Evidence Table 16

Placebo controlled trials of beta blockers for migraine

Author
Year
Country
Study Design
Eligibility criteriaExclusion criteriaInterventions (drug, regimen, duration)Allowed other medications/interventionsMethod of outcome assessment and timing of assessmentAge
Gender
Ethnicity
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%, adverse n/enrolled n)Comments
Fair quality
Atenolol
Forssman
1982
Sweden

Fair quality
RCT Crossover
History of migraine (Ad Hoc Committee)NRAtenolol (ate) 100 mg daily
Placebo (pla) x 90 days; then crossover
Common analgesics and ergotaminePatient forms: 1) number; 2) intensity (3-point scale); 3) duration of attacks; 4) incapacity for work; 5) medication

Integrated headache: score considering combined effect of intensity and duration

Follow-up visits were made after 14, 56, 154, and 254 days
Mean age=40
80% female
Race NR
NRNR/NR/24 enrolled4(16.7%) withdrawn/0 lost to fu/20 analyzedIntegrated headache
Mean values/day: ate=2.38; pla=4.58
Relative mean value/day(ate:pla mean/% difference): (−2.2)/( −48%)
Relative value per patient/day(# pts/%): ate>pla=19/95%; pla>/=ate=1/5%
Number of attacks
Mean values/day: ate=0.17; pla=0.23
Relative mean value/day(ate:pla mean/% difference): (−0.06)/( −26.1%)
Relative value per patient/day(# pts/%): ate>pla=15/75%; pla>/=ate=5/25%
Headache intensity
Comparison of effect per patient(# pts/%): ate>pla=17/18(94.4%)
Ergotamine intake
Comparison of change in intake per patient(# pts w/significant reduction/%): ate>pla=14/14(100%)
Common analgesic intake
Comparison of change in intake per patient: data NR; no difference indicated per patient between periods
NRDizziness of orthostatic type(# pts): ate=6; pla=1
Diffuse tiredness: ate=2; pla=0
Mood alterations: ate=1; pla=0
ate=1
pla=0
Bisoprolol
van de Ven
1997
The Netherlands

Fair quality
RCT
Either sex, 18 to 75 years old; suffering from migraine with or without aura; had a migraine history of at least two years’ duration; developed at least three documented migraine attacks during the 28-day run-in periodCurrent use of drugs for the prevention of migrain; treatment with cardiovascular drugs; usual contrindications for beta blocker use or hypersensitivity to these agentsBisoprolol (bis) 5 mg OR 10 mg daily
Placebo (pla) x 16 weeks
NRPatient diary assessed at 4-wk intervalsMean age: bis
5 mg=38.3;
bis 10
mg=38.9;
pla=38.9
% female: bis
5 mg=78.4%;
bis 10
mg=83.1%;
pla=83.1%
Race NR
Family history of migraine(#patients/%): bis 5
mg=28/37.8%; bis 10
mg=27/35.1%; pla=26/34.7%
Age at onset(yrs): bis 5
mg=18.1; bis 10 mg=20.1; pla=22.7
Migraine with aura(#patients/%): bis 5
mg=17/22.9%; bis 10
mg=22/28.6%; pla=12/16%
Migraine without aura(#patients/%): bis 5
mg=57(77%); bis 10
mg=55/71.4%; pla=63/84%
NR/NR/226 randomized31(13.7%) withdrawn/lost to fu NR/analyzed NRMigraine frequency(4-week mean/% reduction): bis 5 mg=2.6/39%; bis 10 mg=2.6(39%); pla=3.2/22%
Attack duration(mean hours/% reduction): bis 5 mg=9.5/(−53.9%); bis 10 mg=14.3/(−44.6%); pla=13.2/(−43.6%)
NRAdverse event incidence(#patients/%): bis 5 mg=26/35%; bis 10 mg=33/43%; pla=25/33%

Most frequent adverse events(# patients/%):
Fatigue: bis 5 mg=7/9.4%;
bis 10 mg=9/11.7%;
pla=7/9.3%
Dizziness: bis 5 mg=6/8.1%; bis 10 mg=5/6.5%; pla=4/5.3%
Adverse event withdrawals(#patients/%): bis 5 mg=4/74(5.4%); bis 10 mg=7/77(9.1%); pla=4/75(5.3%)
Metoprolol
Andersson
1983
Denmark

Fair quality
RCT
Outpatients of both sexes, with an age over 16 and below 65 years diagnosed to have classical or non-classical migraine (World Federation of Neurology Research Group on Migraine and Headache) of a duration of at least 2 yearsOther types of vascular headaches, chronic daily headache not separable from migraine; contraindication for beta blockers; other severe vascular diseases; oral contraceptives and pregnancyMetoprolol durules (met-d)
200 mg daily
Placebo (pla) x 12 weeks
Acute migraine medication allowed (e.g., ergotamine and analgesics)Patient diary card: 1) frequency; 2) Intensity (1=annoying, but patient not disabled; 2=patient partly disabled (affecting his/her ability to work); 3=patient disabled(unable to work or in bed); 3) consumption of acute migraine-relieving medicineMean age:
pla=37.3; met-d=42.4
%female:
pla=94.6%;
met-d=73.5%
Race NR
Classical migraine(#pts/%):
pla=8/21.6%; met-d=9/26.5%
Non-classical migraine(#pts/%):
pla=29/78.4%; met-d=25/73.5%
% heredity: pla=65; met-d=65
Mean migraine duration(years):
pla=14.6; met-d=22.6 % earlier prophylactic treatment: pla=32; met=38 % earlier acute treatment:
pla=76; met=74
NR/75 eligible/71 randomizedWithdrawn: 4/75(5.3%) prior to randomization; 9/71(12.7%) after randomization/lost to fu
NR/71 analyzed
Per protocol assessment (pla n=35; met-d n=30)
Attack frequency/4 wks(mean/% change): pla=(−0.53)/(−10.3%); met-d=(− 1.3)/(−29.5%)
Migraine days/4 wks(mean/% change): pla=(−0.19)/(−2.4%); met-d=(− 2.3)/(−28.8%)
Sum of severity score(migraine days x intensity)/4 wks(mean/% change): pla=0.18/1.1%; met-d=(−5.68)/(−32.2%)
Acute tablet consumption/4 wks(mean/% change): pla=(−0.49)/(−2.4%); met-d=(−8.85)/(−45.1%)
Subjective evaluation(# pts/%)
Marked/moderate: pla=6(18%); met-d=15(54%)
Slight: pla=10(29%); met-d=7(25%)
Unchanged/worse: pla=18(64%); met-d=6(21%)
NRIncidence(# pts/%): met-d=16(53.3%); pla=10(28.6%)

Most common adverse events(# complaints) at visit 4:
Sleep disturbances: met-d=4; pla=4
Fatigue: met-d=3; pla=0
Gastrointestinal: met-d=2; pla=2
Bradycardia: met-d=2; pla=0
Paraesthesia: met-d=0; pla=1
Depression: met-d=1; pla=1
Others: met-d=0; pla=4
Withdrawals(# pts/%):
met-d=1(3.3%); pla=1(2.8%)
Kangasniemi
1987
Scandinavia

