Dr Robbins & CGRP Part I
We were privileged to have Dr. Lawrence Robbins doing a Facebook Live Chat in our group on May 21, 2019. Dr Robbins talked about the CGRP Medications one year after the first medication was FDA approved, and answered questions about how the efficacy and side effects seen in the pharmaceutical trials are holding up in widespread clinical practice. This document is a transcript of the questions and answers from that event, and the complete video can be viewed here: https://youtu.be/WZ7FAopqch8.
The CGRP and Migraine Community group welcomes anyone who lives with migraine as well as their caregivers. The group exists to support, guide and educate the migraine community through the emergence and use of this new class of migraine medications, CGRP inhibitors. You can find the group at: www.facebook.com/groups/CGRPandMigraine.
Sometimes, when you have hundreds of thousands of people taking a medication you see different side effects than seen in clinical trials with limited participants. Since the CGRP inhibitor medications were first approved we have seen a range of side effects: constipation, increased headaches, joint pain, hair loss, higher blood pressure, fatigue, depression, anxiety, and more. Putting this in context, all classes of medications have side effects but that doesn’t necessarily mean that we are going to stop using them. For example, with Lasik, 1-2% of people have bad side effects, but it is still in widespread use. It becomes a risk versus benefit question for each person.
SIDE EFFECTS QUESTIONS
- There appears to be a small but significant percentage reporting side effects that either were not seen in the clinical trials or which were not considered “statistically significant.” Do we know why these side effects may present a different profile in real life compared to the studies?
If you look at the trials for CGRP vs real life there are many differences in the side effect profile, but in some cases we do not know why the side effects are happening. Sometimes if you give 300,000 people a medication you will see a number of odd side effects that don’t show up in studies with only a few thousand people. It won’t be long till we have 700,000 to a million people on these medications, and we may see even more odd side effects emerge. CGRP itself is sort of a complicated large molecule made up of three or so components. Then there’s the receptor, which is needed for a compound like CGRP to attach to in order to exert its physiologic activity. When the receptor is blocked by Aimovig, then CGRP is inhibited and theoretically you’ll have less inflammation, improved migraine. However, Ajovy and Emgality, as well as Eptinezumab which is an IV version expected to come out next year, all these attach to the CGRP itself and don’t touch the receptor; there’s a lot of different physiologies between the two mechanisms, so it is possible to see side effects to one without seeing it in the other.
Technically, these are large molecule medications which don’t cross into the brain; we call it the blood-brain barrier. However, there are some areas of the brain that aren’t protected, such as the hypothalamus and the pituitary gland, and there is some penetration. Evolution has deemed CGRP very important as a molecule for inflammation, wound healing, protecting the heart and brain from stroke and heart attacks, and more; it is found in almost every organ in the body. We can’t pretend we’re not going to have any side effects going forward for years or decades, and right now we’re seeing how all of this plays out in clinical practice.
- Patients seem to be reporting a wide variety of side effects from the CGRP inhibitors, including severe constipation, worsened migraine, joint pain, fatigue, bloating, weight gain/loss, blood pressure changes, and more. Which ones are you most aware of?
- Migraine: we’ve certainly seen worsened migraine in some people. In general, if migraine attacks are worse for 2-3 weeks or a month we don’t want to continue the medication and then we see that effect going away. In some people the frequency of migraine attacks remains the same, but the severity of them reduces, and that can make all the difference in quality of life to those people.
- Bloating & Weight Changes: weight gain can be a problem, and if significant enough we stop the medication. This does not appear to be as much a problem as with other medications such as Lyrica, Depakote, gabapentin and the tricyclic anti-depressants, but we are seeing it. This could be because our feeding and hunger is centered in the hypothalamus which is not protected by the blood-brain barrier. A few people have lost weight, and if it is significant then we stop the medication.
