Feverfew migraine research Update
Efficacy and safety of 6.25 mg t.i.d. feverfew extract MIG-99 in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study.
Cephalalgia. 2005 Nov;25(11):1031-41.
The efficacy and tolerability of a CO(2)-extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients (N = 170 intention-to-treat; MIG-99, N = 89; placebo, N = 81) suffering from migraine according to International Headache Society criteria were treated for 16 weeks after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per 28 days during the treatment months 2 and 3 compared with baseline. Safety parameters included adverse events, laboratory parameters, vital signs and physical examination. The migraine frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group. Logistic regression of responder rates showed an odds ratio of 3.4 in favour of feverfew. Adverse events possibly related to study medication were 9/107 (8%) with feverfew and 11/108 (10%) with placebo. Feverfew is effective and shows a favourable benefit-risk ratio.
     A stable extract of the popular herbal remedy feverfew, called MIG-99, appears to be particularly effective in preventing migraine, German researchers report in the November 2005 issue of Cephalagia. Feverfew herb has traditionally been used to treat migraine, and clinical trials of the powdered herb have shown promising results. However, tests using extracts of feverfew have been less successful. To evaluate feverfew, the researchers conducted a trial with 170 migraine patients. At the beginning of the trial, migraine frequency was approximately five attacks over a 4-week period. The subjects were then randomly assigned to treatment with feverfew, three times a day or to placebo, or "sugar pill," for up to 16 weeks. In the feverfew treatment group, migraine frequency declined by two attacks per month. In the placebo patients, the corresponding decrease was only one per month. Possible medication-related adverse events occurred in about 8.4 percent of feverfew patients and 10.2 percent of placebo patients. Further analysis of responder rates revealed that feverfew was 3.4-times more effective than placebo.

A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial.
Headache. 2004 Oct;44(9):885-90.
To determine the efficacy for migraine prophylaxis of a compound containing a combination of riboflavin, magnesium, and feverfew herb. Previous studies of magnesium and feverfew for migraine prophylaxis have found conflicting results, and there has been only a single placebo-controlled trial of riboflavin. DESIGN/: Randomized double-blind placebo-controlled trial of a compound providing a daily dose of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo contained 25 mg riboflavin. RESULTS: Forty-nine patients completed the 3-month trial. For the primary outcome measure, a 50% or greater reduction in migraines, there was no difference between feverfew and "placebo" groups, achieved by 10 (42%) and 11 (44%), respectively. Similarly, there was no significant difference in secondary outcome measures, for feverfew versus placebo groups, respectively: 50% or greater reduction in migraine days (33% and 40%; or change in mean number of migraines, migraine days, migraine index, or triptan doses. Compared to baseline, however, both groups showed a significant reduction in number of migraines, migraine days, and migraine index. This effect exceeds that reported for placebo agents in previous migraine trials. CONCLUSION: Riboflavin 25 mg showed an effect comparable to a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo response exceeds that reported for any other placebo in trials of migraine prophylaxis, and suggests that riboflavin 25 mg may be an active comparator. There is at present conflicting scientific evidence with regard to the efficacy of feverfew and these compounds for migraine prophylaxis.

Feverfew for preventing migraine.
Cochrane Database Syst Rev. 2004;(1):CD002286. Department of Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter, Devon, UK, EX2 4NT.
Feverfew (Tanacetum parthenium L.) extract is a herbal remedy used for preventing attacks of migraine. To systematically review the evidence from double-blind randomised controlled trials assessing the clinical efficacy and safety of feverfew versus placebo for preventing migraine. Trials using clinical outcome measures were included. Trials focusing exclusively on physiological parameters were excluded. There were no restrictions regarding the language of publication. Data on patients, interventions, methods, outcome measures, results and adverse events were extracted systematically.  Two reviewers independently selected studies, assessed methodological quality and extracted data. Disagreements concerning evaluation of individual trials were resolved through discussion. Five trials (343 patients) met the inclusion criteria. Results from these trials were mixed and did not convincingly establish that feverfew is efficacious for preventing migraine. Only mild and transient adverse events were reported in the included trials. There is insufficient evidence from randomised, double-blind trials to suggest an effect of feverfew over and above placebo for preventing migraine. It appears from the data reviewed that feverfew presents no major safety problems.

The efficacy and safety of Tanacetum parthenium ( feverfew ) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study.
Cephalalgia. 2002 Sep;22(7):523-32.
Feverfew herb has been used as a prevention for migraine headache. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew herb. Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under feverfew treatment with 6.25 mg t.i.d. compared with placebo. Overall, 52 of 147 (35%) patients reported at least one adverse event (AE). The incidence of AEs in the feverfew treatment groups was similar to that in the placebo group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose-response relationship could not be observed. MIG-99 was shown to be effective only in a small predefined subgroup of patients with at least four attacks during the 28-day baseline period where the most favourable benefit-risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract per day. Because of the low number of patients, these findings need to be verified in a larger sample. The incidence of AEs was similar for all treatment groups.

Feverfew extract and cancer
Suppressed NF-{kappa}B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-{alpha}-induced apoptosis in human cancer cells.
Carcinogenesis. 2004 Nov;25(11):2191-2199.
Parthenolide is the main sesquiterpene lactone found in feverfew with potent anti-inflammatory function. The anticancer property of Parthenolide has been demonstrated in both in vitro cell culture and in vivo animal model, while the molecular mechanisms remain to be further elucidated.

Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer.
Invest New Drugs. 2004 Aug;22(3):299-305.
Feverfew herb is a botanical product that contains parthenolide. Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic activity. Feverfew has been used extensively without any formal pharmacokinetic analysis. A Phase I trial was conducted to evaluate the pharmacokinetics and toxicity of parthenolide given as a component of "feverfew." Feverfew (Tanacet trade mark ) was administered as a daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day was explored with subsequent dose escalations to 2, 3, and 4 mg. Assessment of plasma pharmacokinetics was performed on patients accrued to the trial. Solid phase extraction and mass spectroscopy were used to evaluate parthenolide plasma concentrations. The limit of detection for parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for response after every two cycles. Feverfew extract given on this schedule had no significant toxicity, and the maximum tolerated dose was not reached. When parthenolide was administered at doses up to 4 mg as a daily oral capsule in the feverfew preparation, there was not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed. Feverfew extract, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose-limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.

Bioactive flavonoids of Tanacetum parthenium (feverfew) revisited.
Phytochemistry. 2003 Sep;64(2):567-9.
Bio-guided fractionation of an extract from feverfew showing activity as mitotic blocker allowed the isolation and identification of santin 3, jaceidin 2 and centaureidin 1. The latter two closely related flavonols, which, to the best of our knowledge, are isolated here together for the first time, form a mixture difficult to resolve and which is probably the reason for the confusion in the literature regarding their occurrence.

Feverfew extract as anti-inflammatory substance
Feverfew herb -- The Yale team found that feverfew's active ingredient -- parthenolide -- specifically binds to and inhibits the protein IKK-beta, which plays a role in the body's inflammatory process. Fever is part of the body's inflammatory response, and inflammation contributes to a range of ailments--including migraines. 100 to 300 mg up to qid, 0.2 to 0.4% parthenolide