Fair quality
RCT
Outpatients aged 16–65 years, diagnosed as having classic migraine (NIH Ad Hoc Committee); 2–8 migraine attacks per month, of which at least 50% had to be accompanied by focal aura symptomsDaily use of analgesics and/or total consumption exceeding 40 tablets/month; daily use of ergotamine and/or total consumption exceeding 16 mg/month; treatment with anti-depressive or neuroleptic drugs within the past 2 months; use of narcotic analgestics, chronic treatment with calcium antagonists, clonidine, other beta-blockers or NSAIDSs; change in oral contraceptive therapy 3 months before or during the study; contraindications for beta-blockers; insufficienty treated hypertension; transient ischaemic attacks; epilepsy; hypothyroidism and other severe psychiatric or somatic disease; and pregnancyMetoprolol durules (met-d) 200 mg daily
Placebo (pla) x 8 weeks, then crossover
Former acute migraine medication allowed (not specified)Diary card measuring following variables:
Frequency of migraine attacks/interval headache
Time of onset and duration of migraine attack
Intensity of headache (1=mild; 2=moderate; 3=severe)
Symptoms before and during the headache phase
Global rating of the attack on a visual analogue scale (1–10)
Conumption of analgesics and ergotamine
n=74
Mean
age=37.5
79.7% female
Race NR
Family history: 54(73%)
Attacks per month(mean): 4.3
Duration of migraine(mean years): 17.2
Duration/attack(mean hours): 12.6
Relationship migraine/menstrual cycle(#patients/%): 28/47%
Previous prophylactic treatment(# patients/%): 5/6.8%
Previous acute treatment(#patients/%): 65/87.8%
NR/NR/77 randomized3 withdrawn(1 due to narcotic abuse and 2 due to being “dark horses”)/0 lost to fu/74 analyzedOutcomes per 4 weeks (mean score/% change)
Attack frequency: met=1.8/−52.6%; pla=2.5/−34.2% (P=0.0004)
Days with migraine: met=1.9/−59.6%; pla=2.6/−44.7% (P=0.01)
Days with interval headache: met=1.3/−27.8%; pla=1.6/−11.1% (NS)
Sum of intensity score: met=3.6/−50.0%; pla=4.5/−37.5% (P=0.001)
Sum of global ratings: met=8.6/−53.5%; pla=12.7/−31.4% (P=0.001)
Mean intensity score per attack: met=1.86/−7.0%; pla=2/0.0% (P=0.002)
Mean global rating per attack: met=3.8/−30.9%; pla=4.8/−12.7% (P=0.003)
Mean duration per attack: met=6/−30.2%; pla=8/−7.0% (P=0.027)
Consumption of analgesic tablets: met=1.9/−52.5%; pla=4.4/+10% (P<0.001)
Consumption of analgesic tablets/attack: met=1/−16.1%; pla=2/+66.7% (P<0.001)
Consumption of ergotamine tablets: met=1.5/−68.1%; pla=3/−36.2% (P=0.007)
Recorded at each visit using unspecified stardardized questionnaire on a 3-point scale (1=mild; 2=moderate; 3=severe)Adverse effects incidence(% patients):
met=36%; pla=18%

Most frequent adverse effects(# complaints for weeks 1–4/5–8)
Gastrointestinal: met=7/9; pla=1/2
Fatigue: met=6/7; pla=3/1
Cardiovascular: met=1/2; pla=0/3
Sleep disturbances:
met=3/1; pla=0/0
Others: met=10/6; pla=7/8
NRClassic migraine only
Pindolol
Ekbom
1971
Sweden

Fair quality
RCT
Aged 19–56, with classic or common migraine (Ad Hoc Committee, 1962) at a frequency of at least 4 attacks per 4-week periodBronchial asthma, severe infectious diseases, diabetes mellitus, pregnancy, pathological ECG findingsGroup 1: Pindolol (pin1) 7.5 mg daily (n=7)
Group 2: Pindolol (pin2) 15 mg daily (n=9)
Group 3: Placebo (pla) x 4 weeks (n=10)
ErgotaminesPatient record: 1) frequency, 2) duration; 3) severity (graded on arbitrary 3-point scale); 4) consumption of ergotamineMean age=33.7
86.7% female Race NR
Classic migraine=4(13.3%)
Common migraine=26(86.7%)
Family history=26(86.7%)
Unilateral headache pattern=26(86.7%)
Associated symptoms:
Nausea=28(93.3%)
Vomiting=24(80%)
Photophobia/phonophobia=28(93.3%)
Urina spastica=9(30%)
Diarrhea=9(30%)
NR/NR/30 enrolled4(13.3%) withdrawn/lost to fu NR/26 analyzedHeadache frequency/4 wks(mean/% change from observation period): pin1=(−2)/(−13.3%); pin2=(−2)/(−18.2%); pla=(−2)/(20%)
Headache index/4 wks(mean/% change from observation period): pin1=0; pin2=(−4)/(−20%); pla=(−4)/(−22.2%)
Headache duration/4 wks(mean/% change from observation period): pin1=0; pin2=(−0.1)/(−1.4%); pla=(−0.7)/(−9.2%)
Tablet consumption: data NR; paper indicates pin=pla
NRNRWithdrawals: pin=4; pla=0

Withdrawals due to:
Orthostatic hypotension=2 Increased headache=1
Dizziness/cystopyel itis=1
Sjaastad
1972
Norway

Fair quality
RCT Crossover
Aged 18–62 years, with classical and common migraine; attack frequency of >/= 2/monthNRPindolol (pin) 7.5–15 mg daily
Placebo (pla) x 4 weeks, then crossover
Ergotamine preparations; salicylates; dextropropoxipheni chlorideSpecial form: 1) Severity on 3-point scale (Grade I=just discernible symptoms, not appreciably influencing working capaity; Grade II=pronounced symptoms not necessitating bedrest, but markedly influencing working capacity; Grade III=severe symptoms, necessitating bedrest; 2) Headache indices=headache days times severity of attacksMean age=35.8
78.6% female Race NR
Common headache=14(50%)
Classic headache=14(50%)
NR/NR/28 enrolled4(14.2%) withdrawn/0 lost to fu/24 analyzedReduction in headache indices(# pts/%)
pin "definitely" (>50% reduction in headache indices) better than pla=3(12.%)
pin "slightly" better than pla=1(4.2%)
pin=pla: 12(50%)
pin worse than pla=8(33.3%)
Headache days(group total/4 wks): pla=181; pin=194; increase of 13(7.2%) headache days on pin
Headache indices(group total/4 wks): pla=318; pin=313; decrease of 5 points(1.6%) on pin
NRUntoward effects noted:
Initial lethargy: pin=3;
pla=0
Dizziness/faintness: pin=6;
pla=0
Chest discomfort: pin=1;
pla=1
pin=3/28(10.7%)
pla=0
Propranolol
Borgesen
1974
Denmark

Fair quality
RCT Crossover
Diagnosis of migraine (Ad Hoc Committee on Classification of Headache, 1962); suffered more than one attack per week; did not respond to known prophylacticsCardiac disease; asthma or diabetes mellitus; physical or neurological abnormalitiesPropranolol (pro) 120 mg daily
Placebo (pla) x 12 weeks, then crossover
Symptomatic treatments allowed (e.g., salicylates, ergotamines and narcotics)Patient forms: 1) severity on 3-point scale (severe=forcing patient to stay in bed; moderate=patient able to get up, but incapable of working; mild=patient uncomfortable, but able o work); 2) duration; 3) prodromal and accompanying symptoms; 4) medication used

