Migraine: Mechanism of Action of OnabotulinumtoxinA

Stephen Silberstein, MD: I think it’s important that we talk about concomitant use of Botox and the antibodies, and we can start theoretically or we can talk practically.

Andrew Blumenfeld, MD: We’re starting to talk about the mechanism of action, the theory of how these 2 might work together. Botulinum toxins block the release of vesicles that contain neuropeptides and neurotransmitters, so they interfere with the SNARE [soluble N-ethylmaleimide-sensitive factor activating protein receptor] protein that prevents these vesicles from binding to synaptic membranes and releasing their contents.

If you’re able to get the botulinum toxin to penetrate enough—usually it’s an unmyelinated C fiber that they’re able to penetrate by injecting close to that nerve ending—you will get into that nerve and block the release of all the potential neuropeptides, whether they are CGRP [calcitonin gene-related peptide], or PACAP [pituitary adenylate cyclase-activating polypeptide], or amylin. They all require that vesicle to bind with the presynaptic membrane, so they will globally shut down that nerve from releasing those neuropeptides. There is a theory that there’s some retrograde axonal transport that might also inhibit the release of the neurotransmitters like glutamate from that specific nerve that’s being injected around, as opposed to a monoclonal antibody that specifically targets an individual chemical like CGRP. I think the way of thinking about them is that Botox is more like amitriptyline. Amitriptyline hits multiple receptors, multiple mechanisms of action. Botox hits multiple neuropeptides and neurotransmitters, whereas a monoclonal antibody is more like an SNRI [serotonin and norepinephrine reuptake inhibitor], very targeted to an individual chemical.

Stephen Silberstein, MD: I would extend what you said. Botox works in C fibers, antibodies in the delta fibers. With one you’re hitting 1 nerve type, the other you’re hitting a second and if they’re not synergistic, I would be very disappointed.

Deborah Friedman, MD, MPH: I have a very practical viewpoint of all of this, and it’s similar to what we talked about before and it’s similar to the way we prescribe other preventive treatments. If somebody is on a preventive treatment that has some effectiveness, but not desired level of effectiveness, in practice we would add something else that works differently and determine whether the patient can tolerate it, whether they respond to it, and whether it works better than what they were already on, and then start to simplify their regimens. I approach Botox and a CGRP monoclonal antibody in exactly that same way. I think that the pushback that we’re getting from payers about either not covering them both or, in some cases, requiring that the patient come off Botox first for 4 months, is nothing but cruel and unusual punishment for our patients. It has no basis in science and no basis in rational prescribing.

Stephen Silberstein, MD: The only purpose of their behavior is to save money.

Deborah Friedman, MD, MPH: It’s financial.

Stephen Silberstein, MD: Steph?

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Well, in that case they may wind up losing money when that patient winds up in the ER [emergency room] or hospitalized.

Deborah Friedman, MD, MPH: In the ER, exactly.

Stephen Silberstein, MD: ED [emergency department]. They don’t like that word.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Oh sorry, not a room anymore.

Deborah Friedman, MD, MPH: Emergency department, yes.

Stephanie J. Nahas, MD, MSEd, FAHS, FAAN: Thank you for correcting me.

Stephen Silberstein, MD: How about you, Stew?

Stewart J. Tepper, MD: Well, I’ve capitulated, I’m sorry to say. Our payers are so intransigent about it, and so I have very few patients where I’ve been able to actually leave them on both. I’ve talked to medical directors, I have begged. Occasionally, I have gotten them to approve it, but the vast majority have required me to not have them on concomitant onabotulinum and monoclonal antibody.

Stephen Silberstein, MD: But I’ve done it. The same day they have their injection of Botox, I give them the monoclonal antibody samples and then have a way of following them forward.

Stewart J. Tepper, MD: Unfortunately, Dartmouth prohibits samples.

Stephen Silberstein, MD: In my bias, and when I analyze all of our patients on combination therapy, clinically, they’re synergistic, and I think we have enough patients now to prove it. I think most of my patients I’ve given antibody to were on Botox, few of them had Botox failures, because I wanted to know that question.