Thread by @RGottliebSmith

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How does botulinum neurotoxin (BoNT) work to improve chronic migraine? 🤔

⚡️ Spoiler: it's probably not what you think!

A 🧵 about BoNT & #migraine

#MedTwitter #NeuroTwitter #tweetorial

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Let's start with a definition: what makes a migraine "chronic?"

◾️ Headache occurs at least 1⃣5⃣ days per month
◾️ Of which at least 8⃣ have features of migraine headache
◾️ For 3⃣ months or more

From: Int'l Classification of Headache Disorders ichd-3.org/1-migraine/1-3…

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And a bit of history: botulinum neurotoxin (BoNT) came to be studied for chronic migraine after anecdotes suggested that BoNT injections to treat wrinkles also helped with headaches!

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Two randomized controlled trials called PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) showed that a form of BoNT - onabotulinumtoxinA (onabotA) - worked for the treatment of chronic migraine in adults

pubmed.ncbi.nlm.nih.gov/20647170/
pubmed.ncbi.nlm.nih.gov/20647171/

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PREEMPT pooled results:

◾️ Headache days/28 days actually 🔻 for both placebo & onabotA groups
◾️ But 🔻 more for onabotA group: at week 24, -8.4 for onabotA versus -6.6 for placebo

pubmed.ncbi.nlm.nih.gov/20487038/

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"Standard" PREEMPT protocol:
◾️ 7 head & neck muscles
◾️ 31 injections
◾️ 155 units
◾️ Every 12 weeks

➡️ Could also use "follow-the-pain" approach & inject up to 40 more units

pubmed.ncbi.nlm.nih.gov/20958294/

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So back to the ❓: how does it work?

BoNT acts on peripheral nerves by ✂️ SNARE proteins, which are needed for membrane fusion ➡️ 🚫 neurotransmitter release

pubmed.ncbi.nlm.nih.gov/25882077/

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We mostly think about its effect at the neuromuscular junction (NMJ): 🚫 acetylcholine ➡️ paralysis

📒 For a discussion of how BoNT works at the NMJ when we *don't* want it to, check out this 🧵 on infant botulism:

https://twitter.com/RGottliebSmith/status/1487474908301041673?s=20&t=98ROJ67tn62-36_EjmdFkQ

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But actually: BoNT also acts on sensory neurons! And that's how it's thought to work to treat chronic migraine, a sensory disease

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Through its actions on sensory neurons, BoNT blocks release of glutamate, substance P & calcitonin gene-related peptide (CGRP) -- neurotransmitters all involved in pain signaling

pubmed.ncbi.nlm.nih.gov/32602955/

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& the injection sites per the PREEMPT protocol closely match the sensory innervation of the face, scalp, and cervical region

For a more detailed review:
pubmed.ncbi.nlm.nih.gov/32602955/

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So in summary, for BoNT & chronic migraine:
🔑 Mechanism thought to be sensory, not motor!

⚠️: 🚫 medical advice, & onabotA is not currently FDA approved for chronic migraine in children (used off label)

For great resources on #migraine treatment:
@ahsheadache @amfmigraine