Patients seen at four weekly intervals to record 1) severity; 2) frequency; 3) working capacity; 4) subjective evaluation of the treatment
Mean age=37.6
83.3% female
Race NR
Classical migraine (# pts/%): 15(50%)
Common migraine (# pts/%): 15(50%)
NR/NR/45 entered15(33.3%) withdrawn/0 lost to fu/30 analyzedAttack frequency in propranolol period relative to placebo period (#pts/%): >100%=9/30%; 100%=3/10%; 75–99%=1/3.3%; 50–75%=8/26.7%; 25–50%=2/6.7%; 1–25%=2/6.7%; 0%=5/16.7%
Patient preference (# pts/%): pro=17/56.7%; pla=6/20%; no difference=7/23.3%
Working capacity: data NR; pro>pla (P<0.05)
Medication consumption: data NR; pro=pla
NRData NR; pro=pla for #/severity of complaints of fatigue drowsiness and diarrheapro=0
pla=2
Dahlof
1987
Sweden

Fair quality
RCT Crossover
Aged 18–60 years; history of at least 2 years classical or common migraine (World Federation of Neurological Research Group on migraine and headache); 2–8 well- defined migraine attacks/month and fulfill at least 4 of the following criteria: 1) heredity; 2) pulsating headache; 3) prodromas and/or aura; 4) hemicrania; 5) phonophobia; 6) photophobia; 7) gastrointestinal disturbancesPrevious treatment with a beta blockerPropranolol (pro) 120 mg daily
Placebo (pla) x one month followed by assessment during a 5-month treatment period; then crossover
Use of common acute medication allowed (unspecified)Diary cards: 1) frequency (method NR); 2) intensity (method NR); sent into investigator each monthMean age NR 92.8% female
Race NR
Classical migraine (# pts/%): 20/71.4%
Common migraine (# pts/%): 8/28.5%
NR/NR/28 entered0 withdrawn/0 lost to fu/28 analyzedMigraine frequency(4-week mean): pro=3.2; pla=4.3
Integrated headache(mean): pro=7.6; pla=10.9
Tablets consumed(mean): pro=9; pla=15
NRNRNRLooked at longlasting prophylactic effect following discontinuance
Diamond
1982
United States

Fair quality RCT
Diagnosis of classical or common migraine(Ad Hoc Committee, 1962); a history of at least four attacks per month just prior to starting this trialPatients with migraine associated with other types of headaches, migraine other than classic or common; known contraindications to propranololPropranolol (pro) 160 mg daily
Placebo (pla)

Phase I(single blind): One month of single-blind treatment, then crossover

Phase II(double-blind): 6–14 months' with at least a single crossover, but with an option for two crossovers
Simple analgesics; narcotics; ergot compoundsPatient daily records
Headache Unit Index (HUI): 'Total score of headache severity'(3-point scale: 1=mild/annoying; 2=moderate/interfering; 3=severe/incapacitating)/'total number of days observed'
Relief Medication Unit Index (RMUI): 'Total score of relief medication units'(3-point scale: 1=simple analgesic; 2=narcotic; 3=ergot compound)/'Total number of days observed'
Age range of 21–64
78.7% female Race NR
NRPhase I: NR/NR/245 admitted

Phase II: All 148 patients that responded to propranolol from Phase I
Phase I: 41(16.7%) withdrawn/4(1.6%) lost to fu/204 analyzed

Phase II: 48(32.4%) withdrawn/10(6.7%) lost to fu/100 analyzed
Phase I
Mean HUI: pla=0.791; pro=0.562 (P<0.0001)
Mean RMUI: pla=2.553; pro=1.728 (P<0.0001)
NRFrequency of most common adverse events(#patients/%)
Dizziness: pro=16/6.5%; pla=3/1.2%
Significant nausea: pro=23/9.4%; pla=9/3.7%
Visual disturbances: pro=7/2.8%; pla=0
Diarrhea: pro=18/7.3%; pla=5/2.0%
Epigastric distress: pro=17/6.9%; pla=1/0.4%
Weight gain: 9/3.7%; pla=2/0.8%
Weakness/fatigue: pro=32/13.1%; pla=8/3.3%
Malaise/lethargy: pro=20/8.2%; pla=4/1.6%
Insomnia: pro=17/6.9%; pla=2/0.8%
Chest pain/heaviness: pro=8/3.3%; pla=0
Phases I & II
combined:
pla=3/245(1.2%); pro=14/245(5.7%)
Diener
1996
Germany

Fair quality
RCT
Between the age of 18 and 60 years; male or female; migraine with and/or without aura according to the IHS criteria; migraine history of at least 12 months’ duration; a mean number of 2–10 migraine attacks per month within the last 3 months prior to the studyPregnant or lactating women; psychiatric disorders; concomitant non-migraine headaches 3 times per month within the last three months; intake of centrally acting drugs or migraine prophylactic drugs during the 4 weeks peceding the trial; specific contraindication to beta-blocker (asthma, diabetes, clinically relevant hypotension, etc.) or cyclandelate (acute stroke, glaucoma, coagulation disorder); intake of drugs to treat migraine attacks > 12 days/monthPropranolol (pro) 120 mg daily
Placebo (pla)
Cyclandelate (cyc) 1200 mg daily
Acute migraine medication allowed (not specified)Headache diaryMean age:
pro=40;
pla=39
% female:
pro=76.9%;
pla=74.5%
Race NR
pro n=78; pla n=55
Mean migraine history(years):
pro=21; pla=19
Migraine with aura(#/%patients): pro=18/23.1%; pla=14/25.5%
Migraine without aura(#/%patients): pro=59/75.6%; pla=41/74.5%
Migraine with+without aura(#/%patients): pro=1(1.3%); pla=0
235/214/21440 withdrawn/0 lost to fu/214
analyzed per ITT; 174
analyzed per protocol
pro n=78; pla n=55
Migraine frequency(#/% patients with >/= 50% reduction of attacks):
pro=33/42.3%; pla=17/30.9%(NS)
Mean absolute reduction of migraine duration(hrs): pro=(−34.6); pla=(−13.7)(NS)
NROverall adverse
effects(#/% patients)
: pro=19/24.4%; pla=5/9.1%

Types of adverse effects of propranolol: increased sweating, hypertension, sleep difficulty, depressed modd; drowsiness; gastric pain, respiratory difficulty, kidney pain

Types of adverse effects of place NR
Overall withdrawals due to adverse events(#/%patients):
pro=4/5.1%; pla=0
Forssman
1976
Sweden

Fair quality
RCT Crossover
Diagnosis of migraine; age between 16 and 55 years; at least three attacks per monthPregnancy or suspicion of pregnancy; indication of renal or heart disease, hypertension, diabetes or asthma; history of earlier treatment of migraine with propranololPropranolol (pro) 240 mg daily
Placebo (pla) x 12 weeks, then crossover
Previously prescribed acute medication allowed (not specified); oral contraceptivesPrinted record card: 1) begin/end times; 2) intensity (slight, moderate or severe); 3) note about ability to work; 4) non-attack headaches; 5) amount of analgesics and preparations containing ergotamine or ergotamine derivatives

Integrated headache: Indicates combined effect of duration and intensity; divided by number of days

