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Abstract

Introduction

The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis.

Methods

A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed.

Review

Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q₁₀ and polyunsaturated fatty acids.

Conclusion

Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine.

Keywords

Pediatric migraine migraine prophylaxis nutraceutical headache

Introduction

Public interest in complementary and alternative medicine (CAM) is growing, as is the literature on its use for both adult and pediatric health conditions. Headache is tied with pain as the most common condition for which CAM is studied in the pediatric population (1).

Nutraceuticals are a form of CAM. The term nutraceutical is relatively new, having first been coined by Dr DeFelice of the Institute for Innovation in Medicine in 1989. He defined nutraceutical as ‘any substance that may be considered a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease’ (2).

This review aims to provide a summary of the literature on the use of nutraceuticals for the prophylaxis of pediatric migraine.

Methodology

A literature search was performed in order to identify studies on the efficacy of nutraceuticals for pediatric migraine prophylaxis. Studies were included if they were either observational studies or randomized controlled trials (RCT) on the efficacy of nutraceutical agents for migraine prophylaxis. Both adult and pediatric populations were included. Studies were excluded if there were no data on the nutraceutical in question for migraine prophylaxis in the pediatric population. Case studies were excluded. Six nutraceuticals had evidence that met the above criteria: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q₁₀ and polyunsaturated fatty acids.

In this review, we applied the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) system to review the evidence for the efficacy of nutraceuticals in the prophylaxis of pediatric migraine. The GRADE system allows authors to build recommendations based on two parameters: the quality of the evidence and the strength of the recommendations. There are four levels pertaining to the quality of the evidence: high, moderate, low or very low (see Table 1). A body of evidence comprising RCTs is initially graded as high quality. The body of evidence is subsequently downgraded if problems with the literature lead to a lack of confidence in the results. Factors that lead to downgrading include limitations in study design, inconsistency in the results, indirectness of the evidence, imprecision of the results and reporting bias. Thus, it is possible for evidence based on RCTs to be downgraded to moderate, double downgraded to low, or even triple downgraded to very low. A body of evidence composed of observational studies is first given a low quality rating. However, the level of evidence can then be upgraded if there is a large treatment effect, if a dose–response relationship has been established in the literature, or if biases in the literature would be expected to decrease the magnitude of the treatment effect as opposed to inflating it. In this review, we have limited GRADE quality ratings to high, moderate and low, thereby eliminating the very low category, for the purposes of simplicity.

Table 1.

GRADE quality of evidence levels.

Level	Definition
High	We are confident that the estimate of the effect of the intervention, as reported in the evidence, lies close to the true effect and further research is unlikely to change our confidence in the estimate
Moderate	We are moderately confident that the estimate of the effect of the intervention, as reported in the evidence, lies close to the true effect but further research is likely to change our confidence in the estimate
Low	We have limited confidence that the estimate of the effect of the intervention, as reported in the evidence, lies close to the true effect and further research is very likely to change our confidence in the estimate
Very Low	We have little confidence that the estimate of the effect of the intervention, as reported in the evidence, lies close to the true effect and further research is very likely to change our confidence in the estimate, given that the estimate is very uncertain

The second parameter in GRADE is the strength of the recommendations, of which there are two levels: strong and weak. The strength of the recommendations depends on several factors. First, the desirable and undesirable effects of the treatment are weighed against each other. A strong recommendation for using the treatment is made when the desirable effects clearly outweigh the undesirable effects, and a strong recommendation against using a treatment is made when the opposite is true. Weak recommendations are made when the balance of desirable and undesirable effects is less clear. Other factors that impact on the strength of the recommendation include: the quality of the evidence (as above), the presence of uncertainty or variability in patient values or preferences, and uncertainty about whether a particular intervention constitutes a wise use of resources. Therefore, strong recommendations are made when all or most informed individuals would recommend for or against a particular treatment and weak recommendations are made when most informed individuals would recommend for or against a particular intervention, but a significant number would not (3,4).

Butterbur (Petasites hybridus)

Postulated mechanisms of action

Petasides hybridus is a perennial shrub, growing in Europe, Asia and North America, that has been used for over 2000 years for medicinal purposes (5). It is thought to have anti-inflammatory and vasodilatory effects that may contribute to its postulated role in migraine prophylaxis. Extracts of Petasides hybridus have been shown to inhibit the enzyme cyclooxygenase-2 in vitro, leading to anti-inflammatory action via inhibition of leukotriene production (6). Petasides hybridus extract also inhibits leukotriene production in primed granulocytes (7). Similar to some of the migraine prophylactic medications such as flunarizine, extracts of Petasides hybridus have demonstrated inhibition of L-type voltage gated calcium channels, thereby limiting intracellular calcium accumulation (8).

Importantly, there have been legitimate concerns regarding the use of Petasides hybridus in humans, given that it contains pyrrolizidine alkaloids, which have known hepatotoxic properties. However, the Petadolex formulation has been developed to address these safety concerns, and it is purified so as to contain less than the detection limit of pyrrolizidine alkaloids. Petadolex is manufactured in Germany, but is not currently licensed for sale by the German Federal Institute for Drugs and Medical Devices. Animal and human safety data have demonstrated excellent tolerability of the Petadolex formulation (8), but the safety of other formulations of Petasides hybridus has not been reliably demonstrated. A recent study analyzed several Petasides hybridus compounds that are currently on the market and confirmed that the hepatotoxic pyrrolizidine alkaloids were undetectable in Petadolex. However, this was not true for several other formulations of Petasides hybridus that are also currently on the market (9).

Adult studies

Two double-blind randomized controlled trials (RCT) in adult migraine patients have demonstrated the superiority of butterbur over placebo in reducing migraine frequency (11,12).

The original data from the first RCT showed both excellent tolerability and superiority of butterbur 50 mg bid over placebo in reducing the frequency of migraines (see Table 2 for a summary of all reviewed studies) (11). The data were subsequently independently re-analyzed given several shortcomings in the original data analysis, and the results were confirmed (13).

Table 2.

Summary of included studies.

