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Diagnosis of migraine headache in children can be difficult as it depends on subjective symptoms; diagnostic criteria are broader than in adults. Migraine occurs in 3-10% of children and increases with age up to puberty. Migraine spontaneously remits after puberty in half of children, but if it begins during adolescence it may be more likely to persist throughout adulthood.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute attacks, and of prophylaxis for migraine headache in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: for acute symptom relief (antiemetics, codeine phosphate, non-steroidal anti-inflammatory drugs [NSAIDs], paracetamol, and 5HT1 antagonists [such as triptans]) and for prophylaxis (beta-blockers, dietary manipulation, pizotifen, progressive muscle relaxation, stress management, thermal biofeedback, and topiramate).
Key Points
Diagnosis of migraine headache in children can be difficult as it depends on subjective symptoms; diagnostic criteria are broader than in adults.
Migraine occurs in 3-10% of children and increases with age up to puberty.
Migraine spontaneously remits after puberty in half of children, but if it begins during adolescence, it may be more likely to persist throughout adulthood.
We don't know whether paracetamol,NSAIDs, or codeine phosphate relieve the pain of migraine in children, as few studies have been found. Nevertheless, it is widely accepted good clinical practice that paracetamol, an NSAID such ibuprofen, or both should be the first-line agents for headache relief during acute attacks unless contraindicated.
There is increasing evidence that nasal sumatriptan is likely to be beneficial in reducing pain at 2 hours compared with placebo in children aged 12-17 years with persisting headache.
Oral rizatriptan may reduce nausea but has not been shown to reduce pain compared with placebo.
We don't know whether oral zolmitriptan or eletriptan are effective compared with placebo; data regarding zolmitriptan are conflicting and data regarding eletriptan are limited.
We don't know whether antiemetics are beneficial for treating acute attack of childhood migraine, as we found no studies.
Pizotifen is widely used as prophylaxis in children with migraine, but we found no studies assessing its efficacy.
When used prophylactically, stress management programmes may improve headache severity and frequency in the short term compared with no stress management.
Studies of beta-blockers as prophylaxis in children have given inconsistent results, and propranolol may even increase the duration of headaches compared with placebo.
There is some inconclusive evidence that topiramate may be useful as prophylaxis in children with migraine.
About this condition
Definition
Migraine is defined by the International Headache Society (IHS) as a recurrent headache that occurs with or without aura and lasts 2-48 hours. It is usually unilateral in nature, pulsating in quality, of moderate or severe intensity, and is aggravated by routine physical activity. Nausea, vomiting, photophobia, and phonophobia are common accompanying symptoms. This review focuses on migraine in children younger than 18 years of age. Diagnostic criteria for children are broader than criteria for adults, allowing for a broader range of duration and a broader localisation of the pain (see table 1
). Diagnosis is difficult in young children as the condition is defined by subjective symptoms. Studies that do not explicitly use criteria that are congruent with IHS diagnostic criteria (or revised IHS criteria in children less than 16 years of age) have been excluded from this review. Many children with a symptom cluster that includes headache may not perfectly match the IHS classification, but may benefit from medical interventions currently in use. A liberal approach to symptomatology is therefore likely to be beneficial in clinical practice.
Table 1.
International Headache Society criteria for migraine (text in parenthesis indicates suggested revisions for children under 15 years of age).
At least 5 episodes without aura fulfilling all of criteria 1–3:
OR
At least 2 episodes with aura fulfilling at least three of criteria 1–4:
1.
Headache lasting 2–48 hours (30 minutes–48 hours)
1.
One or more fully reversible aura symptoms including focal cortical, brain stem dysfunction, or both
2.
Headache meeting at least two of the following criteria: a) Unilaterial or bilateral (either frontal or temporal) distribution of pain b) Throbbing c) Moderate to severe intensity d) Aggravated by routine physical activity
2.
At least one aura symptom that develops gradually over more than 4 minutes, or 2 or more symptoms that occur in succession
3.
