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Biohaven Follows Allergan in Announcing Positive Results for Rimegepant – an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine

By: Dr. Mauskop

26-03-2018

Last month Allergan reported that their oral CGRP receptor antagonist, ubrogepant was safe and effective in the acute treatment of migraine attacks (see my post). Today, results of a phase 3 trial of a similar drug, rimegepant were reported. Biohaven is the company developing rimegepant, which it licensed from Bristol-Myers Squibb. Rimegepant was shown to be about as effective as ubrogepant with very few side effects, confirming that one of more of these “gepants” will make it to the market. These drugs are expected to be approved some time in 2020.

One piece of information that was not initially released by Allergan is that 5 patients on ubrogepant developed liver function abnormalities on blood tests, compared to only 1 on placebo. None of the patients taking rimogepant had liver function abnormalities. This could spell trouble for the Allergan drug, as it did for the original Merck drug, telcagepant.

Both Allergan and Biohaven have additional oral CGRP antagonists in development for the preventive treatment of migraines.

Allergan Announces Positive Results for Ubrogepant – an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine

By: Dr. Mauskop

21-03-2018

Chronic migraine, Headache medications, Migraine, New treatments

The first of the four CGRP monoclonal antibodies developed for the prevention of migraines is expected to be approved by the FDA in the next 2-3 months. The other three should be approved within a year. All four will be given by an injection (three subcutaneously and one, intravenously).

Most people prefer tablets to injections and two companies are developing three drugs with the same mechanism of action as the monoclonal antibodies (blocking CGRP), but in a tablet form. The original CGRP drug in a tablet form was developed by Merck and it was very effective for the prevention and acute treatment of migraines, but a few patients developed liver side effects. The side effects were not serious, just abnormal blood tests, which returned to normal once the drug was stopped, but nevertheless Merck stopped the development of telcagepant in 2009. This led pharma companies to shift to the development of monoclonal antibodies, which bypass the liver, but can be given only by injection.

Allergan and Biohaven are two companies that are developing oral CGRP drugs in the hope that they can achieve good efficacy without the side effects. Allergan just released the results of the first phase 3 study of ubrogepant. The study included 1327 U.S. adult patients who were given placebo, ubrogepant 50 mg or 100 mg. They treated a single migraine attack of moderate to severe headache intensity. Both doses were significantly better than placebo in achieving pain freedom at 2 hours after the initial dose. Sensitivity to light, noise, and nausea also significantly improved with the drug, but not placebo. The side effect profile of ubrogepant was similar to placebo without serious liver problems.

Results of the second phase 3 trial are expected in the first half of 2018. Allergan plans to file these results with the FDA in 2019, after which the FDA has a year to review the data and will hopefully approve the drug.

More on intravenous ketamine for migraines

By: Dr. Mauskop

05-11-2017

Alternative Therapies, Headache medications, Migraine, New treatments

Ketamine is a medicine that is sometimes given intravenously for anesthesia. It is a controlled drug because it can induce euphoria and is potentially addictive. In a previous post I mentioned several anecdotal reports about the beneifical effect of ketamine for a prolonged migraine aura, hemiplegic migraine and other types of headaches.

A presentation at the recent annual meeting of the American Society of Anesthesiologists described the results of ketamine infusion on severe migraines in patients admitted to the Thomas Jefferson University Hospital in Philadelphia from 2014 to 2016. 48 of the 61 patients (77%) responded to this treatment, meaning that their pain levels improved by at least 2 points on a 1 to 10 scale. On average, the infusion had to be given for 5 days. Side effects included sedation (51%), blurry vision (38%), nausea or vomiting (38%), hallucinations (28%), vivid dreams (13%), and low blood pressure (5%). The authors described the adverse effects as mild in nature and only 1 patient discontinued treatment. However, having hallucinations, drop in blood pressure or vomiting does no sound like mild side effects to me. On the other hand, these were patients whose migraine did not respond to other treatments and they needed to be hospitalized, so these side effects could in fact be acceptable if the treatment ultimately provides relief.