Rating of therapeutic effect: ‘Good’ = Reduction of attack frequency or of the number of days with headache by at least 50%; ‘Appreciable’ = reduction of up to 50%
Mean
age=37.4
87.5% female
Race NR
Classic migraine=5/32(15.6%)
Common
migraine=27/32(87.3%)
Mean migraine duration(years):
18.9
Family history of migraine(#pts): 39/40(97.5%)
NR/NR/40 included8(20%) withdrawn/0 lost to fu/32 analyzedAttack frequency of propranolol relative to placebo (# patients/%): Good effect(>/= 50% improvement)=11/34.4%; Appreciable effect(< 50 % improvement)=11/34.4%; No change/increase=10/31.3% Reduction of headache days of propranolol relative to placebo(#patients/%): Good effect(>/= 50%)=11/34.4%; Appreciable effect(<50%)=10/31.3%; No change/increase=11/34.4% Integrated headache(mean/% change): pro=(−2.14)/( −41.6%); pla=(−0.37)/( −7.2%)

Ergotamine consumption(change in average number/% of doses per patient per day): pro=(−0.17)/( −51.5%); pla=(−0.08)/( −24.2%) Analgesic consumption(change in average number/% of doses per patient per day): pro=(−0.16)/( −47.0%); pla=(−0.04)/( −11.8%)
NRMost common side effects reported(# pts/%)
Increase in weight > 2 kg: pro=5(13.1%); pla=0
Insomnia: pro=5(13.1%); pla=1(2.6%)
Tiredness: pro=4(10.5%); pla=3(7.9%)
Uncharacteristic dizziness: pro=3(7.9%); pla=2(5.3%)
Feeling of numbness/parasthesia: pro=2(5.3%); pla=1(2.6%)
Nausea: pro=2(5.3%); pla=1(2.6%)
Increased appetite: pro=1(2.6%); pla=0
Palpitations: pro=1(2.6%); pla=1(2.6%)
Malaise: pro=0; pla=0
pro=2
pla=2
Kuritzky
1987
Israel

Fair quality
RCT Crossover
Patients aged 17–53, suffering from classical or common migraine for at least 2 years with at least 3 attacks per monthNRLong acting propranolol (LA pro) 160 mg daily
Placebo (pla)
AnalgesicsDiary: 1) Headache severity on 1–3 scale (unspecified); 2) duration (hours); 3) analgetics useMean age NR
Gender NR
Race NR
Classical migraine (# pts/%): 7/22.6%
Common migraine (# pts/%): 24/77.4%
NR/NR/38 began7(18.4%) withdrawn/0 lost to fu/31 analyzedNumber of migraine attacks (mean): LA-pro=3.23; pla=5.56
Attack severity (mean): LA-pro=15.66; pla=25.66
Attack duration (mean): data NR (P=0.002)
NRMost common side effects: tiredness, insomnia and dizzinessNR
Malvea
1973
United States

Fair quality
RCT Crossover
Age range of 25–57 with common migrainePregnancy, bronchial asthma, congestive heart failure, allergic rhinitis, diabetes mellitus and previous use of propranolol for headachePropranolol (pro) <dose?> mg daily
Placebo (pla) x <duration?>, then crossover
Analgesic, ergot and narcotic drugsPatient record of: 1) headache frequency; 2) headache severity on 3- point scale (1=mild, annoying; 2=moderate or interfering; 3=severe or incapacitating; 3) use of analgesic and ergo drugs

Reviewed at each 6-week period
Mean age NR
87.1% female
Race NR
NRNR/NR/31 enrolled1(3.2%) withdrawn/0 lost to fu/29 analyzedFinal preference(# patients/%): pro=16/55.2%; pla=8/27.6%; neither=5/17.2%
Headache units/day(sum of means for group as a whole/% change):
pro=(−6.8)/(−19.2%); pla=(−2.1)/(−8.3%)
Symptomatic drug use/day(sum of means for group as a whole/% change): pro=(−27)/(−34.2%); pla=(−24)/(−30.4%)
NROverall incidence: NR

Side effects possibly related to the use of propranolol(# pts):
Mild nausea: 5
Fatigue: 5
Numbness: 1
Heartburn: 1
Heaviness in leg/arm=1
Light-headedness=1
Vomiting=1
Tingling in leg/arm=1
Depressed=1
NR
Mikkelsen
1986
Denmark

Fair quality
RCT Crossover
Aged between 18 and 65 years, with history of classic or common migraine (Ad Hoc Committee on Classification of Headache) with at least three migraine attacks per month which had been present for more than one yearAllergy to tolfenamic acid; serious heart, kidney, liver or psychiatric diseases, asthma, bronchitis, diabetes, active ulceration, pregnancy, or breast feeding; any administration of another prophylactic treatment for migraine within the month prior to the start of the study; use of tolfenamic acid within 6 months of study entryPropranolol (pro) 120 mg daily
Tolfenamic acid (tol) 300 mg daily
Placebo (pla) x 12 weeks, then crossover
Other kinds of abortive treatment allowed but not specifiedPatient record sheet
1) Number of attacks
2) Duration of attacks
3) Intensity of attacks (scale of 1–10)
4) Working capacity on 3-point scale (1=ability to work; 2=ability to be ambulant but not able to work; 3=bed confinement)
Mean age=38
Gender(%female)=83.9 %
Race NR
Classic=10/31(32.2%)
Common=21/31(67.7%)
NR/NR/398(20.5%) withdrawn/0 lost to fu/31 analyzedClinical data recorded over last 11 weeks of each treatment period:
Number of attacks(mean): pla=8.81; pro=6.65
Working capacity(Total attacks where patients were confined to bed):
pla=5.48; pro=4.06(NS)
Mean attack duration (hours) of attacks: pla=18.68; pro=14.26(NS)
Pain intensity(on scale of 1–10): pla=6.97; pro=6.94(NS)
NROverall adverse effects(#patients): pla=3;
pro=3(NS)

Adverse events recorded with:
Placebo=slight neurological symptoms, hot flushes, diarrhea
Propranolol=fatigue, polyuria, low back pain
NR
Pita
1977
Spain