At least one of the following symptoms while headache is present: a) Nausea, vomiting, or both b) Photophobia, phonophobia, or both
Migraine occurs in 3-10% of children,
and currently affects 50/1000 school-age children in the UK and an estimated 7.8 million children in the European Union. Studies in resource-poor countries suggest that migraine is the most common diagnosis among children presenting with headache to a medical practitioner. It is rarely diagnosed in children under 2 years of age because of the symptom-based definition, but increases steadily with age thereafter.
It affects boys and girls similarly before puberty, but girls are more likely to suffer from migraine afterwards.
Aetiology/
Risk factors
The cause of migraine headaches is unknown. We found few reliable data identifying risk factors or measuring their effects in children. Suggested risk factors include stress, foods, menses, and exercise in genetically predisposed children.
Prognosis
We found no reliable data about the prognosis of childhood migraine headache diagnosed by IHS criteria. Psychological factors that contribute to symptoms should be taken into account when considering expectations for treatment success. Not all treatments work for every child: some will be non-responders to medicines with the clearest evidence available from controlled trials to support their use. It has been suggested that more than half of children will have spontaneous remission after puberty. Migraine that develops during adolescence often continues in adult life, although attacks tend to be less frequent and severe over time. We found one longitudinal study from Sweden (73 children with "pronounced" migraine and mean age onset of 6 years) with over 40 years' follow-up, which predated the IHS criteria for migraine headache. It found that migraine headaches had ceased before the age of 25 years in 23% of people. However, by the age of 50 years, more than half of people continued to have migraine headaches. We found no prospective data examining long-term risks in children with migraine.
Aims of
intervention
To provide relief from symptoms; to prevent recurrent attacks in the long term; to minimise the disruption of childhood activities, with minimal adverse effects.
Outcomes
Pain relief (usually measured on visual analogue scales); migraine recurrence; functional indicators (such as time off school, behavioural scores, sleep scores, and sleep satisfaction); adverse effects of treatment. Migraine index is a validated scale for measuring severity in adult migraine. Its validity in children is unclear.
Methods
Clinical Evidence search and appraisal May 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies (apart from prophylaxis studies where only those of at least 1 month follow-up were included). We excluded RCTs where participants did not fulfil IHS criteria for migraine. We included all studies described as "blinded", "open", "open label", or not blinded as there are so few data available. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table
). To aid readability of numerical data, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.
Table.
GRADE evaluation of interventions for migraine headache in children
Important outcomes
Symptom relief, adverse effects
Number of studies (participants)
Outcome
Comparison
Type of evidence
Quality
Consistency
Directness
Effect size
GRADE
Comment
What are the effects of treatments for acute attacks of migraine headache in children?
3 (271)
Symptom relief
Ibuprofen v placebo
4
–2
0
0
0
Low
Quality points deducted for sparse data and inclusion of flawed RCTs in meta-analysis
5 (967)
Symptom relief
Sumatriptan v placebo
4
0
0
0
0
High
1 (291)
Symptom relief
Rizatripan v placebo
4
0
0
0
0
High
2 (879)
Symptom relief
Zolmitriptan v placebo
4
–1
–1
0
0
Low
Quality point deducted for incomplete reporting of results, consistency point deleted for conflicting results
1 (274)
Symptom relief
Eletriptan v placebo
4
–1
0
0
0
Moderate
Quality point deducted for incomplete reporting of results
2 (832)
Adverse effects
Sumatriptan v placebo
4
–1
0
0
0
Moderate
Quality point deducted for weak statistical methods
What are the effects of prophylaxis for migraine headache in children?
