DR. DODICK: Welcome to this roundtable discussion entitled “Role of interventional therapies for migraine and headache: onabotulinum toxin A, stimulators, and nerve blocks.” Once a purely cognitive subspecialty, procedural clinics are today, I think, commonplace in headache medicine practices around the country, where injectable treatments and peripheral nerve stimulation have emerged as potentially viable tools in the management of patients with a variety of primary headache disorders. Today, we‘ve assembled a panel of international experts to discuss the role of extracranial nerve blocks, nerve stimulation, and onabotulinum toxin A in headache medicine.
My name is David Dodick. I‘m a Professor in the Department of Neurology at the Mayo Clinic in Phoenix, Arizona. On the line with me today are Drs. Sheena Aurora, Peter Goadsby, and Stephen Silberstein. Please take a moment to introduce yourselves and give your academic affiliations.
DR. AURORA: I‘m Sheena Aurora. I‘m a Clinical Associate Professor at Stanford University in California.
DR. GOADSBY: I‘m Peter Goadsby, and I am a Professor of Neurology, University of California, San Francisco.
DR. SILBERSTEIN: I am Stephen Silberstein, Professor of Neurology, Thomas Jefferson University in Philadelphia.
DR. DODICK: We‘ll start with a few questions about onabotulinum toxin A. Let‘s start with you, Dr. Aurora. We know that within the past 2 years, onabotulinum toxin A has been approved in the United States for the treatment of patients with migraine, who have more than 15 headache days per month. Can you tell us which patients should be considered for treatment with onabotulinum toxin A, and how should patients be counseled with regard to the expectations or results that they might experience?
DR. AURORA: In my opinion, any patient who has had a history of episodic migraine and then has headaches on more than 15 days a month or more than half the time, should be considered for onabotulinum toxin A, but practically, I think what happens is that our patients who have chronic migraines are placed on other oral prophylactic medications, which I think clinically is the practical first step because some of these older medications, although they lack class A evidence, are effective.
In my practice, when I see a patient who has had chronic migraines but already tried other medications, we consider him/her as candidates for onabotulinum toxin A therapy. Suppose a patient comes in who has not had an adequate trial with topiramate, we may choose to start them off with topiramate administration and if they have side effects or failed therapy, then we consider onabotulinum toxin A therapy.
DR. DODICK: So, you believe patients should probably fail one or more conventional oral preventative medications before being tried on onabotulinum toxin A?
DR. AURORA: I think therapy for most patients should be individualized. For example, if I see a patient who has depression, I don‘t think that he/she is a good candidate for beta-blockers because sometimes, this class of drugs can worsen depression. But, in general, if I see 10 patients, I would say that most patients have tried one drug or the other, or usually, I try one drug or the other on them, before I start onabotulinum toxin A administration.
DR. DODICK: Dr. Goadsby, the results of the clinical trials that have evaluated the effectiveness of onabotulinum toxin A for chronic migraine have not been without some controversy. In particular, some feel that the difference in the reduction of days with headache per month between the active and placebo groups was not clinically meaningful. What‘s your opinion on this and your assessment of the data?
DR. GOADSBY: When it is said that the reduction of a few days a month is not clinically meaningful, I think the statement belies a lack of understanding of what a clinical trial delivers. A clinical trial looks at the changes between treated groups, in this case, placebo and onabotulinum toxin. It looks at what one could call “herd response” in the cohort of people who received onabotulinum toxin and who, in this study, had somewhat less headache days than those who received the placebo.
Primary outcome data that summarize group responses are not clinically meaningful, useful, or actually applicable because we don‘t treat herds or groups, we treat individuals. The patient who you treat in front of you is either going to achieve a response that is satisfactory to them or not. So, from a clinical perspective, I find it more useful to use 50% or 75% responder rates to give patients an idea of their chances of reducing half or three-quarters of their headache days. I find that information easier to communicate, and I think it is fair to say it is clinically meaningful.
I think the controversy around the number of days reduced here conflates the issues of clinical significance versus economic significance. Is it valuable to society, broadly speaking, to reduce the number of days in the chronic headache population? I don‘t think that is necessarily a question well asked by physicians, particularly if they don‘t have health economics training. I think the controversy is simply a conflation between 2 related, but not equal issues.
DR. DODICK: Well that‘s a good segue; one of the points you made to this question is regarding cost effectiveness. Dr. Silberstein, onabotulinum toxin is an expensive therapy. Do you believe that it can be cost effective, and what can you tell clinicians about the status of reimbursement in clinical practice?
