Clinical Study Review: Feverfew
Efficacy of Feverfew as Prophylactic Treatment of Migraine, by E. Johnson, N. Adam, D. Hylands, P. Hylands
This blog post is from the archives of Helen’s grad school papers. It is a breakdown of a review assignment for Feverfew, an herb used classically to treat headaches and migraines. This is shared to give insight as to how we are taught to read clinical studies in grad school, what questions to ask, the limitations to consider, and how to objectively interpret such data from clinical studies. This assignment is from 2024.
The link to the study referenced is: https://pubmed.ncbi.nlm.nih.gov/3929876/
The PDF version to read the full text is: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1418227/pdf/bmjcred00463-0017.pdf
Which herb was studied in the clinical trial, and in what form?
This trial looked at Feverfew (Tanacetum parthenium) in freeze dried, powdered form prepared into capsules.
What was the goal of the study (ie what was the research question)?
The goal of the study was to answer the question of whether or not Feverfew is clinically effective in migraine and arthritis relief. There was a proposed mechanism of action, but no trials to refer to for proof of efficacy, so this trial set out to do that.
What was the dosage used, and for what duration? Was the herb standardized, and if so to what constituent and percentage?
The trial was a double blind, placebo controlled comparison between two groups, one that received the feverfew treatment, and one that did not. Patients were asked to take 2 capsules every morning with food for six periods of 4 weeks. Both the feverfew and the placebo capsules were provided in numbered packs. Measures were taken to ensure that the size, color, and smell of the Feverfew and placebo capsules were identical so as to be indistinguishable.
The Feverfew leaves used in the trial were first freeze dried and then separated to those that were one leaf with five leaflets, with an average weight of 25.7mg each. Researchers determined that the mean dose participants took before the trial was 2.44 leaves or about 60g, so they decided that each capsule should contain 25g and patients should receive 2 capsules in each pack, for an amount of 50g per dose.
The herb was not standardized.
What were the primary outcomes of the trial?
The participants in the active group had significant improvements in migraine attacks, with a reduction of 1.3 attacks a month or 7.33 attacks over a six month period, down to 0.7 a month or 1.6 attacks over a six month period after self administered feverfew treatments; this group had continuous treatment from before starting the trial through the duration of the trial. Those in the placebo group had a reduction from 3.94 migraine attacks each month up until the trial, to 1.22 attacks during the trial. Both groups experienced improvement self treating with feverfew previous to the trial, and both groups experienced improvement after the regardless of the active or placebo administration.
How do the results of this clinical trial compare to what we learned in class?
Lecture tells us that Feverfew is an herb for known use for migraines, with the lecturer mentioning the folk tale that you should eat one leaf a day to prevent migraines. This is consistent with what the participants did previous to the study, and to their dose during the study as well. The lecture also tells us that post flowering leaves have the highest amount of the constituent parthenolide, the sesquiterpene lactone that Feverfew gets its name from (MUIH, n.d.). There is a high variability of constituents among plants especially if the time they are harvested or their watering varies, which plays a role in both the results between the participants [that they may not have known to distinguish, a limitation of the study], and the fact that the study used dried leaves of an unknown harvest time for the trial. The dose recommended in class lecture had the highest daily amount of the references I looked at, with 500-1,000mg a day as the standard, beginning with 125mg four times a day and working up to the dose that works best individually (MUIH, n.d.). This is very different than the 50mg a day the participants in the trial received, as well as the 50-200mg dose Braun & Cohen recommend based on a review of clinical trials (Johnson et al., 1985; Braun & Cohen, 2013).
Note: The class lecture cites both 500-1,000mg a day for migraines and 50-200mg a day with no distinction between the two doses (MUIH, n.d.).
Were there any limitations you observed in the clinical trial that may have influenced the outcomes? How would you have designed the study differently based on the clinical indications and usage you have learned in this class?
Researchers should have looked into classical doses for Feverfew instead of relying on participant’s mean usage to determine their dose; if no other clinical studies had been done to indicate a dose to date, in the least they should have looked at classical texts to determine an eclectic appropriate dose. The study was done in the 80’s so perhaps with the lack of internet, this information was not so easily available to them? Instead, they based their dose on the participant’s reported daily amount and did the math from there. Self reporting is always a limitation, both for recollection, for accuracy in parameters of measurement, for how different people describe different symptoms, and there are language differences and barriers that could play a part in reporting and perception as well.
Alongside this, patients could be misinformed about feverfew or herbal medicine in general, they may use different types of Feverfew from different sources harvested at different times, the leaves used could have different constitutional strengths or properties, and they may have all been prepared differently, despite participants reporting that this herb worked for them. Some may not have been as consistent in others in taking the leaves as well. The belief that these leaves worked for them knowing that they should work could have been a placebo of its own for them, too. Researchers wanted the study to be based on previous use so that the amounts taken during the trial as well as the the duration of use were not statistically different than their previous experience, perhaps for the sake of a more accurate comparison on the part of the participants. However, relying on self reporting to determine the dose seems irresponsible, and weakens the argument for the reliability of the results. I would have appreciated taking the participant’s previous reported dose experience into account as a starting point for doing research, and then backing up this dose with traditional use information- or in the least- using participant dose as a comparison to a traditional dose to determine if the clinical trial dose “worked.” I mean this to say, they could have used the mean reported dosages to prove or disprove traditional texts and eclectic doses, and that would have made this study much more relevant, and interesting. Having a previous mean for a dose that works for these participants and then testing that same dose against a placebo did give them good results, though I am not sure the results from this trial could be used to determine a true appropriate clinical dose for Feverfew in migraines.
