Supplemental digital content 1: Search strategy

41

Supplemental digital content 1: Search strategy

MEDLINE via Ovid

(Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid

MEDLINE(R) 1946 to Present)

1 exp Headache Disorders, Primary/

2 headache*.ti,ab,kw.

3 head pain*.ti,ab,kw.

4 cephalalgi*.ti,ab,kw.

5 cephalgi*.ti,ab,kw.

6 cranial pain*.ti,ab,kw.

7 hemicrania*.ti,ab,kw.

8 migraine*.ti,ab,kw.

9 migraineur*.ti,ab,kw.

10 migranous*.ti,ab,kw.

11 or/1-10

12 exp Flunarizine/

13 apo-fluarizine.ti,ab,kw.

14 bartolium.ti,ab,kw.

15 betacap.ti,ab,kw.

16 bercetina.ti,ab,kw.

17 biogran.ti,ab,kw.

18 cebrium.ti,ab,kw.

19 cevadil.ti,ab,kw.

20 cymalium.ti,ab,kw.

21 degrium.ti,ab,kw.

22 dinegal.ti,ab,kw.

23 dizine.ti,ab,kw.

24 dulonor.ti,ab,kw.

25 efigraine.ti,ab,kw.

26 estovon.ti,ab,kw.

27 flerudin.ti,ab,kw.

28 fludan.ti,ab,kw.

29 fludil.ti,ab,kw.

30 flufenal.ti,ab,kw.

31 flugeral.ti,ab,kw.

32 flugraine.ti,ab,kw.

33 flumig.ti,ab,kw.

34 flunagen.ti,ab,kw.

35 flunarca.ti,ab,kw.

36 flunarin.ti,ab,kw.

37 flunariz.ti,ab,kw.

38 flunarizin.ti,ab,kw.

39 flunarizina.ti,ab,kw.

40 flunarizine.ti,ab,kw.

41 flunarizini.ti,ab,kw.

42 flunarizinum.ti,ab,kw.

43 flunatop.ti,ab,kw.

44 flunatrac.ti,ab,kw.

45 flunavert.ti,ab,kw.

46 flunaxyl.ti,ab,kw.

47 flunazon.ti,ab,kw.

48 fluner.ti,ab,kw.

49 flunex.ti,ab,kw.

50 flunit.ti,ab,kw.

51 flurium.ti,ab,kw.

52 flurizin.ti,ab,kw.

53 flurpax.ti,ab,kw.

42

54 flumax.ti,ab,kw.

55 fluver.ti,ab,kw.

56 fluvert.ti,ab,kw.

57 fluxarten.ti,ab,kw.

58 fluxus.ti,ab,kw.

59 fluzine.tw.

60 fluzinstad.ti,ab,kw.

61 fluzy.ti,ab,kw.

62 frego.ti,ab,kw.

63 fribe.ti,ab,kw.

64 funar.ti,ab,kw.

65 funasin.ti,ab,kw.

66 funazine.ti,ab,kw.

67 furnazm.ti,ab,kw.

68 "fu rui lin".ti,ab,kw.

69 gratizin.ti,ab,kw.

70 grenil.ti,ab,kw.

71 "hua xin".ti,ab,kw.

72 imigra.ti,ab,kw.

73 irrigor.ti,ab,kw.

74 issium.ti,ab,kw.

75 kemzin.ti,ab,kw.

76 migon.ti,ab,kw.

77 migrid.ti,ab,kw.

78 minium.ti,ab,kw.

79 nafluryl-or.ti,ab,kw.

80 natil-n.ti,ab,kw.

81 nomigrain.ti,ab,kw.

82 norium.ti,ab,kw.

83 lunatric.ti,ab,kw.

84 narzine.ti,ab,kw.

85 seremig.ti,ab,kw.

86 sibelium.ti,ab,kw.

87 silbellium.ti,ab,kw.

88 sibellum.ti,ab,kw.

89 sibelum.ti,ab,kw.

90 siberid.ti,ab,kw.

91 silum.ti,ab,kw.

92 simoyiam.ti,ab,kw.

93 sinral.ti,ab,kw.

94 sobelin.ti,ab,kw.

95 sufuni.ti,ab,kw.

96 suzin.ti,ab,kw.

97 migarid.ti,ab,kw.

98 migazin.ti,ab,kw.

99 migon.ti,ab,kw.

100 migranex.ti,ab,kw.

101 migrava.ti,ab,kw.

102 minium.ti,ab,kw.

103 mygran.ti,ab,kw.


105 "novo-flunarizine".ti,ab,kw.

106 profigran.ti,ab,kw.

107 promig.ti,ab,kw.

108 provanol.ti,ab,kw.

109 norium.ti,ab,kw.

110 rizelium.ti,ab,kw.

111 unalium.ti,ab,kw.

112 vanid.ti,ab,kw.

113 vasilium.ti,ab,kw.

43

114 vertigium.ti,ab,kw.

115 "vertizine d".ti,ab,kw.

116 xepalium.ti,ab,kw.

117 xmocariz.ti,ab,kw.

118 zentralin.ti,ab,kw.

119 zeroach.ti,ab,kw.

120 zerograin.ti,ab,kw.

121 zinasen.ti,ab,kw.

122 "R 14950".ti,ab,kw.

123 R14950.ti,ab,kw.

124 "R 149,50".ti,ab,kw.

125 "1 [bis(4 fluorophenyl)methyl] 4 cinnamylpiperazine".ti,ab,kw.

126 "1 cinnamyl 4 (4,4' difluorobenzhydryl)piperazine".ti,ab,kw.

127 or/12-126

128 clinical trial.mp.

129 clinical trial.pt.

130 random.mp.

131 tu.xs.

132 or/128-131

133 11 and 127 and 132

134 (133 and Humans/) or (133 not Animals/)

EMBASE via Ovid

(Embase 1974 to 2017 November 11)

1 exp "headache and facial pain"/

2 headache*.ti,ab,kw.

3 head pain*.ti,ab,kw.

4 cephalalgi*.ti,ab,kw.

5 cephalgi*.ti,ab,kw.

6 cranial pain*.ti,ab,kw.

7 hemicrania*.ti,ab,kw.

8 migraine*.ti,ab,kw.

9 migraineur*.ti,ab,kw.

10 migranous*.ti,ab,kw.

11 or/1-10

12 exp Flunarizine/

13 apo-fluarizine.ti,ab,kw.

14 bartolium.ti,ab,kw.

15 betacap.ti,ab,kw.

16 bercetina.ti,ab,kw.

17 biogran.ti,ab,kw.

18 cebrium.ti,ab,kw.

19 cevadil.ti,ab,kw.

20 cymalium.ti,ab,kw.

21 degrium.ti,ab,kw.

22 dinegal.ti,ab,kw.

23 dizine.ti,ab,kw.

24 dulonor.ti,ab,kw.

25 efigraine.ti,ab,kw.

26 estovon.ti,ab,kw.

27 flerudin.ti,ab,kw.

28 fludan.ti,ab,kw.

29 fludil.ti,ab,kw.

30 flufenal.ti,ab,kw.

31 flugeral.ti,ab,kw.

32 flugraine.ti,ab,kw.

33 flumig.ti,ab,kw.

44

34 flunagen.ti,ab,kw.

35 flunarca.ti,ab,kw.

36 flunarin.ti,ab,kw.

37 flunariz.ti,ab,kw.

38 flunarizin.ti,ab,kw.

39 flunarizina.ti,ab,kw.

40 flunarizine.ti,ab,kw.

41 flunarizini.ti,ab,kw.

42 flunarIzinum.ti,ab,kw.

43 flunatop.ti,ab,kw.

44 flunatrac.ti,ab,kw.

45 flunavert.ti,ab,kw.

46 flunaxyl.ti,ab,kw.

47 flunazon.ti,ab,kw.

48 fluner.ti,ab,kw.

49 flunex.ti,ab,kw.

50 flunit.ti,ab,kw.

51 flurium.ti,ab,kw.

52 flurizin.ti,ab,kw.

53 flurpax.ti,ab,kw.

54 flumax.ti,ab,kw.

55 fluver.ti,ab,kw.

56 fluvert.ti,ab,kw.

57 fluxarten.ti,ab,kw.

58 fluxus.ti,ab,kw.

59 fluzine.tw.

60 fluzinstad.ti,ab,kw.

61 fluzy.ti,ab,kw.

62 frego.ti,ab,kw.

63 fribe.ti,ab,kw.

64 funar.ti,ab,kw.

65 funasin.ti,ab,kw.

66 funazine.ti,ab,kw.

67 furnazm.ti,ab,kw.

68 "fu rui lin".ti,ab,kw.

69 gratizin.ti,ab,kw.

70 grenil.ti,ab,kw.

71 "hua xin".ti,ab,kw.

72 imigra.ti,ab,kw.

73 irrigor.ti,ab,kw.

74 issium.ti,ab,kw.

75 kemzin.ti,ab,kw.

76 migon.ti,ab,kw.

77 migrid.ti,ab,kw.

78 minium.ti,ab,kw.

79 nafluryl-or.ti,ab,kw.

80 natil-n.ti,ab,kw.


82 norium.ti,ab,kw.