DR. SILBERSTEIN: Let me just comment on one more thing about what Dr. Goadsby said. I think the issue of clinical meaningfulness is different in a clinical trial and the patient population. In a clinical trial, we look at the herd response to show a difference from placebo. We‘re treating both responders and nonresponders. As Dr. Goadsby clearly said, in real life, we‘re treating individuals.
I‘ll give you a very simple example. Probably the only other reasonably large trial of responsiveness in the chronic migraine population that was done involved topiramate,1 and if you just look at the topiramate trials compared to the botulinum type A trials, response to botulinum toxin type A is superior in efficacy to that of topiramate. This is relevant because topiramate is one of the most commonly used drugs today for both migraines and chronic migraines.
DR. GOADSBY: If we go back for a moment to the triptans, I think most people who think about headaches, most neurologists, and probably physicians who practice would say that they were a spectacular step forward in the management of migraine. However, the 2-hour, pain-free rates of oral triptans are around 30%, which is hardly wonderful.
That‘s clinical trial data, and it‘s very solid clinical trial data. However, I think when you focus on just the clinical trial numbers, which are designed to prove the hypothesis in a population, and put them directly into a clinical practice, it is unhelpful. They‘re not designed that way, and so you can make cheap criticisms if you‘re not careful with the way you use the data. You could say 30% is quite a bad number, but that‘s 100 mg of sumatriptan, and it revolutionized practice.
DR. DODICK: Regarding the expense of this therapy, do you think it is cost effective, and what‘s the status of reimbursement for clinicians out there?
DR. SILBERSTEIN: I think it‘s clearly cost effective, and I think that most insurance carriers today, paradoxically, require that you fail preventive treatments with 2 drugs that have never been approved for a chronic migraine indication. If I wanted to use those drugs for off-label treatments, which they require, the carrier would probably deny it.
From the reimbursement point of view, you need to demonstrate that the patient has chronic migraines and, depending on the insurance carrier, that they have failed 2 or 3 different migraine preventive treatments. They may even require that they fail acute medications, which makes absolutely no sense. Then, the carrier will reimburse it.
We all have certain patients who have chronic intractable headaches. If they wind up in the emergency room for treatment and have a computed tomography scan and magnetic resonance imaging, it can cost more than it would to use onabotulinum toxin A for almost a year. If you determine the cost of this treatment for a year and how it relieves the headache burden and gets the patient back to daily life and work, I think it makes sense to use it.
One, you reduce the cost of neuroimaging. Two, you reduce the cost of emergency room visits. Three, you get the patient back to life, and the total healthcare costs is reduced.
DR. GOADSBY: Dr. Silberstein, about the third thing you said, ie, getting them back to life, unfortunately, insurers and payers worldwide and especially some physicians don‘t really see the value—they don‘t see the cost of the person sitting at home, life and activities ruined.
DR. SILBERSTEIN: Let‘s think about another disorder like multiple sclerosis, where the drug treatments are $20,000 to $40,000 a year. Depending on the cocktail, the benefits are minimal, and you‘re just prolonging the agony. The treatment will not reverse disability, yet people don‘t consider not paying for multiple sclerosis drugs, and the 4 of us have seen patients that have undergone magnetic resonance imaging for their migraines, come in with a few white spots, and start on multiple sclerosis drugs without any problems. Then, we want to treat them with botulinum toxin and cut the cost of the treatments by one-third or one-quarter, and yet we get resistance. That‘s the irony.
DR. AURORA: Yes, I also want to say that the Headache Impact Test (HIT-6) was one of the endpoints and has been shown to be validated as a measure for change that the therapy created, and there was a shift of more than 2.3 (score), which is clinically meaningful.
DR. DODICK: Dr. Aurora, can you just tell us again what HIT-6 is?
DR. AURORA: HIT-6 is a 6-item questionnaire that measures patients‘ ability to function. The questions are rated from 6.0 each, which is the minimum. So, the minimum HIT-6 is 36, and it can go up to 108. In the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies, most of the patients at baseline had an HIT-6 that was severe; on an average, the score was greater than 90. These patients in the placebo-control trials showed a difference in HIT-6 of greater than 2.3. HIT-6 takes into account how the patient is functioning.2
DR. DODICK: I have just 2 more brief questions and then we‘ll move onto another topic. You enlightened us, Dr. Aurora, on who the target patient population is. Can you tell us now, within that population, if there is anything about a particular patient that identifies them as being likely to respond or not respond to botulinum toxin?