Nutraceutical	Study	Design	Dosage	N	Population	Primary outcome measure(s)	Results
Petadolex (Petasites hybridus/Butterbur)	Grossman W and Schmidramsel H, 2000 (11)	Double-blind RCT	50 mg PO bid vs. placebo	60	Adults with migraine (IHS criteria)	Change in the frequency of migraine attacks per month over the 3 month treatment period	Petadolex (3.3 ± 1.5 to 1.7 ± 0.9) vs. placebo (2.9 ± 1.2 to 2.6 ± 1.1); p < 0.05
	Lipton RB et al., 2004 (12)	Double-blind RCT	50 mg PO bid vs. 75 mg PO bid vs. placebo	245	Adults with migraine (IHS criteria)	Change in the frequency of migraine attacks over the 4-month treatment period	Reduction in migraine attack frequency: 75 mg bid group (45%) vs. 50 mg group (32%) vs. placebo group (28%); p = 0.005 for 75 mg vs. placebo; p = 0.04 for 75 mg vs.50 mg

	Pothmann R, Danesch U, 2005 (16)	Open-label trial	50 mg to 150 mg PO daily (at the discretion of investi-gator)	108	Children and adolescents 6–17 years with migraine (IHS criteria)	Headache response (% patients achieving 50% or greater reduction in the monthly frequency of their migraines)	77.2% of the sample were responders
	Oelkers-Ax R et al., 2007 (17)	Partly double-blind RCT	50 mg PO bid to 150 mg PO bid depending on age and response to treatment vs. music therapy vs. placebo	63	Children aged 8–12 years with migraine (IHS criteria)	Change in the frequency of migraine attacks over the 2-month treatment period and at 6-month follow-up	Butterbur was not different from placebo, except in the per-protocol analysis of the 6-month follow-up, where it was superior to placebo (p = 0.044)
Riboflavin (Vitamin B₂)	Schoenen J et al., 1994 (29)	Open-label trial	400 mg PO daily (23/44 received ASA 75 mg daily as well)	44	Adults with migraine (IHS criteria)	Change in migraine severity (score combining migraine severity and monthly frequency before and after treatment)	68.2% improvement in migraine severity score, with no difference between those who received ASA and those who did not (no p value given)
	Boehnke C et al., 2004 (30)	Open-label trial	400 mg PO daily	23	Adults with migraine (IHS criteria)	Change in the monthly frequency of migraine attacks over the 3-month treatment period	Attack frequency decreased from mean of 4 to 2 (p < 0.001)
	DiLorenzo C et al., 2009 (31)	Open-label trial	400 mg PO daily	64	Adults with European maternal ancestors and migraine (IHS criteria)	% responders (% patients with 50% or greater reduction in attack frequency); % responders with mitochon-drial DNA H haplotype vs. other haplotypes	62.5% responders; Haplotype H was associated with reduced chance of being a responder to riboflavin (OR 0.24, 95% CI 0.08–0.71)
	Sandor PS et al., 2000 (32)	Open-label trial	400 mg PO daily vs. bisoprolol 10 mg PO daily or metoprolol 200 mg PO daily	26	Adults with migraine (IHS criteria)	Linear amplitude/stimulus intensity function slope derived from auditory evoked potentials, change in headache frequency	Significant decrease in headache frequency (p < 0.05) in both groups, but there was no difference comparing the two groups to each other
	Schoenen J et al., 1998 (33)	Double-blind RCT	400 mg PO daily vs. placebo	55	Adults with migraine (IHS criteria)	Change in the monthly frequency of migraine attacks over the 4-month treatment period	Riboflavin was statistically superior (p = 0.0001), NNT = 2.8
	Maizels M et al., 2004 (34)	Double-blind RCT	Riboflavin 400 mg + magnesium 300 mg + feverfew 100 mg PO daily vs. placebo (riboflavin 25 mg PO daily)	49	Adults with migraine (IHS criteria)	% responders during the third month of treatment (% patients with 50% or greater reduction in attack frequency)	No difference in responder frequency: 42% of the active group and 44% of the placebo group; p = 0.87
	Condò M et al., 2009 (35)	Retro-spective open-label trial	Riboflavin 200 mg or 400 mg PO daily (chosen by the physician at random)	41	Children and adolescents aged 8–18 years with migraine with or without aura, migraine with tension-type headache (TTH), frequent TTH, basilar migraine or benign paroxysmal vertigo of childhood (IHS criteria)	Change in the monthly frequency of migraine attacks over the 3 -, 4 - or 6-month treatment period	Significant reduction after treatment for 3 or 4 months (21.7 ± 13.7 vs.13.2 ± 11.8, p < 0.01), which was not sustained at 6 months of treatment (19.3 ± 13.4 vs. 11.4 ± 9.6, p > 0.05)
	MacLennon SC et al. 2008 (36)	Double-blind RCT	200 mg PO daily vs. placebo	48	Children and adolescents aged 5–15 years with migraine (IHS criteria)	% responders during the third month of treatment (% patients with 50% or greater reduction in monthly attack frequency)	No difference between the groups (44.4% of the riboflavin vs.66.6% of the placebo group, p = 0.125)
	Bruinj J et al. 2010 (37)	Double-blind cross-over RCT	50 mg PO daily vs. placebo	42	Children aged 6–13 years with migraine (IHS criteria)	Change in the mean frequency of migraines over the 4-month treatment period	No difference between groups (p = 0.44); the riboflavin group had a greater reduction in the frequency of tension-type headaches compared with placebo (p = 0.04)
Ginkgolide B	D’Andrea G et al., 2009 (43)	Open-label trial	60 mg ginkgo biloba terpenes phytosome + 11 mg coenzyme Q₁₀ + 8.7 mg vitamin B₂	50	Adults aged 18–65 years with migraine (IHS criteria)	Change in mean migraine attack frequency over the 4-month treatment period	Decreased from 3.7 ± 2.2 to 2.0 ± 1.9 (p < 0.05)
	Usai S et al., 2010 (44)	Open-label trial	Ginkgolide B 80 mg + coenzyme Q₁₀ 20 mg + vitamin B₂ 1.6 mg + magnesium 300 mg	24	Children aged 8–18 years with migraine without aura (IHS criteria)	Change in the mean monthly migraine attack frequency over the 3-month treatment period	Decreased from 7.4 ± 5 to 2.2 ± 2.8 (p = 0.0015)
	Esposito M and Carotenuto M, 2011 (45)	Open-label trial	Ginkgolide B + coenzyme Q₁₀ + riboflavin + magnesium (doses un-specified)	119	Children with migraine without aura (IHS criteria)	Change in the mean monthly attack frequency over the 3-month treatment period	Decreased from 9.71 ± 4.33 to 4.53 ± 3.96 (p < 0.001)
	Esposito M, 2012 (46)	Open-label trial	Ginkgolide B 80 mg, coenzyme Q₁₀ 20 mg, riboflavin 1.6 mg + magnesium 300 mg vs. L-tryptophan 250 mg, 5-hydroxy-tryptophan 50 mg, vitamin PP 9 mg + vitamin B₆ 1 mg	374	Children with migraine without aura (IHS criteria)	Change in the mean monthly attack frequency over the 6-month treatment period	Greater reduction in the ginkgolide group compared with the other group (9.128 ± 2.842 to 1.734 ± 1.231 vs. 8.78 ± 2.512 to 3.032 ± 1.072)
