Pain reliefa
Pain-freea
Drug
Dose
Age (ys.)
Active drug (%)
Placebo (%)
P-value
Active drug (%)
Placebo (%)
P-value
Reference
Acetaminophen
15 mg/kg
4–16
54
37
–
39
28
–
[8]
Ibuprofen
10 mg/kg
4–16
68
37
–
60
28
–
[8]
7.5 mg/kg
6–12
76
53
.006
44
25
NS
[9]
200/400 mgb
6–18
69
28
<.05
48
7
<.01
[10]
Dihydroergotamine
20/40 μg/kg
5–15
58
17
–
–
–
–
[11]
Sumatriptan oral
50/100 mgc
8–16
30
22
NS
22
9
NS
[12]
25/50 mg
10–17
31
39
NS
24
29
NS
[13]
Sumatriptan nasal
20 mg
6–10
86
43
.03
64
14
.02
[14]
5/10/20 mg
12–17
63d
53
NS
36d
25
<.05
[15]
5/20 mg
12–17
58d
68
.046
44d
30
<.001
[16]
10/20 mgc
8–17
64
39
.003
31
19
NS
[17]
Zolmitriptan oral
2,5 mg
6–18
62
28
<.05
45
7
<.01
[10]
2,5/5/10 mg
12–17
53–58e
54
NS
19–23e
25
NS
[18]
Zolmitriptan nasal
5 mgf
12–17
66
54
NS
39
19
<.01
[19]
Rizatriptan
5 mg
12–17
66
56
NS
32
28
NS
[20]
5 mg
12-17
68
69
NS
39
31
NS
[21]
5/10 mgc
6–17
74 + 73g
36
<.001
35 + 31g
18
.02 + .04
[22]
5/10 mgc,h
6–17
58
53
NS
33
24
<.05
[23]
Almotriptan
6.25/12,5 /25 mg
12–12
67i
55
.02
40i
34
NS
[24]
Eletriptan
40 mg
12–17
57
57
NS
22
15
NS
[25]
Sumatriptan + Naproxen
10/60, 30/180, 85/500 mg
12–17
–
–
–
24–29
10
.003
[26]
Ibuprofen was examined in the study already mentioned [8] – one parallel group study and another crossover study [9, 10]. In the crossover study comparing acetaminophen, ibuprofen and placebo [8], ibuprofen was superior to placebo at 1 h as well as at 2 h for headache relief (OR 3.4, 95 % CI 1.2–10.2 and OR 2.9, 95 % CI 1.0–8.1) and pain-free response (OR 3.1, 95 % CI 1.0–9.9 and OR 3.5, 95 % CI 1.0–11.9), as well as superior to acetaminophen in aborting migraine within 2 h (OR 2.2,. 95 % CI 1.1–4.0).
In the parallel group study [9], patients had to treat one moderate or severe migraine headache under adult supervision. Ibuprofen was superior to placebo in relieving headache 2 h postdose, and with respect to the median pain score, absence of nausea and need for rescue medication, but not in making the children headache-free and stopping other autonomic symptoms at 2 h. Analyzing boys and girls separately, significantly higher response rates was observed for ibuprofen compared to placebo in boys, but no difference whatsoever was noticed in girls.
The second crossover study compared ibuprofen, zolmitriptan and placebo [10]. Ibuprofen was superior to placebo with respect to pain relief at 1, 2 and 4 h, pain-free at 2 and 4 h, sustained pain free as well as absence of nausea and photophobia/phonophobia at 1 and 2 h. Response rates in boys and girls did not differ from each other.
With respect to adverse events (AE) of acetaminophen and ibuprofen, the authors of a systematic review conclude that ibuprofen, acetaminophen and placebo have similar tolerability and safety profiles in terms of gastrointestinal symptoms, asthma and renal AE [27]. Another review also concluded that both acetaminophen and ibuprofen “appear to be exceptionally safe”, but the authors point out the controversy regarding the role of acetaminophen in the development of asthma [28].