83 lunatric.ti,ab,kw.

84 narzine.ti,ab,kw.

85 seremig.ti,ab,kw.

86 sibelium.ti,ab,kw.

87 silbellium.ti,ab,kw.

88 sibellum.ti,ab,kw.

89 sibelum.ti,ab,kw.

90 siberid.ti,ab,kw.

91 silum.ti,ab,kw.

92 simoyiam.ti,ab,kw.

93 sinral.ti,ab,kw.

45

94 sobelin.ti,ab,kw.

95 sufuni.ti,ab,kw.

96 suzin.ti,ab,kw.

97 migarid.ti,ab,kw.

98 migazin.ti,ab,kw.

99 migon.ti,ab,kw.

100 migranex.ti,ab,kw.

101 migrava.ti,ab,kw.

102 minium.ti,ab,kw.

103 mygran.ti,ab,kw.


105 "novo-flunarizine".ti,ab,kw.

106 profigran.ti,ab,kw.

107 promig.ti,ab,kw.

108 provanol.ti,ab,kw.

109 norium.ti,ab,kw.

110 rizelium.ti,ab,kw.

111 unalium.ti,ab,kw.

112 vanid.ti,ab,kw.

113 vasilium.ti,ab,kw.

114 vertigium.ti,ab,kw.

115 "vertizine d".ti,ab,kw.

116 xepalium.ti,ab,kw.

117 xmocariz.ti,ab,kw.

118 zentralin.ti,ab,kw.

119 zeroach.ti,ab,kw.

120 zerograin.ti,ab,kw.

121 zinasen.ti,ab,kw.

122 "R 14950".ti,ab,kw.

123 R14950.ti,ab,kw.

124 "R 149,50".ti,ab,kw.

125 "1 [bis(4 fluorophenyl)methyl] 4 cinnamylpiperazine".ti,ab,kw.

126 "1 cinnamyl 4 (4,4' difluorobenzhydryl)piperazine".ti,ab,kw.

127 or/12-126

128 random.tw.

129 clinical trial.mp.

130 exp health care quality/

131 or/128-130

132 11 and 127 and 131

133 (132 and Humans/) or (132 not Animals/)

CENTRAL (The Cochrane Library)

#1 MeSH descriptor: [Headache Disorders, Primary] explode all trees

#2 headache*:ti,ab,kw

#3 head pain*:ti,ab,kw

#4 cephalalgi*:ti,ab,kw

#5 cephalgi*:ti,ab,kw

#6 cranial pain*:ti,ab,kw

#7 hemicrania*:ti,ab,kw

#8 migraine*:ti,ab,kw

#9 migraineur*:ti,ab,kw

#10 migranous*:ti,ab,kw

#11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

#12 MeSH descriptor: [Flunarizine] explode all trees

#13 apo-fluarizine:ti,ab,kw

#14 bartolium:ti,ab,kw

#15 betacap:ti,ab,kw

#16 bercetina:ti,ab,kw

#17 biogran:ti,ab,kw

46

#18 cebrium:ti,ab,kw

#19 cevadil:ti,ab,kw

#20 cymalium:ti,ab,kw

#21 degrium:ti,ab,kw

#22 dinegal:ti,ab,kw

#23 dizine:ti,ab,kw

#24 dulonor:ti,ab,kw

#25 efigraine:ti,ab,kw

#26 estovon:ti,ab,kw

#27 flerudin:ti,ab,kw

#28 fludan:ti,ab,kw

#29 fludil:ti,ab,kw

#30 flufenal:ti,ab,kw

#31 flugeral:ti,ab,kw

#32 flugraine:ti,ab,kw

#33 flumig:ti,ab,kw

#34 flunagen:ti,ab,kw

#35 flunarca:ti,ab,kw

#36 flunarin:ti,ab,kw

#37 flunariz:ti,ab,kw

#38 flunarizin:ti,ab,kw

#39 flunarizina:ti,ab,kw

#40 flunarizine:ti,ab,kw

#41 flunarizini:ti,ab,kw

#42 flunarizinum:ti,ab,kw

#43 flunatop:ti,ab,kw

#44 flunatrac:ti,ab,kw

#45 flunavert:ti,ab,kw

#46 flunaxyl:ti,ab,kw

#47 flunazon:ti,ab,kw

#48 fluner:ti,ab,kw

#49 flunex:ti,ab,kw

#50 flunit:ti,ab,kw

#51 flurium:ti,ab,kw

#52 flurizin:ti,ab,kw

#53 flurpax:ti,ab,kw

#54 flumax:ti,ab,kw

#55 fluver:ti,ab,kw

#56 fluvert:ti,ab,kw

#57 fluxarten:ti,ab,kw

#58 fluxus:ti,ab,kw

#59 fluzine:ti,ab,kw

#60 fluzinstad:ti,ab,kw

#61 fluzy:ti,ab,kw

#62 frego:ti,ab,kw

#63 fribe:ti,ab,kw

#64 funar:ti,ab,kw

#65 funasin:ti,ab,kw

#66 funazine:ti,ab,kw

#67 furnazm:ti,ab,kw

#68 "fu rui lin":ti,ab,kw

#69 gratizin:ti,ab,kw

#70 grenil:ti,ab,kw

#71 "hua xin":ti,ab,kw

#72 imigra:ti,ab,kw

#73 irrigor:ti,ab,kw

#74 issium:ti,ab,kw

#75 kemzin:ti,ab,kw

#76 migon:ti,ab,kw

#77 migrid:ti,ab,kw

47

#78 minium:ti,ab,kw

#79 nafluryl-or:ti,ab,kw

#80 natil-n:ti,ab,kw

#81 nomigrain:ti,ab,kw

#82 norium:ti,ab,kw

#83 lunatric:ti,ab,kw

#84 narzine:ti,ab,kw

#85 seremig:ti,ab,kw

#86 sibelium:ti,ab,kw

#87 silbellium:ti,ab,kw

#88 sibellum:ti,ab,kw

#89 sibelum:ti,ab,kw

#90 siberid:ti,ab,kw

#91 silum:ti,ab,kw

#92 simoyiam:ti,ab,kw

#93 sinral:ti,ab,kw

#94 sobelin:ti,ab,kw

#95 sufuni:ti,ab,kw

#96 suzin:ti,ab,kw

#97 migarid:ti,ab,kw

#98 migazin:ti,ab,kw

#99 migon:ti,ab,kw

#100 migranex:ti,ab,kw

#101 migrava:ti,ab,kw

#102 minium:ti,ab,kw

#103 mygran:ti,ab,kw

#104 nomigrain:ti,ab,kw

#105 novo-flunarizine:ti,ab,kw

#106 profigran:ti,ab,kw

#107 promig:ti,ab,kw

#108 provanol:ti,ab,kw

#109 norium:ti,ab,kw

#110 rizelium:ti,ab,kw

#111 unalium:ti,ab,kw

#112 vanid:ti,ab,kw

#113 vasilium:ti,ab,kw

#114 vertigium:ti,ab,kw

#115 "vertizine d":ti,ab,kw

#116 xepalium:ti,ab,kw

#117 xmocariz:ti,ab,kw

#118 zentralin:ti,ab,kw

#119 zeroach:ti,ab,kw

#120 zerograin:ti,ab,kw

#121 zinasen:ti,ab,kw

#122 "R 14950":ti,ab,kw

#123 R14950:ti,ab,kw

#124 "R 149,50":ti,ab,kw

#125 "1 [bis(4 fluorophenyl)methyl] 4 cinnamylpiperazine":ti,ab,kw

#126 "1 cinnamyl 4 (4,4' difluorobenzhydryl)piperazine":ti,ab,kw

#127 #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26

or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or

#41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55


#70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84


#99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111

or #112 or #113 or #114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or

#124 or #125 or #126

#128 #11 and #127

48

Supplemental digital content 2: Excluded studies grouped after reason for exclusion

Reason for exclusion Study ID

One group received treatment

not proven effective

Agnoli 1991 [2], Brescia-Morra 1990 [15], Bussone 1987 [16], Bussone

1999 [17], Centonze 1985a [22], Drillisch 1980 [32], Gao 2006 [35],

Gerber 1989 [39], Grotemeyer 1989 [43], Harizanov 1997 [44], Hu 2003

[45], Lafuente 1990 [49], Lamsudin 1993 [50], Langohr 1988 [51],

Lastilla 1990 [52], Lastra 1990 [53], Li 2004 [55], Mei 2001 [63], Nappi

1987 [67], Pothman 1985 [75], Pothman 1987 [76], Steardo 1986 [87],

Yang 2004 [97], Zhong 2009a [100]

No intervention group

receiving flunarizine

Adwan 2010 [1]

Both intervention groups

received flunarizine

Chen 2014 [26]

No control group Augliera 1987 [11], Centonze 1985b [23], Ciancarelli 2004 [27],

Diamond 1983 [29], Micieli 1984 [65], Nattero 1985 [68], Nattero 1987

[69], Pini 1987 [74]

Not randomized Al Deeb 1992 [4], Cerbo 1986 [25], Gracia-Naya 2005 [41], Gracia-

Naya 2012 [40], Thomas 1991 [91], Visudtibhan 2004 [93], Worz 1983

[95]

