Sunday, June 30, 2013

Natural Migraine Prophylaxis & Treatment: Riboflavin, ALA, Magnesium, CoQ10, Feverfew, Melatonin, Butterbur & Co.

Natural migraine protection: Even if supps won't cure it, they can at least reduce the number of "bad days" and the severity of the attacks.
In the last installment of the "Short News" you've learned about the enormous costs chronic pain produces on an annual basis: Roughly $300 billion for its treatment and another $300 billion in form of economic damage. No wonder pain killers, Cox inhibitors and & co are among the top selling and drugs in the world.

Now, migraine is unquestionably among the most debilitating forms of chronic or rather cyclic chronic pain and while women are much often hit by the pain from withing (21.8% v.s 10.0% of the US citizens suffer; NHS 2009). And while I cannot tell you how much of the $2,000 bucks each of you is "spending" on an annual base on treating the pain of his / her fellow citizens, I believe that both of you, my dear mal and female readers, may benefit from the information in today's installment of "On Short Notice" with a comprehensive, but probably not all-encompassing list of promising supplemental agents for migraine prophylaxis and "treatment":
  • magnesium: I have actually mentioned that in a previous SuppVersity post already (read more), but I guess it's well worth mentioning it again. Low brain magnesium levels have been reported in a whole host of observational studies in migraineurs. There have also been a couple of respective trials with overall inconclusive, but rather positive results for the acute treatment of patients with aura and, possibly, perimenstrual migraine prophylaxis.

    The magnesium formulation that has been used in these trials varied, and there is no large(r) scale comparison of different forms and dosing regimen as of now. Corresponding effects have been observed with 250mg of intravenous and 600mg of oral magnesium chelates (Cady. 1998; Mauskop. 1998), for example. Evans and Taylor additionally cite the following four randomized controlled trials (RCTs; my emphases):
    Take a form that does not give you diarrhea! If you look at the success rates it would appear as if  the organic formulas are superior to the inorganic ones. On the other hand, this may be a simple effect of the increased rates in diarrhea reported by many researchers using non-organic formulations. After all, this does not simply reduce magnesium absorption but will also have negative effects on the overall mineral and water balance. Both, dehydration and mineral imbalances could otherwise increase instead of decrease your risk to suffer from migraine attacks.
    "The first RCT of magnesium for migraine prevention involved only 20 subjects and was positive; the active therapy was 360 mg Mg++ pyrrolidone carboxylic acid divided TID. The second RCT, by Peikert et al, involved 81 adult women and 600 mg magnesium (trimagnesium dicitrate) daily demonstrated a 41.6% improvement with verum versus 15.8% for placebo. The third RCT for migraine prophylaxis, published by Pfafferath et al, involved 69 patients taking 486 mg magnesium; no benefit for magnesium was found; at the end of the 3-month treatment phase, the responder rate was 28.6%in the magnesium group and 29.4% in placebo subjects, according to the primary efficacy endpoint. [...] In a last trial, Wang et al gave magnesium oxide 9 mg/kg divided TID to subjects aged 3 to 17 years. Approximately three-quarters of eligible subjects completed the study, with a significant downward trend in headache days in the active treatment group versus placebo; the lack of any difference in the slope of treatment trends, however, was such that no significant superiority of magnesium over placebo could be documented." (Evans, 2006)
    While magnesium's acute effects are usually ascribed to increases in the circulating levels of Mg++ ions, it's efficacy as a prophylactic treatment is most likely a result of increasing tissue levels and requires a minimum of 3 to 4 months for measurable benefits to occur.
  • CoQ10: As a student of the SuppVersity you are well aware of the beneficial (actually vital!) importance of CoQ10 on mitochondrial health. It is an endogenous enzyme cofactor that can be produced by your body. Unfortunately, there are certain conditions and medications that lead to the depletion of CoQ10 and subsequently impair the proton-electron translocation across the mitochondrial membranes.

