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Three Part Question

In [an adolescent with frequent migrainous headache] does the [prescription of pizotifen or propranolol] [reduce the frequency and/or the severity of migraine attacks]?

Clinical Scenario

Once again you find yourself in a busy general paediatric clinic faced with a 14-year-old girl suffering from recurrent headaches for the last 9 months. The history would suggest frequent attacks of a migrainous nature without aura. There is a positive family history in both parents and a sibling, but no obvious precipitating factors. The attacks are now occurring weekly and interfering with normal activities, especially school attendance. She is due to start GCSE coursework soon and both her and her parents are very keen to try a preventative medication. Her neurological examination is normal. They would like her on pizotifen or propranolol as these have helped other family members in the past. She is not asthmatic and otherwise healthy.

Search Strategy

The data for this manuscript was derived from the results of a search carried out in 2003 by an information specialist at Clinical Evidence. The Cochrane Library, Issue 4, 2003 and Medline 1966-date, Embase 1980 to date, Psycinfo 1980 to date.
Primary sources: migraine AND child OR infant OR pediatric OR paediatric OR schoolchild OR teen OR teenager OR adolescent.

Search Outcome

One relevant systematic review found. Primary sources yielded 36 systematic reviews and a further 51 randomised controlled trials. The majority were excluded as they were either irrelevant or of poor quality, leaving just 5 articles.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ludviggson J, 1974, Sweden	32 children with IHS-congruent migraine (aged 7-16 years) Propranolol 60-120mg daily divided in 3 doses v placebo, 3/12 period	Double-blind, crossover RCT (level 2c)	Increased perception of benefit of propanol vs placebo	Pre-crossover results: 13/13 (100%) improved with propranolol v 4/15(27%) with placebo; p<0.001;NNT =1.4	Reliability may be limited because very small trial with 13% of children lost to follow-up
Forsythe WI et al, 1984, England	53 children with IHS-congruent migraine (aged 9-15 years) Propranolol 40-120mg daily v placebo, 30 week period	Double-blind, crossover RCT (level 2c)	Propanol significantly increased headache duration compared with placebo	Pre-crossover results: mean duration of headache: 436 minutes with propranolol v 287 minutes with placebo, p<0.01	Reliability may be limited because only 74% of children completed the study
Olness et al, 1987, USA	33 children with IHS-congruent migraine (aged 6-12 years)Propranolol 3mg/kg/day v placebo, 3/12 period	Double-blind, crossover RCT (level 2c)	No significant difference in the number of episodes of migraine between propanol and placebo at 3/12	Pre-crossover results Mean number of headaches: propranolol 14.9 (95% CI 2, 27.8) v placebo 13.3 (95% CI 3.8, 22.8) p=0.47	Confounding effect: In five participants in whom migraine was thought to be provoked by food, diet was restricted to avoid these foods Reliability also limited by 15% drop-out rate
Gillies D et al, 1986, England	47 children(aged 7-14 years) Two patient groups: A (16 patients, pizotifen 0.5 mg 3/12 then placebo 3/12); B (23 patients, placebo 3/12 then pizotifen 0.25mg 3/12) Dosing in each 3/12 block split into 6/52 b.d. then 6/52 t.d.s.	Double-blind, crossover RCT (level 2c)	No benefit of pizotifen over placebo in reducing attacks, total duration of attacks, duration of longest attack or mean duration of attack	Group A: Pizotifen vs placebo: b.d. dosing: Number of attacks 3.0 vs. 2.5, NS; total duration of attacks 11.25 h vs. 7.8 h, NS; t.d.s. dosing: Number of attacks 1.5 vs. 2, NS; total duration of attacks 7 h vs. 7.0 h, NS; Group B: Placebo vs pizotifen b.d. dosing: Number of attacks 3 vs. 2, NS; total duration of attacks 9 h vs. 7.5 h, NS; t.d.s. dosing: Number of attacks 3 vs. 2, NS; total duration of attacks 8 h vs. 10 h, NS; longest attack 4h vs 4.5h, NS; mean duration of attacks 3 h vs 3.5 h, NS	Study predated the IHS diagnostic criteria for migraine, and participants would not all fulfil the current IHS definition Reliability limited as 17% of children did not complete the study
Salmon MA, 1985, England	40 children (aged 6-15)	Double–blind, placebo controlled, parallel group (level 2c)	Not reliable	No numerical results data published	Study published in abstract form only, so methodology not open to scrutiny Mixed patient group who would not all fulfil the IHS diagnostic criteria for migraine

