The Evolving Treatment Paradigm for Migraine: An Interview With Timothy R. Smith, MD, RPh (Part 2 of 2)

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Timothy R. Smith, MD, RPh, is president and chief executive officer of StudyMetrix Research. He is a fellow of the American College of Physicians and the American Headache Society, a certified physician investigator of the Academy of Clinical Research Professionals, and vice president of the National Headache Foundation. Dr Smith has a special interest in patient and physician issues related to the treatment of headache in primary care. This is part 2 of an interview conducted by an editor from The American Journal of Managed Care®.

The American Journal of Managed Care® (AJMC):

What are the options for acute migraine management? How do you select among the available options for an individual patient?

Timothy R. Smith, MD, RPh: The gold standard for acute migraine management is the triptan class of drugs. In my opinion, triptans are what we should be using for most patients. There are several options, and most are available in generic versions.

The use of triptans in acute migraine management is well established. That said, many patients may be able to mitigate their migraine pain with simple nonsteroidal anti-inflammatories [NSAIDs] or even combination analgesics that they can buy over the counter.

The US Headache Consortium guidelines suggest that patients who don’t respond to NSAIDs or simple analgesics should go to triptans unless they have contraindications such as cardiovascular disease or complicated migraine. The use of triptans during pregnancy is controversial. Many of the triptans have been studied and approved in adolescent populations down to 12 years of age.

Ergots may still have a role. Dihydroergotamine is available in a nasal spray version or it can also be given as an injection or intravenous infusion. Compared with other options, ergots have more side effect issues if used chronically.

What’s the role of opioid-containing combination analgesics or butalbital-containing combination analgesics? I think the consensus is that those medications should be used sparingly or not at all for migraine, and in my experience, we would reserve those kinds of treatments for rescue treatment. And then lastly, sometimes it’s good for migraine sufferers to have an anti-nausea medication on hand.

I think patients with migraine do best with a toolkit approach where they would leverage different treatments and delivery methods to manage their symptoms. They might start with NSAIDs and then go to an oral triptan if that doesn’t work. Or they may need an injectable or nasal spray triptan on standby, for backup. Additionally, some patients may require anti-nausea medications or suppositories if their gastrointestinal symptoms are severe. Then, as a last resort opioids or other combination analgesics may be attempted as rescue to try and keep patients out of the emergency room.


Patients often manage their migraines by self-medicating with a combination of over-the-counter and prescription medications. How common is medication overuse and what are the potential consequences?

Smith: Sometimes this specter of medication overuse headache can come into play. As it turns out, analgesics induce ultrastructural changes in the brain that make it more likely that a headache will come back, and that’s where you get into this medication overuse headache phenomenon. We used to call this “rebound headache.” Now the official name is “medication overuse headache.”

Over time, what happens is that the peaks of migraine activity and headache pain become more and more frequent and patients have less down time in between, and it may evolve to the point that patients always have low-level pain and they’re constantly taking medication. They find that if they don’t take any medication, their headache pain gets worse. They’re stuck in a cycle, and breaking that cycle is very difficult.

The best treatment for medication overuse headache is to prevent it from starting in the first place. And we should start having these conversations with our patients early on. If you see those analgesic or opioid doses escalating or those refill calls increasing and their medication use is escalating, that’s a sign of a potential problem, and we should address that as early as we can to try to either prevent or correct medication overuse headache.


When do you recommend preventive medication? Are there specific clinical criteria? For example, a certain number of headache days per month or severity of pain?


Smith: It’s a judgment call, but we consider patients with 4 or more migraine days per month to be prevention eligible. Not everyone who has 4 migraine days per month needs to be on a preventive medication. For example, if a patient has 1 migraine per week, they take 600 milligrams of ibuprofen, the headache is gone in 2 hours and their life is unencumbered otherwise, their quality of life is normal, that patient doesn’t need preventive medication.

Clinicians should look at the overall picture of migraine frequency, severity, disability, and medication use. By evaluating those 4 parameters, they can make a judgment regarding preventive medications. If a patient is using acute, abortive therapies of any kind, over-the-counter plus prescription, if they’re using those 2 days a week or more with regularity, that patient should probably be on prophylaxis of some sort.


How do you select among the available preventive medication options for an individual patient?

Smith: When you look at the available options from a pharmacotherapeutic standpoint, entry-level treatments would be beta-blockers, tricyclic antidepressants, and anti-epilepsy drugs. Examples of beta-blockers are propranolol and atenolol. In my opinion, any beta-blocker could be potentially helpful. Start a beta-blocker with a low dose and build up; if the patient can’t tolerate it, then go to something else. Divalproex and topiramate are also used for episodic migraine. Again, start with low doses and titrate up. Divalproex has to be used with caution or avoided in women of childbearing potential due to the potential for birth defects.

The 2 most commonly used tricyclics are amitriptyline and nortriptyline. They’re usually well tolerated in low doses, but patients may develop side effects when they start increasing the dose, so sometimes that’s the limitation.

Other medications that are sometimes used are ACE [angiotensin-converting enzyme] inhibitors such as lisinopril and one of the ARB [angiotensin receptor blocker] drugs, candesartan. The evidence for using these medications is quite good.

OnabotulinumtoxinA is FDA approved for chronic migraine only, so that’s 15 migraine days or more per month, and we would use that as a later intervention for patients who don’t respond to the entry-level drugs.

Lastly, we have the new anti-CGRP [calcitonin gene-related peptide] monoclonal antibodies. There are 3 of them that are FDA approved and on the market [at the time of this interview]. They are approved for both episodic and chronic migraine. The efficacy and safety data from the clinical trials on this group of medications is very good, and many thousands of patients have been successfully treated since they have been approved by the FDA.