    No headache, no problem, but not a reason not to consider CoQ10 supplementation. CoQ10 can also help if your exercise performance is what gives you headaches: "300mg CoQ10 Boost Peak Power Increases in Young Elite Athletes. Plus: 140ml of Beet Root Juice, That's all it Takes to Minimize the Oxygen Demands During a Workout" (learn more)
    Against that background and in view of the involvement of mitochondrial malfunction in the etiology of migraine, it is not surprising that Rozen et al. observed in a 2002 open label study in which 61%  of the 31 patients who consumed 150mg CoQ10 daily for 3 months had at least a 50% reduction in migraine days without experiencing any significant adverse events. Interestingly, the supplement took "only" 4 weeks to kick in (a follow up on whether or not it was necessary to stay "on" CoQ10 is not available, but I would consider it likely). In 2005 Sandor et al. conducted one of the few randomized controlled trials: In this particular study, the patients received 100mg of CoQ10 three times daily and saw significant decreases in the attack frequency, the number of headache days, and days with nausea.

    Interestingly the highly soluble version of CoQ10 (a liquid formulation of water dispersed nano-particles comprising a supercooled melt of CoQ10 with modified physicochemical properties; GuttaQuinone) that was used in the Sandor study had some side effects (gastrointestinal disturbances and cutaneous allergy that had not been reported in other studies). Overall, CoQ10 is yet perfectly safe (even if it's nano-sized) and may even yield benefits if you don't suffer from migraine.
  • Tanacetum parthenium: Also known as Feverfew, the dried chrysanthemum leaves have a long history as an analgesic and one huge problem, according to the only available peer-reviewed report, preparations of feverfew have shown a >400% variation in dosage strength of the known active ingredient parthenolide (Rossi. 2005). According to evens Evans & Taylor, some experts even doubt if it can be generally assumed that parthenolide, which has some very promising research to back up its efficacy even is the active ingredient in the plant leaves.
    Feverfew does not look exactly, like powerful medicinal plant, right?
    "In a systematic review, Vogler et al reported on randomized controlled trials (RCTs) involving feverfew for migraine prophylaxis conducted prior to 1998. 11-16 Five studies qualified by Jadad score as adequate; 1 has been published in abstract form only, and only 216 subjects in total have been studied. Vogler et al concluded, “In view of the popularity of feverfew, perhaps the most striking finding was the paucity and low average quality of the existing RCTs on the subject.”
    If you wanted to cut it short you could thus say. It's popular, people swear by it, but according to our current knowledge it may as well be the placebo effect that keeps people coming back to this natural remedy for headaches.