Magnesium	Facchinetti et al., 1991 (51)	Double-blind RCT	Magnesium pyrrolidone carboxylic acid (360 mg/day) vs. placebo	20	Adults with menstrual migraine	Change in overall pain score and number of migraine days over 2-month double-blind treatment period	Both groups had reduced pain, but magnesium group had larger decrease in pain magnitude (p < 0.03); only the magnesium group had less headache days
	Peikert A et al., 1996 (52)	Double-blind RCT	Tri-magnesium dicitrate 600 mg vs. placebo	81	Adults aged 18–65 years with migraine (IHS criteria)	Change in the mean monthly attack frequency over the 3-month treatment period	Greater reduction in the mean attack frequency in the magnesium group compared with the placebo group (41.6% vs.15.8%, p = 0.0303)
	Pfaffenrath V et al., 1996 (53)	Double-blind RCT	Magnesium L-aspartate-hydro-chloride-trihydrate 10 mmol (121.5 mg elemental) PO twice daily vs. placebo	69	Adults aged 18–60 years with migraine without aura (IHS criteria)	% of patients with a 50% or greater reduction in migraine duration or intensity	No difference in response rates (28.6% of the magnesium group vs. 29.4% of the placebo group)
	Köseoglu E et al., 2008 (54)	Double-blind RCT	Magnesium citrate 1830 mg (295.7 mg elemental) PO bid vs. placebo (assign-ment 3:1 to magne-sium)	40	Adults aged 20–55 years with migraine without aura (IHS criteria)	Median ratio of post-treatment attack frequency to pre-treatment attack frequency after the 3-month treatment period	Lower median post/pre-treatment attack frequency ratio in the magnesium group (0.55 vs. 1.00, p = 0.005)
	Esfanjani AT et al., 2012 (55)	Single-blind RCT	Magnesium oxide 500 mg PO daily vs. L-carnitine 500 mg PO daily vs. magnesium oxide 500 mg PO daily + L-carnitine 500 mg PO daily vs. no therapy	133	Adults aged 18–55 years with migraine or similar headaches (no criteria used)	Change in mean migraine attack frequency after 3-month treatment period	Statistically significant reduction in all groups except for the no treatment group (p < 0.001 for all); after post-hoc analyses, only the magnesium group compared with the no treatment group had a statistically superior reduction (p < 0.006)
	Castelli S et al., 1993 (56)	Open-label trial	Magnesium pidolate, doses ranging from 122 to 266 mg of elemental magnesium	40	Children with periodic syndromes: 25 with migraine, 12 with recurrent abdominal pain, three with fever of unknown origin (no criteria specified)	Clinical response over variable treatment period, minimum 1 month (clinical response defined as attack frequency reduced to 33% or less from baseline)	Good clinical response in 72.5% of patients after 1 month of treatment
	Wang F et al., 2003 (57)	Double-blind RCT	Magnesium oxide containing 9 mg/kg of elemental magnesium PO taken tid vs. placebo	118	Children and adolescents aged 3–17 years with headaches suggestive of migraines (at least weekly headaches of moderate-to-severe intensity associated with nausea, vomiting, photophobia, sonophobia, pulsatile quality or relief with sleep)	Change in number of days with headache over the 4-month treatment period	Both groups had a downward trend in number of headache days, with only the magnesium group sustaining the trend past 6 weeks; no significant difference between groups after regression analyses (p = 0.88)
Coenzyme Q₁₀	Rozen TD et al., 2002 (62)	Open-label trial	Coenzyme Q₁₀ 150 mg PO daily	32	Adult patients with migraine (IHS criteria)	% of patients with a 50% or greater reduction in the number of days with migraine over the 4-month treatment period	61.3% of the patients had ≥50% reduction in migraine attack frequency
	Sándor DS, 2005 (63)	Double-blind RCT	Coenzyme Q₁₀ 100 mg PO tid vs. placebo	50	Adults aged 18–65 years with migraine (IHS criteria)	Change in monthly migraine attack frequency over the 4-month treatment period	Greater reduction in migraine attack frequency in the coenzyme Q₁₀ group compared with placebo (-1.19 ± 1.9 vs. –0.09 ± 1.9, p = 0.05)
	Hershey AD et al., 2007 (64)	Open-label trial	Coenzyme Q₁₀ 1–3 mg/kg PO daily	252	Pediatric and adolescent patients with migraine with aura, migraine without aura, chronic migraine or probable migraine (IHS criteria) who were found to be coenzyme Q₁₀ deficient	Change in number of headache days per month after an average of a 3-month treatment period	Significantly reduced after the treatment period (19.2 ± 9.8 vs. 12.5 ± 10.8, p < 0.01)
	Slater SK et al., 2011 (65)	A double-blind, cross-over, add-on RCT	Coenzyme Q₁₀ 100 mg PO daily vs. placebo for 4 months, then cross-over to the other group	120	Children and adolescents aged 6–17 years with migraine (IHS criteria)	Change in headache frequency after the 4-month treatment period	Significant reduction in headache frequency after 4 months of treatment in both groups, but the repeated measures ANOVA failed to show a time × condition interaction (p < 0.05)
Polyunsaturated fatty acids	Wagner W and Nootbar-Wagner U, 1997 (78)	Open-label trial	γ-linolenic acid + α-linolenic acid 1800 mg + vitamin B₆, niacin + D-α-toco-pherol + β-carotene + various other lifestyle inter-ventions	129	Adults with migraine (IHS criteria)	Change in yearly migraine attack frequency after 6-month treatment period	Significant reduction in 86% of patients
	Pradalier A et al., 2001 (79)	Double-blind RCT	Omega-3 poly-un-saturated fatty acid 6 g PO daily or placebo	196	Adults aged 18–65 years with migraine (IHS criteria)	Mean number of migraine attacks during the last 4 weeks of the 4-month treatment period	No difference when comparing the omega-3 group to placebo (1.20 ± 1.4 vs. 1.26 ± 1.11, NS)
	Harel Z et al., 2002 (80)	Double-blind cross-over RCT	Marine n3-ethyl ester concentrate 1 g two capsules PO daily or placebo 1 g two capsules PO daily (see text for details)	27	Adolescents aged 12–21 years with migraine (IHS criteria)	Reduction in migraine attack frequency over the 2-month treatment period	Significant reduction in migraine attack frequency for both groups but no significant difference between the groups (mean number of migraines during treatment 4 ± 1 for both groups)