Review of patient records admitted to the same hospital between 2006 and 2014 showed the mean headache pain rating using a 0-10 pain scale dropped from 7 on admission to 4 on discharge. The majority (55 out of 77, or 71%) of patients responded by the same definition of an at least 2-point improvement in headache pain at discharge. Only a quarter of responders maintained this benefit at their follow-up office visit. The mean length of infusion was also 5 days. And again, most patients tolerated ketamine well with “very few serious side effects”.

Anecdotal evidence also exists for the use of ketamine infusions to treat depression. There are some outpatient clinics that offer ketamine infusions for chronic pain and depression and a few of my patients have gone there, but unfortunately with little success.

Medication overuse (rebound) headache is a myth

By: Dr. Mauskop

18-09-2017

Headache medications, Science of Migraine

Caffeine and opioid (narcotic) drugs, if taken regularly, are proven to worsen headaches. This will not come as a surprise to anyone drinking large amounts of coffee – skipping your morning cup will leave you with a headache. Taking too much Excedrin, Fioricet, or Percocet will also make you want to take these drugs more and more often and with diminishing relief. However, most neurologists and headache specialists believe that triptans (sumatriptan, rizatriptan, et al.) and NSAIDs (naproxen, ibuprofen, et al.) can also cause “medication overuse headaches”. This remains a belief, rather than a scientific fact and it leads to thousands of headache sufferers being unfairly accused of causing or worsening their own headaches. They are being denied a safe and effective treatment that could relieve their suffering and reduce disability. My most popular blog post that so far has elicited 247 comments, is one on the daily use of triptans.

Drs. Ann Scher of Uniformed Services University, Paul Rizzoli and Elizabeth Loder of Brigham and Women’s Hospital have just published an article in a leading neurology journal, Neurology, entitled, Medication overuse headache. An entrenched idea in need of scrutiny. Last year I described a debate on this topic between Dr. Scher and Dr. Richard Lipton of the Montefiore Headache Clinic at the meeting of the American Headache Society. The abstract of this new article can be easily understood by the lay public, so I am including its full text.

“It is a widely accepted idea that medications taken to relieve acute headache pain can paradoxically worsen headache if used too often. This type of secondary headache is referred to as medication overuse headache (MOH); previously used terms include rebound headache and drug-induced headache. In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. A common recommendation is to limit treatment to no more than 10 or 15 days per month (depending on medication type) to prevent headache frequency progression. Medication withdrawal is often recommended as a first step in treatment of patients with very frequent headaches. Existing evidence, however, does not provide a strong basis for such causal claims about the relationship between medication use and frequent headache. Observational studies linking treatment patterns with headache frequency are by their nature confounded by indication. Medication withdrawal studies have mostly been uncontrolled and often have high dropout rates. Evaluation of this evidence suggests that only a minority of patients required to limit the use of symptomatic medication may benefit from treatment limitation. Similarly, only a minority of patients deemed to be overusing medications may benefit from withdrawal. These findings raise serious questions about the value of withholding or withdrawing symptom-relieving medications from people with frequent headaches solely to prevent or treat MOH. The benefits of doing so are smaller, and the harms larger, than currently recognized. The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.”

Triptans (like Imitrex) mix well with antidepressants

By: Dr. Mauskop

01-09-2017

Headache medications

Sumatriptan (Imitrex), rizatriptan (Maxalt) and the other 5 triptans work on serotonin receptors to stop a migraine attack. Many antidepressants, such as fluoxetine (Prozac), escitalopram (Lexapro), that belong to the SSRI family and venlafaxine (Effexor) and duloxetine (Cymbalta), that belong to the SNRI family of drugs also affect serotonin or its receptors. Because both triptans and antidepressants affect serotonin, it is understandable that there has been concern about the potential for serotonin-related side effects when these drugs are used together.

In 2006 the FDA released a warning, “Potentially Life-Threatening Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptan Medications.” Fortunately, this is the case of “fake news”. My colleague in Houston, Dr. Randy Evans under the Freedom of Information Act, requested all the data that the FDA used to issue this warning. He published an article on his findings and concluded that “The data do not support prohibiting the use of triptans with SSRIs or SNRIs.”