Subjects not suffering from

episodic migraine

Baumgartner 2003 [12], Canepari 1985 [18], Cao 2016[21], Elbaz 1988

[33], Lepcha 2014 [54], Pardal 1991 [70]

Pooled migraine and tension

type headache

Garaizar 1998 [36]

No usable headache-related

outcomes

Berilgen 2005 [13], Dogan 2015 [31], Grotemeyer 1988 [42], La 1985

[48], Paterna 1990 [71]

Intravenous administration of

flunarizine

Pfaffenrath 1990 [72]

Only abstract or poster

material available

Cano 1997 [19], Cano 1998 [20], Kangasniemi 1989 [46], Klimek 1992

[47], Solomon 1982 [80], Sorge 1985b [84]

Not retrievable Allais 1997 [6], Andersson 1985 [9], Asole 2014 [10]

Only available in Chinese Li 2002 [56], Wu 2011 [96], Zhang 2009a [98], Zhang 2009b [99],

Zhong 2009b [101]

Review article Akova-Ozturk 2004 [3], Amery 1983 [7], Amery 1985 [8], Gelmers

1985 [38], Lücking 1988 [62], Raveau-Landon 1988 [78], Solomon 1985

[81], Taneri 1998 [90]

41

Supplemental digital content 3: Characteristics of included studies

Allais 2002 [5]

Methods Country: Italy.

Published language: English.

Study design: Prospective, randomized, open, controlled, parallel trial with two arms.

Duration of trial: No information.

Duration of participation: Eight months. Two months run in and six months treatment.

Ethical approval: Unclear.

Participants Setting: Woman’s headache center.

Inclusion criteria: Age ranging from 18–60 years, headache attacks showing the typical

features of migraine without aura according to the International Headache Society

criteria, a minimum of two years history of migraine, more than two migraine crises

per month in the last year.

Exclusion criteria: No past or present disease, no pregnancy or lactation, no

inadequate contraception and no previous treatment with acupuncture or other

mind/body modalities.

Total number randomized: One hundred and sixty patients.

Exclusions and withdrawals: Ten withdrawals, Flunarizine group: Three drowsiness,

three weight gain, one depression. Acupuncture group: two local pain, one change of

abode.

Age: Mean 37.8 years ± 9.8 years. Range 18-59 years.

Sex: One hundred and sixty females.

Race/ethnicity: No information.

Interventions Intervention groups: Flunarizine (n: 80) 10mg/day vs. acupuncture (n: 80).

Details: Flunarizine group were given 10mg daily for the first two months, and then

10mg daily for 20 days per month for the next four months. Acupuncture group

received acupuncture to specific points, the points were punctured with 0.3-mm-

diameter sterile disposable steel needles with a length of 52 mm inserted to a depth of

10 to 30 mm and manipulated until the patient reported the characteristic irradiating

sensation. Acupuncture was always preformed with the same needle manipulation

technique by three of the authors who are qualified and experienced acupuncturist.

Acupuncture was delivered weekly for the first two months, thereafter once a month

for four months.

Outcomes Reported and analyzed in our review:

Migraine frequency: Number of migraine attacks per month.

Intensity of attacks: rated on a four-point scale from no pain – severe pain

Doses of acute medication: Number of analgesics.

Adverse events.

Notes Funders of trial: No information.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence

generation

(selection bias)

Low risk Used computer-made randomization list:

“According to a predetermined computer-made

randomization list”. “The patients had an equal

probability of being assigned to either of the two

treatment groups”.

Allocation

concealment

(selection bias)

Unclear risk No information on allocation concealment.

42

Bordini 1997 [14]

Methods Country: Brazil.

Study design: Prospective, randomized, double-blind, controlled, parallel trial with

three arms.


Duration of participation: One-hundred and eighty-five days. Twenty days baseline

period, 120 days treatment and 45 day period after drug withdrawal.


Participants Setting: Outpatient Headache Clinic at the University Hospital of Ribeirão Preto.

School of Medicine, Brazil.

Inclusion criteria: Migraine diagnosed according to criteria by IHS. One year migraine

history, frequency of two to six attacks a month last six months.

Exclusion criteria: Obesity, cardiovascular disease, diabetes mellitus, history of

psychiatric disease and allergy. Other types of headache attacks or abuse of abortive

agents for headache attacks were later excluded. Women on oral contraceptives.

Total number randomized: Forty-five.

Exclusions and withdrawals: Seven. One got pregnant, one had major depression, two

abused analgesics, three lost to follow-up.

Age: Mean age 31.2 years. Range 17-48 years.

Sex: Forty-one females, 4 males.


Interventions Intervention groups: Flunarizine (n: 15) 10mg/day vs. propranolol group (n: 15)

60mg/day vs. flunarizine + propranolol group (n: 15) 10mg/day + 60mg/day.

Details: Drugs were delivered as dosages of 1 ml three times a day of solutions

containing 20mg/ml Propranolol and 3.3 mg/ml Flunarizine.


Migraine frequency: Mean frequency of migraine per 20 days.

Adverse events.

Reported, but not analyzed in our review:

Vital parameters: Weight, heart rate, systolic blood pressure.

Migraine index: Sum of daily intensity scores of headaches, scored on a four-point

scale.

Global evaluation: response to treatment as poor, good, very good or excellent.


Risk of bias

Blinding of

participants and

personnel

(Performance bias)

High risk Not blinded, no sham or dummy technique was

used.

Blinding of

outcome

assessment

(detection bias)

Low risk Diary outcomes were assessed by blinded personnel.

Incomplete

outcome data

(attrition bias)

Unclear risk Withdrawals reported and relatively equally

distributed. These were not included in the analysis.

Selective reporting

(reporting bias)

Low risk No reason to suspect selective reporting.

Other bias High risk Only women included in the study, this could lead to

selection bias.

43


Random sequence

generation

(selection bias)

Unclear risk No description of randomization procedure.

Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

Unclear risk Reported as double-blind trial. Unclear who was

blinded. Double-dummy medication was used.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diary cards was used. Unclear if outcome

assessors were blinded.

Incomplete

outcome data

(attrition bias)

High risk Possible attrition bias due to many drop outs and

analysis made only on completers.

Selective reporting

(reporting bias)

Low risk The review authors have no reason to suspect selective

reporting.

Cerbo 1985 [24]


Published language: Italian.

Study design: Prospective, randomized, double-blind, controlled, parallel trial with two

arms.


Duration of participation: Three months. One month baseline and two months

treatment.


Participants Setting: Neurological clinic at the university in Rome.

Inclusion criteria: Presence of headache symptoms with a frequency of four to 14

attacks per months. Disease lasting at least two years. Presence of at least three of the

following elements: Positive family history with vasomotor headache; pulsatile pain;

accompanying negative symptoms; prodromal symptoms; positive response to

vasoconstrictive medications.

Exclusion criteria: Organic causes of headache and concomitant illnesses.

Exclusions and withdrawals: Three participants. Two patients did not come in for first

check-up. One patient in pizotifen group quit because facial edema and nausea.

Total number randomized: Thirty patients.

Age: Range 23-54 years.

Sex: Fourteen female, 16 males.


Interventions Intervention groups: Flunarizine (n: 15) 15mg/day vs. pizotifen (n: 12) 1.5mg/day.

Details: Both drugs were provided in identical flasks labelled either “A” or “B”. No

information on co-interventions.


Adverse events.


Migraine frequency: Defined as number of attacks per month.

44

Duration of attacks: Defined as hours per month.

Intensity of attacks: Defined as hours of “intense headache” per month.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)


blinded.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Unclear if outcome assessors were blinded.

Incomplete

outcome data

(attrition bias)

Unclear risk Three drop outs, not likely to introduce bias, but it is

unclear if these were included in the analyses. All

discontinued patients have been accounted for.

Selective reporting

(reporting bias)

Low risk The review authors have no reason to suspect

selective reporting.

Diamond 1993 [28]

Methods Country: USA.

Publication language: English.

Study design: Prospective, randomized, double-blind, placebo-controlled, parallel trial

with two arms.


Duration of participation: Twenty-four weeks. Four weeks baseline and 20 weeks

treatment.


Participants Setting: Outpatient clinics.

Inclusion criteria: Participants had to have at least a two-year history of migraine, with

or without aura, and two to eight migraines per month. Patients considered for

enrolment had previously had successful migraine treatment.

Exclusion criteria: Combined headache, defined as migraine + tension type headache.

Total number randomized: One hundred and forty-three.

Exclusions and withdrawals: Forty-two participants had “insufficient” data to be

evaluated. One hundred and one participants included analyzed.

Age: Mean age 34.5 years in flunarizine group and 35.5 years in placebo group. Range

18-60 years.

Sex: Seventy-five females and 26 males.

Race/ethnicity: Eighty-seven caucasian, eight black and six other.

Interventions Intervention groups: Flunarizine (n: 50) 10 mg/day vs. placebo (n: 51).

Details: Flunarizine was given at night. Placebo was delivered similarly as flunarizine.

Participants were given general information regarding their migraine disease, including

patient education.

45


Migraine frequency: Reported as a frequency index by dividing number of attacks on

number of days evaluated.