A larger study was carried out and compared Petasites extract 50 mg bid, Petasites hybridus 75 mg bid and placebo in a three-arm parallel group RCT. Petasites 75 mg bid was superior to both Petasites 50 mg bid and placebo, and, as in the original study, Petasites was very well tolerated, with the only reported side effect being minor gastrointestinal upset (12).

Given the evidence described above, the American Academy of Neurology (AAN) has recently included butterbur in its updated guidelines for the treatment of episodic migraine in adults. The AAN guideline recommends its use as a preventative migraine therapy and assigns a grade A quality of evidence in favor of butterbur (highest level of evidence, designated when two or more Class I trials have shown efficacy of a treatment) (14). The Canadian Headache Society (CHS) has also recently published guidelines on the prophylaxis of migraines in adults and they strongly recommend the use of the butterbur, based on what they deem to be a moderate quality of evidence according to the GRADE recommendations scheme (15).

Pediatric studies

Two studies have shown promising results for butterbur in pediatric migraine prophylaxis. An open-label trial tested the effectiveness of Petadolex (a standardized, regulated formulation of butterbur) 50 mg to 150 mg daily in 108 children and adolescents and found that 77% of patients achieved at least a 50% reduction in migraine attack frequency (16).

A small RCT compared placebo, Petadolex 50 mg to 150 mg daily and music therapy. The Petadolex group had a significant reduction in migraine frequency during both the post-treatment and follow-up periods. However, the response did not differ from placebo except in the per-protocol analysis of the 6-month follow-up period. Adverse events occurred at similar frequencies across groups, and the side effects reported among the Petadolex group were limited to minor gastrointestinal and cutaneous symptoms. Liver enzymes were monitored and two patients in the Petadolex group were found to have transient and self-limited minor elevations in their liver enzymes, whereas this occurred with three of the placebo patients (17). The results of this study must be interpreted with caution, as the sample size was very small and the study was likely underpowered to detect its primary outcome.

Recommendation

Weak recommendation, low quality evidence

We recommend the use of Petadolex for the prophylaxis of migraine in eligible pediatric migraine patients. We found low quality evidence to support the efficacy of Petadolex for this indication. The body of evidence was downgraded given that the evidence from the adult studies is indirect, and the quality of the pediatric studies was poor. It is important to note that, as above, Petasites hybridus carries a significant risk of hepatoxicity and the safety of formulations other than Petadolex has not been established. Because of this, and because of recent evidence demonstrating that some of the Petasites hybridus formulations that are currently on the market contain toxic pyrrolizidine alkaloids ( 9 ), we strongly recommend against the use of Petasites hybridus formulations other than Petadolex.

Riboflavin (Vitamin B₂)

Postulated mechanisms of action

Riboflavin is a vitamin with two active coenzyme forms: flavin adenine dinucleotide and riboflavin 5′-phosphate. Both are cofactors in oxidation-reduction reactions of flavoproteins during processes such as the Krebs cycle and the electron transport chain. Riboflavin is thus a vital component of mitochondrial energy production (18,19).

Studies have shown evidence for mitochondrial energy depletion in migraine patients, hence providing a theoretical role for preventing migraines by repleting mitochondrial energy stores with riboflavin (20 –27).

Adult studies

The use of riboflavin in migraine prophylaxis was first reported by Smith in 1946. He prescribed riboflavin to 19 of his migraine patients and claimed that every case demonstrated clinical improvement (28).

Years later, a small open-label trial compared riboflavin 400 mg daily alone to riboflavin 400 mg plus aspirin 75 mg daily. There was a 68.2% average improvement in migraine severity, with no difference between riboflavin alone and riboflavin plus aspirin. Riboflavin was well tolerated, with only one patient in the combination group leaving the study for complaints of gastrointestinal (GI) intolerance (29). Another open-label trial subsequently showed that riboflavin reduced migraine frequency, duration and the use of abortive therapies in a small sample of adult migraine patients (30). Finally, most recently, 62.5% of a sample of adult migraine patients responded to riboflavin in an open-label trial. This study also conducted molecular genetic testing on participants in order to determine if they carry mitochondrial DNA H haplotype (H mtDNA) versus other mitochondrial DNA haplotypes (non-H mtDNA), variants of mitochondrial DNA that are believed to confer differential levels of metabolic activity. When comparing the two haplotype groups, the H mtDNA group was less likely to respond to riboflavin compared with the non-H mtDNA group (31). Finally, a small open-label trial in adult migraineurs compared riboflavin to beta-blockers in terms of auditory evoked potential measurements and clinical efficacy. The study demonstrated changes to auditory evoked potentials post-treatment in the beta-blocker group, but not in the riboflavin group. However, the responder rate was significant in both groups (32).

