Petasites for Migraine Prevention: New Data on Mode of Action, Pharmacology and Safety. A Narrative Review

Abstract

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45–90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.

Migraine Management Using Feverfew, Butterbur, Peppermint, and Ginger: Perspectives of Pharmacy Students

“…It was determined that the root extract inhibits the release of calcitonin-generelated peptide (CGRP) of meningeal afferents during migraine attacks. In randomized, doubleblinded, and placebo-controlled trials, the root extract Petadolex® reduced the frequency of migraine attacks significantly at 150 mg/day, and no relevant abnormal liver function was reported (Borlak et al, 2022).…”

New perspectives on migraine treatment: a review of the mechanisms and effects of complementary and alternative therapies

“…Considering that CGRP, as a key peptide, plays an important role in pain signaling, it has been demonstrated that CGRP release can be inhibited using herbs ( 24 ). The transient receptor potential ankyrin (TRPA) mediates CGRP release in neurogenic inflammation, and the study by Benemei et al ( 25 ) demonstrates that Petasin inhibits CGRP signaling, achieving this through desensitization of TRPA.…”

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“…There was noted desensitization of nociception by acting on calcium-conducting transient receptor potential (TRP) ion channels ( selectively TRPA1 and TRPPV1) of primary sensory neurons impairing their dual function of signaling pain and releasing the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP), which mediate neurogenic inflammation. [48,50] Petadolex, introduced in 1972 in Germany and 1998 in the USA, is the only one among many of butterbur extracts, whose clinical efficacy and safety were amply evaluated in the preventive treatment of migraine. [50] Adverse effects of butterbur generally are rare, mild, and well-tolerated, and include gastrointestinal upset, eructation, nausea, diarrhea, headache, dizziness, increased bleeding tendency, and rash.…”