How to Manage CGRP Injection Site Reactions
Posted on June 03 2025,
Managing CGRP Injection Site Reactions
A guide for patients experiencing skin reactions to CGRP medications
Understanding CGRP Monoclonal Antibody Therapy
CGRP (Calcitonin Gene-Related Peptide) monoclonal antibody therapy consists of highly effective treatments for preventing migraine attacks. These medications include erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti). While these medications are generally well-tolerated and effective, some patients may experience skin reactions depending on how the medication is delivered.
Subcutaneous Injections
Medications: Aimovig, Ajovy, Emgality
How it works: Needle penetrates skin and deposits medication directly into the fatty tissue layer (subcutaneous space). The medication sits locally in this tissue where. your immune system encounters it.
Result: Can cause injection site reactions because the medication remains in contact with local tissue.
IV Infusion
Medication: Vyepti (eptinezumab)
How it works: Needle enters a vein and medication flows directly into your bloodstream, circulating throughout your body immediately.
Result: No injection site reactions because no medication is deposited locally in tissue around the needle site.
The Good News
Most injection site reactions from subcutaneous CGRP medications are mild to moderate and don't require stopping your medication. With proper management techniques, the vast majority of patients can continue their effective CGRP treatment while minimizing discomfort from skin reactions. If reactions become problematic, switching to Vyepti (the IV option) completely eliminates injection site reactions.
This guide will help you understand what skin reactions look like, when they occur, and most importantly, how to manage them so you can continue receiving the migraine relief you need.
Types of Injection Site Reactions
There are two main types of skin reactions that can occur with subcutaneous CGRP medications (Aimovig, Ajovy, and Emgality). Understanding the difference helps you know what to expect and how to respond.
1
Immediate Reactions
Occur within hours of injection
followed by
2
Delayed Reactions
Usually appear 24-48 hours later
Immediate Reactions (Within Hours)
These happen right away or within a few hours of injection and are considered normal side effects of the injection process itself. When you get any injection, your body naturally responds with some inflammation at the site.
Why Do Immediate Reactions Happen?
When the needle goes into your skin, it causes minor tissue damage. Your body's natural response is to send inflammatory signals to help heal the area. Additionally, when medication is deposited into the subcutaneous tissue, it can cause local irritation as your body begins to process it. This causes the typical symptoms you might see with any injection - some pain, warmth, and redness. It's actually a sign that your immune system is working normally.
Pain
Brief stinging or soreness at injection site
Warmth
Feeling of heat around the injection area
Redness
Light pink or red coloring of the skin
Itching
Mild to moderate itching sensation
Delayed Reactions (24-48 Hours Later)
These usually appear 24-48 hours after injection and are less predictable. They happen because your immune system has learned to recognize the CGRP medication as something foreign and mounts a stronger response to it in the tissue where it was deposited.
Why Do Delayed Reactions Happen?
CGRP medications are large protein molecules that your immune system can recognize as "foreign." The first time you get the injection, your immune system "learns" about this new protein sitting in your subcutaneous tissue. On subsequent injections, your immune system remembers it and responds more quickly and strongly to the medication depot in your tissue - kind of like how your body builds immunity to vaccines. This immune memory response causes the delayed reactions you see 1-2 days later. This is different from IV infusions where the medication doesn't sit in local tissue long enough for this type of immune response to develop.
Delayed Reaction Symptoms
- Erythema (redness): Red patches that may be larger than immediate reactions
- Induration (hardness): Firm, raised areas under the skin
- Pruritus (itching): Can be more intense than immediate reactions
- Pain or tenderness: May persist for several days
- Swelling: Puffiness around the injection site
- Plaques: Raised, flat-topped areas that can be several centimeters wide
Important Timing
Delayed reactions typically occur after the second or subsequent injections, not the first one. This is because your immune system needs to be "taught" about the medication sitting in your tissue first. If you had no reaction to your first injection, this doesn't guarantee you won't have reactions to future injections - your immune system may still be learning.
Visual Example: Before and After Protocol
Left panel shows extensive reaction without protocol; right panels show significantly reduced reactions with tolerance protocol implementation
Image source: Romero del Rincon C, et al. Management of local and delayed cutaneous hypersensitivity reactions to anti-CGRP antibodies. Neurological Sciences. 2025.
How Common Are These Reactions?
2.9
Erenumab (Aimovig)
Injection site pain reports per 1,000 patients
4.9
Galcanezumab (Emgality)
Injection site pain reports per 1,000 patients
0.8
Fremanezumab (Ajovy)
Injection site pain reports per 1,000 patients
0
Eptinezumab (Vyepti)
No injection site reactions (IV infusion)
While injection site reactions are among the most commonly reported side effects for subcutaneous CGRP medications, they're usually manageable. Research shows that with proper protocols, patients can often continue their treatment successfully.