Comment(s)

Studies in the developed world suggest that migraine is the commonest diagnosis among children presenting to a medical practitioner with headache. There are well-defined diagnostic criteria laid down by the International Headache Society (1988)(3). Girls and boys are affected equally before puberty, but thereafter girls are more likely to suffer migraine (1-3). Propranolol and pizotifen are widely prescribed by paediatricians as prophylactic agents. No systematic reviews were available on the use of B-blockers, though three RCT's with conflicting results were identified which compared propranolol with placebo. Ludviggson (1974) demonstrated in 32 children aged 7-16 years that propranolol (60 to 120mg in three divided doses) produced a significant increase in the perception of benefit compared with placebo. Forsythe et al (1984) showed that propranolol (40-120mg daily) actually increased headache duration compared with placebo in 53 children aged 9 to 15 years. Olness et al (1987) in 33 children aged 6 to 12 years found no significant difference in the number of migraine attacks between propranolol (3mg/kg per day) and placebo. No significant harmful side effects were reported in any of these patient groups. All three studies had methodological flaws, and all because of their small size probably lacked the power to exclude clinically important differences and to yield important information about harms. The interpretation of post crossover results in these 3 RCT's is unreliable because the short washout period may introduce a confounding effect. Very little data was found on the use of pizotifen in this setting. No systematic reviews were identified. One RCT by Gillies (1986) predated the IHS diagnostic criteria and not all participants in this study would fulfil the current criteria (3). This study failed to show any benefit for pizotifen over placebo. An RCT by Salmon (1985) was only published in abstract form and indicated that this study was from a mixed patient group only some of whom had 'classical' migraine. Furthermore, very limited numerical results are included in this abstract and so the conclusions of this study are unreliable on strength of the information provided.

Clinical Bottom Line

There have only been three studies on the use of propranolol as prophylaxis in migraine, and each differs in its conclusion (5); one suggested a benefit (2), a second suggested no benefit (9) and a third concluded that it may actually worsen symptoms (6). There is no reliable published data to support the use of pizotifen in migraine prophylaxis (4).

References

1. Ludviggson J. Propranolol used in the prophylaxis of migraine in children. Acta Neurol Scand 1974;50:109-15.
2. Forsythe WI, Gillies D, Sills MA. Propranolol in the treatment of childhood migraine. Dev Med Child Neurol 1984;26:737-741.
3. Olness K, Macdonald JT, Uden DL. Comparison of self-hypnosis and Propranolol in the treatment of Juvenile Classic Migraine. Pediatrics 1987;79(4):593-597.
4. Gillies D, Sills M, Forsythe I. Pizotifen (Sanomigran) in childhood migraine. A double-blind controlled trial. Eur Neurol 1986;25:32-35.
5. Salmon MA. Pizotifen (BC.105. Sanomigran) in the prophylaxis of childhood migraine [abstract]. Cephalalgia 1985;5 Suppl 3:178.
6. Victor S, Ryan SW. Drugs for preventing migraine headaches in children (Cochrane Methodology Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.
7. International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1-96.
8. Behrman RE, Kliegman RM, Jenson HB, editors. Migraine. In Nelson Textbook of Pediatrics 16th edition. Philadelphia: W.B. Saunders Company 2000
9. Amery WK, Vandenbergh V. What can precipitating factors teach us about the pathogenesis of migraine? Headache 1987;27:146-150.