The trial was based on the participants' previous use of Feverfew as a base, but the participants reported using fresh leaves daily, whereas the trial was based in dried plant material inserted into capsules. This presents both a limitation and an inconsistency in reporting, and could have been a factor in the results.
Upon reading about recommended doses, this trial had an unusual design. Bone & Mills offers the explanation that the scientists considered feverfew to have unknown safety, and since participants were already using feverfew, their trial was based on observing the results of participants unknowingly stopping their herbal feverfew treatment via the placebo, rather than testing the results of the active dose (Bone & Mills, 2013). This feels to me like it is walking the ethical line, so I am not sure it is the proper way to conduct a study. To its credit, and in a backwards way, the study did show that the herb works, as well as what happens when its use is discontinued. This study is therefore assessing the wellness of those taking Feverfew assuming they are taking it consistently, another limitation, by taking it away rather than giving it, and this further limits the study because it leaves out the part of the population without access to fresh or dried Feverfew.
The study did not mention that Feverfew works well if you do loading doses, which upon reading the study, you can deduct that the participants actually did; they should have highlighted this in the discussion section. It was mentioned in the class lecture, but I did not see it reflected in the study beyond my own interpretation, and for the general public, this is an important piece of information for them to note especially since the study is based on people self prescribing this herb. This was a crucial piece of information they left out.
How did they justifying the dose? Was there any clinical backing for the choice either from traditional literature or primary reviewed data?
The choice of dose stemmed from the participant’s reporting of how much feverfew those with previous usage experience normally took. The 17 participants in the study were chosen because of their history of migraines and their previous use of feverfew as a home treatment; all had migraines regularly and all used feverfew to preventatively to treat them, though in the study, 8 participants received the feverfew and nine did not. It is worth noting that two women had to abandon the study because they received the placebo, and their migraines returned resulting unbearable, rendering them unable to continue participating.
The study did not reveal research backing their dose, nor a justification beyond using participant’s previous home treatment dose of two fresh leaves a day as a guideline.
Does the form make sense, from the point of view of dose, compliance and solubility of the active constituents?
From the point of view of the dose, yes, the 50mg dose in the morning with food makes sense, though it is on the low side for the documented recommended doses I found. Braun & Cohen recommend the dried leaf dosages range from 50-200mg, so their dosage aligns with this (Braun & Cohen, 2015). They write about several clinical trials for migraines, including this one, with a lot more clinical trials conducted since my 1985 study- which was the only one I could find that had open access, unfortunately. I would have liked to find open access to a more recent one to look at. A study of 170 participants taking a feverfew treatment of 6.25 mg three times daily (18.75mg total) was showed significant results in reducing frequency of migraines, with most of the effect showing up in the first couple of months and stabilizing afterwards (Braun & Cohen, 2015).
Interestingly enough, Kings American Dispensatory does not list migraines or arthritis among the uses for Tanacetum parthenium, but instead list its use as a tonic, for the intestinal tract, increasing the appetite, improving digestion, promoting secretions, and renal and cutaneous functions (Felter & Lloyd, 1898). Grieve does not mention its use for migraines either, which makes me wonder at what point we went from using this herb as a digestive aid to the herb for migraines (Grieve,
Where did they get the supporting rationale for choice?
They pulled it exclusively from the participant’s self reported previous use to prevent their migraines with success.
Is their treatment approach based on a pathology or wellness strategy? What influence do you think this had on the study?
The treatment approach was based on a wellness strategy. The discussion goes into detail regarding migraine sufferers who turn to feverfew and obtain results over those who had taken medications or vitamins with inconsistent results. The study wanted to show the efficacy for those taking feverfew by looking at what happened when they didn’t take it, since it had proven to be so effective and indispensable for them. The result this most likely had on the study was that participants expected the feverfew to help them, and also those that applied to participate for it had a preconceived notion of the relief that feverfew could provide. The positive side to this was that the scientists weren’t sure of the proper dose for efficacy, so their use of the herb was based in the participant’s known tolerance, known potential side effects, and it stayed under their reported daily dose. The results showed far fewer headaches and migraines with reported with far fewer instances for nausea and vomiting as well, with no negative impacts to blood pressure, heart rate, bodyweight or other biochemical tests which ultimately impacts a migraine sufferer’s life significantly. This is why I say this study was based in wellness- it wasn’t set out to cure migraines but more so to show to the degree with which this herb could help these people.
References:
Bone, K. Mills, S. (2013) Principles and Practice of Phytotherapy, Modern Herbal Medicine 2nd Edition. Churchill Livingston Elsevier. Great Britain.
Braun, L. Cohen, M. (2015) Herbs & Natural Supplements, An evidence based guide.I Vol 2. Elesevier Australia. Chatsworth, NSW.
Felter, H., Lloyd, J. (1989) Parthenium-Feverfew [Monograph] Kings American Dispensatory. Ohio Valley Co. Cincinnati, OH. Scanned version copyright Henriette Kress 1999-2019. Retrieved from: https://www.henriettes-herb.com/eclectic/kings/tanacetum-part.html
Grieve, M. (1931) Feverfew. A Modern Herbal. Brace & Company, New York, NY. botanical.com copywriter 1995-2021. Retrieved from: https://botanical.com/botanical/mgmh/f/feverf10.html
Johnson, E., Kadam, N., Hylands, D., Hylands, P. (1985). Efficacy of feverfew as prophylactic treatment of migraine. British medical journal (Clinical research ed.), 291(6495), 569–573. https://doi.org/10.1136/bmj.291.6495.569 Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1418227/pdf/bmjcred00463-0017.pdf
MUIH. (n.d.) Lecture: Tanacetum parthenium. Material Medica II, Module 8, Fall 2023. HRB705, Section 200. Maryland University of Integrative Health. Laurel, MD.