3 (119)
Symptom relief
Timolol v placebo
4
–1
–1
–1
0
Very low
Quality point deducted for sparse data. Consistency point deducted for conflicting results. Directness point deducted for inclusion of co-intervention
2 (206)
Symptom relief
Topiramate v placebo
4
–1
–1
0
0
Low
Quality point deducted for incomplete reporting of results. Consistency point deducted for inconsistent results
1 (42)
Symptom relief
Progressive muscle relaxation v placebo
4
–2
0
–1
0
Very low
Quality points deducted for sparse data, incomplete reporting of results. Directness point deducted for uncertainty about how outcomes were measured
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies. Directness: generaliseability of population or outcomes. Effect size: based on relative risk or odds ratio.
Glossary
Aura
A premonitory sensation or warning experienced before the start of a migraine headache.
Crossover trial
Administering two interventions one after the other to the same group of patients either randomly or in a specified manner.
Dietary manipulation
A change in diet aimed specifically at reducing or removing from the diet a foodstuff that is thought to provoke migraine headache.
Dietary vasoactive amines
Dietary amines (protein subunits) that may have an effect on cerebral vascular tone.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Stress management
Coping or relaxation strategies that aim to alter the perception of symptoms.
Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Nick Peter Barnes, Northampton General Hospital, Northampton, UK.
Dr Elizabeth Katherine James, King Edward Road Surgery, Northampton, UK.
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We found no direct information of sufficient quality about the effects of paracetamol (acetaminophen) in the treatment of children with migraine headache. NOTE It is widely accepted good clinical practice that children who have migraine should be offered paracetamol unless contraindicated.
Benefits
Paracetamol versus placebo:
We found four systematic reviews (search date not reported,search dates 2004,
search date 2003). All identified the same single RCTthat did not meet Clinical Evidence inclusion criteria. The three-way crossover RCT (106 children) comparing paracetamol, ibuprofen, and placebo had high withdrawal rates (17%) and did not report results before crossover. This may have introduced bias because of continued treatment effects after crossover, and because of unequal withdrawals among groups.
Harms
Paracetamol versus placebo:
We found no RCTs of sufficient quality. See review on paracetamol poisoning for symptoms and treatment of paracetamol overdose.
Comment
Clinical guide:
Despite the absence of strong evidence from RCTs, it is widely accepted good clinical practice that children who have migraine should be offered paracetamol unless contraindicated.
Substantive changes
Paracetamol Categorisation reassessed in line with the clinical consensus that it is widely accepted good clinical practice that children who have migraine should be offered paracetamol unless contraindicated. Categorised as Likely to be beneficial by consensus.
SYMPTOM RELIEF Ibuprofen compared with placebo: Ibuprofen may be more effective for pain relief ( low-quality evidence ). NOTE It is widely accepted good clinical practice that children who have migraine should be offered NSAIDs such as ibuprofen unless contraindicated.
Benefits
Ibuprofen versus placebo:
We found one systematic review (search date not reported, 2 RCTs, 242 children aged under 17 years) comparing ibuprofen versus placebo. It found that ibuprofen 7.5–10 mg daily significantly increased the proportion of children with headache relief at 2 hours (73/125 [58%] with ibuprofen v 45/117 [38%] with placebo; RR 1.50, 95% CI 1.15 to 1.96). Headache response was defined as an improvement of two units in visual analogue pain scales. Ibuprofen also significantly increased the proportion of children who were pain free at 2 hours after treatment (52/125 [42%] with ibuprofen v 25/117 [21%] with placebo; RR 1.92, 95% CI 1.28 to 2.86). Both RCTs included in the meta-analysis had methodological flaws that compromised the validity of their results, including failure to report results before crossover and high withdrawal rates. We found one subsequent RCT (32 children, 29 [90%] of whom were included in the intention-to-treat analysis) that compared three interventions: ibuprofen, zolmitriptan, and placebo. To allow for the three-arm design, the RCT made statistical adjustments for related samples when comparing ibuprofen versus placebo. The RCT found that ibuprofen 200–400 mg single dose significantly increased the proportion of children with pain relief compared with placebo at 1 hour (45% with ibuprofen v 7% with placebo; P less than 0.01), 2 hours (69% with ibuprofen v 28% with placebo; P less than 0.05), and 4 hours after treatment (86% with ibuprofen v 48% with placebo; P less than 0.01; absolute numbers not reported at any time frame). Pain was measured on a 4-point scale (none, mild, moderate, or severe), and pain relief was defined as no or mild headache after moderate or severe headache. The RCT also found that ibuprofen significantly reduced the proportion of children with nausea compared with placebo at 1 hour (proportion with nausea: 41% with ibuprofen v 76% with placebo; P less than 0.01) and 2 hours after treatment (14% with ibuprofen v 62% with placebo; P less than 0.001; absolute numbers not reported at either time frame).