What These Numbers Mean
These rates come from real-world data where patients and doctors report side effects to the FDA. The numbers are relatively low - for example, with galcanezumab (which has the highest rate), only about 5 out of every 1,000 patients report injection site pain. Most reactions are mild and manageable with the right approach. Vyepti shows zero injection site reactions because it's delivered differently - directly into the bloodstream rather than into tissue.
The Tolerance Protocol: Managing Reactions
Medical experts have developed a structured approach to help patients continue their subcutaneous CGRP treatment even when experiencing skin reactions. This protocol involves four key steps that work together to minimize discomfort and inflammation.
How the Protocol Works
The tolerance protocol works by interrupting your body's inflammatory response at multiple points. Think of inflammation like a chain reaction - the protocol breaks several links in that chain. Antihistamines block the "itch and swell" signals, anti-inflammatory medications reduce pain and swelling, and topical steroids calm down the local immune response in your skin where the medication was deposited.
1
Pre-Injection Preparation (30 minutes before)
Taking medications before the injection creates a "shield" against inflammation before it starts.
Oral Antihistamine See options below
Topical Corticosteroid Apply to injection site
2
Injection Site Selection
The abdomen has more cushioning fat tissue, experiences less movement, and tends to be better tolerated than arms or thighs. This can make a real difference in how you feel after the injection and, is therefore, the preferred site of injection.
3
Immediate Post-Injection Care
Quick action right after injection helps prevent the inflammatory response from building up.
Oral NSAID Ibuprofen 600 mg or equivalent
Cold Compress Apply immediately and as needed
Topical Corticosteroid Reapply to injection site
4
Ongoing Home Care (Until symptoms resolve)
Keep up the treatment for the critical 48-72 hour period when delayed reactions typically show up.
- Continue oral antihistamine daily (use same medication as pre-injection)
- Apply topical corticosteroid twice daily
- Use cold compresses as needed for comfort
- Monitor symptoms and document any changes
First Monitored Injection
When starting this protocol, your healthcare provider may want to observe you for 30 minutes after the first injection to ensure the protocol is working and to provide reassurance. Once tolerance is confirmed, you can usually continue with home injections using the same protocol.
Medication Details and Alternatives
Here are common medications used in the tolerance protocol, with alternatives if you can't use the specific drugs mentioned:
Antihistamines (choose one)
Note: The original research protocol used ebastine 10 mg, which is not FDA-approved in the United States. US patients should use one of these FDA-approved alternatives:
Loratadine (Claritin) 10 mg daily
Cetirizine (Zyrtec) 10 mg daily
Fexofenadine (Allegra) 180 mg daily
Levocetirizine (Xyzal) 5 mg daily
Topical Corticosteroids (choose one)
Methylprednisolone aceponate Apply thin layer twice daily
Hydrocortisone 1% Over-the-counter option
Triamcinolone 0.1% Prescription strength
NSAIDs (choose one)
Ibuprofen 600 mg (or 400 mg, if sensitive)
Naproxen 220 mg twice daily
Aspirin 650 mg (if others not tolerated)
Important Safety Notes
- Check with your doctor before starting any new medications
- Make sure NSAIDs don't interact with your other medications
- Don't use topical steroids for more than 2 weeks without medical supervision
- If you have stomach problems, kidney disease, or heart conditions, discuss NSAID use with your doctor first
What to Expect: Success Stories
Research shows this protocol can be highly effective. Here are examples of how patients have successfully continued their CGRP treatment:
Patient 1
53-year-old woman
Had 7 cm hard, red, itchy reactions. With protocol, continued fremanezumab with only mild reactions
Patient 2
60-year-old woman
Extensive reactions to fremanezumab and galcanezumab. Protocol reduced reactions to minimal wheals only
Patient 3
35-year-old woman
Large thigh reactions to fremanezumab. The picture of this patient's reaction is seen above. Protocol significantly reduced intensity and discomfort
100%
Success Rate
All patients in the study were able to continue their CGRP treatment with the protocol
When to Contact Your Healthcare Provider
Seek Immediate Medical Attention If You Experience:
- Difficulty breathing or shortness of breath
- Swelling of face, lips, tongue, or throat
- Widespread rash or hives all over your body
- Dizziness, fainting, or rapid heartbeat
- Severe nausea or vomiting
- Any symptoms that feel like a severe allergic reaction
Contact Your Doctor Within 24-48 Hours If:
- Injection site reactions are getting worse instead of better
- Reactions spread beyond a 10 cm area around the injection site
- You develop fever or feel generally unwell
- The reaction lasts longer than one week
- You notice signs of infection (pus, red streaking, increased warmth)
- The protocol isn't helping reduce your symptoms
- You're having trouble managing the discomfort
Remember: Most Reactions Are Not Dangerous
Local skin reactions, while uncomfortable, are generally not dangerous and don't increase your risk of serious allergic reactions. However, it's always better to check with your healthcare team if you're concerned.