Two small RCTs have tested riboflavin for the prophylaxis of migraine in adult patients. One RCT compared riboflavin to placebo and showed that riboflavin was superior to placebo in reducing the frequency of migraine attacks after 4 months of treatment, with a number needed to treat of 2.8 (33). Finally, low dose riboflavin (25 mg daily) was compared with a combination of high dose riboflavin (400 mg), magnesium and feverfew in adult migraine patients. There was no difference between the groups in any of the outcome measures (34). It is unclear whether the 25 mg riboflavin acted as a placebo or an active treatment, and it is therefore difficult to draw conclusions from this study.

Based on the literature, the latest AAN guideline concludes that riboflavin is probably effective in the prophylaxis of migraine in adults, based on level B evidence (second highest level of evidence where one Class I or two Class II studies have shown efficacy of the treatment) (14). The CHS strongly recommends the use of riboflavin in adults based on low quality evidence, given its promising results and low side effect profile (15).

Pediatric studies

A small retrospective open-label trial in children and adolescents with migraine, basilar migraine, tension-type headache and benign paroxysmal positional vertigo of childhood evaluated the efficacy of riboflavin 200 mg or 400 mg daily and found that there was a significant reduction in headache frequency compared with baseline during the first 3 or 4 months of treatment, but this was not sustained after 6 months of treatment (35). The inclusion of paroxysmal phenomena other than migraine makes the results difficult to extrapolate to the migraine population.

An RCT compared riboflavin 200 mg daily to placebo in pediatric patients with migraine. After completion of 4 months of treatment, there was no statistically significant difference in the responder rates. However, the placebo response in this study was unusually high (66.6% of placebo patients were responders). Also, their sample size calculations were based on the assumption that they would detect a 40% difference in responder rates between the groups, which is ambitious in the setting of the high placebo response rate seen in pediatric migraine trials. They also did not reach their sample size goal, and enrolled fewer patients than planned given an interim analysis showing no difference between placebo and treatment (36). The study was therefore not powered to detect a small or moderate difference between the groups, and this might explain their negative results. A subsequent cross-over RCT compared riboflavin 50 mg daily with placebo in a group of children. Again, there was no statistically significant difference in responder rates when comparing placebo to riboflavin after 4 months of treatment. A proportion of children suffered from tension-type headaches (TTH) in addition to migraine, and riboflavin was superior to placebo in reducing the frequency of TTH (37). Although this study was well designed overall, they did use a much lower dose of riboflavin compared with other studies. It is therefore possible that their null results reflect suboptimal dosage as opposed to lack of efficacy.

Recommendation

Weak recommendation, low quality evidence

Based on the current evidence, we cannot recommend the use of riboflavin for the prophylaxis of pediatric migraine. We found low quality evidence that riboflavin lacks efficacy in the prevention of pediatric migraine. This evidence was derived from one poor quality open-label trial showing efficacy of riboflavin ( 35 ), one good quality RCT that failed to show a difference between riboflavin and placebo ( 37 ), and one small RCT of poor quality that failed to show a difference between riboflavin and placebo ( 34 ). The adult literature, which was deemed to be of low quality overall, was taken into consideration but did not factor in heavily because of the indirectness of this evidence for the pediatric population. Because of the low quality of evidence and the relatively benign side effect profile of riboflavin, the strength of the recommendation against its use is weak. Also, the half-life of riboflavin is only approximately 1 hour ( 38 ), and it is therefore possible that the once daily dosing in the literature is insufficient to achieve steady state levels of riboflavin for the purposes of preventing migraines. Hence, we conclude that the current literature does not support the use of riboflavin in pediatric migraine prevention, but further research is necessary.

Ginkgolide B

Postulated mechanisms of action

Ginkgolide B is a diterpene extracted from the leaves of the ginkgo biloba tree, one of the oldest living tree species on earth originating from Asia (39). Ginkgolide B is a platelet-activating factor (PAF) receptor antagonist. PAF has many roles within the CNS: it can induce intracellular calcium mobilization, it may play a role in long-term potentiation of synapses, it can modulate apoptosis and it may have an effect on ACTH levels. Moreover, PAF is a pro-inflammatory agent that modulates cytokine release (40). During a migraine attack, PAF levels increase (41). In addition, PAF has been shown to induce more serotonin secretion from platelets in patients with migraine compared with controls (42). Therefore, PAF may play a role in the pathogenesis of migraine and ginkgolide B, via its PAF receptor antagonism, has a theoretical basis for migraine prophylaxis.

Adult studies

There is only one adult study examining the efficacy of ginkgolide B in the prophylaxis of migraine. In this open-label trial, participants were given a combination of ginkgo biloba terpenes phytosome at a dose of 60 mg, 11 mg of coenzyme Q₁₀ and 8.7 mg vitamin B₂ (Migrasoll) administered bid for a 4-month treatment period. There was a statistically significant decrease in the monthly frequency of migraines during the treatment period (43). Problems with this study include its small sample size, its open-label design, the use of a preparation combining ginkgolide B with coenzyme Q₁₀ and vitamin B₂, as well as its lack of statistical precision.

Ginkgolide B was not reviewed in the recent AAN or CHS guidelines (14,15).

Pediatric studies

The first pediatric study evaluating the efficacy of ginkgolide B in migraine prophylaxis was a small open-label trial. A combination of 80 mg of ginkgolide B, 20 mg of coenzyme Q₁₀, 1.6 mg of vitamin B₂, and 300 mg of magnesium was administered orally bid for 3 months. Participants did experience a reduction in the monthly frequency of their migraines (44). There are several obvious limitations to this study including its small sample size, the open-label design, the high rate of drop-outs (only 58.3% of participants were involved at the 6-month follow-up) and the use of a preparation combining ginkgolide B with three other nutraceuticals.

Another prospective open-label trial assessed the efficacy of a combination of ginkgolide B, coenzyme Q₁₀, riboflavin and magnesium in reducing the frequency of migraines in pediatric patients. The doses of each component of the compound were not specified. After 3 months of treatment, the monthly frequency of migraines was significantly lower (45). Although this study had a larger sample size, it shares many limitations with the previous studies in terms of its design.