Acetaminophen and ibuprofen appear to be safe and well tolerated in children and adolescents. Regarding their efficacy for treating acute migraine attacks, there is limited evidence for ibuprofen and poor evidence for acetaminophen.
13.2.2 Ergotamines
Only one very small crossover study on oral dihydroergotamine (DHE) in 13 patients has been published (Table 13.1) [11]. Treatment with oral dihydroergotamine is limited by its low bioavailability. In addition, it is no longer on the market in many countries. DHE nasal spray, orally inhaled and intravenous DHE have not been examined in randomized placebo-controlled studies in children and adolescents up till now.
Oral dihydroergotamine seems not to be useful for the treatment of acute migraine attacks in children and adolescents.
13.2.3 Triptans
There are a total of 16 full-paper, randomized, placebo-controlled studies on triptans for acute migraine attacks in children and adolescents (Table 13.1). Oral sumatriptan was used in two studies and sumatriptan nasal spray in four studies. Zolmitriptan was examined in three studies (2 oral, 1 nasal), rizatriptan in four studies and almotriptan as well as eletriptan in one study each. In addition, a fixed combination of oral sumatriptan and naproxen was used in one study. In most studies, triptan efficacy rates were comparable to those in adults; however placebo rates were much higher. Therefore, several studies failed to demonstrate superiority over placebo.
For adolescents aged 12–17 years, nasal sumatriptan and nasal zolmitriptan have been approved in several European countries and almotriptan has been approved by the Food and Drug Administration (FDA). Furthermore, rizatriptan has been licensed for patients aged 6–17 years by the FDA. In children and adolescents, use of oral sumatriptan, oral zolmitriptan, eletriptan, naratriptan, frovatriptan as well as sumatriptan-naproxen fixed combination is off-label both in Europe and the US. In addition, use of almotriptan and rizatriptan is off-label in Europe and use of nasal sumatriptan and nasal zolmitriptan is off-label in the US.
13.2.3.1 Sumatriptan
Oral sumatriptan was not superior to placebo in a small single-center study including 23 patients from Finland as well as in a multicenter study from Japan including 178 patients [12, 13].
In contrast, there is good evidence for nasal sumatriptan, even though it was not consistently superior to placebo in four available studies (Table 13.1) [14–17]. A small study in 14 children with migraine refractory to “commonly used antimigraine drugs” was the first suggesting efficacy of nasal sumatriptan in young migraineurs [14]. Apart from the small patient number, the study has several other limitations [29]. Considering that 2 of the other studies on sumatriptan nasal spray—including only adolescents aged 12–17 years and the third study including patients between 8 and 17 years—did not provide separate analyses for children, the evidence for nasal sumatriptan in patients below the age of 12 years is poor.
In a large parallel group study [15], 510 patients aged 12–17 years were analyzed. Patients were treated for 1 moderate or severe migraine attack with sumatriptan 5, 10, 20 mg, or placebo. The endpoints comprised headache relief (i.e. reduction in pain severity from severe or moderate to mild or none), complete relief and associated symptoms 15, 30, 60, 90 and 120 min postdose as well as headache recurrence (i.e. worsening of pain from no/mild 2 h postdose to moderate or severe 2–24 h postdose) and use of rescue medication. The primary endpoint was headache relief at 2 h postdose. Compared to placebo, headache relief was achieved significantly more often with sumatriptan 10 and 20 mg 1 h postdose and with sumatriptan 5 mg (but not 20 mg) 2 h postdose in the intention-to-treat population. In the per-protocol population, sumatriptan 20 mg was superior to placebo with respect to pain relief 2 h postdose. Complete relief was achieved significantly more often with sumatriptan 20 mg than with placebo 2 h postdose (Table 13.1). Further statistically significant results comprised the prevalence of photophobia 2 h postdose for sumatriptan 20 mg and the prevalence of phonophobia for sumatriptan 5 mg 2 h postdose and for sumatriptan 20 mg at 30 min, 60 min and 2 h. Nausea, vomiting, headache recurrence and rescue medication did not differ between sumatriptan 5 mg, 10 mg or 20 mg and placebo at any time point.
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