- Constipation: this is an issue of course, probably more from Aimovig, which is a receptor blocker, than Ajovy and Emgality which attach to the CGRP peptide itself. People who have an issue with constipation (e.g. IBS-C) may need to have caution using these medications.
- Depression & Anxiety: we’ve seen some central psychological side effects for some reason.
- Heart-Rate: There are not a lot of case reports about this, but it has been seen on occasion.
- High or Low Blood Pressure: I’ve seen a few people, more with higher blood pressure. However, it hasn’t been a huge problem in general, and we’ve even had people with high blood pressure go on these medications without a major problem. Since blood pressure can go up for a number of reasons, sometimes the only way to know if a medication is causing it is to stop the medication and see if your blood pressure normalizes, bearing in mind that these medications have a long half life so it could take a while to get the answer.
- Hair Loss: this is a frequently seen side effect, but no one has any idea why, and it’s a real phenomenon. Sometimes we use Centrum Silver which is a multivitamin with some extra zinc, biotin, or certain B vitamins, but hair loss is a very, very tough thing to treat and understand.
- Vision Changes: we haven’t seen much of this. A lot of medications cause vision changes (e.g. amitriptyline, topiramate), but we’re not seeing this so much with the CGRP medications.
- Joint Pain: this is commonly being seen, sometimes even moderate to severe. In some people this improves but not in everyone.
- Tiredness/Fatigue: this is also commonly being seen, sometimes even moderate to severe. In some people this improves but not in everyone.
- Gastrointestinal Issues: in theory these medications may inhibit the healing of ulcers, and they do affect the GI tract because there’s a lot of CGRP in your stomach and GI tract. How much this is actually happening remains to be seen. The same goes for reflux (GERD) – a lot of people with migraine have reflux also so it can be challenging to know if the CGRP medications are aggravating or causing this. Also, in comparison with the anti-inflammatories, they appear to be safer on the gut in the long term.
- Auras: since these medications can somewhat get into the brain, they can potentially irritate the occipital nerve lobe which can start auras. For someone whose auras are severely worsened, losing vision, numbness or weakness, I would stop the medication. Daily auras can potentially turn into a stroke and we are concerned about that, particularly for those people who are on the birth control pill and/or who smoke. However, bear in mind that while the relative risk may increase, the absolute risk is still low.
- Breathing Issues: this is very rare and not reported much.
- TMJ or Jaw Problems: it is unlikely that these medications cause jaw problems.
- Tinnitus: this is very common with people who have migraine and unfortunately can happen with any medication. However, NSAIDS and anti-depressants are more likely to trigger tinnitus than the CGRP medications. If you get tinnitus, you should see an ENT.
- Mast Cell Activation Syndrome: Mast cells are a part of your inflammatory response system, and when activated they release inflammatory proteins. We call it the inflammatory soup (bradykinin, histamine and substance b). In some people these proteins are very active and constantly releasing, causing allergic type symptoms. Mast cells are very important in this whole immune cascade.
- Are the side effects we’re seeing something to be concerned about?
Most people have mild side effects to the CGRP medications, if they have any side effects at all. Also, to put it in context, ALL medications have side effects (e.g. topiramate can cause kidney stones, severe spaciness, anxiety, depression, and sometimes bipolar; anti-depressants have a whole slew of side effects; all the anti-convulsants and blood pressure medications used for migraine have a variety of side effects, particularly tiredness and weight gain). So, it’s not as if just because a class of medications has side effects in 10-20% of people that we’re necessarily going to stop using it. As with anything new, we will know more over time.
- Are side effects more common in people who have comorbid conditions such as fibro, etc.?