For most patients, it is best to start with an entry-level treatment like a tricyclic antidepressant, beta-blocker, or anti-epilepsy drug. Usually we would try 1 or 2 options, and if the patient doesn’t tolerate these drugs or doesn’t get benefit from them, then the use of a higher-end product like the CGRP monoclonal antibodies would certainly be in order.


How do the anti-CGRP agents differ from other preventive medications?

Smith: CGRP was identified as the principal central nervous system protein that causes perivascular inflammation, debilitation, and enhanced pain transmission through the trigeminal vascular system for many patients with migraine. If you block CGRP, you can take away all of that, and among patients [for whom] CGRP is the driver of their migraine, these anti-CGRP agents can be highly effective.

These are the first drugs specifically developed for migraine prophylaxis. To see the anti-CGRP agents on the market and to see the profound impact of effective treatment on patients’ lives has been very gratifying.

There are very few contraindications with the anti-CGRP monoclonal antibodies. The only contraindication is hypersensitivity reaction to the compound. We don’t use them in pregnancy because we don’t have any data on that. Also, they’re not approved in children age 17 and under.

Anti-CGRP agents are metabolized through the reticuloendothelial system, so you don’t have to worry about renal or hepatic metabolism. There are no drug interactions, and safety and tolerability are excellent across the board.


What are some of the potential adverse events with the anti-CGRP agents, and how common are they?

Smith: There have been cases of hypersensitivity reactions—for example, patients may experience urticaria or bronchospasm. These hypersensitivity reactions occur in a very small percentage of patients—less than 1% for all 3 of the marketed products. Anaphylaxis is rare but has been reported.

As far as other side effects, the only one that has been reported across the board and with higher frequency than with placebo is injection site reactions—pain, redness, and bruising at the injection site. These are typically mild, and these occurred at a rate that differed from placebo by just a few percentage points. Almost no one in the clinical trial programs discontinued because of injection site reactions.

Besides injection site reactions, constipation is the only other adverse event in the erenumab trials that occurred in more than 2% of patients and where the incidence differed from placebo. In the double-blind, placebo-controlled portion of the erenumab studies, the 140-milligram dose of erenumab had an incidence of constipation of 3%, and in the placebo arm and the 70-milligram arm the rate was 1%. Notably, constipation seemed to be less of an issue over time. In long-term, open-label extensions, patients continued treatment for up to 3 years, and constipation was not among the commonly reported adverse events.

It is possible that patients dropped out of the study because of constipation, or they learned how to treat it, or perhaps they just stopped reporting it. However, constipation did not seem to be a big issue over the long haul.


How important is it to initiate preventative medication in a timely fashion? What are some of the complications that patients may experience due to delays in initiating preventive medication?

Smith: I think timely initiation of prophylaxis agents is very important because the longer patients go with uncontrolled migraine, the more likely they are to undergo a chronification process. Their condition transforms into something more chronic, and they may wind up developing chronic daily headache problems.

If you can intervene earlier and try to prevent migraine, I think you can stop that escalation and keep these people from becoming more and more disabled and having their lives disrupted. So, for me that’s the big problem with delaying implementation of preventive medication.


From your standpoint, how do managed care policies affect patient access to treatment or preventative medications?

Smith: In my area, the commercial payers are generally paying for the higher-end treatments. We mentioned onabotulinumtoxinA earlier in the interview. Once it was approved for chronic migraine, there was a complicated prior authorization process that most payers implemented. It was predicated on ensuring that patients have chronic migraine, and that would be 15 days or more per month. And then, once the patient has initiated treatment with onabotulinumtoxinA, we have to ensure that they are getting a significant reduction in migraine days. So, we would have patients keep a diary of their migraine days, and if we could demonstrate that they improved, then the insurance companies would continue to cover the treatment. And that still pretty much goes on today. I think a lot of headache clinics and neurology clinics have learned how to manage that prior authorization process, and the patients have learned that that’s just part of the way that we go forward.

Switching to other treatments, with the CGRP monoclonal antibodies, the Institute for Clinical and Economic Review reviewed this class just as erenumab was being marketed [in May 2018], and they gave it a favorable rating in terms of cost-effectiveness. So, I think a lot of people were happy with that. I think that most providers, most patients, and even most payers are happy with the value that the CGRP monoclonal antibodies bring to this difficult-to-treat population.

We have heard of restrictions—for example, that only neurologists can prescribe the CGRP monoclonal antibodies, or only UCNS [United Council for Neurologic Subspecialties] certified headache specialists can prescribe it. There are only about 600 of those specialists in the country, so that didn’t seem like a reasonable restriction. I haven’t seen this in my region of the country, but I work with the National Headache Foundation and we have a large patient constituency, some members of which have reported some of these anecdotes.

Hopefully what we will see going forward is more acceptance of these treatments for patients who have 4 or more migraine days per month and who have failed 1 or sometimes 2 first-line drugs and have a significant level of disability. But I think most commercial insurance plans are not having a problem approving these.


What can we look forward to within the next 5 to 10 years?

Smith: Looking down the road 5 years from now, I think the CGRP angle has potential to be transformative in the way that we think about and treat migraine, and I think that all these different interventions—neuromodulation, CGRP blockade, interventions currently in development—I think that all of these are going to have a transformative role.

I think that 5 to 10 years from now, the healthcare community will look at migraine completely differently than they have for the past several decades. I think this is going to change the way that we think about patients with migraine and certainly how we treat them. This is an exciting time, especially for me as a migraine researcher.