546C88), a NO-synthase inhibitor, on spontaneous migraine attacks. In a double-blind study design, 18 patients with migraine without aura randomly received 546C88 (6 mg/kg) or placebo (5% dextrose) iv given over 15 mm for a single migraine attack (546C88 placebo, 15:3). Furthermore, 11 placebo-treated patients from previous double-blind trials with almost identical design were added to the placebo group in the statistical evaluation. Two hours after the infusion, 10 of 15 L -N^Gmethylarginine hydrochloride-treated patients experienced headache relief compared to 2 of 14 placebo-treated patients ( p =0.0l). Symptoms such as phono- and photophobia were also significantly improved. A similar trend for nausea was not significant. We conclude that NO may be involved in the pain mechanisms throughout the course of spontaneous migraine attacks.     

Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double-blind placebo-controlled study

This multicentre, double-blind, randomized, placebo-controlled, parallel study was designed to evaluate the efficacy of combined oral lysine acetylsalicylate and metoclopramide (LAS-MCP) in the acute treatment of migraine attacks. A total of 266 patients, 18–65 years old, with two to six attacks of migraine with or without aura (IHS criteria) per month were included. The patients had to treat two migraine attacks with LAS-MCP (1620 mg lysine acetylsalicylate-the equivalent of 900 mg aspirin- combined with 10 mg metoclopramide) or placebo. The main outcome measure was headache relief (reduction in headache severity from grade 3 or 2-severe or moderate-to grade 1 or 0-mild or none) 2 h after treatment. LAS-MCP was superior to placebo for headache relief (56% vs 28%) and for the following secondary outcome measures: complete headache relief (18% vs 7%; p < 0.001), nausea (28% vs 44%; p < 0.001), vomiting (3% vs 11%; p = 0.001), use of rescue medication (47% vs 68%; p < 0.001), global efficacy judged as good or excellent (32% vs 14%; p < 0.001). The tolerability was considered as good in 94% of treated attacks in both groups. Combined oral lysine acetylsalicylate and metoclopramide is an effective and well-tolerated acute treatment of migraine attacks.     

Tolfenamic Acid Rapid Release Versus Sumatriptan in the Acute Treatment of Migraine: Comparable Effect in a Double-Blind, Randomized, Controlled, Parallel-Group Study

The efficacy and safety of tolfenamic acid and oral sumatriptan in the acute treatment of migraine was studied at five neurological centers in Finland. One hundred forty-one patients experiencing 289 migraine attacks, fulfilling the diagnostic criteria for migraine with or without aura as defined by the International Headache Society, were randomized.
For first attacks, 77% of patients receiving tolfenamic acid experienced a reduction of the initial severe or moderate headache to mild or no headache after 2 hours, as compared to 79% in the sumatriptan group and 29% in the placebo group. No significant difference was found between active treatments ( P =0.85, 95% Cl [−22%, 18%]), however, both active treatments were significantly better than placebo; P =0.001, 95% Cl (26%, 69%) for tolfenamic acid and P =0.001, 95% Cl (28%, 71%) for sumatriptan. For second attacks, results were similar with 70% of patients receiving tolfenamic acid experiencing relief, as compared to 64% in the sumatriptan group and 39% in the placebo group.
No significant differences were observed in accompanying symptoms.
Both drugs were well tolerated with the frequency of adverse events; 30% for tolfenamic acid and 41% for sumatriptan, a nonsignificant difference.
In this study, tolfenamic acid and oral sumatriptan are comparably effective in the acute treatment of migraine. When comparably effective, factors like individual effect, tolerance, and cost of treatment should be considered when prescribing migraine medication.     

EEG during attacks of common and classical migraine

The Copenhagen acute headache clinic offered an opportunity to record EEG during migraine attacks in eleven patients with common migraine and ten patients with classical migraine. The median duration of the attacks was 9 h in common migraine. Three patients were studied during prodromes of classical migraine and seven in the early headache phase. The EEG was recorded in the resting state, during hyperventilation and during photic stimulation. No abnormalities were encountered in patients with common migraine nor in eight patients with classical migraine. In two patients with classical migraine mild abnormalities were seen during prodromes and in the early headache phase, but they were also present at a control EEG taken outside an attack. The present study indicates that migraine attacks are rarely associated with EEG abnormalities.     

Effects of symptomatic treatments on cutaneous hyperalgesia and laser evoked potentials during migraine attack

Previously an amplitude enhancement of laser evoked potentials (LEPs) was detected during migraine attack: we further examined pain threshold to CO2 laser stimuli and LEPs during attacks, evaluating the effect of almotriptan, lysine-acetylsalicylate and placebo treatment on cutaneous hyperalgesia to thermal stimuli delivered by CO2 laser and on LEP components. Eighteen patients suffering from migraine without aura were analysed. They were divided into three groups of six patients each, randomly assigned to lysine acetyl-salicylate, almotriptan or placebo treatments. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and not symptomatic side in all patients. The LEPs were recorded by 25 scalp electrodes. During attacks, the P2 wave was significantly enhanced; the amplitude of the P2 component obtained by the stimulation of the supraorbital zone during the attack on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. Both almotriptan and lysine acetyl-salicylate significantly reduced the P2 amplitude but they showed no effects on hyperalgesia to laser stimulation; headache relief following therapy was correlated with the reduction of the P2 amplitude. The cortical elaboration of laser-induced experimental pain seemed increased during migraine attack, and the severity of headache was mainly related to the increase of the later LEPs components expressing the attentive and emotive compounds of suffering. Reversion of this process appeared to be primarily responsible for the efficacy of drugs in treating migraine, though both almotriptan and lysine-acetil salicilate seemed to have no effect in reducing sensitization at second and third order nociceptive neurons.     

Treatment of migraine attacks with a long-acting somatostatin analogue (octreotide, SMS 201–995)

Long-acting somatostatin analogue (SMS 201–995) inhibits serotonin, bradykinin, prostaglandins, substance P, and vasoactive intestinal peptide, which may be involved in migraine. We therefore decided to test the efficacy of SMS 201–995 in relieving the pain of acute migraine attacks. Headache relief was defined as a reduction in severity from grade 3 or 2 (severe or moderate) to 1 or 0 (mild or none). Patients experiencing migraine attacks were evaluated clinically. A double-blind parallel group trial was performed in which patients randomly received either a subcutaneous injection of placebo (saline) or SMS 201–995 (100 μg). SMS 201–995 was significantly more effective than placebo in reducing headache grade at 2 h (1.5 0.6 vs 2.2 0.7; p < 0.01), 4 h (1.6 ± 0.6 vs 2.1 ± 0.8; p < 0.05) and 6 h (0.8 ± 0.9 vs 2.1 ± 0.8; p < 0.001) after the initiation of treatment. By 6 h, apparent headache relief (reduction in severity from grade 3 or 2 to 1 or 0) was experienced in 76.5% of SMS 201–995 treated patients and 25% of the placebo-treated group. Headache relief was significantly better in patients taking SMS 201–995 ( p < 0.02). Furthermore, none of the patients became pain-free (headache grade 0) on placebo, while significantly more patients (47%) were pain-free on SMS 201–995 at 6 h ( p < 0.01). Headache improvement started significantly earlier in those patients treated with SMS 201–995 than with placebo. SMS 201–995 significantly improves the pain of migraine attacks, 2 h after the beginning of treatment. Additionally, we observed no side effects of SMS 201–995. We therefore conclude that a single dose of 100 μg given subcutaneously is an effective and well-tolerated agent for the treatment of migraine attacks.