***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: OBJECTIVE To investigate the effect of low-intensity acenocoumarol treatment ( target INR 1.5 to 2.0 ) on the frequency and severity of migraine attacks .  BACKGROUND The positive effect of anticoagulation on  migraine  has been described in case reports and observational studies . METHODS We conducted a r and omized , open , crossover study in migraine patients . After a run-in period of 8 weeks , all patients received acenocoumarol or propranolol during a period of 12 weeks and , after a washout period of 2 weeks , propranolol or acenocoumarol during a second period of 12 weeks . RESULTS Nineteen patients fulfilling the criteria were included . In 12 patients with complete data collection , only one good responder could be noted . In the other patients , treatment with low-intensity acenocoumarol did not show improvement of migraine symptoms compared with the run-in period . Treatment with propranolol showed a trend towards improvement compared with the run-in period . No serious adverse events were observed . CONCLUSIONS Overall , low-intensity acenocoumarol treatment has no prophylactic effect in migraine patients OBJECTIVE This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate ( a Food and Drug Administration approved and widely accepted treatment for prevention of migraine ) in individuals with chronic migraine ( CM ) . METHODS A total of 59 subjects with CM were r and omly assigned to one of 2 groups : Group 1 ( n = 30 ) received topiramate plus placebo injections , Group 2 ( n = 29 ) received onabotulinumtoxinA injections plus placebo tablets . Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period . The primary endpoint was the Physician Global Assessment , which measured the treatment responder rate and indicated improvement in both groups over 12 weeks . Secondary endpoints , measured at weeks 4 and 12 , included headache days per month , migraine days , headache-free days , days on acute medication , severity of headache episodes , Migraine Impact & Disability Assessment , Headache Impact Test , effectiveness of and satisfaction with current treatment on the amount of medication needed , and the frequency and severity of migraine symptoms . At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period . Subjects not reporting a > 50 % reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these , 20 subjects , 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group , volunteered for this extension from weeks 14 to 26 . RESULTS This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM . Overall , the results were statistically significant within groups but not between groups . By week 26 , subjects had a reduction of headache days per month compared with baseline . This was a significant within-group finding . CONCLUSION OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures The calcium-entry blocker flunarizine ( Sibelium ; Janssen ) was compared with the beta-adrenoreceptor-blocking agent propranolol in the prophylaxis of  migraine . Fifty-eight patients were entered into a double-blind 4-month treatment trial . Patients in whom beta-blockers were contraindicated were excluded from the trial . At the end of the trial 28 patients had received 10 mg flunarizine  at night during the study , 29 patients had received 60 mg propranolol  3 times a day and 1 patient was withdrawn . Both groups responded well ; and there was a 4-fold drop in frequency of attacks . There was no significant difference between the two groups in terms of patient profile , onset of response to therapy , final response to therapy , incidence of dropout from the trial or incidence of side-effects . Side-effects for flunarizine were weight gain ( 9 patients ) and tiredness ( 6 ) , and for propranolol sleep disturbances including nightmares ( 6 ) , tiredness ( 8) , mental changes ( e.g. irritability ) ( 3 ) and weight gain ( 4 ) . Both flunarizine and propranolol are useful drugs for migraine prophylaxis and can be used effectively as first-line drugs . The low incidence of generally mild side-effects with flunarizine may make it preferable to many of the agents at present in use for migraine prophylaxis Acute treatment of menstrual migraine ( MM ) attacks is often incomplete and unsatisfactory , and perimenstrual prophylaxis with triptans , oestrogen supplementation or naproxen sodium may be needed for decreasing frequency and severity of the attack . In this pilot , open-label , non-r and omised , parallel group study we evaluated , in 38 women with a history of MM , the efficacy of frovatriptan ( n=14 ) 2.5 mg per os or transdermal oestrogens ( n=10 ) 25 μg or naproxen sodium ( n=14 ) 500 mg per os once-daily for the short-term prevention of MM . All treatments were administered in the morning for 6 days , beginning 2 days before the expected onset of menstrual headache . All women were asked to fill in a diary card , in the absence of ( baseline ) and under treatment , in order to score headache severity .  All women reported at least one episode of MM at baseline . During treatment all patients taking transdermal oestrogens or naproxen sodium and 13 out of the 14 patients ( 93 % ) taking frovatriptan  had at least one migraine attack ( p=0.424 ) . Daily incidence of migraine was significantly ( p=0.045 ) lower under frovatriptan than under transdermal oestrogens or NS . At baseline , the overall median score of headache severity was 4.6 , 4.2 and 4.3 in the group subsequently treated with frovatriptan , transdermal oestrogens and naproxen sodium , respectively ( p=0.819 ) . During treatment the median score was significantly lower under frovatriptan ( 2.5 ) than under transdermal oestrogens ( 3.0 ) and naproxen sodium ( 3.9 , p=0.049 ) . This was evident also for each single day of observation ( p=0.016 ) . Among treatments differences were particularly evident for the subgroup of patients with true MM ( n=22 ) and for frovatriptan vs. naproxen sodium . This study suggests that short-term prophylaxis of MM with frovatriptan may be more effective than that based on transdermal oestrogens or naproxen