Responders to treatment: 50% reduction in frequency or severity

Severity index.

Duration index.

Relief medication index.

Relative strength value of relief medications.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)


blinded. Placebo was delivered similarly as

flunarizine.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diary was used. Unclear if outcome


Incomplete

outcome data

(attrition bias)

High risk Hundred and forty-three recruited, but only 101

completed the study with “sufficient” data to be

evaluated. The reason for 42 exclusions is not

described, and may be source to significant bias.

Selective reporting

(reporting bias)

High risk Limited transparency of reporting. It is unclear at

what time-points different participants were

assessed.

Other bias High risk Only previous treatment responders were included.

This may give a biased effect estimate.

Diener 2002 [30]

Methods Country: Belgium, Denmark, France, Germany, Italy, Spain, Switzerland and Portugal.

Study design: Prospective, randomized, double-blind, comparative, parallel trial with

three arms.

Duration of trial: April 13th 1992 to March 29th 1996.

Duration of participation: Twenty weeks. Four weeks placebo run-in-phase and 16

weeks treatment.

Ethical approval: Yes, approved by ethics committees of all participating centres.

Participants Setting: Clinics in the participating countries.

Inclusion criteria: (1) Male or female; (2) Age 18 – 65; (3) two to six migraine attacks

every month for the preceding two months; (4) migraine present for at least one year;

(5) migraine with or without aura as defined by the International Headache Society; (6)

occurrence of interval headaches was permitted if the attacks could be recognized by

the patient and occurring less than six days per months.

46

Exclusion criteria: (1) Use of prophylactic migraine therapy in the 2 preceding months;

(2) previous unsuccessful adequate use of propranolol or flunarizine for migraine; (3)

history of depressive illness; (4) extrapyramidal disorders; (5) chronic obstruction

airway disease, bronchospasm or asthma; (6) heart failure, sinus bradycardia, 2nd

degree AV block, hypotension or peripheral vascular disease; (7) serious diseases such

as diabetes, serious hepatic, renal, cardiovascular, respiratory or malignant illness; (8)

alcohol or drug dependence; (9) pregnancy, lactation or child bearing potential without

adequate contraception; (10) absence of well-defined pain-free intervals of at least 24h

between headache attacks; (11) poor compliance during run in period.

Total number randomized: Eight-hundred and ten patients, 783 were included in ITT.

Exclusions and withdrawals: Two did not receive treatment. Twenty-five patients had

no 1 month baseline and were not included in the ITT-analysis. One-hundred and

forty-two participants discontinued prematurely. Forty-four subjects from flunarizine 5

mg-group, 53 from flunarizine 10mg-group and 45 from propranolol group.

Age: Median age 37 years. Range 17–66 years.

Sex: Six-hundred and fifty-eight females, 150 males.

Race/ethnicity: 97.9% Caucasian.

Interventions Intervention groups: Flunarizine 5mg group (n: 263) 5mg/day vs. flunarizine 10mg

group (n: 275) 10mg/5 days out of 7 vs. propranolol group (n: 270) 160mg/day.

Details: All three intervention groups received identical appearing capsules, containing

either 5- or 10mg flunarizine, 80- or 160mg propranolol or placebo. The flunarizine

10mg group received placebo capsules two days out of seven from the ninth week. The

propranolol group received 80mg/day first week and 160mg/day from second week.

No information on co-interventions.


Migraine frequency: Mean frequency the last 28 days of double-blind period and mean

attack frequency per four weeks during treatment.

Responders to treatment: 50% or greater reduction in migraine frequency.

Duration of attacks: Mean duration of migraine attack defined in hours and minutes.

Doses of acute medication: Number of migraine attacks treated with symptomatic

treatment.

Adverse events.

Notes Funders of trial: The study was supported by a grant from Janssen Beerse, Belgium.

Other: The trial was monitored by BRI International. Ragheno Business Center.

Risk of bias


Random sequence

generation

(selection bias)

Low risk Computer-generated randomization code prepared

by Janssen Research Foundation.

Allocation

concealment

(selection bias)

Low risk Medication was randomized in block of six, with

two of each treatment in each block. Each

investigator was provided with six sequentially

numbered boxes of trial medication.

Blinding of

participants and

personnel

(Performance bias)


blinded. Both groups received dummy medication to

match the drug they did not received.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diaries were used. Unclear if outcome


47

Incomplete

outcome data

(attrition bias)

Low risk Drop outs accounted for and evenly distributed

among the three groups. ITT-analysis made.

Selective reporting

(reporting bias)



Frenken 1984 [34]

Methods Country: The Netherlands.



with two arms.


Duration of participation: Three months.


Participants Setting: Headache patients presenting to their family doctor.

Inclusion criteria: Common or classic migraine as defined by the IHS Ad Hoc Cmttee.

They had to have had on average one attack per month during the last six months. In

addition secondary inclusion criteria had to be met concerning the nature of the

migraine attacks (throbbing or pulsating pain only), their severity (severe or

unbearable, i.e. interfering with daily tasks of necessitating bed rest) and their

frequency (over the last six months an average of at least one attack monthly).

Required 12 weeks absence of anti-migraine drugs prior to inclusion.

Exclusion criteria: Cluster headache, pregnancy, nursing women and uncompliance.

Total number randomized: Thirty-five.

Exclusions and withdrawals: None.

Age: Range 20-51 years.

Sex: Twenty-nine females, six males.



Details: Flunarizine administered as two 5 mg capsules at night. Placebo administered

identical to active preparation. No information on co-intervention.


Migraine frequency: Mean monthly incidence of attacks.

Responders to treatment: Percentage reduction in frequency of migraine attacks.

Extracted from graph as those with more than 50% reduction.

Adverse events.


Total evaluation of treatment as beneficial or not.


Risk of bias


Random sequence

generation

(selection bias)

Unclear risk. No description of randomization procedure.

Allocation

concealment

(selection bias)

Unclear risk No information of allocation concealment.

Blinding of

participants and



flunarizine.

48

personnel

(Performance bias)

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

Low risk No attrition.

Selective reporting

(reporting bias)

Low risk The review authors have no suspicion of selective

reporting.

Gawel 1992 [37]

Methods Country: Canada.

Study design: Prospective, randomized, double-blinded, controlled, parallel trial with

two arms.


Duration of participation: Five months. One month single-blind placebo wash out and

baseline period and four months treatment.

Ethical approval: Ethics Committee approval was obtained at each centre.

Participants Setting: Four Canadian centres.

Inclusion criteria: Between two and eight migraine headaches as defined by the World

Federation of Neurology Research Group in Migraine and Headache per month.

Exclusion criteria: Non-migrainous headache, previous unresponsiveness to more than

two antimigraine prophylactic drugs; pregnancy or lactation; asthma; depression; or

significant cardiovascular, renal or hepatic disease.

Total number randomized: Ninety-four patients.

Exclusions and withdrawals: Five participants did not provide baseline data, thus 89

participants were included in the analysis. Thirteen of the 89 participants did not

complete four months of treatment.

Age: Mean 35.7 years. Range 18–65 years.

Sex: Eighty-five females, 9 males.


Interventions Intervention groups: Flunarizine group (n: 46) 10mg/day vs. propranolol group (n: 48)

160mg/day.

Details: Flunarizine was delivered as 5mg at night first six days, followed by 10mg at

night the remaining period. Propranolol was started as 40mg at night and increased by

40mg every third day up to a maintenance dose at 160mg/day for the rest of the period.

Double placebo medication was used to maintain blinding.


Migraine frequency: Mean number of migraine attacks per month.

Intensity of attacks: Mean migraine attack severity on a severity grading scale from 1-

10 and difference from baseline.

Duration of attacks: Mean weighted duration of migraine attack and difference from

baseline. The paper does not clarify how the weighting is performed.

Adverse events.


Doses of acute medication: The paper does not report correct figures for extracting

data.

Headache unit index.

Notes Funders of trial: Janssen Pharmaceutica Inc. Mississauga, Ontario, Canada.

Other: Statistical support of MacDougall Scientific.

49

Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk Eighteen participants not completing the four-month

trial. No information on reason for withdrawal.

Selective reporting

(reporting bias)

High risk Limited reporting of adverse events.

Louis 1981 [57]

Methods Country: Belgium.

Language of publication: English.


with two arms.


Duration of participation: Three months.


Participants Setting: Trial run in general practices.

Inclusion criteria: All patients had to complain of typical attacks of throbbing or

pulsating headache to avoid tension type, and mixed headache. Furthermore a

diagnosis of classical or common migraine, with at least six attacks during the

preceding six months was required.

Exclusion criteria: None mentioned.

Total number randomized: Fifty-eight


Age: Mean age 29 years. Range 20-47 years.

Sex: Twenty-nine females and 29 males.



Details: Flunarizine administered as two 5 mg capsules twice daily. Placebo supplied

as identical looking capsules. No information co-interventions.


Migraine frequency: Number of migraine attacks during 3 months of double-blind

treatment.

Responders to treatment: Reduction in days with severe headache. Extracted from

graph as those with more than 50% reduction.

Adverse events.

50


Global appreciation by patient.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



flunarizine.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

Low risk No attrition.