Alternative Strategies and Tips
Injection Site Rotation and Selection
Where you inject can make a difference in how you tolerate the medication:
Best Injection Sites for Tolerance
1. Abdomen (Preferred): The abdominal area has several advantages:
- More subcutaneous fat tissue to cushion the injection
- Less muscle movement that could irritate the area
- Generally better tolerated than arms or thighs
- Easier to apply topical treatments
2. Outer Thigh: Second choice if abdomen isn't suitable
3. Back of Upper Arm: Usually the most reactive site - avoid if having reactions
Additional Comfort Measures
Cold Therapy
Ice packs for 10-15 minutes several times daily
Loose Clothing
Avoid tight clothing over injection sites
Cool Showers
Avoid hot water which can worsen inflammation
Don't Scratch
Scratching can worsen reactions and cause infection
Understanding Why This Happens
Understanding the science behind injection site reactions can help you feel more confident about managing them.
Why Do Delayed Reactions Occur?
Delayed reactions happen because your immune system recognizes the CGRP medication deposited in your subcutaneous tissue as "foreign" and mounts an inflammatory response. This is different from a true allergy - it's more like your immune system being overly cautious about a new substance sitting in your tissue. Your body is trying to protect you, but it's causing some temporary discomfort in the process.
The Immune Response Process
1
First Injection
Usually no reaction occurs - your immune system is "learning" about the medication in your tissue
2
Immune Learning
Your immune system creates a "memory" of the medication and where it was deposited
3
Later Injections
Immune system recognizes the medication in tissue and may react more strongly
4
With Protocol
Reactions become controlled and manageable
This explains why reactions often start with the second or third injection, not the first. Your immune system needs time to "learn" about the medication sitting in your tissue before it reacts. This also explains why IV infusions like Vyepti don't cause this issue - the medication never sits in tissue long enough for this immune learning process to occur.
Good News About Safety
Research shows that local skin reactions do NOT increase your risk of serious systemic allergic reactions. Having injection site reactions doesn't mean you're more likely to have dangerous allergic responses to the medication.
Comparing CGRP Medications
Different CGRP medications have slightly different rates of injection site reactions. If you're having significant problems with one, your doctor might consider switching to another.
Aimovig
Erenumab
Moderate injection site reaction rates. Monthly injection. Targets CGRP receptor.
Ajovy
Fremanezumab
Lower reported reaction rates. Monthly or quarterly injection options.
Emgality
Galcanezumab
Higher reaction rates reported. Monthly injection after loading dose.
Vyepti
Eptinezumab
IV infusion - no injection site reactions. Quarterly treatments in clinic.
Switching Medications
If injection site reactions are severe with one subcutaneous CGRP medication, your doctor might switch you to a different one. Each medication has a slightly different molecular structure, so you might tolerate one better than another. Eptinezumab (Vyepti) is given as an IV infusion, eliminating injection site reactions entirely because the medication goes directly into your bloodstream rather than sitting in tissue.
Keeping Track: Reaction Diary
Keeping a simple diary of your reactions can help you and your healthcare provider optimize your treatment plan.
What to Track
Date of Injection When did you inject?
Injection Site Abdomen, thigh, or arm?
Reaction Onset How many hours/days after injection?
Symptoms Redness, swelling, pain, itching?
Size Diameter of the reaction in centimeters
Duration How long did it last?
Protocol Used Did you use the tolerance protocol?
Effectiveness Did the protocol help? How much?
Photos Can Help
Taking photos of reactions (with good lighting and a ruler for scale) can be very helpful for your healthcare provider to assess the severity and track improvements over time.
Cost Considerations
The tolerance protocol uses common, inexpensive medications that are usually covered by insurance or available over-the-counter.
$15-30
Initial Cost
Most components of the protocol are relatively cheap and may be used several times
Comparing Costs
The tolerance protocol costs much less than switching to a different CGRP medication or stopping treatment altogether. When you consider the mental, emotional, and economic costs of discontinuing a CGRP medication, spending $15-30 every few months on a tolerance protocol is very cost-effective.
Frequently Asked Questions
Will the reactions get worse over time?
Not necessarily. Many patients find that reactions become more predictable and manageable over time, especially when using the tolerance protocol consistently. Some patients even see reactions diminish after several months of treatment.
