Category: Preventive

According to the World Health Organization (WHO), headache disorders are among some of the most common nervous system disorders, and around 15% of the world’s population experiences migraine attacks.¹⁹ It’s estimated that up to 5% of people diagnosed with migraine meet the criteria for chronic migraine: having a headache at least 15 days per month, with at least eight of those days featuring migraine symptoms, for over three months.

While there are various preventive medications for chronic migraine on the market, many come with a host of side effects, making them uncomfortable or undesirable. Of these preventives, Botox injections typically come without systemic side effects and do not require a daily or even monthly dose. Botox has been shown to be an effective preventive medication for chronic migraine, with over a million people receiving treatment as of 2023.

If you’ve been wondering about Botox treatment for chronic migraine, read on for a primer on this popular treatment, and get prepared for your next doctor’s appointment.

What is Botox?

Botox comes from the toxin onabotulinumtoxinA, produced by the bacteria Clostridium botulinum. The pharmaceutical company Allergan, owned by AbbVie, treats and purifies this botulinum toxin to create a protein that, when injected, stops muscle contractions. It does this by interfering with the release of neurotransmitters at the neuromuscular junction, where the nerves and muscles meet.⁹ This interrupts the pain pathway. Once the protein is created, the dose is calculated and put into vials containing 100 or 200 units, and it is called Botox.

History of Botox as Treatment for Chronic Migraine:

Botox is commonly associated with cosmetic use, which minimizes facial wrinkles and fine lines. While cosmetic use accounts for half of all Botox treatments, it has also been used as a medical treatment for various conditions besides migraine, such as strabismus (crossed eyes), since the 1970s.

Botox Medical Treatments

Condition	Symptoms
Cervical Dystonia	severe neck and muscle spasms
Blepharospasm	eye twitch
Hyperhidrosis	severe and excessive sweating
Strabismus	misaligned/crossed eyes
Bruxism	grinding of teeth
Overactive Bladder	urge to urinate that’s difficult to control
Chronic Migraine	for over three months, having 15 or more headache days per month, 8 of which feature migraine symptoms

In 1998, Beverly Hills cosmetic surgeon Dr. William Binder documented that several patients who received Botox on their foreheads and around their eyes reported improved migraine attacks. This led to several scientific studies centered on Botox’s potential for treating migraine.

For example, the PREEMPT study, ending in 2008, resulted in Botox being FDA-approved in the United States for the prevention of chronic migraine in 2010.³ Botox was also approved for migraine prevention by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom that year.⁶ The Therapeutic Goods Administration (TGA) in Australia quickly followed suit with its formal approval of Botox for chronic migraine in 2011.¹

How Botox Helps Prevent Migraine Attacks

Botox is used differently depending on the condition being treated. Receiving treatment for one condition will not necessarily affect another condition. Dr. Andrew Blumenfeld, a primary researcher in the PREEMPT clinical trial, says that Botox is injected shallowly into the muscle at “31 dedicated injection sites, all of which are around pain fibers … since these sites are at sensory nerve-ending sites, they won’t have the effect as if injected into cosmetic sites.”

The PREEMPT clinical trial produced the injection site locations and eventually led to the FDA approval of Botox as a migraine preventive treatment. The purpose of injecting at these sites is to suppress the peripheral pain nerves connecting the brain with painful stimuli involved in migraine. Since the mechanisms of migraine are complex and not fully understood, it is hard to fully understand what makes Botox work. 

Often, a person with migraine will try to control their triggers to minimize the number of episodes. However, many individuals with migraine are easily triggered by everyday things that are often unavoidable, such as a glare, loud environment, or strong smell. Botox decreases this hypersensitization and allows for better control of environmental triggers.

Figuring Out if Botox is a Good Fit

For 30 years, researchers have been searching for biomarkers indicating whether Botox will be successful for individual patients.¹⁵ While more research is needed to say who specifically will benefit from Botox, several factors can indicate that it may not be the correct preventive medication for some. 