People with migraine often have a very sensitive central nervous system. We call these central sensitization syndromes, and people often have more than one of them such as: fibromyalgia, chronic pelvic pain, complex regional pain syndrome (CRPS), irritable bowel syndrome, POTS, TMD/TMJ. Most of our serotonin is in the GI tract, and the serotonin system with people who have migraines doesn’t work quite right, so we see a lot of IBS, cramps, reflux, constipation, diarrhea, etc. People who have 2 or more of these syndromes have a very sensitive central nervous system and are likely to have more side effects from certain medications, in particular the CGRP inhibitors, so it’s important to “go low and slow” when trying them. However, many of the more prevalent side effects we’ve seen are with people who don’t have sensitive central nervous systems but just have migraine; they start these medications and they get tired, have joint pain, constipation, or worse migraine.
- Have you seen an issue with healing inhibition, especially relating to surgery?
In theory CGRP medications can inhibit healing and decrease healing, and so in theory we should taper off before surgery. However, clinically we haven’t seen healing inhibition much at all or even heard of it.
- If a patient tries one CGRP inhibitor with no results but lots of side effects, is it worthwhile trying another?
That’s a million dollar question and I’ve written two studies, one on Aimovig and one on Ajovy and Emgality from clinical experience. I think that if people have a lot of side effects and/or lack of efficacy from either Emgality or Ajovy then they are likely to have the same or similar results from the other one since they both attach to CGRP. However, this is not yet proven, and in other classes of medication, if people don’t do well on one SSRI for depression, or one beta blocker for blood pressure, they may do well with another one. So, it doesn’t necessarily mean we just have to stop the medication, or not switch. In general, if people have side effects to Emgality or Ajovy, and they are more than mild, I’m not switching them to the other one because I’ve seen similar side effects when switching. Having said that, because Aimovig has a different mechanism by attaching to the receptor, I do tend to switch to or from that one.
- We have been told that these medications don’t cross the blood-brain barrier, but your articles intimate that there are some areas of the brain which are not protected. Can you please amplify on that?
As a whole, these are protected from going into the brain by the blood – brain barrier, but there are several crucial areas that are not protected from the blood – brain barrier such as the hypothalamus & the pituitary gland (where we have a lot of hormones) There are some hormonal issues which I think can happen that did not show up in the studies and impact things such as the menstrual cycle, depression, and anxiety. There’s also a part of the brain called the “area postrema” that’s not protected, and because this is the nausea center in the brain, and this can result in or aggravate existing nausea. Sometimes this goes away during medication use, but not always.
- In your opinion, do these medications potentially impact the immune system even though officially they have been “modified” so that this doesn’t happen?
The CGRP medications work on the immune system by dampening down the immune response. They specifically help reduce inflammation around the head which is theoretically caused by CGRP. However, we are not totally clear yet how these medications work, so there are a lot of questions.
- When do you expect the medication package inserts to be updated with these side effects?
The FDA is slow to change the labeling, and it may take a year to do this or even longer. We’re trying to effect this change sooner, and I’ve sent some letters to the FDA. March 31, 2019, Erenumab (Aimovig) FDA reports came out on FDA adverse effects website, FAERS. They had 12,000 side effects reported since May 2018, with about 1,200 of them being serious. It is unlikely that all of these are caused by Aimovig rather than being coincidental, but there is still a significant amount of side effects that should be included in the package insert. A lot of doctors are not aware of the potential side effects because the original insert doesn’t list them, so they say, “There’s no side effects,” even when patients are reporting to them. That’s a problem – we’re not legitimizing what the patient despite the insert having an unrealistic side effect profile. What is interesting is that the efficacy profile seems to be holding true, but the side effects one needs updating.
CONTRAINDICATIONS & SAFETY
- Are these meds contraindicated for people with an immune condition such as CVID or lupus?