Selective reporting

(reporting bias)

High risk Authors intend to report intensity and duration of

migraine attacks without doing so.

Louis 1982 [58]

Methods Country: Belgium and the Netherlands.



arms.


Duration of participation: Four months. Four months treatment, no run in.


Participants Setting: Outpatients recruited from several general practices.

Inclusion criteria: Participants diagnosed as suffering from either classical or common

migraine defined by Ad Hoc Cttee on Classification of Headache. Had to be able to

report moderate to severe headache of the throbbing or pulsating type during attacks.

At least six attacks during the preceding six months.

Exclusion criteria: None stated.

Total number randomized: Seventy-five participants.

Exclusions and withdrawals: Three participants were considered defaulters. Two due to

irregular intake of the medication. One due to not completing the diary card. Six of the

remaining 72 were only partially included in the analyses because they were treated for

two months or less.

Age: Mean 37 years. Range 17–57 years.

Sex: Forty females, 32 males.


Interventions Intervention groups: Flunarizine (n: 38) 10mg/day vs. pizotifen (n: 34) 2-3 mg/day

Details: The capsules were provided in two double-blind sets. Flunarizine group

received 10mg Flunarizine at night time and placebo at morning and noon. The

Pizotifen group received active drugs at all time points and were started at a dose of 1

51

mg, which was increased to 2-3 mg depending on response and adverse events. 18 of

34 participants where maintained on 2 mg, the others received 3 mg except for two

who received 2.5 mg daily.


Migraine frequency: Mean percentage reduction in migraine frequency per month

Adverse events.


Responders to treatment: 50% or greater reduction in migraine frequency. Extracted

from figure.

Intensity of attacks: Attack severity on a four-point scale.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diary cards were used. Unclear if outcome


Incomplete

outcome data

(attrition bias)

Unclear risk Dropouts accounted for and evenly distributed.

Analysis made on completers for each time point.

Selective reporting

(reporting bias)

High risk Duration not reported even though it was mention as

outcome. Only a mentioning that it was not

significantly reduced.

Ludin 1989 [59]

Methods Country: Switzerland.


Study design: Prospective, randomized, double-blind, controlled, parallel study with

two arms.


Duration of participation: Five months. One month placebo run in, four months

treatment.


Participants Setting: The Neurological Clinic at University of Berne, Switzerland.

Inclusion criteria: Age between 16 and 65 years of age suffering from migraine,

defined as attacks of headache which interfere with their activities and which have at

least three of the following features: pulsating pain, frequently unilateral, accompanied

by nausea, vomiting, photophobia, scotoma and a positive family history.

Exclusion criteria: Non-compliance, contraindications to one of the active compounds,

pregnancy or inadequate contraception, posttraumatic headaches and pathological

52

neurological findings between the attacks.

Total number randomized: Seventy-one patients.

Exclusions and withdrawals: Twenty-three total. Twelve patients dropped out during or

at the end of the placebo period. During treatment: Three patients from flunarizine

group and eight patients from propranolol group withdrew. Five dropped out due to no

effect, five due to side effects and one due to non-compliance.

Age: Mean age 34.3 years (SD 11.8).

Sex: Fifty-one females, 20 males.


Interventions Intervention groups: Flunarizine group (n: 27) 10mg/day vs. propranolol group (n: 32)

120mg/day.

Details: Propranolol was delivered as 40mg three times a day. Medication was

provided as identical tablets in neutral containers. Unclear if flunarizine group received

placebo to match the three-times dosing of propranolol.


Migraine frequency: Number of attacks last month of active treatment month.

Responders of treatment: 50% or greater reduction in migraine frequency.

Intensity of attacks: Scored on a three-point scale.

Duration of attacks: Hours pr. attack last month of active treatment.

Doses of acute medication.

Adverse events.


Total duration of attacks.

Migraine index: Duration multiplied by severity.

Global evaluation.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

High risk Reported as double-blind trial. Unclear who was

blinded. Unclear if flunarizine group was given

dummy-treatment to match the three tablets per day

that the propranolol group was given.

Blinding of

outcome

assessment

(detection bias)

Low risk Reports using a blind study coordinator.

Incomplete

outcome data

(attrition bias)

Low risk Reported reasons for drop-out. All participants were

included in the analysis with “last observed value

carried forward”.

Selective reporting

(reporting bias)

Low risk No reason to suspect selective reporting.

53

Luo 2012 [60]

Methods Country: China.

Study design: Prospective, randomized, open, controlled, parallel trial with three arms.

Duration of trial: March 2007 to July 2009.

Duration of participation: Thirteen months. One month observation and 12 months

treatment.

Ethical approval: The local Ethics Committee approved the study.

Participants Setting: Participants included were regular patients seen in the headache center of the

First Affilated Hospital of Sun Yat-sen University.

Inclusion criteria: Migraine diagnosis according to ICHD-2, with two or more days per

month that produce disability despite the lack of acute treatment. Aged 18-65 years.

Exclusion criteria: (1) Use of migraine prophylactic in month before trial entry or

flunarizine within three months before trial entry; (2) prior poor response to migraine

prophylaxis; (3) overuse of analgesics and abortive migraine medication; (4) history of

depressive illness; extrapyramidal disorders; chronic obstructive pulmonary disease,

bronchospasm or asthma; heart failure, sinus bradycardia (<45 bpm), second-degree

atrioventricular block, hypotension or peripheral vascular disease; serious diseases

(diabetes, serious hepatic, renal, cardiovascular, respiratory, or malignant illness); (5)

pregnancy, lactation, or child-bearing potential without adequate contraception; and (6)

history of allergy to flunarizine or topiramate.

Total number randomized: One hundred and fifty.

Exclusions and withdrawals: Twentyfour discontinued prematurely (11 in flunarizine

group, six in topiramate group, seven in flunarizine + topiramate group). Thus 126 are

described in these characteristics. The main reasons for premature discontinuation

were: adverse events (five in topiramate group, and four in flunarizine + topiramate

group), lack of efficacy (eight in flunarizine group) and lost to follow-up (three in the

flunarizine group, one in the topiramate group, and three in the flunarizine +

topiramate group).

Age: Mean age 43.0 years +/- 12.9 years.

Sex: Ninety females and 36 males.


Interventions Intervention groups: Flunarizine (n: 39) 5 mg/day. vs. topiramate (n: 44) 25-100mg/day

vs. flunarizine + tompiramate (n: 43) 5mg/day + 25-100mg/day.

Details: Topiramate started at 25 mg/day and increased by 25 mg/week until reaching

target dose of 100 mg/day. Decrease to tolerated dose in case of adverse events. No

information co-interventions.


Migraine frequency: Monthly number of migraine attacks, and total number of days

with headache every month.

Adverse events.


Responders to treatment: 50% reduction in migraine frequency compared to baseline.

Intensity of attacks: Severity of every attack assessed on a visual analog scale (0-10).

Doses of acute medication: Time and dosage of rescue medication.

Notes Funders of trial: This study was funded by the National Natural Science Foundation

(No. 81171101), Science and Technology Item of Guangdong Province of China (No.

2009B080701072 and No. 2009B060700041), Natural Science Foundation of

Guangdong Province, China (No. 9451008901002160).

Other: Inclusion criteria states participants must have chronic migraine according to

ICHD-2, but lists the criteria and characteristics of participants as episodic migraine.

We interpret this as a language mismatch and that episodic migraine participants were

in fact included.

Risk of bias


54

Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

High risk No form for blinding mentioned.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diary cards was used. Unclear if the

outcome assessors were blinded.

Incomplete

outcome data

(attrition bias)

High risk Serious attrition from flunarizine group due to

ineffectiveness, and only completers are included in

analyses.

Selective reporting

(reporting bias)

High risk Duration of migraine attacks is mentioned as an

outcome in methods, but not reported sufficiently

under results.

Lutschg 1990 [61]

Methods Country: Switzerland.

Published language: German.

Study design: Prospective randomized, double blind, controlled, parallel trial with two

arms.


Duration of participation: Five months. One month placebo run-in and four months

treatment.


Participants Setting: No information.

Inclusion criteria: Children with classical or common migraine with three of the

following criteria fulfilled: pulsating pain, unilateral pain, nausea, vomiting,

photophobia, visual disturbances and family history of migraine. In addition at least six

attacks in the preceding six months.

Exclusion criteria: Secondary headaches, obstructive bronchial disease, bradychardia

and hypotonia, diabetes, allergies to the study drugs, uncooperative patients and

pathological neurological exam.

Total number randomized: Thirty-three.

Exclusions and withdrawals: One participants dropped out due to adverse events.

Age: Mean age 10.5 +/- 3.1 years. Range 3-15 years.

Sex: Seventeen females, 16 males.


Interventions Intervention groups: Flunarizine (n: 17) 5-10mg/day vs. propranolol (n: 16) 30-

120mg/day.

Details: Dosing regime was decided through three weight groups: A (15-25 kg), B (25-

35 kg), and C (over 35 kg). Group A received 5 mg flunarizine, while group B and C

received 10 mg flunarizine, all as evening doses. Group A received 10 mg x 3, Group

B received 20 mg x 3, and group C received 40 mg x 3 in morning, midday and

evening. Placebo was given to flunarizine group at morning and midday. No



Migraine frequency: Number of migraine attacks per month.

