Table 5. Secondary outcomes of comparative effectiveness trials.

Drug1	Comparison, Time Point	Weighted Mean Difference (95% CI)	Heterogeneity	Quality of Evidence
Headache Days Weighted Mean Difference (95% CI)
Metoprolol	Clonidine
	Baseline	0.0 (-3.7 to 3.7)	—	Low
	8 Weeks	-1.8 (-5.7 to 2.14)	—
	Metoprolol + Fluoxetine
	8 weeks	0.83 (0.63 to 1.0)	—	Low
Nadolol (80mg)	Nadolol (160mg)
	Baseline	2.3 (-3.4 to 7.9)	—	Low
	4 weeks	-0.22 (-5.9 to 5.4)	—
	8 weeks	-0.05 (-5.9 to 5.8)	—
	12 weeks	2.2 (-7.9 to 3.6)	—
Pindolol (7.5mg)	Pindolol (15mg)
	Baseline	0.05 (-0.94 to 1.0)	—	Low
	4 weeks	0.28 (-0.72 to 1.3)	—
Propranolol	Acupuncture
	Baseline	0.0 (-1.0 to 1.0)	—	Low
	12 weeks	0.70 (-0.43 to 1.8)	—
	Atenolol
	8 weeks	0.06 (-1.8 to 1.9)	—	Low
	Behavioral Management
	Baseline	0.50 (-0.88 to 1.9)	—	Low
	40 weeks	-0.10 (-1.3 to 1.1)	—
	64 weeks	0.10 (-1.1 to 1.3)	—
	Candesartan
	12 weeks	0.45 (-1.2 to 2.1)	—	Low
	Clonidine
	16 weeks	0.10 (-2.1 to 2.3)	—	Low
	Cyclandelate
	Baseline	-0.60 (-2.5 to 1.3)	—	Low
	4 weeks	-1.1 (-2.8 to 0.64)	—
	8 weeks	0.40 (-1.2 to 2.0)	—
	Femoxetine
	8 weeks	-1.6 (-4.5 to 1.3)	—	Low
	Flunarizine
	Baseline	-0.80 (-2.2 to 0.59)	—	Low
	4 weeks	1.4 (0.02 to 2.8)	—
	8 weeks	0.50 (-0.91 to 1.9)	—
	12 weeks	-0.5 (-1.9 to 0.96)	—
	16 weeks	0.61 (-0.91 to 2.1)	—
	Metoprolol
	Baseline	-0.31 (-1.3 to 0.68)	—	Low
	4 weeks	-0.60 (-4.3 to 3.1)	—	Low
	8 weeks	-0.17 (-0.96 to 0.51)	Q = 0.73 df = 1, I2 = 0.0%	Moderate
	16 weeks	0.06 (-1.9 to 2.02)	—	Low
	24 weeks	-2.2 (-4.2 to -0.24)	—	Low
	Naproxen
	12 weeks	-2.8 (-3.6 to -1.9)	—	Low
	Nifedipine
	Baseline	-0.80 (-3.3 to 1.7)	—	Low
	4 weeks	-3.6 (-7.0 to -0.16)	—
	16 weeks	-2.2 (-4.0 to -0.32)	—
	28 weeks	-0.80 (-2.6 to 1.0)	—
	Propranolol (80mg v 160mg)
	Baseline	0.0 (-1.7 to 1.7)	—	Low
	12 weeks	-2.7 (04.9 to -0.5)	—
	Tolfenamic Acid
	Baseline	0.0 (-1.6 to 1.6)	—	Low
	12 weeks	-0.22 (-2.1 to 1.6)	—
	Topiramate
	Baseline	0.12 (-0.3 to 0.55)	—	Low
	24 weeks	-0.25 (01.13 to 0.63)	—
Headache Index, Standardized Mean Difference (95% CI)
Metoprolol	Clonidine
	Baseline	0.0 (-0.49 to 0.49)	—	Low
	8 Weeks	-0.24 (-0.76 to 0.29)	—