Finally, a large open-label study in school-aged children compared a complex of ginkgolide B 80 mg, coenzyme Q₁₀ 20 mg, riboflavin 1.6 mg and magnesium 300 mg to a complex of L-tryptophan 250 mg, 5-hydroxytryptophan 50 mg (from Griffonia simplicifolia), vitamin PP 9 mg and vitamin B₆ 1 mg PO bid for a 6-month treatment period. Both preparations yielded a statistically significant reduction in monthly headache frequency with the ginkgolide B complex preparation showing significant superiority over the other preparation. The complex containing ginkgolide B was well tolerated, with a small subset of patients (4.27%) reporting minor gastrointestinal upset that resolved after the first week of treatment (46).

Recommendation

Weak recommendation, low quality evidence

We recommend against the use of ginkgolide B preparations for the prophylaxis of pediatric migraine. We found low quality evidence, derived exclusively from open-label studies, that preparations containing ginkgolide B and other nutraceuticals are effective in pediatric migraine prevention. All of the evidence in favor of ginkgolide B is derived from trials where ginkgolide B was combined with other nutraceuticals known to have a possible effect in reducing migraine frequency. Therefore, because of the heterogeneity of the studies, which combined ginkgolide B with various other elements, we cannot confidently say that the ginkgolide B is effective in isolation.

Magnesium

Postulated mechanisms of action

There is a considerable amount of evidence indicating that pediatric migraine patients are magnesium deficient (47 –49). Magnesium deficiency could mediate migraine pathogenesis in a multitude of ways given its ubiquity in brain physiological processes. The numerous theories on how magnesium deficiency could play a role in migraine pathogenesis are well-detailed elsewhere (19).

Adult studies

Interest in magnesium as a prophylactic agent for migraine emerged in the 1990s. The first RCT in this area randomized patients with menstrual migraine to magnesium pyrrolidone carboxylic acid (360 mg/day) or to placebo. The first 2 months of treatment proceeded in a double-blind fashion. After 2 months, blinding was broken and the trial proceeded as an open-label study. For the double-blind portion of the trial, pain was reduced in both groups, with a larger magnitude decrease in the magnesium group (p < 0.03). Only the magnesium group had a reduction in the number of headache days over the 2-month period. Interestingly, in this trial, patients with menstrual migraine had lower baseline magnesium levels, which increased with therapy (51).

Another RCT, of good quality, compared trimagnesium dicitrate 600 mg PO daily to placebo. After 3 months of treatment, magnesium was significantly better than placebo in reducing the frequency of migraine attacks both in the intention-to-treat analysis and in the protocol-correct analysis (52). Almost 25% of the participants in the magnesium group reported significant GI side effects, but only 3.7% of the patients in this group dropped out because of side effects. Later the same year, a multicenter RCT randomized patients to receive either 10 mmol of magnesium L-aspartate-hydrochloride-trihydrate twice daily or placebo for a 3-month period. The planned sample size was 150 participants, but only 69 participants were recruited in the end because of a lack of any difference between the two study arms on an interim data analysis, with both groups showing responder rates in the placebo range. Almost 50% of the magnesium group reported side effects compared with just under 25% of the placebo group. The most common side effects reported by the magnesium group were soft stools and diarrhea, which raises the possibility that these patients were not adequately absorbing the magnesium salts, and may explain the lack of efficacy in this trial. Also, the authors acknowledge that the patients in this study were primarily longstanding migraineurs, and over 50% had used prophylactic migraine therapies in the past. The study population was therefore perhaps biased, arguably comprising refractory migraine patients who are unlikely to respond to prophylactic therapies in general (53).

Another RCT randomized 30 adult migraine patients to receive 600 mg of elemental magnesium (in the form of magnesium citrate) PO daily and 10 patients to receive placebo for a 3-month treatment period. The magnesium group had significantly lower median post/pre-treatment ratios in terms of migraine frequency and severity compared with placebo (54). It is, however, very difficult to draw any conclusions from this study as the sample size was small, the treatment arms were imbalanced and the statistics were opaque.

A recent single-blind RCT compared magnesium oxide 500 mg PO daily, L-carnitine 500 mg PO daily, combination magnesium oxide 500 mg PO daily + L-carnitine 500 mg PO daily to no therapy in a group of adult migraine patients. After the 3-month treatment period, all of the treatment groups except for the no therapy group had statistically significant reductions in migraine frequency, severity and index. However, after post-hoc analyses, only the magnesium group had a statistically larger reduction in migraine frequency compared with the no treatment group (55). Limitations of this study include the single-blind design, the lack of a proper placebo group and the fact that there was no washout period prior to the treatment phase: all participants continued treatment as usual throughout including standing prophylactic therapies.

The AAN guideline states that magnesium is probably effective for adult migraine prophylaxis on the basis of Level B evidence (14). The CHS guidelines more or less echo the AAN guidelines: strongly recommending consideration of magnesium for adult migraine prophylaxis based on low quality evidence (15). Note that both of these guidelines were published prior to publication of the latest trial in this area (55). However, it is our opinion that the results of that study would not yield significant changes in the recommendations given its methodological limitations.

Pediatric studies

One small, prospective, open-label study evaluated the efficacy of magnesium pidolate 122–366 mg PO daily in 40 children and adolescents presenting with periodic syndromes, of whom 25 had migraine as their primary presentation. After 1 month of treatment, 72.5% of the participants had a reduction in the frequency of their periodic syndromes to 33% or less compared with baseline (56). It is difficult to interpret the results of this small trial given that it included patients with other periodic syndromes.

There is one published RCT in which children and adolescents were randomized to receive either magnesium oxide capsules containing 9 mg/kg of elemental magnesium per day divided tid or placebo. There was a statistically significant, and sustained, downward trend in migraine frequency in the magnesium group but not in the placebo group. However, regression analyses comparing magnesium to placebo did not yield any statistically significant difference between the groups in terms of these downward trends. There was a significant difference between the groups in terms of side effects: the magnesium group reported more soft stools and/or diarrhea compared with the placebo group (19% vs 7%) (57). Of note, no strict migraine criteria were used in recruiting participants and thus it is very likely that a significant proportion of the sample had non-migrainous headaches.