Other NSAIDs versus placebo:
We found no RCTs.
Harms
The systematic review gave no information on adverse effects. The subsequent RCT found no significant difference in the proportion of people with adverse effects between ibuprofen and placebo (28% with ibuprofen v 13% with placebo; reported as non-significant, P value not reported).The adverse effects were not specified other than to state that they were primarily gastrointestinal or nervous system-related.
Comment
Clinical guide:
Despite the absence of strong evidence from large RCTs, it is widely accepted good clinical practice that children who have migraine should be offered NSAIDs such as ibuprofen unless contraindicated.
Substantive changes
NSAIDs One small RCT added, which found that ibuprofen reduced pain compared with placebo. Categorisation reassessed in line with the clinical consensus that it is widely accepted good clinical practice that children who have migraine should be offered NSAIDs such as ibuprofen unless contraindicated. Categorised as Likely to be beneficial by consensus.
We found no direct information about the effects of codeine phosphate in the treatment of children with migraine headache.
Benefits
We found no systematic review or RCTs.
Harms
We found no RCTs. Known adverse effects of codeine include nausea, vomiting, constipation, drowsiness, potential for respiratory depression in overdose, difficulty for micturition, and dry mouth.
Comment
Although the use of codeine in this clinical setting has not been effectively evaluated, it would seem reasonable to use it for the relief of acute headache refractory to simple analgesics.
SYMPTOM RELIEF Sumatriptan compared with placebo: Nasal sumatriptan is more effective at reducing symptoms of migraine ( high-quality evidence ). Rizatriptan compared with placebo: Rizatriptan is no more effective at relieving pain at 2 hours, but is more effective at relieving nausea (high-quality evidence). Zolmitriptan compared with placebo: We don't know whether zolmitriptan is more effective at reducing symptoms of migraine ( low-quality evidence ). Eletriptan compared with placebo: We don't know whether eletriptan is more effective at reducing symptoms of migraine ( moderate-quality evidence ). ADVERSE EFFECTS Sumatriptan compared with placebo: Sumatriptan increases taste disturbance (moderate-quality evidence).
Benefits
Sumatriptan versus placebo:
We found one systematic review (search date not reported, 5 RCTs, 1475 children aged under 17 years) comparing sumatriptan (primarily intranasal) versus placebo. It found that nasal sumatriptan single dose 20–50 mg significantly increased the proportion of children with headache relief at 2 hours (5 RCTs, 308/474 [65%] with sumatriptan v 254/493 [51%] with placebo; RR 1.26, 95% CI 1.13 to 1.41). Headache response was defined as an improvement of two units in visual analogue pain scales. Sumatriptan single dose 20–50 mg also significantly increased the proportion of children who were pain free at 2 hours after treatment (4 RCTs, 144/356 [40%] with sumatriptan v 94/362 [26%] with placebo; RR 1.56, 95% CI 1.26 to 1.93). Several of the RCTs included in the meta-analysis had weak methods, including failure to report pre-crossover results, high withdrawal rates, and a protocol that allowed use of rescue medications, which may have confounded results.