A new study presented at the 59th Annual Scientific Meeting of the American Headache Society confirmed Dr. Evans’ conclusion. Dr. Yulia Orlova and her colleagues at the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston conducted a population-based study using information on more than 6.5 million patients. Over a 14-year period, about 19,000 were prescribed both triptans and SSRI or SNRI antidepressants. Between 4 and 7 patients (0.02% to 0.04%) developed serotonin syndrome.

In most cases serotonin syndrome is mild and consists of shivering, sweating, and diarrhea. Only very rarely it can be life-threatening with high body temperature, agitation, and seizures.

This is an important issue because migraine is 2-3 times more common in those suffering from depression and anxiety, while depression and anxiety are 2-3 times more common in people with migraines. This means that millions of people suffer from both conditions. Most experts agree that combining SSRIs and SNRIs with triptans is very safe.

A similar issue is the prohibition on mixing different triptans within 24 hours. There is not a slightest shred of clinical or scientific evidence for this contraindication. Nevertheless, the FDA-approved label has this warning for every triptan.

Sumatriptan injections still underutilized. New lower dose, easy-to-use device could help

By: Dr. Mauskop

30-07-2017

Headache medications, injections, Migraine

Sumatriptan (Imitrex) injection was introduced 25 years ago, but it remains extremely underutilized. Of course, why would you inject yourself if a pill does the job. Unfortunately, for many migraine sufferers sumatriptan and other triptan tablets do not provide complete or fast enough relief. In many patients tablets do not work well because some wake up with a severe migraine, in some it starts very suddenly, and in others it is accompanied by nausea and vomiting. All these conditions require a quickly acting drug that bypasses the stomach. Zolmitriptan (Zomig) and sumatriptan nasal sprays or sumatriptan nasal powder (Onzetra) sometimes work well and quickly enough, but the gold standard in the abortive treatment of migraines (and cluster headaches) is sumatriptan injection.

Sumatriptan injection works within 10-15 minutes and often provides complete relief of the headache and associated symptoms – nausea, sensitivity to light and noise, and other. Because of a sudden surge in the sumatriptan level in the blood, side effects are more common than with tablets. These can include pins-and-needles like sensations, tightness in the neck or chest, or temporary worsening of the headache. These side effects last only 15-20 minutes and do not prevent most patients from using injections.

Sumatriptan injections were originally released only in a 6 mg dose. A few years later, 4 mg dose became available. Last year, a simple-to-use autoinjector with 3 mg of sumatriptan (Zembrace) was approved by the FDA. Studies presented at the recent annual meeting of the American Headache Society in Boston compared the efficacy of 3 mg and 6 mg injections. Surprisingly, they were equally effective and well tolerated. The manufacturer of the 3 mg auto-injector also compared their injection device with two older devices. Findings of this study were not a surprise – Zembrace was easier to use with fewer mistakes and faster preparation and administration. Zembrace requires only two steps – pulling off a cap and pressing the pen-like device against the thigh (and holding it pressed for 10 seconds). Also, of all auto-injectors Zembrace has the thinnest needle.

One potential difficulty is the insurance coverage. Since Zembrace is more expensive, the insurers may offer to pay only for the old type devices with 4 or 6 mg of sumatriptan. The manufacturer does offer discounts and coupons, which you can find online.

The bottom line, if you are not getting good relief of your migraine headaches, ask your doctor about sumatriptan injections. If you have tried injections in the past and did not like the side effects – check if the dose you tried was 6 mg and if yes, you may want to try 3 or 4 mg injections.

Sumatriptan injection is the only FDA-approved treatment for cluster headaches. Cluster headaches are very sudden and brief attacks of excruciating headaches that pills rarely have a chance to control.

Conflict of interest disclosure: last year Zembrace manufacturer paid me to participate in an advisory board meeting.