1. Episodic migraine is not currently considered a good fit for Botox; this is because the injection sites developed during the PREEMPT study were found while focusing on individuals with chronic migraine with a stable headache history.³
2. Individuals who have had a craniotomy, or skull surgery, should inform their provider. If a person has an implanted stimulator in their scalp, the injector must know where to avoid damaging the leads.¹⁰
3. Botox should be avoided if there is an infection at the proposed injection site or if the individual is hypersensitive to any botulinum toxin preparation.¹²
4. Individuals who have Myasthenia Gravis, Lambert-Eaton Syndrome, Amyotrophic Lateral Sclerosis (ALS), and neuropathies are also not considered candidates for Botox.¹²

Defining Successful Preventive Treatment

Of the PREEMPT study, Dr. Blumenfeld states, “We typically saw a 50% response rate. This means that the study participant felt 50% better.” One in four study participants saw a 75% response rate. Participants also frequently noted dramatic improvement in their neck and shoulder pain. Many of the physicians who spoke with the Migraine World Summit have seen even better results among their patients than those of the PREEMPT Trial.13 Their reported results were sometimes as good as 75% of patients expressing a marked decrease in headache days and migraine attacks.

The FDA recommends repeating Botox every 12 weeks. However, 44-62.9% of patients who receive Botox to treat their chronic migraine report noticing a wearing off around weeks 9-10.¹⁵ Some patients have benefitted from a shortened time window between injection sessions.

Getting Access to Botox Treatment for Migraine

Insurance Requirements

Access to Botox through insurance companies involves several administrative hurdles before being considered. First, an individual must meet the FDA standards for chronic migraine.⁷  This includes each attack lasting at least four hours per day.

Many insurance companies in the U.S., as well as the U.K.’s National Institute for Health and Care Excellence (N.I.C.E.), require the person with migraine to try two to three different classes of preventive treatment without seeing results.⁸ Frequently, insurance companies will then need prior authorization for the treatment, which must be updated every year.

While Botox may be considered an expensive preventive option, Botox can be cost-saving compared to emergency room visits, urgent care visits, imaging studies, or other medication costs. It does not take many emergency room visits to pay for Botox treatment. Getting approved for migraine preventive treatment with Botox can be challenging and time-consuming, but the option may be a viable one for many.

One thing to note: Many insurance companies will deny Botox if a patient already uses a CGRP medication. This differs across the healthcare industry. It is recommended that you speak to your insurance company to get their criteria. 

There is a Botox savings program in the United States for those with commercial insurance. This program helps cover some of the costs of the medication and procedure. It is designed to help cover the out-of-pocket costs after insurance.

Finding the Right Physician

Finding the right physician to administer Botox is crucial to getting good results from Botox for chronic migraine. Ideally, look for a headache specialist or neurologist who has been specifically trained in the use of Botox for chronic migraine. A dermatologist or cosmetic surgeon focused on cosmetics would not place the injections at the nerve sites needed to treat chronic migraine. A good place to start is Allergan’s search tool for finding a Botox Specialist. It links to physicians who are experienced in treating chronic migraines with Botox. 

Before undergoing preventive treatment with Botox, ask questions such as: 

1. Does the provider inject the full 31 injection sites? 
2. What dose does the provider use? 
3. How many patients has the provider treated for chronic migraine? 
4. Have their patients experienced drooping eyelids or neck pain? 
5. What percentage of patients decides to continue the preventive treatment?

How Botox Treatment Feels

Choosing Botox can be scary, as people fear the pain of repeatedly getting injected in the head and neck. While no injection is entirely comfortable, going into the appointment with informed expectations can help ease the fear.

The needles used for Botox are slightly thicker than an acupuncture needle and about half an inch long. With both the small needles and the injection’s shallowness, some say it feels like a very fast pinch with some sting. The Botox administrator usually uses conversation as a distraction; for most, this is enough for the injection to go unnoticed.

The exception is usually when the patient is in a pain flare, perhaps during an active migraine attack or allodynia. Since the pain structures of the head and neck are already hypersensitive, the injections can cause more discomfort, with some patients describing it as similar to a bee sting. While the discomfort usually passes quickly, here are a few things that can help mitigate some of this discomfort:

1. Take Tylenol before the appointment.
2. Ask for a local anesthetic.
3. Use ice to numb the injection sites before and after the injection.

Potential Side Effects

In a conversation with the Migraine World Summit, Dr. Bronwyn Jenkins discussed the most common side effects of Botox. “The most common is minor skin irritation, such as redness, a small bump at the injection site, and some bruising. Flu-like symptoms, such as fatigue, chills, and muscle stiffness, have also been reported.” These side effects usually fade within a few days of onset. 