Fair quality
RCT Crossover
Migraine (Ad Hoc Committee) at a frequency of at least 3–4 attacks monthly and have a history of not responding to prophylactic therapyConcomitant neurological or psychiatric disorders as well as diabetes mellitus, asthma or cardiac diseasePropranolol (pro) 160 mg daily
Placebo (pla) x 2 months; then crossover
Symptomatic analgesic treatment (unspecified)1) Frequency; 2) duration; 3) severity rated on 3-point scale (e.g., I=uncomfortable but able to work; II=patient unable to work but not needing bedrest; III=patient necessitating bedrest)Mean age=32
77.8% female
Race NR
Common(#/% patients):
5/9(55.6%)
Classic(#/% patients):
4/9(44.4%)
NR/NR/91(11.1%) withdrawn/0 lost to fu/8 analyzedWhole frequency/month: data NR; narrative indicates pro>pla
Mean frequency/month: data NR; narrative indicates pro=pla
Mean Grade(severity)/month: data NR; narrative indicated pro>pla for Grade III
Preference(# patients): pro=7/8; pla=1/8
NR NR NR
Pradalier
1989
Fair - Poor
RCT
Suffering from migraine for at least two years with or without aura according to the criteria of the new International Headache
Society classification
History of congestive heart failure or asthma; heart block; bradycardia (<50 beats/min); Raynaud phenomenon; hypertension; resistant to two previously well-followed prophylactic treatmentsPlacebo (pla)
Long-acting propranolol (LA pro) 160 mg daily x 12 weeks
Usual medicationPatient form documenting frequency and details of the headache (method NR)Mean age: LA
pro=37.1;
pla=37.7
Gender(%female): LA
pro=77.5%;
pla=73.5%
Race NR
Familial history of migraine: LA
pro=65%; pla=52.9%
Mean age at onset: LA
pro=20.8; pla=19.1
Migraine frequency/week: LA
pro=1.66; pla=1.40
Type of migraine
Aura: LA pro=15%; pro=5.9%
No Aura: LA pro=80%; pla=85.3%
Aura+No Aura: LA pro=5%; pla=8.8%
Severity of crisis(# pts. with severe crisis): LA pro=52.5%; pla=;47.0%
NR/NR/74 entered33 withdrawn(19 prior to randomization)/9(16.3%) lost to fu/analyzed NRChange in mean crises/month: LA pro= (−2.96/−48.4%); pla= (+0.41/+6.8%)Volunteered information (e.g., “How did you tolerate the treatment?”) and a standardized 17- item questionnaireAnswers to adverse event questionnaire at Day 84 (LA pro n=22; pla n=19)
Cold extremities: LA
pro=0; pla=3(15.8%)
Tiredness: LA
pro=3(13.6%); pla=2(10.5%)
Dyspnea: LA
pro=3(13.6%); pla=1(5.3%)
Dyspepsia: LA
pro=1(4.5%); pla=0
Diarrhea: LA pro=1(4.5%); pla=0
Constipation: LA
pro=2(9.1%); pla=2(10.5%)
Insomnia: LA pro=2(9.1%); pla=2(10.5%)
Depression: LA pro=0; pla=1(10.5%)
LA pro=0
pla=1(due to psoriasis)
Rao
2000
India

Fair quality
RCT
Patients with two or more migraine attacks per weekNRPlacebo (pla)
Cyproheptadine (cyp) 4 mg
daily
Propranolol (pro) 80 mg daily
Cyproheptadine 4 mg
daily+Propranolol 80 mg
daily (cyp+pro)
NRMigraine attack frequency, severity and duration rated by patient using 5-point scale
4=100%, “total” relief
3=75% relief
2=50% relief
1=25% relief
0=0% relief, no change
Mean
age=28.6
67.2% female
Race NR
NRNR/NR/259 recruited55 withdrawn/lost to fu
NR/204 analyzed
Frequency (mean response): pla=1.77; pro=2.85
Duration (mean response): pla=1.77; pro=2.83
Severity (mean response): pla=1.64; pro=2.87
NRIncidence(# patients):
pla=1/69(1.4%);
pro=11/62(17.7%)
NR
Wideroe
1974
Norway

Fair quality
RCT Crossover
Patients diagnosed with cassic or common migraine (Ad Hoc Committee, 1962) in whom the result of open treatment with propranolol 160 mg daily as part of a pilot study was rated as “excellent” (e.g., reduction of attack rate of more than 50%NRPropranolol (pro) 160 mg
daily
Placebo (pla) x 3 months, then crossover
Analgesic and antimigraine drugsPatient record of a) frequency; b) intensity; c) duration; d) change in premonitory symptoms; e) quality of the attack; f) degree of invalidity; g) consumption of analgesic/antimigraine drugs
Treatment rating by physician: 1) excellent-a reduction in attack rate of more than 50%; 2) moderate-a reduction in attack rate of less than 50%; 3) no effect; 4) an increase in attack rate x monthly
Mean age=38
Gender(%female)=86.7 %
Race NR
Classic=6/30(20%)
Common=24/30(80%)
NR/NR/304 withdrawn/lost to fu
NR/analyzed 26
Average rate of migraine attacks/month(mean/% change): pro=0.4(−86.7%); pla=1.7(−58.8%)NRNRNR
Poor quality
Propranolol
Ahuja
1985
India

Poor quality
RCT Crossover
Suffering from migraine (Ad Hoc Committee on Headache) at a frequency of > 2 attacks per month in the previous 3 monthsIntercurrent illnessPropranolol (pro) 120 mg daily
Placebo (pla) x 8 weeks, then crossover
NRSeverity: rated on 3-point scale (3=severe; 2=moderate, incapacitating; 1=inconvenient, mild)
Severity index: calculated by multiplying the number of attacks /8 weeks with severity points
Attack duration: scored on 5-point scale (5=duration of attack exceeding pretreatment duration; 4=duration equal before and after treatment; 3=duration of attacks was 75 percent of pretreatment; 2=duration of attacks was 50 percent of pretreatment; 1=duration of attacks was 25 percent of pretreatment)
Duration index: multiplying number of attacks/8 weeks with duration score
Age range of 17–55
46.1% female
NRNR/NR/26 enrolledNR/NR/NRAttack frequency/8 weeks(mean): pro=8.58; pla=14.46 (P<0.05)
Severity Index/8 weeks(mean): pro=20.69; pla=38.00 (P<0.05)
Duration index/8 weeks(mean): pro=23.58; pla=52.19 (P<0.01)
NRdata NR; no significant side effects of propranolol were observed during the trial periodNR
Borgensen
1976
Denmark

Poor quality
RCT Crossover
(a) Diagnosis of migraine (Ad Hoc Committee on Headache, 1962)
(b) > 1 migraine attack/week
(c) Intractability with known prophylactics
Cardiac disease, asthma, diabetes mellitus, physical or neurological abnormalitiesPropranolol (pro) 120 mg daily
Placebo x three months, then crossover
NRNRNRMigraine Frequency(#patients):
2–5 attack/4 weeks=1
NR/NR/45 patients15(33.3%) withdrawn/lost to fu NR/30 analyzedAttack frequency in pro period as percentage of that in pla period(number/% patients):
> 100%=9/30%
100%=3/10%
75–99%=1/3.3%
50–75%=8/26.7%
25–50%=2/6.7%
1–25%=2/6.7%
0%=5/16.7%
NRNRNR
Diamond
1976
United States Poor quality

RCT Crossover
Classic or common migraineAsthma, cardiac disease, diabetes mellitus or any physical or neurologic abnormalitiesFlexible dosing:
Propranolol (pro) 80–160 mg daily
Placebo (pla) x 4–8 weeks; then crossover x 8 weeks
Common analgesics, narcotics, ergot medicationsSeverity rated on 3-point scale (severe/3 headache units(HU)=incapacitation unable to perform their duties; moderate/2 HU=annoying headache with difficulties to carry out activities; mild/1 HU=bothersome headache which permit fulfillment of obligations with minimal or no difficulties)
Relief medication units(RMU): ergotamine=3 RMU; narcotic=2 RMU; common analgesic=1 RMU
Headache Index(HI): HU total/# days observed
Headache Index Ratio: pla HI/pro H(1=no change; >1=better on pro; <1=better on pla)
Relief medication index(RMI): total of RMU/# days observed
Relief medication index ratio(RMIR): pla RMI/pro RMI(1=no change; >1=better on pro; <1=better on pla)
Average age=38.1
80.7% female
Race NR
Common migraine: 57 pts.(91.9%)
Classic migraine: 5 pts(8.1%)
NR/NR/8321 pts(25.3%) withdrawn/lost to fu NR/62 analyzedResponders (# pts preferred treatment): pro=34/62(54.8%); pla=17/62(27.4%)
Corroboration of HIR/RMIR scores relative to treatment preference (#pts/%): pro=27/34(79.4%); pla=10/17(58.8%)
Comparison of HIR:RMIR relative to treatment preference (pro responder=34; pla responder=17)
Low ratio value (HIR/RMIR): pro resP=0.70/0.00; pla resP=0.37/0.00
Medium ratio value (HIR/RMIRO: pro resP=2.03/1.95; pla resP=0.75/0.75
High ratio value (HIR/RMIR): pro resP=14/?; pla=1.44/5.91
NRIncidence(# pts/%): pro=15/83(18.1%);
pla=9/83(10.8%)