Rizatriptan versus placebo:
We found one systematic review that identified one RCT (360 children aged 12–17 years), which compared oral rizatriptan versus placebo. The RCT found no significant difference between rizatriptan and placebo in partial or complete pain relief at 2 hours (pain free: 48/149 [32%] with rizatriptan v 40/142 [28%] with placebo; P = 0.47; partial pain relief: 98/149 [66%] with rizatriptan v 80/142 [56%] with placebo; P = 0.08). We also found one subsequent RCT (147 children aged 6–16 years, crossover design) comparing oral rizatriptan versus placebo that did not meet Clinical Evidence inclusion criteria, as only 96/147 (65%) of children completed the trial.
Zolmitriptan versus placebo
:
We found one systematic review (search date not reported), which identified one RCT.We also found two subsequent RCTs.
The RCT (850 children aged 12–17 years, 699 [82%] treated for at least one migraine attack) identified by the review compared four interventions: oral zolmitriptan 10 mg, 5 mg, or 2.5 mg, or placebo. The RCT only performed a direct comparison of zolmitriptan 10 mg versus placebo. It found no significant difference in headache response rates at 2 hours after treatment between zolmitriptan and placebo (proportion who responded: 54% with zolmitriptan 10 mg v 58% with placebo; reported as non-significant, no further data reported). Pain intensity was recorded on a 4-point scale, where 0 = no pain and 4 = severe pain. Response was defined as improvement in headache pain intensity to mild or no pain. The higher response rates to placebo makes the trial results difficult to interpret. The RCT also found no significant difference in the proportion of children who were pain free at 2 hours (pain free: 25% with zolmitriptan 10 mg v 20% with placebo; reported as non-significant, no further data reported). The first subsequent RCT (32 children, 29 [90%] of whom were included in the intention-to-treat analysis) compared three interventions: ibuprofen, zolmitriptan, and placebo. To allow for the three-arm design, the RCT made statistical adjustments for related samples when comparing zolmitriptan versus placebo. It found that oral zolmitriptan single-dose 2.5 mg significantly increased the proportion of children with pain relief compared with placebo at 1 hour (45% with zolmitriptan v 7% with placebo, P less than 0.01), 2 hours (62% with zolmitriptan v 28% with placebo, P less than 0.05), and 4 hours (83% children with zolmitriptan v 48% with placebo, P less than 0.01; absolute numbers not reported at any time frame) after treatment. Pain was measured on a 4-point scale (none, mild, moderate, or severe) and pain relief was defined as no or mild headache after moderate or severe headache. The second subsequent RCT had a crossover design and did not meet Clinical Evidence inclusion criteria, as it did not report results pre-crossover.
Eletriptan versus placebo:
We found one RCT (348 children aged 12–17 with moderate or severe headache pain) comparing eletriptan 40 mg versus placebo. The intention-to-treat population comprised of 274 (80%) participants who completed treatment consistent with the study protocol. Headache response was defined as improvement in headache pain intensity from moderate to severe at baseline to mild or no pain after treatment. The RCT found no significant difference in the proportion of children with headache response at 2 hours between eletriptan and placebo (80/141 [56.7%] with eletriptan v 76/133 [57.1%] with placebo; P greater than 0.05). Post hoc analysis found that eletriptan was significantly more effective than placebo in achieving a sustained headache response at 24 hours after treatment (proportion with sustained response: 73/141 [52% ] with eletriptan v 52/133 [39%] with placebo, P less than 0.05).
Harms
Sumatriptan versus placebo:
The systematic review gave no information on adverse effects.One RCT reported that taste disturbance was more common with sumatriptan than placebo, but did not assess the significance of the difference among groups (60/238 [25%] with sumatriptan 20 mg v 48/255 [19%] with sumatriptan 5 mg v 4/245 [2%] with placebo). Another RCT (129 children, 94 included in the intention to treat analysis) also reported that taste disturbance was significantly more common with sumatriptan compared with placebo (results after crossover: 26/90 [29%] attacks with sumatriptan v 3/87 [3%] attacks with placebo; P less than 0.001).The results of the RCT should be interpreted with caution as it randomised children but assessed results in relation to number of attacks; this may have led to bias. Neither study found any significant difference in rates of other adverse effects.