New information on cluster headaches

By: Dr. Mauskop

17-07-2017

Blocks, Botox, Cluster headaches, Headache medications

Cluster headache is one of the most painful conditions that has lead some patients call it a suicide headache. A new observational study done by researchers at the Eli Lilly company and Stanford University was presented at the recent annual scientific meeting of the American Headache Society.

Considering that cluster headaches are relatively rare, the major strength of this study is its size – 7589 patients. These patients were compared to over 30,000 control subjects without headaches. We’ve always known that cluster headaches are more common in men with previous studies indicating that male to female ratio is between 5:1 and 3:1. However, only 57% of patients in this new report were males. This does not reflect my experience – I see at least five times as many men as women. It is possible that I underdiagnose cluster headaches in women or the study used unreliable data. In fact, the study data was collected from insurance claims, so I suspect that the truth is closer to my experience and to the older published data.

The study did find that thoughts of suicide were 2.5 times more common in patients with cluster headaches compared to controls, while depression, anxiety and sleep disorders were twice as common. Cluster headache patients also were 3 times more likely to have drug dependence. The most commonly prescribed drugs were opiates (narcotics) in 41%, which partially explains high drug dependence rates, steroids, such as prednisone (34%), triptans, such as sumatriptan (32%), antidepressants (31%), NSAIDs (29%), epilepsy drugs (28%), blood pressure drugs, such as verapamil (27%), and benzodiazepines, such as Valium or Xanax (22%).

It is very unfortunate that over a period of one year only 30% of patients were prescribed drugs recommended for cluster headaches. We know that narcotics and benzodiazepine tranquilizers are not very effective and can lead to dependence and addiction. Drugs that are effective include a short course of steroids (prednisone), sumatriptan injections, blood pressure drug verapamil (often at a high dose), some epilepsy drugs and occasionally certain antidepressants. The report did not mention oxygen, which can stop individual attacks in up to 60% of cluster headache sufferers. Nerve blocks and to a lesser extent, Botox injections can also provide lasting relief. It is possible that the data on oxygen, nerve blocks and Botox was not available.

Opioid hydromorphone (Dilaudid) does not help migraine

By: Dr. Mauskop

26-06-2017

Headache medications, Migraine

Unfortunately, opioid hydromorphone (Dilaudid) is still administered to 25% of patients with an acute migraine visiting an ER. Benjamin Friedman and his colleagues at the Montefiore Medical Center in the Bronx compared the efficacy of 1 mg of intravenous hydromorphone with an intravenous nausea medicine, prochlorperazine (Compazine), 10 mg plus diphenhydramine (Benadryl), 25 mg.
They presented their findings last month at the annual meeting of the American Headache Society. The study was blinded, but a safety monitoring committee stopped it early because the results were so lopsided. Prochlorperazine with diphenhydramine was twice as effective (60%) as hydromorphone (31%) in stopping a migraine and in preventing it from coming back within 48 hours.
So, if you end up in an ER for your migraine, refuse hydromorphone (Dilaudid), meperidine (Demerol), or any other opioid (narcotic) medication. Here is my old post with drugs other than prochlorperazine that are also effective.

A new book for migraine sufferers and their families

By: Dr. Mauskop

14-06-2017

Alternative Therapies, Botox, Headache medications, Headaches

Searching on Amazon for books on migraines yields over 2,291 items. Do we need another book? Having just read the latest book on migraines, Understanding Your Migraines, the answer is a definite yes.

The book is written by two colleagues who for many years co-directed the Dartmouth Headache Clinic. Dr. Morris Levin is now the Director of the Headache Center and a Professor of Neurology at UCSF, while Dr. Thomas Ward is Professor of Neurology Emeritus at the Geiser School of Medicine at Dartmouth and the editor of the journal Headache. They are clearly highly qualified to write such a book, but qualifications are not enough – you need to be a good writer as well. And in fact, excellent writing style and case-based discussion are two of the major strengths of the book.

The book consists of 17 chapters, which cover diagnosis and our understanding of the underlying causes of this condition. What the readers will find most useful is the treatment approaches. Drs. Levin and Ward go into great detail about various non-drug options, including nutrition, exercise, meditation, acupressure, herbal products, vitamins and minerals. They also present pros and cons of various medications, nerve blocks and describe in detail the most effective and the safest preventive treatment for chronic migraines, Botox injections.