Rare side effects include:¹⁵

• Difficulty lifting eyebrows, droopy eyelids (less than 3%) 
• Headache, neck stiffness, and muscle spasms (4%) 
• Discomfort in the neck muscles (9%) 

Many of these side effects are short-lived, and having a well-trained Botox administrator can minimize many of them.

There are some very rare and severe effects of Botox such as: difficulty swallowing, speaking, or breathing. This can be due to weakening of associated muscles, can be severe and result in loss of life. You are at the highest risk if these problems are preexisting before injection. Swallowing problems may last for several months.

There is also the risk of the Botox toxin spreading to surrounding tissues after the treatment. This can lead to: loss of strength and all-over muscle weakness, double vision, blurred vision, drooping eyelids, hoarseness or change or loss of voice, trouble saying words clearly, loss of bladder control, trouble breathing, and trouble swallowing.¹²

Safety Considerations and Misconceptions

Since Botox has become widely known and accepted, there are a few myths and fears that many have when considering Botox for treating migraine. These include:

The Bottom Line

Botox is considered a safe and effective migraine preventive option for many. Due to its high success rates, it has proven popular with both patients and providers. With over a million people with chronic migraine having received Botox, it is safe to say that Botox is a preventive option that deserves more attention.

Calcitonin gene-related peptide (CGRP) inhibitors represent a new class of drugs uniquely designed to treat migraine. There are two types of CGRP inhibitors: monoclonal antibodies which are designed for migraine prevention, and gepants which can be used as both preventive and acute migraine therapies. Several options are available within both categories. While these treatments are not a cure for migraine disease, they have proven to be safe and effective.

What is CGRP?

CGRP is the acronym for calcitonin gene-related peptide. CGRP is a small molecule made up of 37 amino acids that is produced naturally by the body.¹ CGRP is involved in body functions in the gut, the reproductive tract, and blood vessels.²

CGRP may be helpful in protecting against cardiovascular issues, such as high blood pressure and heart disease. For example, in the midst of a heart attack or a stroke, CGRP may be released to help prevent such an event.¹

While CGRP is found in everyone and is helpful to some of our body functions, the effects of CGRP can also contribute to migraine attacks.

What is the role of CGRP in migraine?

CGRP is released into the body during the migraine process.¹⁸ CGRP affects the trigeminal nerve, which communicates pain and sensitivity to touch and temperature. It is released throughout the peripheral and central nervous systems during a migraine attack. When CGRP attaches to its receptors in the brain, it perpetuates the migraine process, leading to inflammation and headache pain.^{3 4} In patients who have chronic migraine disease, CGRP levels remain elevated during a migraine attack, as well as between attacks.¹⁹

Clinical studies have shown that when CGRP is injected into the body it causes moderate to severe headaches in people who have not been diagnosed with migraine disease, and migraine-like headaches in people who have migraine disease.^{1 18} This information suggests that people with migraine disease may be particularly sensitive to CGRP.¹⁸

The initial development and studies of drugs that target and reduce the amount of CGRP in the body began in the late 1990s.¹⁸ The first CGRP inhibitors to prevent, reduce, and or treat migraine attacks were approved by the FDA in 2018.³

What are CGRP Inhibitors?

CGRP inhibitors generally fall into two classes of drugs: Monoclonal antibodies and receptor antagonists.³

Monoclonal antibodies

Monoclonal antibodies work by blocking the CGRP pathway. They are a preventive treatment due to the longer duration  they remain in the bloodstream.¹ Monoclonal antibodies are FDA approved for migraine with and without aura.⁶

The following monoclonal antibodies work by binding to the CGRP molecule itself, “mopping up” the CGRP in the body.⁷ They are FDA approved for the preventive treatment of migraine in adults.

