Tanacetum parthenium and Salix alba (Mig-RL) Combination in Migraine Prophylaxis

R. Shrivastava; J.C. Pechadre; G.W. John

Disclosures

Clin Drug Invest. 2006;26(5):287-296. 

In This Article

Discussion

Twelve weeks of Mig-RL® therapy markedly affected the primary efficacy criterion investigated: attack frequency was reduced in nine of ten patients by 61.7% (p < 0.029), with 70% of patients experiencing a reduction of >50%. The secondary efficacy criteria of pain intensity and attack duration were reduced in ten out of ten patients by 62.6% (p < 0.004) and 76.2% (p < 0.001), respectively, with 70% of patients experiencing a reduction in intensity of >50%. In addition, Mig-RL® improved patient self-assessment of general health, physical performance, memory and anxiety by the end of the 12-week treatment period, and was well tolerated with no adverse effects. Importantly, attack frequency, pain intensity and duration were all reduced significantly by 6 weeks, and a further slight but non-significant reduction was noted after 12 weeks. These data suggest that Mig-RL® can produce effective migraine prevention by 6 weeks. In addition, Mig-RL® also notably produced a 'psychological' improvement, as shown by self-assessed general, physical and mental health, which became significant by the end of the study. Indeed, seven out of ten patients expressed their wish to continue the treatment.

In double-blind, randomised, placebo-controlled investigations of T. parthenium prophylaxis in migraine (summarised in Table III ), attack frequency was significantly reduced by 23.4%,[28] 39.2%[29] and 45.2%,[30] with no changes reported by De Weerdt et al.[31] and Pfaffenrath et al.[32] A placebo response of approximately 30% is generally observed in migraine prophylaxis studies.[6,33] Interestingly, in the study by Murphy et al.,[28] when data were divided into patients with migraine and aura and those with migraine but no aura, attack frequency was significantly reduced by 32.6% in patients with aura compared with a non-significant 20.4% reduction in patients without aura. These observations suggest that T. parthenium is less effective in preventing migraine without aura than that with aura. In all the reported placebo-controlled trials of T. parthenium ( Table III ), no distinction was made between patients presenting migraine with or without aura, with the exception of that by Murphy et al.[28] Although further investigation will be required to confirm this observation, it may nevertheless suggest that Mig-RL® could be even more efficacious in reducing attack frequency in patients presenting migraine with aura, although there are no data to support this at present.

It has recently been observed that S. alba, like T. parthenium, recognises 5-HT2A and 5-HT2C receptors, and, unlike T. parthenium, also recognises 5-HT1D receptors.[26] Although the mechanism of action of T. parthenium in migraine prevention is still a matter of debate, two possible hypotheses arise from this observation. Firstly, if indeed 5-HT2A and/or 5-HT2C receptors play a role in migraine prophylaxis,[5,6,14,20]S. alba may consolidate the effects of T. parthenium on attack frequency. Secondly, since S. alba, but not T. parthenium, interacts with 5-HT1D receptors in a positive cooperative manner,[26]S. alba may favour the effects of endogenous serotonin at these receptors during trigeminovascular activation, resulting in a triptan-like effect (i.e. reducing neuronal firing, reducing the release of sensory neuropeptides, ensuing cranial vasodilatation and neurogenic inflammation). Consequently, pain intensity and duration may be expected to be reduced by S. alba by this mechanism over and above any beneficial (non-5-HT1D receptor) effect mediated by T. parthenium. The well known anti-inflammatory activity of S. alba[35] is weak and ostensibly seems unlikely to play a major role in the migraine-preventive effects of Mig-RL®. Interestingly, however, parthenolide, purported to be the main active ingredient of T. parthenium, has been reported to act on the transcription factor nuclear factor (NF)-κB,[36,37] which activates inflammatory gene expression,[37] and on IκB kinase β (IKKβ), which regulates NFκB activity.[38] Such activity is compatible with neurogenic antiphlogistic activity in the trigeminovascular system[39] and could even underlie central sensitisation,[37,39] currently considered to be involved in migraine-associated allodynia.[40] These properties of T.parthenium could therefore provide additional anti-inflammatory properties to those of S. alba alone, and thus contribute to the migraine prophylactic efficacy of Mig-RL®. In the current study, the combination of T. parthenium and S. alba was remarkably effective in reducing attack frequency, pain intensity and duration, findings that are supportive of synergistic activity. Indeed, a marked reduction in attack frequency occurred in all but one of the patients. This is a notable preliminary result given that conventional prophylactic treatments reduce attack frequency in only around half of patients.[5]

The total daily doses of T. parthenium and S. alba employed were 600mg each, which is higher than those reported in previous studies. Although the number of patients investigated was small, no notable adverse effects or adverse events were noted and Mig-RL® was well tolerated. However, since two capsules were to be taken twice a day, three out of ten patients complained about the number of capsules that had to be taken, and the fact that they had to be taken more than once a day.

The main limitations of the study are inherent in its design, namely the absence of placebo control and the small number of patients investigated, which underpowers the trial. It is probable that there was a considerable placebo effect in this trial,[33,41] and comparisons with randomised, placebo-controlled trial data are therefore difficult. The results of open-label trials in migraine prophylaxis should be treated with caution.

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