55

Adverse events.


Patient evaluation.


Risk of bias


Random sequence

generation

(selection bias)

Unclear risk No information on randomization procedure.

Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



flunarizine.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diaries were used. Unclear is outcome


Incomplete

outcome data

(attrition bias)

Low risk Only one dropout. The rest of the participants were

included in analyses.

Selective reporting

(reporting bias)

High risk Methods describe assessment of duration, intensity,

and use of acute medication, but these are

insufficiently reported.

Mendenopoulos 1985 [64]

Methods Country: Greece.



with two arms.


Duration of participation: Five months. One month baseline and four months treatment.


Participants Setting: Patients referred to the neurological and psychiatric department.

Inclusion criteria: Migraine diagnosis according to the Ad Hoc Cmttee on

Classification of Headache, and four or more moderate to severe attacks during the last

3 months.

Exclusion criteria: Other headaches. Pregnancy and oral contraception.

Total number randomized: Thirty entered the study. Most likely only 20 were

randomized (see exclusions and withdrawals).

Exclusions and withdrawals: Ten participants failed to show up during second month,

and were not included in analyses. Thus the remaining twenty were randomized. Five

participants did not complete last month of treatment period.

Age: Median 44 years. Range 20-65 years.

Sex: Sixteen females, four males.


56

Interventions Intervention groups: Flunarizine (n: 9) 10mg/day vs. placebo (n: 11).

Details: Flunarizine administered at night. Placebo administered to match active drug.

No information on co-interventions.


Responders to treatment: Percentage reduction in frequency of migraine attacks.

Extracted from graph as those with more than 50% reduction.

Adverse events.


Change in migraine attack duration.

Headache severity graded on a 1 to 4-point scale.

Migraine index calculated as monthly number of attacks multiplied by mean monthly

severity of the attack.

Migraine index corrected calculated as migraine index multiplied by mean monthly

duration of the attack.


Risk of bias


Random sequence

generation

(selection bias)

Low risk Randomization was done according to a computer-

drawn randomization list.

Allocation

concealment

(selection bias)

Unclear risk No information of allocation concealment.

Blinding of

participants and

personnel

(Performance bias)



flunarizine.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk Considerable attrition. Ten of thirty participants

dropped out with sparse explanation for reason to

drop out. Analyses only made on completers. In

addition only 15 of 20 participants completed fourth

month of treatment.

Selective reporting

(reporting bias)

High risk Insufficient reporting of outcomes at fourth month of

trial. In light of the high attrition at this point,

serious bias may be present.

Mitsikostas 1997 [66]

Methods Country: Greece.


Study design: Prospective, randomized, double-open, controlled, parallel design with

two arms.


Duration of participation: Twelve weeks. Four weeks observation and eight weeks

treatment.

Ethical approval: Obtained by institutional board of the Athens Naval and Veterans

Hospital.

57

Participants Setting: Randomly selected among regular patients attending the Headache Service of

the Athens Naval and Veterans Hospital.

Inclusion criteria: (1) patients suffering from migraine according to IHS (ICHD-2); (2)

aged 15-60 years; (3) at least 3 migraine attacks per month for previous 6 months; and

(4) negative brain CT-scan.

Exclusion criteria: (1) Other headache disorders; (2) other migraine prophylaxis; (3)

contraindications to the drugs; (4) abnormal liver and kidney functions; (5) pregnancy

or pregnancy intentions; and (6) chronic medication use, including contraceptives and

anti-hypertensive drugs.

Total number randomized: Forty-four.

Exclusions and withdrawals: Three withdrawals. Two dropped out from flunarizine

group, one during observation for loss to follow-up, and one for severe somnolence.

One dropped out from the valproate group due to ineffective treatment.

Age: Mean age 36.1 years in flunarizine group and 34.6 years in valproate group.

Sex: Thirty-one females, 13 males.


Interventions Intervention groups: Flunarizine (n: 22) 10mg/day vs. sodium valproate (n: 22)

1000mg/day.

Details: Flunarizine group started at 5mg for seven days, then increased to 10mg, given

in a single evening dose. Valproate started at 250mg and was increased by 250mg

every third day up to a dose of 1000mg per day, administered as 500mg twice daily.

No information on co-interventions. Use of acute medication allowed.


Responders to treatment: More than 50% reduction in migraine frequency.

Adverse events.


Migraine frequency: Frequency of migraine attacks per month (four weeks).

Duration of attacks: Mean duration of migraine attacks in hours.

Intensity of attacks: Mean severity of migraine attack on 11-point scale.

Doses of acute medication: Average use of symptomatic drugs.

Mean state of physical activity during the migraine attack.

Migraine characteristics.

Response to acute drug administration.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

High risk The study was double-open.

Blinding of

outcome

assessment

(detection bias)

High risk The study was double-open and no information

suggests that outcome assessment was made by

blinded personnel.

58

Incomplete

outcome data

(attrition bias)

Unclear risk There are few dropouts. Analyses are made only on

completers.

Selective reporting

(reporting bias)



Pini 1985 [73]




with two arms.

Duration of trial: May 1983 to March 1984.

Duration of participation: One hundred and eighty days. Two months baseline and

hundred and twenty days treatment.


Participants Setting: Outpatients at the Headache Study Centre of the University of Modena.

Inclusion criteria: Diagnosis of classical or common migraine.

Exclusion criteria: None stated.

Total number randomized: Twenty-nine.


Age: Mean age 39.5 years.

Sex: Twenty-four females, five males.


Interventions Intervention groups: Flunarizine (n: 14 or 15) 10 mg/day vs. placebo (n: 14 or 15).

Details: Flunarizine administered in doses of 10 mg twice a day for two weeks,

thereafter 10 mg at bedtime. No details on placebo. No information on co-

interventions.


Migraine frequency: Defined as a headache unit index with number of headaches

divided by number of days in evaluation.


Number of spikes in electronystagmographic recordings.

Notes Funders of trial: The work was partially supported by C.N.R. grant n. 8202180F9.

Risk of bias


Random sequence

generation

(selection bias)

Unclear risk Randomization only mentioned in preliminary

results (ref Pini 1986).

Allocation

concealment

(selection bias)

Unclear risk Randomization only mentioned in preliminary

results (ref Pini 1986).

Blinding of

participants and

personnel

(Performance bias)


blinded.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Unclear if outcome assessors were blinded.

59

Incomplete

outcome data

(attrition bias)

Low risk No dropouts, but still unclear how many were

allocated to each arm.

Selective reporting

(reporting bias)

High risk Very insufficient reporting of migraine intensity,

drug consumption and adverse events.

Rascol 1986 [77]

Methods Country: France.



arms.


Duration of participation: Four months, no run-in period.


Participants Setting: Headache outpatient clinics.

Inclusion criteria: Participants had to be diagnosed according to the Ad Hoc Cttee on

Migraine, had to have migraine symptomatology for at least two years with at least six

attacks last six months.

Exclusion criteria: Other headache than migraine. Participants with glaucoma, prostate

adenoma and pregnant women were also excluded.

Total number randomized: Thirty-five.

Exclusions and withdrawals: Three, one in flunarizine group cause of weight gain and

drowsiness. Two in pizotifen group, one because of weight gain and asthenia, and one

because of inefficacy.

Age: Median age 38 years. Range 28–59 years.

Sex: Twenty-five females, 10 males.


Interventions Intervention groups: Flunarizine group (n: 21) 10mg/day vs. pizotifen group (n: 14)

2.19 mg/day.

Details: Flunarizine was delivered as 10mg in the morning for the first three days, then

10 mg in the evening in the next three days, then 5 mg two times in the night. Dosing

of pizotifen was progressively increased during the first week. 0.73 mg/day for the first

three days, then 1.46 mg/day for the next three days, and 2.19 mg/day for the rest of

the treatment period. Both intervention groups received the same number of tablets

during the whole treatment period by giving matching placebo to the flunarizine group


Migraine frequency: Mean percentage reduction in monthly incidence of migraine

attacks.

Adverse events.


Investigators evaluation.


Risk of bias


Random sequence

generation

(selection bias)

Low risk Computer-generated randomization list was used.

Allocation

concealment

(selection bias)


60

Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk One withdrew cause to lack of efficacy, other

withdrawals is documented. There was significant

difference in intervention group size, one inefficacy

drop out was reported in pizotifen group, together

this may introduce attrition bias.

Selective reporting

(reporting bias)

High risk Insufficient reporting of intensity and duration.

Shimell 1990 [79]

Methods Country: South Africa.



arms.


Duration of participation: Four months treatment.

Ethical approval: Yes, approved by Witwatersrand Human Ethics Cttee.

Participants Setting: Polyclinic and medical and neurological outpatients at Johannesburg hospital.

Inclusion criteria: Either common or classic migraine as defined by the Ad Hoc Cttee

on Classification of Headache. To be admitted to the trial the patients had to have

suffered 2–8 attacks of common or classic migraine monthly for six months before

entry, and not to have used any prophylactic agent within the preceding month.