Recommendation

Weak recommendation, low quality evidence

We recommend the use of magnesium for migraine prophylaxis in eligible pediatric patients. We found low quality evidence in support of the use of magnesium for this indication. The evidence was considered to be of low quality because of the heterogeneity in study results, methodological flaws in the studies and the indirectness of the evidence derived from adult studies. Although many of the available studies tested magnesium levels, subgroup analyses based on pre-treatment magnesium status are lacking (i.e. it is not clear if magnesium-deficient patients would benefit more from magnesium therapy than non-magnesium-deficient patients). Because of these problems with the evidence and the significant incidence of GI side effects with magnesium, the recommendation is weak in strength. Clinicians can offer magnesium oxide 9 mg/kg/day divided tid to eligible pediatric patients. Because of the higher incidence of side effects with magnesium L-aspartate-hydrochloride-trihydrate compared with the other magnesium formulations in the literature, clinicians should consider avoiding this particular formation.

Coenzyme Q₁₀

Postulated mechanisms of action

As above, a multitude of studies support the concept that migraineurs are in a state of mitochondrial energy depletion (20 –27) and there is growing support for the mitochondrial theory of migraine (58 –61), which views migraine pathogenesis as a process intimately linked to mitochondrial energy failure. Coenzyme Q₁₀ is pivotal in sustaining mitochondrial energy stores given that it is an electron carrier in the mitochondrial electron transport chain. Hence, if migraine is even partly engendered by mitochondrial energy depletion, then the use of coenzyme Q₁₀ in migraine prophylaxis may be justified.

Adult studies

A small open-label study in adults evaluated the efficacy of coenzyme Q₁₀ 150 mg daily for migraine prophylaxis. After the 3-month treatment phase, 61.3% of the participants were deemed to be responders (62). Obviously, the small and open-label nature of this trial limits our ability to draw conclusions from its results. In addition, coenzyme Q₁₀ levels were not assessed and it is therefore not possible to draw conclusions from this study regarding differential efficacy of coenzyme Q₁₀ based on pre-treatment levels.

Later, an RCT randomized adults with migraine to coenzyme Q₁₀ 100 mg tid or to placebo. The coenzyme Q₁₀ group had a significantly larger reduction in migraine attack frequency from baseline to the end of the 4-month treatment period. There was only one reported adverse event in the treatment group: a cutaneous allergy (63). Once again, the lack of measurement of baseline coenzyme Q₁₀ levels precludes us from drawing conclusions regarding whether or not coenzyme Q₁₀ may be more efficacious in patients who are deficient at baseline.

Based on the above evidence, the AAN guideline considers coenzyme Q₁₀ ‘possibly effective’ based on grade C quality evidence (defined as one less rigorous study suggesting efficacy) (14). The CHS guideline strongly recommends offering coenzyme Q₁₀ to eligible patients based on low quality evidence (15).

Pediatric studies

An open-label study was conducted among 252 pediatric migraine patients who were found to have coenzyme Q₁₀ levels below the reference range. They were offered coenzyme Q₁₀ supplementation at doses ranging from 1 to 3 mg/kg/day. At follow-up, coenzyme Q₁₀ levels normalized and were significantly higher than at baseline. Both migraine frequency and pediatric migraine disability assessment scores were significantly reduced (64).

The same group later published a cross-over RCT evaluating the efficacy of coenzyme Q₁₀ for pediatric migraine prophylaxis in children with chronic and episodic migraine. After 1–4 months of treatment, chronic migraine patients in the coenzyme Q₁₀ group had a significantly greater decrease in the frequency of their migraines compared with placebo, but this was not sustained beyond the initial treatment period. Analyses of variance demonstrated that both treatment and placebo arms had a statistically significant decrease in migraine frequency, but there was no difference between the groups in the time × treatment analysis (65). Interpretation of these results is limited by the fact drop-out rates were very high in this study (58%). The authors acknowledge that this limited the power of the study. In addition, as with many of the trials in the nutraceutical body of literature, recruitment was not limited to patients deficient in coenzyme Q₁₀, and subgroup analyses based on pre-treatment coenzyme Q₁₀ levels were not undertaken. The lack of differentiation between deficient and non-deficient patients in this study and in others may limit the ability of the trial(s) to detect efficacy.

Recommendation

Weak recommendation, low quality evidence

We recommend the use of coenzyme Q₁₀ for migraine prophylaxis in pediatric patients. We found low quality evidence from one open-label trial in coenzyme Q₁₀ deficient pediatric patients, one open-label trial in adults and one RCT in adults, that coenzyme Q₁₀ is effective for migraine prophylaxis. The one randomized cross-over trial in pediatric patients failed to show a difference between coenzyme Q₁₀ and placebo, but the power of the study was compromised by high drop-out rates and it is therefore difficult to conclude that coenzyme Q₁₀ is inefficacious based on that data set. The strength of the recommendation is weak given that, despite good tolerability, there are significant methodological flaws in the literature, the results are inconsistent and the evidence from adult trials in indirect, thus rendering the evidence for its efficacy low. It remains to be seen, in future research, whether or not pre-treatment coenzyme Q₁₀ levels impact efficacy of supplementation. It is unclear what the optimal coenzyme Q₁₀ dose is for pediatric patients. Clinicians can consider using the dosing schedule from the Hershey et al trial ( 62 ): coenzyme Q₁₀ 1–3 mg/kg/day.

Polyunsaturated fatty acids

Postulated mechanisms of action

Polyunsaturated fatty acids (PUFAs) have well-established anti-vasopressor effects (66 –71). The vascular theory of migraine, which is now seen as largely outdated and overly simplistic, postulates that migraine aura is caused by vasoconstriction of cerebral vessels and that the pain experienced in migraine is caused by vasodilation of pain-sensitive cerebral vessels (72). Hence, the anti-vasopressor properties of PUFAs could theoretically increase the threshold for a migraine aura. PUFAs also have anti-inflammatory properties (73), and there are theories linking neurogenic inflammation to the pathogenesis of migraine (74 –77).

