Critical review of the evidence
4. Specific acute treatments
For people with migraine, which specific acute treatments are effec-tive in increasing the probability of response or pain-free at 2 h?
How great are the adverse events?
Chapter 5: Acute migraine attacks 31
Table 5.2 Non-specific acute treatments for migraine.
Types of study Intervention Outcome Number of Control Absolute NNT
(reference) patients (number group risk risk reduction (95% CI)
of trials)
SR [20] Tolfenamic acid 200 mg 2 h response 84 (1) 29% 48% 2.1 (1.5–3.5)
versus placebo
SR [20] Aspirin 900 mg plus 2 h response 749 (N/A) 25% 32% 3.2 (2.6– 4.0)
metoclopramide 10 mg 2 h pain-free 753 (3) 7% 11% 8.6 (6.2–14)
versus placebo
SR [20] Paracetamol 500 mg plus 2 h response 1220 (3) No data No data 3.9 (3.2–4.9)
aspirin 500 mg plus caffeine 130 mg versus placebo
SR [20] Paracetamol 1000 mg 2 h response 289 (1) 39% 19% 5.2 (3.3–13)
versus placebo
RCT [19] Aspirin 1000 mg 2 h response 401 (1) 34% 18% 5.6
versus placebo 2 h pain-free 6% 14% 7.1
RCT [17] Ibuprofen 200 mg versus 2 h response 729 (1) 50% 14–22% 4.5–7.1
400 mg versus 600 mg 2 h pain-free 13% 12–16% 6.3–8.3
versus placebo
RCT [18] Diclofenac 50 mg (tablet 2 h response 328 (1) 24% 17.5–22% 4.5–5.7
or sachet) versus placebo 2 h pain-free 12% 7–13% 7 sachet (5.5–13.4)
15.8 tablet (8.6–96.2)
SR: systematic review; RCT: randomised controlled trial; NNT: number needed to treat; CI: confidence interval.
Triptans
Sumatriptan, the first triptan to become available, was ini-tially available in its subcutaneous form. At least 11 placebo-controlled trials have been consistent in showing that 6 mg of subcutaneous sumatriptan is better than placebo in pro-viding headache relief at 1 h [23]. Sixteen trials have com-pared oral sumatriptan with placebo and findings are consistent in showing that oral sumatriptan is an effective drug for the treatment of a single acute attack of migraine.
It is well tolerated, though minor adverse events are not uncommon [24]. Overall, the proportion of patients reporting relief with oral sumatriptan is lower than that with subcuta-neous sumatriptan [25].
Six triptans have become available since sumatriptan appeared on the market: almotriptan, eletriptan, frovatriptan, naratriptan rizatriptan and zolmitriptan. Eletriptan and riza-triptan have been subject to Cochrane Reviews confirming efficacy [26,27]. A systematic review and meta-analysis that took data from 53 trials involving over 24,000 patients compared the oral triptans, using oral sumatriptan (at a dose
of 100 mg) as the comparator [25]. All the triptans were found to be more effective than placebo at relieving the headache and other symptoms of migraine. The typical end-point was the headache response at 2 h (a positive response being defined as reduction of pain from moderate or severe at baseline to absent or mild by 2 h) (Figures 5.1 and 5.2).
More stringent parameters are pain-free at 2 h (reduction of pain from moderate or severe at baseline to absent by 2 h), sustained pain-free at 24 h (reduction of pain from moderate or severe at baseline to absent by 2 h, headache does not return and no other headache medication taken) and adverse event data are shown in Table 5.3.
A number of conclusions can be drawn about the effica-cies of the various oral triptans:
• Fastest onset to effect is with subcutaneous sumatriptan.
• Eletriptan and rizatriptan are the most rapidly acting oral triptans, with effect seen from 30 min.
• Oral almotriptan, sumatriptan and zolmitriptan act within 45–60 min.
32 Part 2: Neurological symptoms/problems
(a) Response at 2 h (b)
Placebo-subtracted Absolute (%)
0 20 40 60 80
25 mg
2.5 mg
2.5 mg
2.5 mg 12.5 mg 5 mg
5 mg 10 mg
20 mg 40 mg 80 mg 50 mg 100 mg Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Eletriptan
Almotriptan
Frovatriptan
25 mg
2.5 mg
2.5 mg
12.5 mg 5 mg
5 mg 10 mg
20 mg 40 mg 80 mg 50 mg 100 mg Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Eletriptan
Almotriptan
0 10 20 30 40 50
Placebo-subtracted Absolute (%) Pain free at 2 h
Figure 5.1 Data (mean and 95% CI) for headache response at 2 h (a) and pain free at 2 h (b) are shown for each triptan. Absolute and placebo subtracted outcomes are presented with the hatched region being the 95% CI envelope for sumatriptan 100 mg (adapted from Ferrari et al. [25] with permission).