Pindolol (7.5mg)	Pindolol (15 mg)
	Baseline	0.05 (-0.94 to 1.04)	—	Low
	4 weeks	0.27 (-0.72 to 1.3)	—
Propranolol	Amitriptyline
	Baseline	0.05 (-0.42 to 0.52)	—	Low
	6 weeks	-0.42 (-0.89 to 0.06)	—
	Amitriptyline + Biofeedback
	Baseline	0.08 (-0.37 to 0.53)	—	Low
	6 weeks	-0.24 (-0.69 to 0.21)	—
	Amitriptyline + Propranolol
	Baseline	0.01 (-0.44 to 0.46)	—	Low
	6 weeks	0.06 (-0.39 to 0.51)	—
	Amitriptyline + Propranolol + Biofeedback
	Baseline	-0.04 (-0.52 to 0.44)	—	Low
	6 weeks	0.25 (-0.23 to 0.74)	—
	Biofeedback
	Baseline	0.17 (-0.31 to 0.64)	—	Low
	6 weeks	-0.35 (-0.83 to 0.13)	—
	Biofeedback + Propranolol
	Baseline	-0.03 (-0.50 to 0.44)	—	Low
	6 weeks	0.39 (-0.09 to 0.86)	—
	Aspirin
	Baseline	0.00 (-0.65 to 0.65)	—	Low
	6 weeks	0.25 (-0.56 to 1.05)	—
	Atenolol
	6 weeks	0.01 (-0.59 to 0.62)	—	Low
	Femoxetine
	Baseline	0.00 (-0.57 to 0.57)	—	Low
	8 weeks	-0.24 (-0.70 to 0.21)	—
	12 weeks	-0.35 (-0.92 to 0.22)	—
	Flunarizine
	Baseline	0.12 (-0.17 to 0.42)	Q = 1.59, df = 2, I2 = 0.0%	Moderate
	4 weeks	-0.18 (-0.82 to 0.46)	Q = 2.45, df = 2, I2 = 59.3%
	8 weeks	-0.13 (-0.75 to 0.48)	Q = 2.27, df = 1, I2 = 55.9%
	12 weeks	0.16 (-1.1 to 1.4)	Q = 8.7, df = 1, I2 = 88.5%
	16 weeks	-0.08 (-0.48 to 0.32)	Q = 3.13, df = 2, I2 = 49.3%
	Flunarizine + Propranolol
	Baseline	0.42 (-0.30 to 1.1)	—	Low
	4 weeks	0.29 (-0.43 to 1.0)	—
	8 weeks	0.17 (-0.54 to 0.89)	—
	12 weeks	0.47 (-0.26 to 1.2)	—
	16 weeks	0.67 (-0.07 to 1.4)	—
	Metoprolol
	Baseline	0.00 (-0.29 to 0.29)	Q = 0.00, df = 1, I2 = 0.0%	Moderate
	8 weeks	0.06 (-0.24 to 0.35)	Q = 0.23, df = 1, I2 = 0.0%
	Nadolol
	Baseline	0.41 (-0.09 to 0.90)	—	Low
	4 weeks	0.34 (-0.16 to 0.83)	—
	8 weeks	0.44 (-0.08 to 0.96)	—
	12 weeks	0.29 (-0.22 to 0.81)	—
	Timolol
	Baseline	0.00 (-0.31 to 0.31)	—	Low
	12 weeks	0.17 (-0.14 to 0.48)	—
	Valproic Acid
	Baseline	-0.09 (-0.56 to 0.38)
	10 weeks	-0.03 (-0.50 to 0.44)	—	Low
Propranolol + Flunarizine	Topiramate
	Baseline	0.07 (-0.36 to 0.57)	—	Low
	12 weeks	0.99 (0.53 to 1.4)	—
Episodic Migraine, 50% reduction in Headaches
Comparison		RR (95% CI)	Heterogeneity	Quality
Metoprolol	ASA	2.4 (0.88 to 6.7)	—	Low