Rizatriptan versus placebo:
The RCT identifed by the review reported that one child taking rizatriptan developed transient jaundice and hyperglycaemia, which resolved within 1 week.
Zolmitriptan versus placebo:
The RCT identified by the review found that more children receiving zolmitriptan than placebo had adverse effects, and that rates of adverse effects were higher with the highest dose of zolitriptan, but the RCT did not assess the significance of the difference among groups (proportion with adverse effects: 79/178 [44%] with zolmitriptan v 45/174 [26%] with zolmitriptan 5 mg v 49/171 [29%], 22/176 with placebo). In the first subsequent RCT, significantly more children taking zolmitriptan compared with placebo had adverse effects (34% with zolmitriptan v 13% with placebo; P less than 0.05, absolute numbers not reported). Details of adverse effects were not reported.
Eletriptan versus placebo:
The RCT found that more children taking eletriptan than placebo had adverse effects, including somnolence and dizziness, but did not assess the significance of the difference between groups (43% with eletriptan v 28% with placebo; absolute numbers and P value not reported).
Comment
Clinical guide:
There is some evidence to support the use of nasal sumatriptan for the relief of acute symptoms in children.
Substantive changes
5HT1 antagonists One systematic review added, which found that sumatriptan increased the proportion of children with headache relief at 2 hours. One RCT added found that zolmitriptan did not reduce headache response rates at 2 hours compared with placebo,and another RCT suggested that it may reduce pain at 1 hour compared with placebo.Categorisation of triptans changed to Beneficial.
SYMPTOM RELIEF Timolol compared with placebo: We don’t know whether timolol may be more effective at preventing symptoms of migraine headache in children ( very low-quality evidence ). We found no direct information about other beta-blockers for prophylaxis of migraine in children.
Benefits
We found three systematic reviews (search date 2007, search date 2004, search date 2002). None of the reviews performed a meta-analysis owing to heterogeneity of outcome data reported, so we report the results of the individual RCTs that met Clinical Evidence quality criteria here.
Propranolol versus placebo:
The reviews all identified the same three RCTs.
The first RCT (double-blind, crossover, 32 children aged 7–16 years) found that propranolol (60–120 mg/day divided in 3 doses) significantly increased perception of benefit compared with placebo during a 3-month period (report of “some benefit” before crossover: 13/13 [100%] with propranolol v 4/15 [27%] with placebo; P less than 0.001). However, reliability may be limited because 13% of people were lost to follow-up and the clinical relevance of the reported outcome is unclear. The second RCT (double-blind, crossover, 53 children aged 9–15 years) compared propranolol 40–120 mg daily with placebo. It found that propranolol was significantly less effective in reducing headache duration compared with placebo (results before crossover; mean duration of headache: 436 minutes with propranolol v 287 minutes with placebo; P less than 0.01). The third RCT (double-blind, crossover, 33 children aged 6–12 years) found no significant difference in the number of episodes of migraine between propranolol 3 mg/kg daily and placebo at 3 months (results before crossover; mean number of headaches: 14.9 with propranolol v 13.3 with placebo; P = 0.47). In five children (15%) in whom migraine was thought to be provoked by food, diet was restricted to avoid certain foods (no details about type of foods reported). This may have confounded apparent treatment effects.
Timolol versus placebo:
The reviews identified one RCT (19 children) that was too small and methodologically flawed to meet Clinical Evidence inclusion criteria.
Other beta-blockers versus placebo:
The reviews identified no RCTs.
Harms
Propranolol versus placebo:
The first RCT identified by the reviews reported insomnia in 2/13 (18%) children taking propranolol, but did not report on adverse effects in the placebo group. The second RCT identified by the reviews found no significant difference in adverse effects between placebo and propranolol (12 children affected in each group). Adverse effects in both groups included abdominal pain, increased appetite, worsening of headaches, and fatigue. However, the trial was too small to yield reliable information about harms. The third RCT identified by the reviews did not report on adverse effects. All RCTs probably lacked power to detect clinically important differences between groups.