• Fremanezumab (Ajovy) is self-administered as a subcutaneous injection every month or every 3 months, depending on dosage.⁸
• Galcanezumab (Emgality) is self-administered as a subcutaneous injection every month for the preventive treatment of migraine. A different dosage is approved for the treatment of episodic cluster headache.⁹
• Eptinezumab (Vyepti) is administered in the doctor’s office as a 30 minute intravenous infusion every 3 months. It is approved for the preventive treatment of migraine in adults.¹⁰

A fourth FDA approved option, erenumab (Aimovig), works by binding to the CGRP receptor, so that the CGRP cannot be activated and result in a migraine attack.⁷ Aimovig is self-administered as an injection every month, and is approved for the preventive treatment of migraine in adults.¹¹

Gepants

Gepants are small molecule CGRP receptor antagonists that bind to and block CGRP receptors. Gepants are generally marketed for acute migraine treatment due to the shorter length of time they stay in the bloodstream, but some gepants may be used daily as a preventive treatment.^{1 4 5 12 13}

The following gepants are FDA approved for the acute treatment of migraine in adults:

• Rimegepant (Nurtec ODT) is a disintegrating 75 mg single dose oral tablet. It is also approved for the preventive treatment of episodic migraine.¹⁴
• Ubrogepant (Ubrelvy) is prescribed as a 50 or 100 mg oral tablet. A second tablet can be taken in 2 hours if the migraine pain returns. The maximum dose is 200 mg per day.¹³ It is approved for the acute treatment of migraine attacks with or without aura; it is not approved for the prevention of migraine headaches.¹⁵

A third option, atogepant (Qulipta) is FDA approved for the preventive treatment of episodic migraine in adults. It is prescribed as a daily 10 mg, 30 mg, or 60 mg oral tablet.¹⁶ At this time it is not FDA approved for acute migraine treatment.

Risks

What are the side effects?

Side effects of the CGRP monoclonal antibodies include:

• constipation¹¹
• high blood pressure¹¹
• injection site reactions, such as pain, redness, or swelling^{8 9 10 11}

Side effects of gepants include:

• constipation¹⁶
• fatigue^{15 16}
• nausea^{14 15 16}

Who is contraindicated?

CGRP inhibitors are generally well tolerated and can be used safely by patients who do not have an allergic reaction to the drug or its ingredients. 

Before taking the drug, patients should tell their healthcare provider about all medical conditions and medications, as some interactions may exist.

CGRP inhibitors have not been adequately studied for safety in pregnant women, unborn infants, or their presence and effect in human milk, milk production, or breastfeeding infants.^{13 19} Patients should tell their healthcare provider if they are pregnant, breastfeeding, plan to become pregnant, or plan to breastfeed.

Safety and effectiveness in children has also not been established.¹⁹ None of the CGRP inhibitors discussed in this article have been approved for the treatment of migraine in children.

How much relief can be expected?

In clinical trials, more than half of people found that their migraine days and/or severity of their migraine attacks dropped by 50% when using a CGRP inhibitor.⁴ Fortunately, about 70% of people see some level of improvement.¹⁷

Some people may need to take the medication for three to six months to achieve an optimal response.^{4 6} There is currently no method to predict who will have good results, and which drug within the treatment class will be the most effective.² If a patient does not find relief on one CGRP inhibitor, or has not tolerated it due to side effects, it is advisable to try another drug.¹²

CGRP inhibitors can be an equally effective option regardless of whether you have:

• Failed to see migraine improvement on one or dozens of other preventive therapies.
• Been using or overusing acute medications.
• Been newly diagnosed with migraine disease or have had migraine for a lifetime.

Costs

With a new class of medication such as CGRP inhibitors, there may be challenges for patients to access these treatments. Commercial insurance companies in the U.S. generally require failure of at least two, if not three, preventive medications from three different classes before providing prior authorization to cover these new medications. This is usually due to the high cost of the CGRP inhibitors.⁶ Without insurance coverage, a year of treatment with a CGRP inhibitor can cost a patient several thousand dollars.¹³

To assist patients in obtaining these medications, some drug companies offer programs that offer free trial doses, temporary coverage of medication, or copay assistance. These programs may not be available to patients who have government insurance.⁴

Summary

CGRP inhibitors are the first medications specifically designed for the prevention and treatment of migraine attacks. They have few side effects, and a high degree of efficacy in reducing migraine frequency and/or severity. While cost and insurance coverage of these new medications may pose a challenge for some patients, there are payment assistance programs available. CGRP inhibitors bring new hope to many patients who have struggled to find an effective migraine treatment.

Additional Resources

Links to outside organizations and articles are provided for informational purposes only and imply no endorsement on behalf of Migraine World Summit.

• What happens to your brain during a migraine – Marianne Schwarz (YouTube):  https://youtu.be/qwZypa0iKq8

• Financial assistance guides from the Coalition for Headache and Migraine Patients (CHAMP): https://headachemigraine.org/migraine-financial-assistance-guides/