	Clonidine	1.3 (0.62 to 2.9)	—	Low
	Flunarizine	1.1 (0.98 to 1.3)	—	Low
	Nebivolol	1.1 (0.56 to 2.2)	—	Low
	Pizotifen	0.69 (0.36 to 1.3)	—	Low
Metoprolol + Flunarizine	Flunarizine	1.3 (1.0 to 1.6)	—	Low
Propranolol	ASA	1.3 (0.88 to 1.9)	Q = 2.44, df = 1, I2 = 59.1%	Moderate
	Acupuncture	0.88 (0.57 to 1.3)	—	Low
	Candesartan	0.93 (0.61 to 1.4)	—	Low
	Clonidine	1.6 (0.86 to 3.1)	—	Low
	Cyclandelate	1.0 (0.71 to 1.5)	Q = 4.39, df = 2, I2 = 54.4%	Moderate
	Femoxetine	3.5 (0.43 to 29.4)	—	Low
	Flunarizine	1.0 (0.89 to 1.2)	Q = 3.30, df = 5, I2 = 0.0%	High
	Flunarizine + Propranolol	0.86 (0.59 to 1.2)	—	Low
	Metoprolol	0.86 (0.60 to 1.2)	Q = 0.11, df = 1, I2 = 0.0%	Moderate
	Nadolol	0.66 (0.27 to 1.6)	Q = 6.20, df = 2, I2 = 67.8%	Moderate
	Nifedipine	2.2 (1.3 to 3.8)	—	Low
	Nortriptyline	1.5 (0.54 to 4.2)	—	Low
	Nortriptyline + Propranolol	1.1 (0.48 to 2.7)	—	Low
	Propranolol (80 vs. 160mg)	0.94 (0.72 to 1.2)	—	Low
	Timolol	1.1 (0.84 to 1.4)	—	Low
	Topiramate	1.2 (0.98 to 1.4)	Q = 0.05, df = 2 I2 = 0.0%	Moderate
	Valproic Acid	0.96 (0.77 to 1.2)	Q = 0.16, df = 2, I2 = 0.0%	Moderate
Propranolol + Amitriptyline	Amitriptyline	1.02 (0.92 to 1.1)	—	Low
Propranolol + Flunarizine	Nimodipine + Diazepam + Oryzanol	1.5 (1.2 to 2.0)	—	Low
Propranolol + Nadolol	Behavioral Management	0.98 (0.58 to 1.7)	—	Low
Propranolol + Nadolol	Behavioral Management + Propranolol	0.44 (0.30 to 0.66)	—	Low
Medicine Use (doses/month)
Comparison		Weighted Mean Difference (95% CI)	Heterogeneity	Quality of evidence
Metoprolol	Bisoprolol
	Baseline	0.0 (-0.31 to 0.31)	—	Low
	12 weeks	0.01 (-0.30 to 0.32)	—
	Clomipramine
	4 weeks	-0.55 (-1.2 to 0.08)	—	Low
	Clonidine
	Baseline	0.0 (-0.50 to 0.50)	—	Low
	8 weeks	-0.52 (-1.0 to 0.02)	—
Propranolol	5-Hydroxytryptophan
	Baseline	0.48 (-0.16 to 1.1)	—	Low
	16 weeks	0.22 (-0.41 to 0.85)	—
	Candesartan
	12 weeks	-0.45 (-0.82 to -0.09)	—	Low
	Cyclandelate
	Baseline	-0.49 (-1.0 to 0.02)	—	Low
	4 weeks	-0.70 (-1.2 to -0.19)	—
	8 weeks	-0.19 (-0.69 to 0.32)	—
	Femoxetine
	Baseline	0.00 (-0.57 to -0.57)	—	Low
	12 weeks	-0.83 (-1.4 to -0.24)	—
	Flunarizine
	Baseline	0.08 (-0.10 to 0.26)	Q = 1.98, df = 2, I2 = 0.0%	Moderate