    The latter would be nasty, since Feverfew does actually have a handful of side effects that range from a sore mouth and tongue (including ulcers), over swollen lips, loss of taste, abdominal pain, and GI disturbances, up to the occasional report of what Evans & Taylor call the "post-feverfew syndrome" of joint stiffness and aches that were accompanied by (guess what) increasing headaches! In the MIG-99 trials, which used an isolated and highly standardized 6.25 mg dose of parthenolide the number of adverse events were similar. It would thus seem very likely that many of the side effects are brought about either by the initially mentioned natural fluctuations in the active or - and this is even more likely - by other agents in the feverfew leaves.
  • Riboflavin: Also and probably better known as vitamin B2, riboflavin has only few quality trials to support its efficiency with its importance in the mitochondrial energy chain and its role in the electron transport within the citric acid cycle, it does, however, appear to be likely that the otherwise often overlooked "yellow-green pee"-vitamin may actually help reduce the number of migraine attacks by >50% (that's 35% more than w/ 25mg/day; Schoenen. 1998), when it is consumed in doses of 400mg/day.
    This table shows the nutrient combination of a supplement that has been found to optimize mitochondrial function in a 2011 study (learn more) and it has not just riboflavin, but also lipoic acid and coQ10, both of which are also on the list of "anti-migraine supplements" - certainly no coincidence! Migraine is after all about mitochondrial health and disease.
    The only known side effects researchers observed in the few available randomized controlled trials were diarrhea and polyuria - and those were pretty rare. Evans & Taylor do yet point out that despite its non-toxicity and the non-existence of a tolerable upper intake level they wouldn't recommend high-dose riboflavin consumption to pregnant women, simply because the possible health effects on the unborn child are not known yet.
  • Alpha lipoic acid: Certainly less known and not well-researched are the potential benefits of ALA (it is thus not necessary to buy R-ALA, which was in the formula of the supplement mentioned on the label of the table above). A double-blind, placebo-controlled trial by Magis et al. from the year 2007 was yet able to show a reduced monthly attack frequency with alpha lipoic acid at dosages of 600 mg daily after 3 months. It must be said, though that these results were not significantly different from those in the placebo group. Within-group analyses did yet reveal a significant reduction in attack frequency, headache days and headache severity in patient treated with alpha lipoic acid, but not in the placebo group (Magis. 2007)
  • Buttebur:
    A note of caution: The Butterbur plant contains pyrrolizidine alkaloids which are
    hepatotoxic and carcinogenic, these compounds have to be removed before you can safely use this plant from the genus of Asteraceae  to counter / prevent headaches.
    Petasites hybridus or rather extracts of its root have gotten some attention as a potential migraine treatment, as well. Petasites is thought to act through calcium channel regulation and inhibition of peptideleukotriene biosynthesis. These cells are thought to play an important role in the inflammatory cascade associated with a migraine (Sheftell. 2000; Pearlman. 2001). A randomized, double-blind, placebo-controlled trial by Grossman & Schmidrams (2000) found that the consumption of 50 mg of butterbur twice daily yielded significantly reduced number of migraine attacks and migraine days per month. Similar results with 50mg of Petasites extract were also reported by Lipton et al. (2004). Finally, a multicenter prospective open-label study of butterbur in 109 children and adolescents with migraine resulted in 77% of all patients reporting a reduction in migraine frequency of at least 50% (Pothmann. 2005).