Adult studies

A prospective, open-label trial recruited 168 adult migraine patients for a trial of regular daily intake of capsules containing 1800 mg of gamma-linolenic acid and alpha-linolenic acid, as well as vitamin B₆, niacin, D-α-tocopherol and beta-carotene. Participants were also asked to restrict the amount of arachidonic acid in their diets and to consume a carbohydrate to protein ratio of 5:1. In addition, participants were taught stress reduction and progressive muscle relaxation techniques. After 6 months of treatment, 86% of the participants reported a reduction in yearly migraine attack frequency (78). Extrapolating results from this study is not possible given its many methodological failures: open-label design, multiple manipulations other than the addition of PUFAs to the diet and opaque statistics and data reporting.

An RCT randomized 196 adult migraine patients to 4 months of treatment with either Maxepa six capsules daily, each containing 1 g of omega-3 PUFAs, or placebo (olive oil and lactose). At the completion of treatment, there was no difference in the mean number of migraines when comparing the PUFAs group to the placebo group in the intention-to-treat analysis. However, there was a statistically significant difference between the groups in the per-protocol analysis, with the PUFAs group having a lower mean number of migraines throughout and a greater reduction in the frequency of migraines compared with the placebo group. Notably, although the mean number of attacks was lower in the treatment group with the per-protocol analysis, this only translated to one less migraine in the 4 month period compared with placebo (79), which is not clinically significant.

The AAN and CHS guidelines do not review the use of PUFAs for the prophylaxis of migraine in adults (14,15).

Pediatric studies

A randomized, double-blind, crossover study in 27 adolescents examined the efficacy of PUFAs for chronic migraine prophylaxis. Participants were randomized to treatment with 1 g of marine n3-ethyl ester concentrate (containing 378 mg of eicosapentaenoic acid, 249 mg of docosahexaenoic acid and 2 mg of tocopherol) two capsules daily or 1 g of placebo (olive oil ethyl ester concentrate with 691 mg of oleic acid, 106 mg of palmitic acid, 62 mg of linoleic acid and 2 mg of tocopherol) two capsules daily for 2 months, followed by a 1-month washout period, and then by 2 months of cross-over treatment. There was no difference between the groups in reducing migraine frequency or severity. The authors conclude that perhaps both the fish oil and the olive oil are effective in migraine prophylaxis (80), although this conclusion is overstated in the context of such a small study without a proper placebo group.

Recommendation

Strong recommendation, low quality evidence

We strongly recommend against the use of PUFAs for pediatric migraine prophylaxis, based on low quality evidence. There is one open-label trial hinting at efficacy for PUFAs in adult migraine prophylaxis. However, the RCT in adults showed no difference between placebo and PUFAs, and a pediatric cross-over trial also failed to prove that PUFAs are effective for chronic migraine prophylaxis. In the context of both the evidence reviewed above and a questionable scientific basis for the use of PUFAs for this indication, we feel that there is no evidence for the use of PUFAs in pediatric migraine prophylaxis. Despite their benign side effect profile, we feel that the lack of evidence for efficacy clearly outweighs their good tolerability profile, thereby making the strength of this recommendation strong.

General conclusions

Nutraceuticals are being increasingly used and studied for pediatric migraine prophylaxis. Overall, the quality of this body of literature is low. This review summarized the evidence for the efficacy of six nutraceuticals in pediatric migraine prophylaxis. The GRADE system was utilized in order to generate recommendations based on the current evidence, and these are summarized in Table 3. There is a need for high quality, adequately powered RCTs testing the efficacy of some of the more promising nutraceuticals for pediatric migraine prophylaxis: Petadolex, magnesium and coenzyme Q₁₀. In addition, if further trials of magnesium and coenzyme Q₁₀ are to be undertaken, we feel that they should address the issue of differential efficacy based on pre-treatment magnesium or coenzyme Q₁₀ levels, seeing as this issue has not been resolved in the current body of literature.

Table 3.

Summary of recommendations.

Recommended for use in pediatric migraine prophylaxis
Treatment	Recommendation strengtd	Level of evidence
Coenzyme Q₁₀	Weak	Low
Magnesium	Weak	Low
Petadolex	Weak	Low
Not recommended for use in pediatric migraine prophylaxis
Treatment	Recommendation strength	Level of evidence
Petasites hybridus (butterbur) formulations other than Petadolex	Strong	Low
Polyunsaturated fatty acids	Strong	Low
Ginkgolide B	Weak	Low
Riboflavin	Weak	Low

Clinical implications

There is growing interest in the use of nutraceuticals for pediatric migraine prophylaxis.

Overall, the quality of studies on the efficacy of nutraceuticals for pediatric migraine prophylaxis is poor.

Based on the current evidence, we recommend the use of Petadolex, magnesium and coenzyme Q₁₀ for pediatric migraine prophylaxis in eligible patients. We recommend against the use of riboflavin, gingkgolide B, formulations of butterbur other than Petadolex and polyunsaturated fatty acids for this indication in pediatric patients.

In the face of growing public interest, further research is warranted in this area in order to determine whether there is efficacy for nutraceutical agents in pediatric migraine prophylaxis.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

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Nutraceuticals in the prophylaxis of pediatric migraine: Evidence-based review and recommendations

Abstract

Introduction

Methods

Review

Conclusion

Keywords

Introduction

Methodology

Butterbur (Petasites hybridus)

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Weak recommendation, low quality evidence

Riboflavin (Vitamin B2)

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Weak recommendation, low quality evidence

Ginkgolide B

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Weak recommendation, low quality evidence

Magnesium

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Weak recommendation, low quality evidence

Coenzyme Q10

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Weak recommendation, low quality evidence

Polyunsaturated fatty acids

Postulated mechanisms of action

Adult studies

Pediatric studies

Recommendation

Strong recommendation, low quality evidence

General conclusions

Clinical implications

Footnotes

Funding

Conflict of interest

References

Riboflavin (Vitamin B₂)

Coenzyme Q₁₀