The immune system and migraine go way back. In 198I, when I was new in practice, I became convinced the immune system was the key in headaches. We did some studies on Helper Suppressor Cells and found some interesting things. CGRP works on the neuro-immune system and is an immune blocker, dampening down the immune response. With migraine, we get a lot of inflammation around the head with a release of inflammatory proteins that feed to the bottom of the brain then go up into the brain stem and the brain itself. If we can cut that inflammation out and block CGRP from starting the inflammation, it can theoretically help the migraine attacks. However, it’s not always clear how something works or what is happening. For example, the CGRP medications have a long half-life (around a month), and once you’re at a steady state they should last quite a while in your system. We’ve had a number of patients where the medications stop working after a week or two. Theoretically, that shouldn’t happen! This tells me, there’s a lot we don’t know about why these work and why these don’t work. So, in short, there’s no absolute contraindication with immune deficiency, CVID, Lupus or Rheumatoid Arthritis that we know of yet, but we are monitoring it.
- What are your thoughts on lower doses for people who are very sensitive to meds in general?
I’m big on lower doses in general. The problem with these medications is that except for Aimovig we only have one dose available. Technically with Emgality you’re supposed to do two of the shots the first time (a loading dose), but I tend not to do that in case people are sensitive to it. I’d rather start low and take another month or two for it to work than risk side effects.
- What are your thoughts on the safety of CGRP medications for patients with faulty heart valves, congestive heart failure, stroke, thrombosis, or other cardiovascular conditions?
We don’t know conclusively, but so far this has not proven to be a problem. However, with stroke in particular, I think that in someone who is post-stroke or at high risk for stroke I would tend not to use these. I have seen reports of strokes in a few people, but this is out of 300-500K people, so it is likely to be fairly rare, but it’s a consideration. Also, in congestive heart failure or other cardiovascular conditions it’s a million dollar question! If someone has bad arteries in their heart or are high risk for heart attack, I have not been using these medications. In reality, we haven’t seen very much in the way of heart problems with the CGRPs, but that’s not that it can’t happen, or that it won’t happen in the future.
- Do you recommend a “wash-out” period for patients who are not experiencing success before they try a different CGRP medication? What about those who stop due to side effects?
Every doctor does this differently. I tend to wait 5 weeks after the last dose of CGRP. Some doctors are waiting two months or even longer, others are more cautious if the switch is due to side effects, and some are waiting one month and not worried about it. Clinically we have not seen a problem switching so far.
- Can these medications be used with other biologics?
There are some people with Rheumatoid Arthritis on Humira or Enbrel, or Multiple Sclerosis on monoclonal antibodies. We haven’t seen too much in terms of interactions with these, and theoretically they can be used together.
- Can they be used in combination with Xarelto or people who have blood factors that lead to coagulation problems?
Xarelto and Coumadin are blood thinners and there haven’t been contraindications yet. For those with blood factors, probably these drugs do not increase risk. However, we don’t know yet if there are going to be rare side effects emerging.
- Are the CGRP medications ok to take if you have a history of cancer?
In theory we haven’t seen a reason why they should be contraindicated.
- Are they contraindicated with a pituitary adenoma?
The CGRP inhibitors do get into the Pituitary, where all your crucial hormones are, particularly growth hormones in kids and the thyroid hormones, so these can be affected. So far there have not been studies done on this and that is an area of concern.
- Can we combine these with other drugs?
The good news with CGRPs is that there are no real drug interactions with all our oral drugs such as Inderal, Amitriptyline, and the Triptans. They also don’t hurt the big organs such as the liver or kidneys because they aren’t cleared through them but rather are metabolized through the lymphatic system.
- If someone is not responding to 70mg Aimovig have you had success by increasing it to 140mg?
A person isn’t getting much benefit on 70mg of Aimovig we would increase to 140mg. We used to have the 2-70mg injections, now this has now been replaced by the single 140mg injection which puts us at a little bit of a disadvantage because it limits our ability to prescribe 70mg every 2 weeks for those who stopped responding at the two week mark each month. That prescribing was off-label, and I’m not sure that even worked, but this option has now been taken away from us.
- We have heard reports of people responding to the medications and then the efficacy wearing off each month before the next dose. Have you seen that and why would that be?