Benign adverse reactions occurring on both pro and pla(data NR): nausea, light headedness, fatigue, difficulty catching breath, mild depression, heartburn

Benign side effects on pro only(data NR): diarrhea, abdominal cramps, irritability, insomnia, sleepiness
pro=6/83(7.2%)
pla=1/83(1.2%)
Fuller
1990
London

Poor quality
RCT
Common or classical migraine as defined by the Ad Hoc Committee; migraine of one year’s duration; with attacks occurring between once a week and once every four months; age between 16 and 65Contraindications to propranolol or paracetamol; pre-existing migraine prophylaxis or beta-blocker therapy for other indications; non-migrainous headaches that are not clearly distinguishable from migrainePropranolol 40 mg
Placebo
ParacetamolPatient record cards n=14
Median
age=31
78.6% female
Race NR
Common
migraine=9/14(64.3%)
Classical
migraine=5/14(35.7%)
NR/NR/27 recruited14 analyzedChange in headache severity(2 hours post-dose):
1–3 point deterioration(# patients): pro=1(7.1%); pla=4(28.6%)
No change(# patients): pro=7(50%); pla=4(28.6%)
1–6 point improvement(# patients): pro=6(42.8%); pla=6(42.8%)
Patient analysis of response to treatment:
No effect: pro=3(21.4%); pla=6(42.8%)
Poor: pro=4(28.6%); pla=3(21.4%)
Fair: pro=5(35.7%); pla=4(21.4%)
Good: pro=2(14.3%); pla=1(7.1%)
Excellent: pro=0; pla=0
NRPropranolol(# patients):
Light-headedness=1
Stomach pains=1
Sleepiness=1
Placebo(# patients):
Sleepiness=2
Nausea=2
Dizzness=1
NR Study of abortive treatment of migraine
Johnson
1986
New Zealand

RCT Crossover
Aged 22–80, with a history of least one migraine attack during the month preceding the trial; attacks associated with at least two of the following: 1) a strong family history, 2) nausea or vomiting, 3) some response to vasoconstrictors, 4) a classical prodromeNRMefanamic acid (mef) 500 mg daily
Propranolol (pro) 80 mg daily
Placebo (pla) x 3 months; then crossover
Acute medication allowed (not specified)Patient charts: 1) frequency; 2) duration; 3) severity (scale 1–10); 4) associated symptoms; 5) acute medication usage; 6) side effects; 7) disability scored on a 5-point scale (1=mild disability; 5=severe, confinement to bed in a darkened room)

Patients assessed monthly
Per protocol analysis (n=17)
Mean age=42
76.5% female
Race NR
Per protocol analysis (n=17)
Common migraine=11(64.7%)
Classical migraine=6(35.3%)
NR/NR/29 enrolled12(41.4%) withdrawn/9(31%) lost to fu/17 analyzedNumber of attacks/3 months(median/mean): pro=11/13.8
pla=15/20
Median/% change(pro:pla): -4/-26.7%
Mean/% change(pro:pla): -6.3/-31.3%
Total duration (hours) of attack(median/mean):
pro=75/115
pla=138/184
Median/% change(pro:pla): -63/-45.6%
Mean/% change(pro:pla): -69/-37.5%
Average duration (hours) of attacks(median/mean):
pro=24/40
pla=26/40
Median/% change(pro:pla): -2/-7.7%
Mean/% change(pro:pla): 0
Recorded by patients in chartsIncidence: pro=2(8.7%);
pla=1(4.2%)

Adverse events on:
pro=depression, gastrointestinal symptoms pla=dizziness
Withdrawals:
pro=1
pla=1
Kaniecki
1997
United States

Poor quality
RCT Crossover
Single blind
18 to 65 years of age; meeting diagnostic criteria for migraine without aura as defined by the IHS; migraine frequency of 2–8 times/month, with a maximum of 15 headaches days per month, and a migraine history of greater than 1 yearPast trials of valproate or propranolol; failure of greater than 2 adequate trials of migraine prophylactic agents; severe medical or psychiatric illness; analgesic use of more than 15 days per month; presence of alcohol or drug abuse; use of no contraception by women of childbearing potential; unable to complete a headache diary or differentiate various headache typesSustained release propranolol (SR pro) 180 mg daily
Divalproex sodium (div) 1500 mg daily
Placebo (pla)
Symptomatic medication allowed (unspecified)Patient diary
Assessments performed at weeks 4, 8, 20, 24, and 36
Mean age NR
81.1% female
Race NR
NR/NR/375(13.5%) withdrawn)/0 lost to fu/32 analyzedReduction in mean migraine frequency/4 weeks(#/% patients): pla=6/19%; pro=20/63%
Reduction in mean migraine days/4 weeks(#/% patients): pla=7/22%; pro=22/69%
Documented on forms (not specified)Adverse event profile for SR propranolol (# events):
nausea=2
Fatigue=3
Dizziness=3
Weight gain=1
Depression=2
Increased headache=1
Impotence=1
Insomnia=1
Memory loss=1

Adverse event profile for placebo NR
Overall withdrawals due to adverse events=5(15.6%)
Nadelmann
1986

Poor quality
RCT Crossover
Fulfilled diagnostic criteria for classic and/or common migraine headaches (Ad Hoc Committee on the Classification of Headache); had at least four headaches per month during a one-month observation periodMigraine other than classic or common, or other headaches known to be associated with migraine, or if they had known contraindications to beta blockersPropranolol (pro) 80–320 mg daily
Placebo (pla) x 30 weeks (6- week dose-finding, 24-week double-blind)
Analgesics
Tranquilizers
Ergot
Narcotics
Data recorded at two-week intervals
Daily patient diaries
Headache Unit Index (HUI)
A mild headache=Annoying=1unit
A moderate headache=Interfering=2 units
A severe headche=Incapacitating=3 units for headaches lasting 2 days
A very severe
headache=Incapacitating=4 units/day for severe attacks lasting 2 or more days
Relief Medication Unit Index(RMUI)
Simple analgesic, tranquilizer=1 unit
Narcotic=2 units
Ergot compound=3 units
Age(%)
18: 1.6
20–29=37.1
30–39=30.6
40–49=24.2
50–59=4.8
60=1.6

Gender(%)
Female=85.5
Male=14.5

Race(%)
White=96.8
Black=3.2
Diagnosis(%)
Common migraine=56.5
Classic/common migraine=43.5
Classic migraine=0