	4 weeks	-.44 (0.02 to 0.86)	—	Low
	8 weeks	-0.15 (-0.57 to 0.28)	—	Low
	12 weeks	-0.23 (-0.43 to -0.04)	Q = 0.06, df = 1, I2 = 0.0%	Moderate
	16 weeks	-0.07 (-0.41 to 0.27)	Q = 0.01, df = 1, I2 = 0.0%	Moderate
	Metoprolol
	Baseline	0.00 (-0.29 to 0.29)	Q = 0.00, df = 1, I2 = 0.0%	Moderate
	8 weeks	-0.19 (-0.49 to 0.11)	Q = 1.00, df = 1, I2 = 0.5%
	Nadolol
	Baseline	-0.31 (-1.1 to 0.45)	—	Low
	24 weeks	-0.73 (-1.5 to 0.05)	—
Health Related Quality of Life
Comparison		Standardized Mean Difference (95% CI)	Heterogeneity	Quality of evidence
Metoprolol	Nebivolol (MOS SF36)
	Baseline	-0.21 (-0.93 to 0.51)	—	Low
	16 Weeks	-0.46 (-1.2 to 0.27)	—
Propranolol	Acupuncture (MOS SF36)
	Baseline	-0.19 (-0.56 to 0.19)	—	Low
	12 weeks	-0.47 (-0.84 to -0.10)	—
	Behavioral Management
	Baseline	0.14 (-0.24 to 0.52)	—	Low
	40 weeks	0.48 (0.10 to 0.86)	—
	64 weeks	0.23 (-0.15 to 0.60)	—
	Behavioral Management + Propranolol
	Baseline	0.07 (-0.28 to 0.43)	—	Low
	40 weeks	0.68 (0.31 to 1.0)	—
	64 weeks	0.61 (-.24 to 0.97)	—
	Candesartan
	12 weeks	-0.18 (-0.54 to 0.19)	—	Low
	Riboflavin (MIDAS)
	Baseline	-0.06 (-0.46 to 0.33)	—	Low
	4 weeks	0.00 (-0.39 to 0.39)	—
Propranolol + Topiramate	Topiramate (MIDAS)
	24 weeks	0.01 (-0.39 to 0.41)	—	Low
Headache Severity
Comparison		Standardized Mean Difference (95% CI)	Heterogeneity	Quality of evidence
Metoprolol	Aspirin
	8 weeks	0.33 (-0.20 to 0.86)	—	Low
	Acupuncture
	17 weeks	-0.46 (-0.91 to -0.002)	—	Low
	Bisoprolol
	Baseline	0.00 (-0.31 to 0.31)	—	Low
	12 weeks	0.19 (-0.13 to 0.3)	—
	Flunarizine
	Baseline	0.46 (0.14 to 0.79)	—	Low
	4 weeks	0.13 (-0.22 to 0.48)	—
	8 weeks	0.38 (0.02 to 0.73)	—
	12 weeks	0.13 (-0.22 to 0.48)	—
	16 weeks	0.75 (0.39 to 1.1)	—
	20 weeks	0.42 (0.07 to 0.77)	—
	Nebivolol
	16 weeks	0.19 (-0.53 to 0.91)	—	Low
	Pizotifen
	Baseline	0.00 (-0.47 to 0.47)	—	Low
	8 weeks	-0.91 (-1.4 to -0.40)	—
Metoprolol + Flunarizine	Flunarizine
	12 weeks	-0.25 (-0.79 to 0.26)	—	Low
	24 weeks	-0.55 (-1.1 to -0.02)	—
	36 weeks	-0.49 (-1.0 to 0.047)	—
	48 weeks	-0.54 (-0.72 to -0.19)	—
Propranolol	Acupuncture
	Baseline	0.26 (-0.13 to 0.65	—	Low