These medications have long half lives in the body, taking around a month to be at 50%, so in theory they shouldn’t stop working once they have built up in the body. However, in some people they appear to work and then stop working after 2-3 weeks. This theoretically shouldn’t happen and just goes to emphasize that there is so much we don’t know yet. In general, when this happens we have not seen an increase in efficacy again and we tend to switch medications. However, bear in mind that there are a lot of triggers that come into play with migraine, so the change could also be impacted by things such as the weather, etc.
- What is your experience with people who initially respond but then stop after a few months?
In my studies, sometimes they stop working. I think that pretty much at the end of two months you can predict what is going to happen going forwards, but this is not always the case. Right now, we don’t know why certain people stop experiencing success after several months.
- How do we know whether someone is going to respond to the medication or not?
In my experience, the first two months generally give an indication for how people will respond going forwards. If someone has done really well they are probably going to continue doing well, and vice versa. However, this is not always the case. I like to give these medications two or three months, and I don’t think it’s necessary to wait 6 months to know. I’m studying any predictors of why people might have an excellent response vs non response – 0, 10 or 15% response. The only predictors out of the 20 items we looked at so far that seemed to predict poor response are daily opioid use and severe refectory headaches (severe generally meaning decades of headaches, multiple medical problems, central sensitization syndromes like fibromyalgia, and a history of treatment resistance). These patients are less likely to respond.
- Is it possible to have the CGRP stop the pain of migraine but not the other symptoms such as nausea, photophobia, etc.?
That can happen, just as with the triptans or any other medication.
- Have you seen success with traumatic brain injury, cervicogenic headache or occipital neuralgia?
I have not seen success in this area. In general, if patients have not had migrainous-type headaches, or if they have daily chronic headache without migraine features, these medications do not seem to work. The same is likely to be true for cervicogenic caused headaches and occipital neuralgia.
- Does it help body pain that comes with migraine?
If the body pain is associated with the migraine and happens during the migraine attack, often any drug that helps with the migraine will help the body pain also.
- Are you having any success with Hemiplegic migraine or basilar migraine?
Hemiplegic migraine causes severe neurologic deficits or problems usually on one side, coordination and visual problems, numbness, and weakness, lasting about 20-30 minutes. I tend to stay away from the CGRPs for these patients because I think the risk for stroke is too high. Hemiplegic migraine is tough to treat. Sometimes we use preventatives like Valproic, beta blockers, or amitriptyline which might cut down on the cortical spreading depression and the brain firing, as well as anti-convulsants such as verapamil. The two most commonly used medications for hemiplegic migraines appear to be Verapamil and Depakote. For basilar migraine I think there are more side effects possible, and in particular I worry about stroke, so I don’t tend to use these medications for basilar migraine even though it’s not officially contraindicated yet.
- Have you seen any success with people who have cluster headaches, either episodic or chronic?
We have had some luck with cluster headaches and Emgality in particular has some potential. Emgality was just FDA approved for preventive treatment of episodic cluster headaches. I had one chronic cluster patient go “off label” on Aimovig. He had a 50 year history of severe headaches every day and he’s had no headaches for 4 months on Aimovig which was amazing, since nothing else had worked!
- In those patients who are not super-responders but have some positive response, are you seeing increased efficacy at the six month mark or longer?
That can happen. Some people are better at 6 months than at 2 months.
- Are you seeing the same efficacy as seen in the trials, even though the side effect profile is very different?
The side effects profile is turning out to be very different than the studies and there are a lot of reasons for that. However, the effectiveness profile is around the same. In short, about 50% of people get about 50% relief or better. There’s a group of people (around 10-15%) who have an excellent response. Then there’s a group who get zero response. If you’re an excellent responder, it’s wonderful, but for those who have had severe refractory migraine for many years then even a 20-25% improvement can change your quality of life.
- What is the placebo effect and how much does this come into play?