sodium AIM Topiramate is a small molecule widely used for the treatment of epilepsy , migraine , bipolar disorders and alcoholism , and its availability as a generic formulation could significantly reduce the National Health Service expenditure . A generic formulation , available in Italy under the trademark Sincronil , recently showed superimposable blood levels , after oral administration to healthy volunteers , with the reference formulation . In the present study we report the results of an open label , parallel group , r and omized , controlled study performed to evaluate the efficacy , tolerability and impact on disability of two different formulations of topiramate ( Sincronil and Topamax ) in patients with migraine without aura . METHODS Sixty patients aged between 18 and 65 years , suffering from migraine without aura with an attack frequency of 3 - 15 attacks/month were enrolled and received , after a titration phase lasting 20 days , r and omly either Sincronil or Topamax at the dose of 25 mg twice daily for 3 months . RESULTS Fifteen out of the 30 patients who were administered Sincronil reported an improvement in the clinical condition , with a decrease in the frequency of attacks at the 3rd month of treatment higher than 50 % with respect to the run-in period , 9 reported their clinical condition as being substantially unchanged and 6 reported that they had suspended the treatment within the first 4 weeks of therapy due to side effects . Among the 24 patients who continued treatment up to the 3rd month , the frequency of attacks during the 3rd month of treatment was significantly decreased from 7 ± 3.6 to 3.7 ± 3.7 ( P<0.0001 ) , migraine severity was reduced from 2.5 ± 0.5 to 1.7 ± 0.7 ( P<0.0005 ) and the MIDAS score was reduced from 14.3 ± 4.9 to 8.6 ± 5.5 ( P<0.0001 ) . Sixteen out of the 30 patients who were administered Topamax reported an improvement in the clinical condition with a reduction in the attack frequency at the 3rd month of treatment higher than 50 % with respect to the run-in period , 10 reported a substantially unchanged clinical condition and 4 stopped the treatment within the first weeks due to side effects . Among the 26 patients who continued treatment up to the 3rd month , headache frequency during the 3rd month of treatment was significantly reduced , from 7.3 ± 2.6 to 3.5 ± 2.7 ( P<0.0001 ) , migraine severity decreased from 2.4 ± 0.6 to 1.6 ± 0.8 ( P<0.0005 ) and the MIDAS score from 14.1 ± 4.2 to 6.8 ± 4.8 ( P<0.0001 ) . CONCLUSION In conclusion , in this study Topamax ( reference product ) and Sincronil ( generic formulation ) have proven therapeutically equivalent and both products were well tolerated The clinical efficacy of flunarizine and of propranolol for the prevention of migraine attacks  was assessed in a multicenter double-blind study lasting four months which was preceded by a single-blind placebo period of one month . For both drugs , more than half of the patients judged the effect to be good or very good . When considering the patients ' daily logs , both drugs produced a significant reduction of the number of attacks .  Propranolol furthermore significantly reduced the severity of attacks and the number of analgesics used during the attacks . In both groups no severe side effects were observed Migraine can not be cured and the aim , shared with the patient , is to minimise the impact of the illness on the patient 's life and lifestyle . The aim of prophylaxis is to reduce the number of migraine attacks . Prophylaxis should be considered when appropriately used acute management gives inadequate control of symptoms . The efficacy and safety of topiramate 50 mg/d and thioctic acid ( α-lipoic acid ) 300 mg/d either as monotherapy or in combination were investigated as migraine prophylactic agents . Forty secondary school migraineur girls were enrolled in the study . The study was conducted in two phases , a prospect i ve baseline phase and 1-month treatment phase . Combined topiramate/thioctic acid therapy was more effective than either topiramate or thioctic acid monotherapy as a migraine-preventive treatment . Combined topiramate/thioctic acid therapy  decreased the mean monthly migraine frequency from 5.86 ± 1.2 to 2.6 ± 0.98 ( p ⩽ 0.05 ) , topiramate ( 50 mg/d ) from 5.71 ± 1.4 to 4.75 ± 1.5 and thioctic acid ( 300 mg/d ) from 5.68 ± 1.6 to 5.22 ± 1.8 . Reduction in mean monthly migraine days was also significantly greater in the group receiving combined topiramate/thioctic acid ( from 12.32 ± 1.85 to 5.74 ± 1.1 ) compared to those receiving either topiramate 50 mg/d ( from 12.7 ± 1.34 to 11.85 ± 1.35 ) or thioctic acid 300 mg/d ( from 12.5 ± 1.72 to 11.65 ± 1.44 ) . The responder rate ( % of patients showing ⩾50 % reduction in monthly migraine frequency ) was 85 % in patients receiving combined topiramate/thioctic acid therapy compared to 30 % and 20 % in patients receiving either topiramate or thioctic acid , respectively . The incidence of adverse events was higher in patients receiving topiramate ( 50 mg/d ) monotherapy . The most common adverse events were nausea , fatigue , paraesthesia and taste perversion . We conclude that combined topiramate/thioctic acid  therapy is more effective and better tolerated  than topiramate monotherapy . The combination has lower monthly medication costs compared to the traditionally used topiramate 100 mg monotherapy In patients with migraine with or without aura the prophylactic effect of amitriptyline ( AMT ) and venlafaxine ( VLF ) was compared in a r and omized double-blind crossover study . Intolerable side effects result ed in drop out of five patients on AMT  ( due to hypersomnia , difficulty in concentration and orthostatic hypotension ) and one patient on VLF ( because of nausea and vomiting ) . Following the run-in period the patients ( n = 52 ) were r and omly treated with one of the study medications for 1 
    Output:
    
Conclusions The majority of comparative , prophylactic migraine RCTs do not include a placebo arm .
Failure to include a placebo arm may result in failure to demonstrate efficacy of potentially effective migraine-prophylactic agents .