	12 weeks	0.63 (0.23 to 1.03)	—
	5-hydroxytryptophan
	Baseline	0.18 (-0.45 to 0.81)	—	Low
	16 weeks	0.00 (-0.63 to 0.63)	—
	Biofeedback
	Baseline	-0.07 (-0.36 to 0.21)	—	Low
	24 weeks	0.13 (-0.15 to 0.42)	—
	Cyclandelate
	Baseline	-0.07 (-0.58 to 0.43)	—	Low
	4 weeks	-0.17 (-0.68 to 0.33)	—
	8 weeks	-0.01 (-0.51 to 0.48)	—
	Flunarizine
	Baseline	0.00 (-0.32 to 0.32)	Q = 0.0, df = 1, I2 = 0.0%	Moderate
	4 weeks	-0.24 (-0.66 to 0.17)	—	Low
	8 weeks	-0.57 (-1.0 to -0.13)	—	Low
	12 weeks	-0.25 (-0.69 to 0.19)	—	Low
	16 weeks	0.17 (-0.52 to 0.85)	Q = 79.7, df = 3, I2 = 92.9%	High
	Metoprolol
	Baseline	0.0 (-0.37 to 0.37)	—	Low
	8 weeks	0.0 (-0.38 to 0.38)	—
	Nadolol
	Baseline	0.00 (-0.67 to 0.84)	—	Low
	24 Weeks	0.86 (0.07 to 1.7)	—
	Naproxen
	12 weeks	0.14 (-0.29 to 0.56)	—	Low
	Nimodipine
	24 weeks	-0.50 (-0.89 to -0.11)	—	Low
	Propranolol (80 v 160mg doses)
	Baseline	0.00 (-0.40 to 0.40)	—	Low
	8 weeks	0.00 (-0.51 to 0.51)	—
	12 weeks	0.00 (-0.43 to 0.43)	—
	Riboflavin
	Baseline	0.32 (-0.08 to 0.71)	—	Low
	4 weeks	0.33 (-0.07 to 0.72)	—
	8 weeks	0.21 (-0.18 to 0.60)	—
	12 weeks	0.42 (0.02 to 0.82)	—
	24 weeks	0.11 (-0.29 to 0.50)	—
	Timolol
	Baseline	0.00 (-0.31 to 0.31)	—	Low
	12 weeks	0.14 (-0.17 to 0.45)	—
	Tolfenamic Acid
	Baseline	0.26 (-0.37 to 0.68)	—	Low
	12 weeks	0.15 (-0.63 to 0.93)	Q = 4.53, df = 1, I2 = 77.8%	Moderate
	Topiramate
	Baseline	-0.44 (-0.95 to 0.07)	—	Low
	4 weeks	-0.19 (-0.69 to 0.32)	—
	8 weeks	0.23 (-0.28 to 0.74)	—
Headache Duration
Comparison		Weighted Mean Difference (95% CI)	Heterogeneity	Quality of evidence
Bisoprolol (5mg)	Bisoprolol (10 mg)
	Baseline	2.4 (-4.3 to 9.1)	—	Low
	12 weeks	-4.8 (-9.9 to 0.31)	—
Metoprolol	Acupuncture
	12 weeks	-2.4 (-6.5 to 1.7)	—	Low
	Bisoprolol
	Baseline	0.0 (-4.9 to 4.9)	—	Low
	12 weeks	0.30 (-4.2 to 4.8)	—
	Clomipramine
	4 weeks	-2.8 (-4.4 to -1.2)	—	Low
	Flunarizine
	Baseline	-1.3 (-3.7 to 1.1)	—	Low
	4 weeks	-3.2 (-5.7 to -0.69)	—
	8 weeks	-3.3 (-5.9 to -0.66)	—
	12 weeks	-2.4 (-4.9 to 0.11)	—
	16 weeks	-0.40 (-3.2 to 2.4)	—
	20 weeks	-1.3 (-4.1 to 1.5)	—
	Metoprolol + Fluoxetine
	Baseline	0.10 (-0.15 to 0.35)	—	Low