History of migraine(% yrs duration)
1–5=22.6
6–10=27.4
11–15=14.5
16–20=9.7
21–25=8.1
26+=17.7
NR/NR/67 registered26 withdrawn/2 lost to fu/ Sequence 1: contrast between mean change in placebo and propranolol treatment periods
Sequence 2: contrast between mean change in propranolol and placebo treatment periods
HUI
Sequence 1: 0.33 ( P =0.03)
Sequence 2: (−0.18) (NS)

RMUI
Sequence 1: 0.66 (NS)
Sequence 2: (−0.72) (NS)
NR% Incidence
Malaise: pro=14.1; pla=3.6
Fatigue: pro=40.6; pla=5.4
Lethargy: pro=26.6;
pla=3.6
Bradycardia: pro=7.8;
pla=0
Nausea: pro=15.6; pla=5.4
Diarrhea: pro=10.9;
pla=1.8
Epigastric distress:
pro=17.2; pla=3.6
Depressed moods:
pro=7.8; pla=0
Vivid dreams: pro=10.9;
pla=1.8
NR
Nair
1974
India

Poor quality
RCT Crossover
History typical of migraine; duration of headache of more than one year; attack rate exceeded 5 or more/monthNRPropranolol (pro) 80 mg daily
Placebo (pla)
All patients used prochlorperazine 15 mgms daily throughout the duration of the study.

Use of metamizole and ergotamine tartrate also allowed as abortive treatment
Patient charts(2): 1) # of headaches suffered in one month; 2) # of tablets of metamizole and ergotamine tartrate consumed in one monthMean
age=27.2
50% female
Race NR
NRNR/NR/200 withdrawn/0 lost to fu/20 analyzedHeadache frequency(mean/month)
pla=6.25
pro=3.15
Mean/% change(pro:pla): (−3.1)/(−49.6%)
NRNRNR
Palferman
1983
London

Poor quality
RCT Crossover
Outpatients with migraine, defined as episodic headache with other accepted disorders of cerebral function including visual disturbances and vomiting, and those with "non-migraine", defined as recurrent 'simple' or 'tension' headaches without the disorders of cerebral functionPatients under 16 or over 65 years; use of beta blockers contraindicated; patients with the possibility of other pathology, disclosed by history, examination or investigations, which might lead to headachesPropranolol (pro) 120 mg daily
Placebo (pla) x 8 weeks, then crossover
NRPatient diary card
Subjective daily syptoms graded 0–4 (0=no headache, 1=mild, 2=moderate, 3=severe, 4=worst possible) x 4 weekly intervals
All patients (n=22)
Mean age=37.8
69.4% female
Race NR

Migraine patients only (n=10)
Mean age=41.4
80% female
Race NR
All patients
Average symptom duration(yrs): 11.3

Migraine patients only
Average symptom duration(yrs): 17.5
NR/NR/22 patients (10 migraine patients) enrolled14(38.8%) withdrawn/10(27.8%) lost to fu/22 analyzedAverage number of days with headache in 56 days:
All patients (N=22): pla=26; pro=23 (NS)
Migraine patients only (n=10): pla=24; pro=21 (NS)

Average headache score
All patients: pro=55; pla=47 (P=0.26)
Migraine patients only: pro=52; pla=47 (NS)
NRNRNR
Standes
1982
Norway

Poor quality
RCT Crossover
Outpatients of both sexes between the ages of 18 and 65 years with a history of between two and six common migraine attacks (Ad Hoc Committee) per monthOther types of headache (including classical migraine) and major head injuries; contraindications to beta- blocking agents; use of oral contraceptives; pregnant women; use of timolol or propranolol for other reasons than migrainePropranolol (pro) 160 mg daily
Timolol (tim) 20 mg daily
Placebo (pla)
Ergotamine and analgesicsPatient record: 1) incidence; 2) severity; 3) durationAge range: Men=20–57;
Women=22- 57
80% female
Race NR
NRNR/NR/25 recruited7(28%) withdrawn/0 lost to fu/18 analyzedReduction in mean attacks/month(mean/% change): pro=(− 3.43)/(51.6%); pla=(−2)/(−30.1%)
Ergotamine use(change in % of attacks during which pain relieving tablets were taken): pro=(−18 percentage points); pla=(−13.4 percentage points)
Other pain relief tablet use(change in % of attacks during which pain relieving tablets were taken): pro=(−29 percentage points); pla=(−35 percentage points)
Reduction in frequency of attacks:
Good(>/= 50% reduction): pro=13 pts./72.2%; pla=6 pts./33.3%
Some(33.3–49% reduction): pro=0 pts.; pla=1 pt./5.5%
No effect(0=33.2% reduction); pro=3 pts/16.7%; pla=8 pts./44.4%
Negative effect(increased frequency): pro=2 pts/11.1%; pla=3 pts/16.7%
Patient reportIncidence(# pts/%):
pro=6/25(24%);
pla=5/25(20%)
Most common adverse events:
Tiredness: pro=3/25(12%);
pla=4/25(16%)
Nausea: pro=1/25(4%);
pla=1/25(4%)
Sunburn feeling:
pro=1/25(4%); pla=0
Depression:
pro=1/25(4%); pla=0
2/25(8%) treatment
NR
Tfelt-Hansen
1984
Scandinavia

Poor quality
RCT Crossover
Outpatients of both sexes between ages of 18 and 65 years with a history of between 2 and 6 common migraine attacks per month (Ad Hoc Committee)Other types of headache (including classical migraine) and major head injuries; contraindications to beta blockers; oral contraceptive use; heart rate < 54 after 3 min of rest and with supine DBP >/= 100 mmHgTimolol (tim) 20 mg daily
Propranolol (pro) 160 mg daily
Placebo (pla)
NRPatient diary card: 1) frequency; 2) duration; 3) severity of attacks; 4) number of responders (e.g., >/= 50% reduction in frequency of attacks compared to baseline; 5) frequency of attacks with associated symptoms; 6) frequency of attacks requiring medication; 7) headache index=frequency x severity x attack duration in hours; 8) second headache index: attack frequency x severityMean age=39.5
73.9% female
Race NR
Clinical characteristics(mean)
Duration of migraine(years):
20.9
Attack frequency/28 days: 5.7
Attack with nausea
frequency/28 days: 2.6
Attack with ergotamine therapy
frequency/28 days: 2.4
Attack with any therapy
frequency/28 days: 5.1
Duration of attacks(hours): 9.8
Severity of attacks: 2.0
NR/NR/96withdrawn=27(28.1%)/6(6.2 %) lost to fu/80 analyzedMean frequencies per 28 days/mean(%) change for propranolol relative to placebo
Frequency of attacks: pro=3.69; pla=4.84/−1.15(−23.8%)
Frequqency of attacks with nausea: pro=1.37; pla=1.89/−0.52(−27.5%)
Frequency of attacks with any therapy: pro=3.24; pla=4.20/−0.96(−22.8%)
Severity of attacks: pro=1.83; pla=1.93/−0.10(−5.2%)(NS)
Duration of attacks(hours): pro=7.38; pla=7.95/−0.57(−7.2%)(NS)
Headache index2: pro=6.66; pla=9.03/−2.37(−35.6%)
Headache index1: pro=50.3; pla=50.7/−19(−27.4%)