    Serious adverse events were not observed in any of the few hitherto published studies. Overall, butterbur was well tolerated and the most frequently reported adverse reactions were mild gastrointestinal events, predominantly eructation (burping). 
  • Melatonin: Yep, you will be hard pressed to find anything melatonin the pineal sleep hormone is not good for. So it is probably not very surprising that it is on the list or rather the end of a list potential natural(*) anti-migraine supplements (some critics will probably say that supplementing with melatonin is not "natural").
    • Sleep is good for everything and if you look back at the past SuppVersity articles on the pineal hormone this seems to apply to melatonin, as well.
      1999, Leone et al. were among the first to report beneficial effects of 10mg of melatonin on cluster headaches; yet while this worked magically in some, other patients did not appear to benefit at all (Leone. 1999)
    • melatonin appears to be an effective alternative for indomethacine in idiopathic stabbing headache (Rozen. 2003)
    • cluster migraine which often goes hand in hand with a lack of melatonin secretion has been shown to respond to 9 mg melatonin taken at bed time (Peres. 2001)
    In a 2005 review of the literature Peres does yet point out a multitude of mechanisms by which melatonin could help alleviate headaches, including "its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin" (Peres. 2005). Despite the fact that large(r) scale randomized controlled trials are absent, up to know. I personally would certainly give it a try.
Aside from "real medications" (I wonder where you can make the distinction between a supplement like thiotic acid aka ALA and a medicinal agent like aspirin?), there is also a "consistent level of evidence"for the usefulness of acupuncture, which has proven to be superior to no or placebo treatment and works as an adjunct to conventional treatment (Schiaparelli. 2010).
There is one thing left to mention that may even work better than any of the previously enumerated supplements: Prevention! While many people don't really know the cause of their migraine attacks there are a couple of known food triggers you may want to avoid or even test (Peatfield. 1984; Scharff. 1995):
  • MSG in fast food is a problem (learn more about MSG)
    Alcohol -- 29-35% of people with migraine are sensitive to mankind's most consumed poison
  • Chocolate -- 19-22% of the migraine sufferers worldwide are sensitive to the sweet superfood
  • Cheese -- 9-18% don't tolerate the tyramine which can also be found in other fermented foods
  • Caffeine -- 14% of the patients report that the vasoconstrictive effects of caffeine make the headaches significantly worse
  • MSG -- 12% of the migraine sufferers report that eating high mono-sodium glutamate foods gives them the "Chinese Restaurant Migraine"
Theoretically, each and every food item could trigger migraine attacks, therefore I would not suggest relying on this list all too much. Instead of just testing those 5 and resigning, when you are unable to trigger/avoid migraines by consuming/abstaining from them, I'd strongly advise to start a food diary, in which you log everything you eat, drink and supplement (nitrates are by the way notorious for triggering headaches, as well) + your migraine symptoms. Once you go through the notes you should be able to identify what causes the problem, if it has any dietary cause at all.
  • Cady RK, Farmer K, Altura BT, et al. The effect of magnesium on the responsiveness of migraineurs to a 5-HT1 agonist.Neurology.1998;50(suppl 4):A340. 
  • Evans RW, Taylor FR. "Natural" or alternative medications for migraine prevention. Headache. 2006 Jun;46(6):1012-8. Review.
  • Grossman M, Schmidrams H. An extract of Petasites hybridus is effective in the prophylaxis of migraine.Int J Clin Pharmacol Ther.2000;38:430–435.
  • Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996 Nov;16(7):494-6.  
  • Lipton RB, Gobel H, Einhaupl KM, et al. Petsites hybridus root (butterbur) is an effective preventive treatment for migraine.Neurology.2004;63:2240–2244.
  • Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007 Jan;47(1):52-7.
  • Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines.Clin Neurosci.1998;5:24-27.
  • Pearlman EM, Fisher S. Preventive treatment for childhood and adolescent headache: role of once-daily montelukast sodium.Cephalalgia.2001;21:461
  • Peatfield RC, Glover V, Littlewood JT, et al. The prevalence of diet-induced migraine.Cephalalgia.1984;4:179–183.
  • Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia. 2001 Dec;21(10):993-5.
  • Peres MF. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia. 2005 Jun;25(6):403-11. 
  • Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract.Headache.2005;45:196–203.  
  • Rossi P, Di Lorenzo G, Malpezzi MG, et al. Prevalence, pattern and predictors of use of complementary and alternative medicine (CAM) in migraine patients attending a headache clinic in Italy.Cephalalgia.2005;25:493-506. 
  • Rozen TD, OshinskyML, Gebeline CA, et al. Open label trial of Coenzyme Q10 as a migraine preventive. Cephalalgia. 2002;22:137–141.
  • Rozen TD. Melatonin as treatment for idiopathic stabbing headache. Neurology. 2003 Sep 23;61(6):865-6. 
  • Sandor PS, DiClemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology. 2005;64:713–715.
  • Scharff L, Turk DC, Marcus DA. Triggers of headache episodes and coping response of headache diagnostic groups. Headache.1995;35:397–403. 
  • Schiapparelli P, Allais G, Castagnoli Gabellari I, Rolando S, Terzi MG, Benedetto C. Non-pharmacological approach to migraine prophylaxis: part II. Neurol Sci. 2010 Jun;31 Suppl 1:S137-9.
  • Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial.Neurology.1998;50:466-470 
  • Sheftell F, Rapoport A, Weeks R, et al. Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers.Headache.2000;40:158–163. 
  • Srivastava KC, Mustafa T. Ginger (Zingziber officinale) in rheumatism and musculoskeletal disorder. Med Hypotheses.1992;33:342–348.
  • Sun-Edelstein C, Mauskop A. Foods and supplements in the management of migraine headaches. Clin J Pain. 2009 Jun;25(5):446-52.