	12 weeks	-0.53 (-0.75 to -0.31)	—
	Nebivolol
	16 weeks	11 (-18.6 to 40.6)	—	Low
	Nifedipine
	Baseline	1.0 (-14.3 to 16.3)	—	Low
	4 weeks	15.8 (0.49 to 31.1)	—
	28 weeks	12.2 (0.66 to 23.7)	—
Pindolol (7.5 mg)	Pindolol (15 mg)
	Baseline	-0.70 (-7.9 to 6.6)	—	Low
	4 weeks	-0.80 (-8.2 to 6.5)	—
Propranolol	5-hydroxytryptophan
	Baseline	6.1 (-1.1 to 13.3)	—	Low
	16 weeks	3.6 (-3.7 to 10.9)	—
	Biofeedback
	Baseline	0.04 (-2.5 to 2.6)	—	Low
	24 weeks	0.33 (-1.3 to 2.0)	—
	Candesartan
	12 weeks	6.3 (-1.9 to 14.5)	—	Low
	Cyclandelate
	Baseline	6.7 (-22.5 to 9.1)	—	Low
	4 weeks	-12.6 (-37.4 to 12.2)	—
	8 weeks	6.6 (-18.2 to 31.4)	—
	12 weeks	-4.5 (-26.6 to 17.6)	—
	Flunarizine
	Baseline	2.7 (-1.2 to 6.6)	—	Low
	4 weeks	-0.55 (-4.8 to 3.7)	Q = 0.06, df = 1, I2 = 0.0%	Moderate
	8 weeks	0.29 (-3.3 to 3.9)	Q = 0.08, df = 1, I2 = 0.0%	Moderate
	12 weeks	-0.21 (-3.3 to 2.9)	Q = 0.09, df = 1, I2 = 0.0%	Moderate
	16 weeks	1.4 (0.23 to 2.6)	Q = 4.33, df = 4, I2 = 7.6%	High
	Mefenamic Acid
	12 weeks	7.0 (-27.3 to 41.3)	—	Low
	Metoprolol
	Baseline	-24.0 (-40.3 to -7.7)	—	Low
	4 weeks	4.2 (-12.1 to 20.5)	—
	16 weeks	0.0 (-12.3 to 12.3)	—
	28 weeks	33.0 (6.3 to 59.7)	—
	Nadolol
	Baseline	-8.1 (-11.4 to -4.8)	—	Low
	24 weeks	-19.5 (-31.8 to -7.1)	—
	Nifedipine
	Baseline	-1.0 (-16.3 to 14.3)	—	Low
	4 weeks	-15.8 (-31.1 to -0.49)	—
	16 weeks	-12.2 (-23.7 to -0.66)	—
	28 weeks	20.0 (0.97 to 39.0)	—
	Nimodipine
	24 weeks	-4.0 (-7.9 to -0.08)	—	Low
	Propranolol (80 mg vs 160mg)
	Baseline	0.0 (-1.2 to 1.2)	—	Low
	8 weeks	-0.30 (-6.9 to 6.3)	—
	12 weeks	0.20 (-1.8 to 2.2)	—
	Riboflavin
	Baseline	0.10 (-0.29 to 0.49)	—	Low
	4 weeks	0.10 (-0.31 to 0.51)	—
	8 weeks	0.00 (-0.26 to 0.26)	—
	12 weeks	-0.10 (-0.39 to 0.19)	—
	24 weeks	0.30 (-0.06 to 6.6)	—
	Timolol
	Baseline	0.00 (-2.6 to 2.6)	—	Low
	12 weeks	-0.03 (-2.3 to 2.3)	—
	Tolfenamic Acid
	Baseline	6.4 (-21.9 to 34.7)	—	Low
	12 weeks	1.7 (-4.6 to 8.0)	Q = 0.05, df = 1, I2-0.0%	Moderate
	Topiramate
	Baseline	-1.3 (-4.8 to 2.3)	—	Low
	4 weeks	-1.2 (-4.6 to 2.3)	—
	8 weeks	1.0 (-1.9 to 4.0)	—
	Valproic Acid
	Baseline	-1.4 (-9.9 to 7.2)	—	Low
	10 weeks	-0.70 (-4.0 to 2.6)	—