One chapter is devoted to specifics of migraines in pregnancy and another one to children and adolescents. The book also includes individual chapters on tension-type headaches, cluster and other less common headache types, and postconcussion headaches.

The authors also mention an exciting new treatment option, which we expect to be approved by the end of 2018. Four companies are racing to bring to the market CGRP monoclonal antibodies, which act like vaccines against migraines. A single injection will provide 1 to 3 months of relief with very few side effects. It is likely that this treatment will help about 60% of patients with both episodic and chronic migraines. Cluster headache patients might also benefit from these biologic drugs.

Reading so much information can make it difficult to understand how to actually use it and how to talk to your doctor about all these options. The authors successfully tackle this problem by providing many real-life cases and by including a chapter, How to Communicate with Your Medical Team.

I am sure that this book will help many migraine sufferers find relief. You can buy it on Amazon.

A new drug is approved for temporal arteritis, cause of headaches in those over 50

By: Dr. Mauskop

31-05-2017

Headache medications, Headaches, New treatments

Temporal arteritis occurs in one out of 5,000 people over 50. Women are 3-4 times more likely to be affected. It is not common below the age of 60 and becomes more prevalent with the advancing age. Temporal arteritis is also known as giant cell arteritis because it causes inflammation of arteries with giant cells seen under the microscope.

Headache is often the first symptom and it is typically localized to one temple, but it can involve other parts of the head and occur on both sides. If left undiagnosed and untreated temporal arteritis can cause a stroke and blindness, which can affect both eyes.

Besides headaches, temporal arteritis can cause neck and jaw pain, weakness, muscle aches, and a mild fever. The preliminary diagnosis is made by blood tests (ESR and CRP) and it is confirmed by a biopsy of the temporal artery. Polymyalgia rheumatica is a related rheumatological condition, which can occur alone or with temporal arteritis and it causes severe muscle pains.

Temporal arteritis (and polymyalgia rheumatica) are treated with steroid medications, such as prednisone. Although the initial dose is high, relatively small doses are usually effective for maintenance. Since the condition can last for years and long-term intake of prednisone can cause many potentially serious side effects it is very important to perform a temporal artery biopsy in most cases, rather than rely just on blood tests and clinical diagnosis.

Subcutaneous injection of Actemra (tocilizumab) was just approved by the FDA for the treatment of temporal arteritis. This drug has been available since 2010 for the treatment of rheumatoid and other forms of arthritis. Actemra was injected every two weeks for a year along with prednisone, but more patients were able to get off prednisone if they received Actemra rather than a placebo injection. Unfortunately Actemra also has potentially dangerous side effects, such as serious infections and it requires regular blood tests.

Because headache is one of the main symptoms of giant cell arteritis, the condition is often diagnosed by a neurologist or a primary care doctor. The treatment though is typically handled by a rheumatologist and they are already familiar with tocilizumab.

Low dose naltrexone (LDN) for pain

By: Dr. Mauskop

04-03-2017

Alternative Therapies, Headache medications, Pain

Naltrexone, along with naloxone are narcotic (opioid) antidotes, that is they counteract the effect of narcotics and are used to treat overdoses with heroin, fentanyl, Percocet, Vicodin, and other opioid drugs. Surprisingly, low doses of naltrexone (LDN) seem to be effective in treating pain. LDN has been also used to treat symptom in conditions such as depression, fibromyalgia, Crohn’s disease, multiple sclerosis, complex regional pain syndrome (which used to be called reflex sympathetic dystrophy), and autoimmune disorders.