Exclusion criteria: Patients who were likely to suffer potentially dangerous side-effects

from propranolol prophylaxis (asthma, hypertension, arrhythmias or cardiac failure)

were excluded from the study.

Total number randomized: Fifty-eight.

Exclusions and withdrawals: Nine. One lost to follow up, three discontinued because

of inefficacy, two in flunarizine group and one in propranolol group. Five had adverse

events that caused them to drop out.

Age: Mean 34.5 years. Range 16–61 years.

Sex: Forty females, 17 males.


Interventions Intervention groups: Flunarizine (n: 28) 10mg/at night vs. propranolol (n: 29)

180mg/day.

Details: Propranolol was started at 60mg, and the dosage was increased every 4th day

by 30mg till a maintenance dose of 180mg at the end of day 20. No information on co-

interventions.


Migraine frequency: Number of attacks per month.

Adverse events.


Migraine intensity: Only reported as no significant change.

Headache duration: Only reported as no significant change.

Notes Funders of trial: Janssen Pharmaceutica ltd.

Risk of bias

61


Random sequence

generation

(selection bias)

Unclear risk States randomization is made by number allocation;

it is unclear what this means.

Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

Low risk All participants except the one lost to follow-up was

included in the analysis.

Selective reporting

(reporting bias)

High risk Sparse reporting of several outcomes, herein

associated neurologic outcomes. No reporting of

variance of outcomes.

Sorge 1985a [82]




with two arms.


Duration of participation: Three months treatment.


Participants Setting: Headache Centre at the Department of Neurology, 2nd Medical School, Via

Pansini.

Inclusion criteria: Children with migraine diagnosed according to the Valquist criteria.

Exclusion criteria: No information.

Total number randomized: Forty-eight.

Exclusions and withdrawals: Six. Three in the flunarizine group due to side effects.

Three in the placebo group due to inadequate pain relief.

Age: 10.7 years ± 3.29 years in the flunarizine group and 10.58 years ± 3.25 years in

the placebo group.

Sex: Twenty-seven females and 21 males.


Interventions Intervention groups: Flunarizine (n: 24) 5mg/day vs. placebo (n: 24).

Details: No information on details of similarity between drug and placebo. No



Migraine frequency: Number of migraine attacks during three months of therapy.

Headache duration: Mean duration of migraine attacks in hours. Average of three

months.

Adverse events.


Responders to treatment: 50% reduction of both frequency and duration.

62


Risk of bias


Random sequence

generation

(selection bias)

Unclear bias No description of randomization procedure.

Allocation

concealment

(selection bias)

Unclear bias No information on allocation concealment.

Blinding of

participants and

personnel

(Performance bias)

High risk No information on who was blinded. Uncertain if

placebo medications were alike to flunarizine.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk Dropouts accounted for. Three dropouts in placebo

group due to inefficacy. Analysis made only on

completers.

Selective reporting

(reporting bias)

Low risk The review authors have no suspicion of selective

reporting.

Sorge [83]



Study design: Prospective, randomized, double-blind, placebo-controlled, cross-over

trial with two arms.


Duration of participation: Eight months. One month run-in, three months treatment,

one month washout and three months treatment.


Participants Setting: Patients from the Headache Centre, Department of Neurology, 2nd Medical

School of Naples.

Inclusion criteria: Presence of common migraine as defined by Valquist criteria; three

of more attacks per month in the past three months, at least one of them requiring bed

rest; age range 5-11 years; at least six-month history of headache; no objective or

neurologic or internal disorders.


Total number randomized: Seventy.

Exclusions and withdrawals: Seven. Two starting with flunarizine, one because of

excessive daytime sedation, and the other because of ineffective therapy. Five from

placebo group because of ineffectiveness.

Age: Mean age 10.6 years. Range 5-11 years.

Sex: Thirty-six females, 34 males.


Interventions Intervention groups: Flunarizine (n: 35) 5mg vs. placebo (n: 35)

Details: One group received a flunarizine-placebo sequence. The other group received

interventions in opposite order. Each sequence was introduced with four weeks wash-

out. Placebo was delivered in identical shape and colour as the active drug. No


63


Migraine frequency: Mean number of attacks per month in period before washout.

Duration of attacks: Average hours of pain per attack per month in period before

washout.

Adverse events.


Risk of bias


Random sequence

generation

(selection bias)

Unclear risk No information on randomization procedure.

Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

Low risk Both patients and physician were blinded.

Flunarizine and placebo were identical.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk Dropouts accounted for. Five dropouts on placebo

due to ineffectiveness. Analysis made only on

completers.

Selective reporting

(reporting bias)



Soyka 1987a [85]

Methods Country: West-Germany.

Published language: German.


arms.


Duration of participation: Two-week run-in, four months treatment.


Participants Setting: Twelve outpatient clinics.

Inclusion criteria: Classic or common migraine with recurrent headache lasting several

hours. Two of following additional criteria: Nausea and vomiting during attacks,

scintillating scotoma, neurological symptoms, hemicranias, familial occurrence. At

least two attacks the preceding six months. Age 20-65 years.


Total number randomized: Eighty-seven patients, 69 patients included.

Exclusions and withdrawals: Eighteen excluded. Tree due to unacceptable concomitant

medication and fifteen due to early discontinuation.

Age: Flunarizine group 42 years mean ±12 years. propranolol group 43 years mean ±

13 years.

Sex: Flunarizine group: Fifty-one females, 18 males.


Interventions Intervention groups: Flunarizine (n: 35) 10mg/day vs. propranolol (n: 34) 120mg/day.

Details: Flunarizine was given as a single dose in the evening. They also received

64

placebo at morning and noon to match the propranolol dosing regimen. Propranolol

was started at 80mg/day during first two weeks, and then 120mg/day for the remaining

period. No information on co-interventions.



Duration of attacks: Total hours of headache per month.

Adverse events.


Intensity of attacks: Increase or decrease in intensity.

Doses of acute medication: Increase or decrease use of acute medication.

Notes Funders of trial: no information

Other: Wolfgang Oestreich is Director Medical Development Department in Janssen

GmbH. Rainer Schmidt is Assistant Medical Development Department in Janssen

GmbH.

Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk Eighteen patients were excluded or withdrawn

without reported reason. Only participants with

“accepted rating sheets” were analysed. Criteria for

accepting rating sheets are not stated.

Selective reporting

(reporting bias)

High risk Sparse information about the dropouts, this gives

reason to suspect selective reporting.

Soyka 1987b [86]

Methods Country: West-Germany.



arms.


Duration of participation: Four months and two weeks. Two weeks run-in, four months

treatment.


Participants Setting: Ninety-nine medical practices.

Inclusion criteria: Classic or common migraine with recurrent headache lasting several

hours. Two of following additional criteria: Nausea and vomiting during attacks,

scintillating scotoma, neurological symptoms, hemicranias, familial occurrence. At

65

least two attacks the preceding six months. Age 20-65 years.


Total number randomized: Four-hundred and thirty-four patients, 336 patients included

in analysis.

Exclusions and withdrawals: Ninety-eight participants had unacceptable rating sheets

and were excluded.

Age: Flunarizine group: age 42 years mean ±12 years, propranolol group: age 42 years

mean ±11 years.

Sex: Two-hundred and sixty-five females, 61 males.


Interventions Intervention groups: Flunarizine group (n: 166) 10mg/day vs. propranolol (n: 170)

120mg/day.

Details: Flunarizine was given as a single dose in the evening. They also received

placebo at morning and noon to match the propranolol dosing regimen. Propranolol

was started at 80mg/day during first two weeks, and then 120mg/day for the remaining

period. No information on co-interventions.



Duration of attacks: Total hours of headache per month.

Adverse events.


Intensity of attacks: Increase or decrease in intensity.

Doses of acute medication: Increase or decrease use of acute medication.


Other: Wolfgang Oestreich is Director Medical Development Department in Janssen

GmbH. Rainer Schmidt is Assistant Medical Development Department in Janssen

GmbH.

Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)



Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

High risk 98 patients were excluded or withdrawn without

reported reason. Only participants with “accepted

rating sheets” were analysed. Criteria for accepting

rating sheets are not stated.

Selective reporting

(reporting bias)

High risk Sparse information about the dropouts, this gives

reason to suspect selective reporting.

66

Sørensen 1986 [88]

Methods Country: Denmark.


Study design: Prospective, randomized, double-blind, placebo-controlled, cross-over

trial with two arms.


Duration of participation: Forty weeks. Four weeks run-in, 16 weeks treatment, four

weeks wash-out and then 16 weeks treatment.

Ethical approval: Yes, approved by local ethics committee.

Participants Setting: Outpatients at the Acute Headache Clinic, Rigshospitalet, Copenhagen.

Inclusion criteria: Migraine diagnosis by the Ad Hoc Cmttee, modified by Olesen et.

al., and at least one year duration of disease and 2-6 attacks per month.

Exclusion criteria: “Excluded were patients suffering from renal or hepatic

dysfunction, heart disease, arterial hypertension, glaucoma, psychiatric disorders, or

other brain diseases. Fertile women, who did not use a medically accepted method of

contraception, pregnant women and nursing women were not admitted to the study.