Timolol versus placebo:
We found no RCTs.
Other beta-blockers versus placebo:
We found no RCTs.
Comment
For the use of beta-blockade in this setting, the results of RCTs are inconclusive. Further evaluation in larger trials should be undertaken if feasible.
We found no direct information about the effects of pizotifen in children with migraine headache.
Benefits
Pizotifen versus placebo:
We found four systematic reviews (search date 2007, search dates 2004,
, search date 2002), all of which identified the same two RCTs, neither of which met Clinical Evidence inclusion criteria. The first RCT (47 children aged 7–14 years) pre-dated the International Headache Society diagnostic criteria for migraine and children included did not fulfil the current IHS definition criteria. The second RCT has only been published in abstract form and so we could not reliably review its methods.
Harms
We found no systematic review or RCTs.
Comment
Clinical guide:
Although pizotifen is almost universally used for paediatric migraine, there is no evidence from well-conducted trials that it is beneficial. RCTs would be feasible and should be undertaken.
SYMPTOM RELIEF Compared with placebo: Topiramate may reduce headache frequency over 4–5 months ( low-quality evidence ).
Benefits
We found two systematic reviews (search dates 2007),
both of which identified the same RCT. We also found one subsequent RCT.
Topiramate versus placebo:
The RCT (162 children aged 6–15 years) identified by the reviews compared topiramate (15 mg per day titrated over 8 weeks to 2–3 mg/kg/day) versus placebo for 5 months. It found no significant difference between topiramate and placebo in the mean reduction in monthly migraine days over 5 months (reduction of 2.6 days with topiramate v 2.0 days with placebo; P = 0.06). However, it found that topiramate was associated with a significantly higher mean reduction in monthly migraine days during the last 28 days of treatment compared with placebo (reduction of 3.1 days with topiramate v reduction of 2.4 days with placebo; P = 0.02). There was no significant difference between topiramate and placebo in the proportion of children who had a greater than 50% reduction in monthly migraine days over 5 months (55% with topiramate v 47% with placebo; P = 0.39, absolute results presented graphically). However, topiramate significantly increased the proportion of children who had a greater than 75% reduction in monthly migraine days compared with placebo (32% with topiramate v 14% with placebo; P = 0.02, absolute results presented graphically). During the last 28 days of treatment, the difference between groups in the proportion of children with a greater than 50% reduction in mean monthly days of migraine remained non-significant (70% with topiramate v 53% with placebo; P = 0.05, absolute results presented graphically). The proportion of children achieving a greater than 75% reduction in mean monthly days of migraine during the last 28 days of treatment remained significant (51% with topiramate v 31% with placebo; P = 0.02, absolute results presented graphically). There was no significant difference between topiramate and placebo in the proportion of children who were completely headache free during the last 28 days of treatment (34% with topiramate v 20% with placebo; P = 0.092, absolute results presented graphically).
Harms
In the first RCT, there were fewer adverse effects in the topiramate group, with no serious adverse effects were reported. In the second RCT, adverse effects that occurred more frequently in the topiramate-treated group included weight loss (proportion who lost weight: 17/21 [81%] with topiramate v 3/21 [14%] with placebo), lack of concentration in school (4/21 [19%] with topiramate v 0/21 [0%] with placebo), and paraesthesias (5/21 [24%] with topiramate v 0/21 [0%] with placebo; significance not assessed for any outcome).
Comment
The reviews identified several RCTs suggesting topiramate as beneficial for migraine prophylaxis in population groups that included children.
However, the mean age of participants in each RCT was at least 33 years, and none of the studies indicated how many participants were children or reported subgroup analyses in children.
Substantive changes
Topiramate New option for which we identified two RCTs
that found inconsistent results, although they provide some evidence that topiramate may be effective as prophylaxis in children with migraine. Insufficient evidence to draw firm conclusions; categorised as Unknown effectiveness.