Low dose naltrexone is not a typical pain killer, but may be helping pain by reducing inflammation. Instead of opioid receptors, it works on Toll-like receptor 4 (TLR4) receptors on glial cells. Glial cells surround the nerve cells and play important functions in the brain, beyond just a supporting role that had been assigned to them for many years. Opioid drugs are known to promote inflammation through the brain immune system leading to worsening of pain over time. Recent discoveries have shown that the Toll-like receptors are involved in triggering these inflammatory immune events. These discoveries have led many researchers to look at ways to block TLR4, but so far no such drug has been developed. We do have several existing medications that seem to block TLR4. Besides LDN, amitriptyline (Elavil) and cyclobenzaprine (Flexeril) are two other drugs that block TLR4 and that have been used for years to treat pain.

No large controlled studies of LDN for migraines, pain or any other condition have been conducted to date. Despite the fact that the evidence is only anecdotal and that LDN my work purely through the placebo effect, advantages of LDN are that it is inexpensive and safe. Naltrexone is available in 25 and 50 mg tablets, while the amount used for LDN is between 1.5 to 4.5 mg. This means that it can be obtained only from a compounding pharmacy. Naltrexone is not a controlled substance, but it does require a prescription from the doctor.

Blood pressure drugs prevent migraines but may cause depression

By: Dr. Mauskop

15-11-2016

Headache medications, Migraine

Beta blockers, such as propranolol (Inderal) and timolol (Blocadren) are the oldest drugs for the prevention of migraine headaches. They’ve been used for this indication for the past 50 years. Calcium channel blockers are not as effective and never received FDA approval, but are also used treat migraine headaches. Verapamil is more effective for the prevention of cluster headaches, but is not approved for this indication either. A third category of blood pressure drugs effective for the prevention of migraines are ACE receptor blockers (ARBs) such as candesartan (Atacand) and olmesartan (Benicar) and ACE inhibitors such as losartan (Cozaar).

Main side effects of these drugs tend to be related to lowering of blood pressure and include fatigue and dizziness. This is a major limitation of blood pressure medications when used in migraine sufferers because they tend to be young women with low blood pressure to begin with. Verapamil is also known to cause constipation.

Beta blockers and to a lesser extent calcium channel blockers, have long been reported to cause depression. A new study just published
in the journal Hypertension explored the association between blood pressure drugs and admission to to the hospital for mood disorders (depression and bipolar). The researchers examined a large hospital database of 525,046 patients with follow-up for 5 years. Patients on ACE inhibitors or ARBs had the lowest risk for mood disorder admissions, and compared with this group, those on beta blockers and calcium channel blockers showed higher risk, whereas those on no blood pressure medications and those on diuretics showed no significant difference. The authors concluded that calcium channel blockers and beta blockers may be associated with increased risk of admission for mood disorders, while ACE inhibitors and ARBs blockers may be associated with a decreased risk of mood disorders.

Migraine sufferers are at 2-3 higher risk of mood disorders even if they are not on blood pressure medications and we often see depression and anxiety in many of our patients. This study makes a strong argument for the use of ACE inhibitors and ARBs ahead of other blood pressure medications. Another advantage of these drugs is that they do not slow down the heart rate, which is the case with beta blockers. Slowing of the heart rate often interferes with the ability to exercise and exercise is probably the most effective preventive treatment for migraine headaches.

I should also mention that epilepsy drugs such as topiramate (Topamax) can also cause depression, even with suicidal thoughts. Besides blood pressure and epilepsy drugs, antidepressants is another category of drugs used for the prevention of migraines, but even these medications can sometimes cause or worsen depression. All drugs have other side effects as well and this is why we always advise starting with sleep hygiene, healthy diet, aerobic exercise, meditation, magnesium, and other supplements.

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Biohaven Follows Allergan in Announcing Positive Results for Rimegepant – an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine

Allergan Announces Positive Results for Ubrogepant – an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine

More on intravenous ketamine for migraines

Medication overuse (rebound) headache is a myth

Triptans (like Imitrex) mix well with antidepressants

Sumatriptan injections still underutilized. New lower dose, easy-to-use device could help

New information on cluster headaches

Opioid hydromorphone (Dilaudid) does not help migraine

A new book for migraine sufferers and their families

A new drug is approved for temporal arteritis, cause of headaches in those over 50

Low dose naltrexone (LDN) for pain

Blood pressure drugs prevent migraines but may cause depression

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