• Frovatriptan and naratriptan are the slowest, taking up to 4 h before effect is seen.
• Intranasal zolmitriptan is faster acting than oral zolmitriptan.
• Pain-free rates at 2 h and sustained pain-free rates over 24 h are higher for almotriptan, eletriptan and rizatriptan than for sumatriptan.
• The highest likelihood of consistent success is with almotriptan, eletriptan and rizatriptan.
• The lowest rate of adverse events is with almotriptan, eletriptan and naratriptan.
Guidelines published suggest the following approach to symptomatic treatment of migraine, based on the available evidence and expert consensus [21,28]:
• Initial treatment with and NSAID a prokinetic anti-emetic is a reasonable choice for mild to moderate migraine.
• Initial treatment with any triptan is a reasonable choice when the headache is moderate to severe or when the migraine, whatever its severity, has failed to respond to non-specific medication in the past.
• Intranasal zolmitriptan or subcutaneous sumatriptan may be useful in patients with nausea and vomiting or when a rapid response is important.
A rational hierarchy of the use of triptans has been pro-posed (Table 5.4).
Triptans are more effective when taken while the headache is mild. They are ineffective if taken before the onset of headache, during premonitory symptoms or aura [29].
Relapse of headache, typically the day following initial treatment, is a significant problem in clinical practice, the rate being between 15–40%. The highest relapse rate is associated with subcutaneous sumatriptan and the lowest with naratriptan and frovatriptan. If migraine relapses after successful treatment, a second dose of triptan can be given.
There is also some evidence that the combination of a trip-tan and an NSAID reduces the likelihood of relapse [30].
Contraindications to triptans include untreated arterial disease, Raynaud’s disease, pregnancy, lactation and severe renal or liver failure.
Chapter 5: Acute migraine attacks 33
0
Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Electriptan
Almotriptan
10
25 mg
2.5 mg
2.5 mg
12.5 mg 20 mg
2–24 h 4–24 h
10 mg
40 mg 80 mg 5 mg
5 mg 50 mg 100 mg
Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Electriptan
Almotriptan 25 mg
2.5 mg
2.5 mg
12.5 mg 20 mg 10 mg
40 mg 80 mg 5 mg
5 mg 50 mg 100 mg 20
Recurrence of headache 2–24 h %
(a) (b)
30 40 50 0 10 20
Sustained pain-free %
30
Figure 5.2 Data (mean and 95% CI) for headache recurrence from 2 h to 24 h (a) and sustained pain free (b) are presented with the hatched region being the 95% CI envelope for sumatriptan 100 mg. For naratriptan the recurrence rate is given for the time period 4–24 h post-dose (as presented in the original publications) and for 2–24 h post-dose (after recalculating the data) (adapted from Ferrari et al. [25] with permission).
Ergot derivatives
The evidence for the efficacy of ergot derivatives in the symptomatic treatment of migraine is inconsistent, and their use is largely based on long-standing and wide clinical expe-rience. A review of 18 trials found that oral ergotamine was more effective than placebo for some parameters in seven trials, but no better than placebo in three trials [31].
There are few studies on non-oral routes of ergotamine (rectal, sublingual, nasal, inhaled). Since oral bioavailability
is poor, these other routes should, theoretically, be advanta-geous. An evidence-based expert consensus statement has produced recommendations for the use of ergotamine (Table 5.5).
Dihydroergotamine can be administered intramuscularly, intravenously, subcutaneously and intranasally but few tri-als have assessed its efficacy.
Ergot derivatives have been used less commonly since the triptans became available, but they still have a place in the 34 Part 2: Neurological symptoms/problems
Table 5.4 Proposed rational hierarchy for the use of triptans (adapted from Steiner et al. [28] with permission).