Can I prevent reactions entirely?
While you may not be able to prevent reactions completely, the tolerance protocol can significantly reduce their severity and discomfort. Many patients go from having large, painful reactions to barely noticeable mild redness.
Do I need to use the protocol for every injection?
Yes, for best results, use the protocol consistently with every injection. Consistent use helps maintain the anti-inflammatory effects and provides reliable symptom control. While skipping the protocol won't make reactions worse than baseline, you'll likely experience your usual reaction pattern without the protective benefits.
What if I'm allergic to one of the protocol medications?
There are alternatives for each component. If you can't take NSAIDs, focus on the antihistamines and topical steroids. If you're allergic to one antihistamine, try a different class. Work with your doctor to find suitable alternatives.
Can I exercise after injection?
Light activity is usually fine, but avoid intense exercise for 24-48 hours after injection, as increased blood flow and sweating might worsen reactions. Swimming in chlorinated pools should also be avoided for a day or two.
Should I worry about injection site reactions affecting the medication's effectiveness?
No. Injection site reactions don't affect how well your CGRP medication works for preventing migraine. The medication is still being absorbed and working even if you have local skin reactions.
Why doesn't Vyepti cause injection site reactions if it also uses a needle?
The key difference is where the medication ends up. Subcutaneous injections (Aimovig, Ajovy, Emgality) deposit medication directly into tissue under your skin, where it sits and can trigger local immune responses. Vyepti uses an IV, so the medication flows directly into your bloodstream and circulates throughout your body immediately - no medication is left sitting in local tissue to cause reactions.
Working with Your Healthcare Team
Managing injection site reactions is a team effort between you and your healthcare providers. Here's how to get the best support:
Before Your Appointment
- Bring your reaction diary and any photos
- List all medications you're currently taking
- Note any allergies or sensitivities you have
- Prepare questions about the tolerance protocol
- Consider bringing a family member for support
Questions to Ask Your Doctor
Important Questions
- "Which specific medications do you recommend for my tolerance protocol?"
- "Are there any interactions with my current medications?"
- "How long should I try the protocol before considering other options?"
- "What reaction size or severity would make you want to switch medications?"
- "Would switching to Vyepti be a good option for me?"
- "Should I see an allergist or dermatologist?"
- "Are there any warning signs that should make me stop the medication immediately?"
- "How often should I follow up about my reactions?"
Healthcare Team Members Who Can Help
Neurologist
Primary prescriber, medication adjustments
Pharmacist
Medication interactions, over-the-counter options
Allergist
Specialized testing and desensitization protocols
Success Tips and Final Recommendations
Be
Consistent
Use the protocol every time for reliable symptom control and best results
Stay
Patient
It may take 2-3 injections to see the full benefit of the protocol
Track
Progress
Keep detailed records to show your healthcare provider
Consider
All Options
Remember that Vyepti eliminates injection site reactions entirely
Remember: You're Not Alone
Many patients experience injection site reactions, and healthcare providers are experienced in helping you manage them. Don't let fear of reactions prevent you from getting the migraine relief you deserve. With the right approach, most patients can continue their effective CGRP treatment comfortably. And remember, if injection site reactions become too problematic, switching to Vyepti completely eliminates this issue while providing the same migraine prevention benefits.
Resources
Emergency Contacts
Keep these numbers easily accessible:
- Your neurologist's office
- After-hours nurse line
- Your pharmacy
- Emergency services: 911 (in US)
- Poison control: 1-800-222-1222 (in US)
Important Medical Disclaimer
This information is for educational purposes only and should not replace professional medical advice. Always consult with your healthcare providers before starting any new treatment protocol. The tolerance protocol described here should only be used under medical supervision. Individual responses to medications vary, and what works for one patient may not work for another.
Sat, Jun 14, 25
One FREE month of Neura Health
Get One Month Free with Neura Health Specialized headache care with no commitment LIMITED TIME OFFER CEREBRALTORQUE2025 Enter at app.neurahealth.co/onboarding(enter code CEREBRALTORQUE2025 when prompted) Your Free Month Includes: Care coaching...
Read MoreTue, Jun 10, 25
Acute Migraine Treatment
Complete evidence-based guide to acute migraine treatment for adults. Learn optimal dosing for triptans, NSAIDs, CGRP antagonists & emergency protocols. Includes treatment pearls, medication selection strategies, and prevention of medication...
Read MoreTue, Jun 10, 25
Vestibular Migraine
Comprehensive guide to vestibular migraine: symptoms, diagnosis, and evidence-based treatment options for migraine-related vertigo and dizziness. Learn about causes, triggers, medications, and long-term management strategies for this common but underdiagnosed...
Read More