Number of responders(# pts with 50% reduction in frequency): pro=48;
pla=24/24(+50%)
Patient reportIncidence[# pts(%)]:
pro=35(42.2%);
pla=23(27.7%)
Most commonly reported
side effects:
Fatigue/tiredness:
pro=11(13%);
pla=15(18%)
Dizziness: pro=4(5%);
pla=2(2%)
Nausea: pro=5(6%);
pla=2(2%)
Sleep disturbances:
pro=3(4%); pla=2(2%)
Depression: pro=3(4%);
pla=0
Abnormal dreaming:
pro=0; pla=0
pro=6/89(6.7%)
pla=2/90(2.2%)
Weber
1972
United States

Poor quality
RCT Crossover
Met criteria for diagnosis of migraine and that were recognized as therapeutic management problemsAbnormal neurological examinations; disorders that could be aggravated by beta blockers (namely cariac disease, asthma, diabetes mellitus)Propranolol (pro) 80 mg daily
Placebo (pla)
NR1) Frequency and 2) severity assessed at 4-week intervals

Definitions of symptomatic responses Excellent: all or nearly all symptoms of migraine absent after first week of study
Good: more than 50% reduction in frequency or severity of headaches
Fair: minimal symptomatic improvement
No effect: unspecified
Mean
age=40.6
52% female
Race NR
Classic: 13(68.4%)
Common: 6(31.6%)
NR/NR/25withdrawn=6/25(24%)/lost to fu NR/analyzed 19Symptomatic response(# pts/%)
First 3 months(pro n=8; pla n=11)
Good/Excellent: pro=5(63%); pla=0
Fair: pro=2(25%); pla=1(9.1%)
No effect: pro=1(12.5%); pla=11(91%)
Second 3 months(pro n=11 who received placebo first; pla n=8 who received pro first)
Good/Excellent: pro=10(91%); pla=2(25%)
Fair: pro=0; pla=0
No effect: pro=1(9.1%); pla=6(75%)
Irrespective of sequence
pro>pla(#/% pts): 15/79%
pro=pla(#/% pts): 4/21%
NRAbdominal cramps/diarrhea:1 patientNR
Schellenberg
2008
head-to-head
Outpatients of both sexes between the ages of 18 and 65 years with confirmed migraine diagnosis with onset of migraine history <50 years of age, history of migraine <12 months, documented record of at least 2 migraines per month in previous 3 months, 2–6 migraine attacks in the 4 weeks prebaseline, adequate acute, symptomatic treatment of attacks, current contraception accepted if >3months adn unchanged during trial.Prophylactic migraine treatments in previous 3 months, concomitant b-blocker, calcium antagonist, concomitant nondrug migraine treatment, use of symptomatic treatment for >10 days per month, change in current symptomatic treatment for migraine, history of hypersensitivity to metoprolol or nebivolol, history of substance abuse, pregnant or breast feeding, congestive HF, heart rate <50bpm, systolic blood pressure <100 bpm, peripheral arterial occlusive disease, uncontrolled DM, history of bronchospasm, clinically relevant abnormal laboratory valuesWeek 1: metoprolol (met) 47.5 mg; OR nebivolol (neb) 5 mg
Week 2: met 95 mg OR neb 5 mg
Weeks 3–16: met 142.5 mg OR neb 5 mg
Week 17: met 95 mg OR neb 5 mg alternate days
Week 18: met 47.5 mg OR neb 5 mg every two days
NRPrimary endpoint: frequency of migrane attacks reported by patients during the last 4 weeks of the 14 week treatment. Secondary endpoints: time to therapeutic effect (evaluated 4- weekly), duration of attacks, intensity of headache, consumption of analgesics, evaluation of accompanying symptoms, migrane disability assessment, clinical global impression, patients global impression, quality of life, responder rates -- defined as a decrease of at least 50% in number of attacks from baseline to endpoint.Mean age= 39
female 86%
Race NR
Migraine disability assessment (MIDAS)
mild impairment: 2 (6%)
moderate impairment: 6 (20%)
severe impairment: 22 (73%)
Days with headache (per month prior 3 months) mean 18
Screened: 38
Eligible: 30
Enrolled: 30
met 14; neb 16
2/NR/30Preimary endpoint:
Frequency of migraine attacks (mean): met 1.3; neb 1.6
Secondary endpoints:
Onset of action (attacks during weeks 0–4) mean:
met 1.9; neb 2.2
Responder rate at endpoint %:
met 57%; neb 50%
Duration of migrane attacks at endpoint (mean hours)
met 26; neb 15
severity at endpoint (measured on 100-mm visual analogue scale)
met 54; neb 50
Patients using pain medication at endpoint (%)
met 77%; neb 67%
Differences between the two groups was NS
AE reporting were completed during clinic visits.Number reported events:
met 44; neb 32
number of treatment
related events: met 13; neb 11
Patients reporting events:
mild: met 1 (7%); neb 4 (25%)
moderate: met 12 (86%); neb 6 (38%)
severe: met 6 (43%); neb 2 (13%)
patient withdrawl due to adverse events:
met 1 (7%); neb 1 (6%)
most common reported events:
fatigue: met 11; neb 7
bradycardia: met 5; neb 1
hypotension: met 2; neb 1
supraventricular
extrasystoles: met 2; neb 1
6.6% (2/30)head-to-head trial need to move from placebo table
Siniatchkin
2007
Germany
RCT
parallel-group
Outpatients of both sexes between the ages of 18 and 60 years with migraine history of ≥ 12 months and a mean of 2–10 migraine attacks per month within last 3 months.Pregnancy or lactaion; abuse of ergotamine, triptans or analgesics; any prophylactic treatment of migraine during 6 months preceeding the trial; neurological, psychiatric or internal disease during the treatment in the last year; all specific contradictions for b-blockers; concomitant non-migraine headaches more than 3 X per month w/in last 3 months; substance abuse; change in oral contraceptive use 3 months prior to the study.Metoprolol (met) titrated by 50 mg weekly until the maximum dose of 200 mg.
Placebo titrated by 50 mg weekly until the maximum dose of 200 mg
X 3 months
After 3 months met was decreased at 50 mg/week.
Usual abortive treatment allowed -- not specified.
Patients were asked not to change their treatment during the study.
Headache diary: days in which migraine occured, duration in hours, intensity (3 assessment times per day using visual analogue scale), dosage of all medications taken and side-effects.Mean Age:
met 36.7;
placebo 37.3
female: met
20%; placebo
10%
Race: NR
duration of disease in years:
met 23.9; placebo 20.7
attack frequency days/mo:
met 5.2; placebo 4.0
attack duration (hours):
met 18.6; placebo 17.3
intensity (scale 1–10): met 9.4;
placebo 9.2
analgesics/triptans use
(tablets/months): met 6.4;
placebo 7.3
Recruited: 20
ENRolled: 20
0/NR/20Migraine days/month:
Reported Z Scores
met 2.8; pla 1.9
Attack intensity:
met 3.9; pla .9
Duration of headache
met 2.9; pla 1.1
P<0.05
patient diarymet: n=4 (40%):
tiredness 2 (20%)
dizziness 1 (10%)
cardovascular 1 (10%)

placebo: n=3 (30%)
gastrointestinal
distrubances 2 (20%)
tiredness 1 (10%)
0 (0/20)

From: Beta Adrenergic Blockers: Evidence Tables

Cover of Drug Class Review: Agents for Overactive Bladder
Drug Class Review: Agents for Overactive Bladder: Final Report Update 4 [Internet].
McDonagh MS, Selover D, Santa J, et al.
Portland (OR): Oregon Health & Science University; 2009 Mar.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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