Furthermore, we excluded patients who used beta-blockers, psychotropic drugs and

other drugs used in the prophylaxis of migraine, and patients taking more than 20 mg

ergotamine a month or morphinomimetic drugs for treatment of attacks.”

Total number randomized: Twenty-nine.

Exclusions and withdrawals: Two. One on placebo due to increasing number of

migraine attacks. One on flunarizine due to daytime sedation.


Sex: Twenty-three females, six males.


Interventions Intervention groups: Flunarizine (n: 14) 10mg/daily vs. placebo (n: 15).

Details: One group received a flunarizine before cross over, and then placebo. The

other group received placebo before cross over, and flunarizine after. No information

on appearance and dosing of placebo. No information on co-interventions.


Migraine frequency: Number of attacks in four-week period. Migraine frequency

before cross-over extracted from figure.


Migraine index calculated as migraine attack severity times migraine attack duration.

Headache index calculated as severity times duration of both migraine attacks and

interval headaches.

Number of days with interval headache.

Duration of attacks: Duration of attack.

Intensity of attacks: Severity of attacks.

Doses of acute medication: Drug consumption expressed in analgesics units

corresponding to 500mg acetyl-salicylic acid or one dose ergot compound.

Adverse events.


Risk of bias


Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


67

Blinding of

participants and

personnel

(Performance bias)



flunarizine.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

Unclear risk Two dropouts, analyses made only on completers.

Selective reporting

(reporting bias)



Sørensen 1991 [89]

Methods Country: Denmark.



arms.


Duration of participation: Six months. One month run in, five months treatment.

Ethical approval: Yes, approved by local committee on ethics and Danish national

board of health and welfare.

Participants Setting: Outpatients in six neurology departments.

Inclusion criteria: Migraine with or without aura, after the Headache Classification

Committee of IHS. Other criteria for inclusion were age 18-65 years; history of

migraine with at least one years duration; frequency of migraine attacks of 2-8 attacks

per month.

Exclusion criteria: Other types of headache and serious somatic disease. Other disease

contraindicating use of beta-blockers or calcium channel blocker. Fertile women who

did not use medically accepted methods of contraception. Pregnant or nursing women.

Total number randomized: One hundred and forty-nine

Exclusions and withdrawals: Twenty-two. Two participants in the flunarizine group

had no baseline data. There were 14 dropouts in the flunarizine group and six dropouts

in the metoprolol group.


Sex: One hundred and eighteen females, 31 males.


Interventions Intervention groups: Flunarizine (n: 74) 10mg/day vs. metoprolol (n: 75) 200mg/day.

Details: Both groups received one placebo capsule, appearing identical, to match the

active drug they did not receive. No information co-interventions.


Migraine frequency: Days with migraine per month.

Adverse events.


Duration of attacks: Duration of attack in hours within one day.

Intensity of attacks: Attack severity judged by patient on scale from 1-3.


Risk of bias


68

Random sequence

generation

(selection bias)


Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

Low risk Blinding of both doctors and patients described

sufficiently. Both groups received dummy

medication to match the drug they did not receive.

Blinding of

outcome

assessment

(detection bias)



Incomplete

outcome data

(attrition bias)

Low risk Difference in numbers of drop-outs in each group,

but not likely to introduce bias. Furthermore,

Intention-To-Treat analyses is made on subjects who

completed one-month treatment.

Selective reporting

(reporting bias)



Vijayalakshmi 2014 [92]

Methods Country: India.


Study design: Prospective, randomized, open, controlled, parallel trial with two arms.


Duration of participation: Thirty days treatment.


Participants Setting: Psychiatry and Neurology outpatient department of Gur Tegh Bahadur

Hospital, Dehli.

Inclusion criteria: Migraine diagnosed according to the International Classification of

Headache Disorder-2 criteria. Age 20–40 years, both sexes, having recurrent attacks in

the past one year, more than five per year.

Exclusion criteria: Secondary headache or co-morbid psychiatric and neurological

disorder and those under drug therapy like B-blockers, triptans and ergots were

excluded from the study.

Total number randomized: Sixty patients.


Age: No information.

Sex: No information.


Interventions Intervention groups: Flunarizine (n: 30) 20mg/day vs. acupuncture (n: 30).

Details: Acupuncture received electro acupuncture with acupoints chosen according to

traditional Chinese channels and collaterals for migraine for 10 sittings over a period of

30 days. No sham or dummy medication was used. Both intervention groups were

allowed to use paracetamol 500mg as abortive agent. No information on co-

interventions.


Quality of life: WHO Quality of Life Biomedical Research and Education Foundation:

Physical-, psychological-, social- and environment domain.


MIDAS score.

69


Risk of bias


Random sequence

generation

(selection bias)

Low risk Randomization by computer generated

randomization list.

Allocation

concealment

(selection bias)


Blinding of

participants and

personnel

(Performance bias)

High risk Not blinded.

Blinding of

outcome

assessment

(detection bias)

Unclear risk Headache diary cards was used. Unclear if the

outcome assessors were blinded.

Incomplete

outcome data

(attrition bias)

Low risk No drop outs. No reason to suspect attrition bias.

Selective reporting

(reporting bias)


selective reporting bias.

Wang 2011 [94]

Methods Country: China.


Study design: Prospective, randomized, single-blinded, controlled, parallel trial with

two arms.

Duration of trial: June 2007 and February 2009.

Duration of participation: Twenty weeks. Four weeks run-in, four weeks treatment, 12

week follow up.

Ethical approval: Yes, the protocol was approved by the Research Ethical Committee

of Beijing Traditional Chinese Medical Hospital affiliated with Capital Medical

University on May 2007.

Participants Setting: Outpatient departments of acupuncture at five hospitals.

Inclusion criteria: Diagnosed as migraine without aura according to the diagnostic

criteria specified by the International Classification of Headache Disorders. more than

two migraine attacks within four weeks; age between 18 and 65 years old; history of

migraine at least one year before study entry; no prophylactic treatment of migraine

with acupuncture or drugs in the past three months; and written informed consent.

Exclusion criteria: Tension-type headache, cluster headache; other primary headache

disorders; secondary headache disorders; neuralgia of the face or head; pregnancy,

lactation, or insufficient contraception; the use of b-blockers, antipsychotics, or

antidepressants within the last three months; participation in another clinical trial;

having history of depression, Parkinson’s disease, or other extrapyramidal diseases.

Total number randomized: One hundred and forty patients.

Exclusions and withdrawals: Twenty. Seventeen dropped out prematurely during the

treatment period because of time restrictions, change of residence, dissatisfaction or

fear of needling (nine from flunarizine group, eight from acupuncture group). The

other three patients lost to follow up due to change of contact information.

Age: Flunarizine group: average 39.9 years ±10.9 years, acupuncture group: average

39.2 years ± 13.1 years.

70

Sex: One hundred and nineteen females, 21 males.


Interventions Intervention groups: Flunarizine group (n: 70) 10mg/day vs. acupuncture (n: 70).

Details: Flunarizine group received active medication plus sham acupuncture.

Acupuncture group received acupuncture plus placebo medication. Flunarizine was

given as 10 mg the first two weeks and then 5mg the rest of the treatment period. Sham

acupoints were defined as unrelated to headache. The same needle manipulation and

procedure were used to maintain blinding. Both groups received 30 minutes

acupuncture sessions. The acupuncture group had obligatory acupoints plus additional

points for different migraine syndromes. Appearance of placebo was similar to

flunarizine.


Migraine frequency: Defined as number of migraine days per month.

Intensity of attacks: pain on a VAS-scale.

Doses of acute medication: Number of patients using acute medication.

Quality of life: SF-36.

Adverse events.


Responders to treatment: 50% or greater reduction of migraine days.

Notes Funders of trial: funded by the Capital Medical Development Re- search Fund (No.

SF-2005-2).

Risk of bias


Random sequence

generation

(selection bias)

Low risk The randomization was computer made by the

Research Centre of Clinical Epidemiology affiliated

with Peking University.

Allocation

concealment

(selection bias)

Low risk “Randomization numbers with a block of 4 were

sealed in a predetermined computer-made

randomization opaque envelope. The patients’

screening sequence numbers were printed outside

the envelope, whereas the group names were printed

inside “.

Blinding of

participants and

personnel

(Performance bias)

Low risk “Blinding was implemented by means of double-

dummy with verum acupuncture plus placebo

medication in the acupuncture group and flunarizine

plus sham acupuncture in the control group. The

follow-up assessors and statisticians, who were

uninvolved in clinical management, were blinded

throughout the study. Due to the procedure of the

acupuncture technique, acupuncture practitioners in

this trial were unable to be blinded. Additionally, the

appearance of placebo medication was exactly the

same as that of flunarizine.”

Blinding of

outcome

assessment

(detection bias)

Low risk “The outcome measurements were evaluated by

blinded assessors who were unaware of patient

allocation “.

Incomplete

outcome data

(attrition bias)

Low risk Attrition evenly distributed between the two groups.

Reasons for withdrawal plausible and not likely to

be related to outcome. Intention-to-treat analysis

made.

71

Selective reporting

(reporting bias)


selective reporting even though some of the primary

outcomes were changed to secondary outcomes from

the protocol to the manuscript.

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