We found no direct information about the effects of dietary manipulation in children with migraine headache.
Benefits
We found one systematic review (search date 2004), which identified four RCTs that did not meet Clinical Evidence inclusion criteria. The first RCT (40 people) had only a 3-week follow-up. The second RCT (27 people) on fish oil used olive oil as a placebo, which is not an inert comparator. The third RCT (61 children) pre-dated the International Headache Society criteria for migraine, and a large proportion (36%) of participants withdrew from treatment. In the fourth RCT, assessing oligoantigenic diet (involving exclusion of dietary vasoactive amines), 11/43 (26%) of participants withdrew from the trial, all from the group randomised to diet.
Harms
The review identified no RCTs of sufficient quality.
Comment
Clinical guide:
There is little satisfactory evidence of benefit from dietary manipulation, so clinicians may need to rely on observational evidence, plausible biomedical hypotheses and their own experience to endorse the use of such.
We found no direct information about the effects of thermal biofeedback in children with migraine headache.
Benefits
We found two systematic reviews (search dates 2004),
which identified no RCTs that met Clinical Evidence inclusion criteria. Both reviews identified the same RCT, which used a repeated measures design to assess outcomes over 6 months and had a 46% loss to follow-up by 6 months; the design did not allow for independent assessment of results at earlier time frames.
SYMPTOM RELIEF Compared with placebo: We don't know whether progressive muscle relaxation reduces headache pain and frequency ( very low-quality evidence ).
Benefits
We found two systematic reviews (search dates 2004),
which identified one RCT (51 children) comparing three interventions: progressive muscle relaxation, cognitive coping, and 'placebo'. The placebo intervention involved 'stress reduction training' so it is unclear whether it was an inert comparator. The RCT found that in 42/51 (82%) of children who completed the trial, both progressive muscle relation and cognitive coping significantly reduced the headache index and reduced headache frequency compared with placebo (P less than 0.05 for either intervention v placebo). It found no significant difference in duration of headache or headache peak intensity between progressive muscle relaxation, cognitive coping, and placebo. (P value reported as non-significant for either intervention v placebo). Details of possible total score on the headache index and timescales for measuring headache frequency were not reported; therefore, we could not assess the clinical importance of the absolute changes in headache pain and frequency. Both reviews also identified two RCTs that did not meet Clinical Evidence inclusion criteria.
The first RCT (99 people aged 9–17 years) compared progressive muscle relaxation versus 'placebo'. The 'placebo' was psychological counselling, which is not an inert comparator, and high loss to follow-up (30%) precluded reliable conclusions. The second RCT comparing three interventions (relaxation alone, thermal biofeedback plus relaxation, and waiting list control) had a 35% loss to follow-up.
Harms
We found no RCTs.
Comment
Clinical guide:
RCTs with acceptable follow-up rates into the effects of progressive muscle relaxation have not been, and are unlikely to be, undertaken. In recommending it, clinicians may need to rely on observational evidence, plausible biomedical hypotheses, and their own experience.
SYMPTOM RELIEF Compared with no stress management programme or a stress management programme delivered by the clinic: A self-administered stress management programme is more effective at reducing the frequency and severity of migraine headaches at 1 month ( moderate-quality evidence ).
Benefits
We found one systematic review (search date 2004), which identified one RCT (87 people, aged 11–18 years). It found that a self-administered stress management programme reduced headache severity and frequency compared with a stress management programme delivered by the clinic, and compared with no stress management at 1 month (16/24 [67%] improved with self-administered treatment v 10/23 [44%] with treatment delivered by the clinic v 6/25 [24%] with no stress management; P less than 0.01 for differences among all three groups).
Harms
The RCT gave no information on adverse effects.
Comment
Clinical guide:
RCTs with acceptable follow-up rates into the effects of stress management have not and are unlikely to be undertaken. In recommending it, clinicians may need to rely on observational evidence, plausible biomedical hypotheses, and their own experience.