Use Dose regimen
Appropriate for first use of a triptan Almotriptan 12.5 mg, eletriptan 40 mg, sumatriptan 50 mg or zolmitriptan 2.5 mg orally When greater efficacy is needed Eletriptan 80 mg or rizatriptan 10 mg, sumatriptan 100 mg or zolmitriptan 5 mg orally or
sumatriptan 20 mg nasal spray
When a rapid response is important above all Sumatriptan 6 mg subcutaneously or zolmitriptan 5 mg intranasal When nausea or vomiting precludes oral therapy Sumatriptan 6 mg subcutaneously or zolmitriptan 5 mg intranasal When side effects are troublesome with other triptans Naratriptan 2.5 mg or almotriptan 12.5 mg orally or frovatriptan 2.5 mg When headache relapse is a problem Ergotamine tartrate 1–2 mg may be helpful
Table 5.3 Meta-analysis of triptans: NNTs of 2-h pain-free and 24-h sustained pain-free and NNH (adapted from Ferrari et al. [25] with permission).
Intervention Number of participants Outcome Absolute risk reduction/ NNT or NNH Ratio of
(number of trials) increase (95% CI) (95% CI) NNH/NNT
Sumatriptan 100 mg 2071 (9) 2 h pain-free 19.5 (17.3; 21.8) 5.1 (4.6–5.8) 1.5
versus placebo 24 h sustained pain-free 20.0 (18.2; 21.3) 5.0 (4.7–5.5) 1.5
Adverse events 13.2 (8.6; 17.8) 7.6 (5.6–11.6)
Sumatriptan 50 mg 583 (3) 2 h pain-free 18.0 (11.7; 24.3) 5.6 (4.1–8.5) 2.3
versus placebo 24 h sustained pain-free 19.8 (17.8; 21.8) 5.1 (4.6–5.6) 2.5
Adverse events 7.8 (2.6; 13.1) 12.8 (7.6–38)
Zolmitriptan 2.5 mg 1320 (3) 2 h pain-free 20.4 (15.6; 25.1) 4.9 (4.0–6.4) 1.3
versus placebo 24 h sustained pain-free 19.0 (16.1; 21.8) 5.3 (4.6–6.2) 1.2
Adverse events 15.9 (9.6; 22.1) 6.3 (4.5–10.4)
Zolmitriptan 5 mg 1596 (5) 2 h pain-free 25.2 (16.9; 33.5) 4.0 (3.0–5.9) 1
versus placebo 24 h sustained pain-free 21.9 (19.3; 24.6) 4.6 (4.1–5.2) 0.9
Adverse events 24.5 (15.5; 33.5) 4.1 (3.0–6.5)
Rizatriptan 10 mg 4437 (11) 2 h pain-free 30.4 (27.5; 33.2) 3.3 (3.0–3.6) 2.2
versus placebo 24 h sustained pain-free 25.3 (23.7; 26.9) 3.9 (3.7–4.2) 1.9
Adverse events 13.5 (10.6; 16.3) 7.4 (6.1–9.4)
Eletriptan 40 mg 2894 (7) 2 h pain-free 27.2 (25.2; 29.2) 3.7 (3.4–4.0) 3.7
versus placebo 24 h sustained pain-free 20.9 (19.1; 22.7) 4.8 (4.4–5.2) 2.9
Adverse events 7.3 (2.7; 11.8) 13.7 (8.5–37)
Almotriptan 12.5 mg 1074 (3) 2 h pain-free 21.0 (13.3; 28.7) 4.8 (3.5–7.5) 11.7
versus placebo 24 h sustained pain-free 25.9 (22.7; 29.1) 3.9 (3.4–4.4) 14.3
Adverse events 1.8 (2.7; 6.2) 56 (16.1–no harm)
Naratriptan 5 mg 2023 (5) 2 h pain-free 14.1 (10.7; 17.5) 7.0 (5.7–9.3) 6.0
versus placebo 24 h sustained pain-free 15.9 (13.4; 18.5) 6.3 (5.4–7.5) 6.7
Adverse events 2.4 (2.2; 7.0) 42 (14.2–no harm)
Frovatriptan 2.5 mg 2892 (5) 2 h pain-free Approximately 10
versus placebo
NNT: number needed to treat; NNH: number needed to harm; CI: confidence interval.
management of migraine, not least because there are some patients who do better with ergots than with triptans.
Contraindications to ergot derivatives include untreated arterial disease, Raynaud’s disease, pregnancy, lactation and severe renal or liver failure. Toxicity and misuse potential are greater risks with ergotamine than with triptans so the frequency of intake should be restricted to a maximum of 10 days per month.