The placebo effect comes into play quite a bit, but it tends to go away over time, often around 2-3 months. There’s also the “nocebo” effect which works in the opposite way. There’s also placebo by proxy where for example if a parent says a medication worked really well for them I’m more likely to give it to their 18 year old daughter – this isn’t just placebo by proxy, but there’s also a genetic component with parents and kids and drugs. This works vice versa so that if something was terrible for a parent I won’t give it to their child.
- Do these medications help with New Daily Persistent Headache (NDPH)?
This is always more severe and tougher to treat. The CGRPs could work if the new daily persistent headache has more of a migraine type component, however, if it’s just chronic daily headache: aching, hurting with no throbbing component or associated symptoms like sensitivity to light and sound, they are less likely to help.
- What about using them with Medication Overuse Headache (MOH)?
I think MOH is over diagnosed and poorly defined. A lot of people are designated with MOH or rebound headaches, but is it true? Many people may be using a lot of medication, but to prove that they have MOH from that medication is not easy to know; we have to take a careful history and take them off the medication to know for sure. It’s complicated and easy to confuse “medication overuse” with “medication overuse headache.” Over-diagnosing MOH stigmatizes people, especially when we don’t give them enough abortive medication and preventive medications have not helped. Only about 45% of people find a preventative that works long term and which they can tolerate. In short, the CGRPs can work even if you have MOH and even without stopping the other medications. They give us another tool that is invaluable.
- There is a lot of discussion about whether the injections should be taken every 28 days or once a month. In your experience and opinion is there a preferable way or is it ok to be flexible?
I think that it shouldn’t be a big problem which specific day you take it on within that range.
- Should we wean off after a year?
We used to do this with some drugs in the past and take what we call a “drug holiday” for a certain amount of time. However, with the CGRPs, there’s no evidence that this will help or is necessary. What I’m worried about are the long term side effects, because mostly what we have been talking about are the short term ones. We don’t know right now whether there will be serious long term side effects. There is some pretty decent data on Aimovig for 5-6 year usage, but it’s a very limited number of patients. The question is, over 10-20 years, and once we go over a million patients, what’s going to happen? We don’t know the answer to that. CGRP does a lot in the body, which is why I don’t want to use them in kids under age 18 or even 20 if we can really help it. We don’t know hormonally your long term issues. Hopefully we’ll get lucky and won’t have any serious long term issues, but that remains to be seen.
IN THE PIPELINE
- What are the differences between the three CGRP inhibitors currently approved and eptinezumab, the IV version expected to be approved early 2020?
The three that are out are subcutaneous injections. Alder has one expected to be approved early 2020 which is intravenous every 3 months. It’s a little stronger according to the data and it works reasonably well. In addition, it could work faster since the administration is different.
- What are the gepants?
The gepants, which are expected to start being FDA approved late 2019, are small molecule CGRP inhibitors. They do penetrate the blood brain barrier and so may have more side effects; however, they also have much shorter half-lives. They are mostly going to be used to abort or stop a headache in progress and the efficacy remains to be seen. The most important thing is that they don’t shrink the arteries, unlike the triptans, so someone at high risk for heart problems or stroke may be able to take them. It will probably be tried in people where triptans have not worked or who cannot take triptans.
- If the CGRP monoclonal antibodies aren’t working, are the gepants likely to work?
They work differently. They are both CGRP inhibitors but that doesn’t mean the gepants necessarily won’t work if the monoclonal antibodies don’t. What I have unfortunately seen from the studies on some of the gepants is that the effectiveness is relatively low so they are unlikely to be a huge miracle for anybody, however they may be worth trying. In addition to these, there is another medication expected to be approved by the end of 2019 called Lasmiditan. This is NOT a CGRP inhibitor and is more like a triptan but doesn’t affect the heart. Lasmiditan causes dizziness as well as other side effects, and may also not be as effective as the triptans, so unlikely to be any great miracle, but could provide a great option for those who can’t take triptans or who don’t respond to them.
- Can we combine the gepants with other drugs?
The small molecule gepants do go through the liver so we’re going to have to do liver tests.