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CGRP Inhibitors May Offer Significant Benefits for Migraine Patients

Patients with migraine have a diverse set of options to prevent or manage acute or chronic attacks, but depending on a patients’ migraine-associated symptoms and potential adverse reactions to treatment, health care professionals may opt for other drug classes, medical devices, and methods of treatment delivery to help their patients manage the disease.

With the advent of calcitonin gene-related peptide (CGRP) inhibitors, which are either monoclonal antibodies or CGRP receptor agonists that block CGRP proteins in the head and neck, another treatment option has emerged for patients where other therapies have failed. Despite their cost, CGRP inhibitors may also be useful for patients who have costly side effects as a result of migraine-related treatments.

Migraine is characterized by severe headache pain that can last several hours to several days, and is usually focused on one side of the head. Prior to a migraine, up to one-third of people will have visual, sensory, motor, or verbal disturbances that signal the beginning of a migraine. During an attack, a person will have sensitivity to light, and attacks may also consist of gastrointestinal, cognitive, and vestibular symptoms. After a migraine attack, a person may feel dizzy, tired, or have difficulty concentrating.1

Migraines can be acute or episodic, or chronic in nature, and according to the International Headache Society, the diagnostic criteria for chronic migraine is 15 attacks or more per month.

“These are attacks that last for hours to a couple of days,” explained Stephanie J Nahas-Geiger, MD, a neurologist and assistant director of Jefferson University Hospital’s neurology residency program in Philadelphia. “The pain tends to have qualities such as pounding or throbbing in nature. Moderate to severe intensity tends to be more on one side of the head than the other, tends to be made worse by a physical activity or the presence of the attack causes the avoidance of physical activity.”

Epidemiology and burden of disease 

According to data from the Centers for Disease Control and Prevention, US Census Bureau, and the Arthritis Foundation, migraine is more common than asthma and diabetes combined, at 27.9 million individuals, and affects women three times more than men.3 Between 12% and 15% of the
population is estimated to be affected by migraine, and it is most common in younger people and in middle age, between 25 years and 55 years old.4

On an individual basis, migraine can have a school, work, and social burden. A study published in 2001 found over half of people who suffered from migraine attacks said their work and school productivity was affected, 76% said they were unable to do household chores or housework, 67% reported their household work productivity had declined by at least half, and 59% missed family or leisure activities.5

The actual cost of migraine burden on the economy is significant. It is estimated that between 3.2 days and 89.2 days (average, 10.2 days) of school and work are lost each year from migraine attacks. One study looking at the effects of migraine in children found that 10.6% of children who suffer from migraine attacks miss an average of 4.1 school days per year. When children or adults who experience migraine attacks do attend school, presenteeism is a huge issue that impacts productivity.6

Migraine attacks also have an interictal element, where patients may not be entirely asymptomatic following an attack, and may consciously or unconsciously avoid situations that could bring on a migraine attack. Patients may be also reluctant to tell family or their peers about their interictal symptoms: Results from a 2016 study showed 26% of patients with migraine had interictal symptoms, 10.6% had interictal anxiety, and 14.8% compromised their lifestyle to avoid potential migraine attacks.7 

“We need to focus not just on the attacks themselves, but the whole person with migraine and how they live with migraine on a day-to-day basis,” said Dr Nahas-Geiger. Overall, the total estimated unadjusted health care expenditure for migraine is $56.31 billion per year.1 

Treatment and Clinical Practice Guidelines 

Guidelines for the treatment of acute migraine recommend treatment options based on the severity of the disease.8 For mild or moderate migraine attacks, simple analgesics such as nonsteroidal anti-inflammatory drugs are recommended as first-line therapy. If a patient suffering from a migraine attack is severely nauseous or vomiting, oral or rectal antiemetic drugs such as metoclopramide, chlorpromazine and prochlorperazine are recommended.

Moderate to severe migraine attacks should be treated with oral triptans and combination sumatriptan-naproxen, with nonoral migraine-specific medications indicated for cases of nausea and vomiting such as subcutaneous sumatriptan, nasal sumatriptan and zolmitriptan, nonoral antiemetic agents, and ergotamine preparations such as parenteral dihydroergotamine. Migraine attacks that vary in severity, onset, and change with regard to nausea and vomiting require developing two or more options for patients to use in acute migraine cases with and without these complications, such as oral medication for situations without nausea and vomiting and nonoral medications for cases where nausea and vomiting are present. Guidelines from the American Headache Society suggest titrating up slowly from a low dose for oral medications, but clinicians should be aware that some newer medications may not need titration.9,10

In cases where patients with migraine present in an emergency room, many of the same treatment options are available, but health care providers should consider that the patient is likely presenting because they are having a severe attack and their usual self-administered migraine treatment has failed. In these situations, triptans, antiemetics, dihydroergotamine, and ketorolac are all reasonable options. However, opioids should only be used as a last resort, keeping in mind that some studies have shown that first-line opioids for treatment of migraine attacks result in a higher rate of return to the emergency department within 7 days.11

“It’s a short-term fix for a lot of folks,” said Dr Nahas-Geiger. “At some institutions, [clinicians] are going by their old guidelines or their old practices, and it can be hard to get the word out. It can be hard for people to change their ways. But things are improving.”

For preventive migraine, b–blockers such as metoprolol and propranolol, antidepressants such as amitriptyline and venlafaxine, and anticonvulsants such as valproate and topiramate are indicated by randomized controlled trials, with other nonpharm =acologic options such as cognitive behavioral therapy, and biofeedback having shown some evidence of benefit as well.

There has also been some evidence that neuromodulation is beneficial for patients in the treatment of acute and chronic migraine. Single-pulse transcranial magnetic stimulator was effective in treating migraine with aura in 201 patients in a sham trial, with “freedom from pain” after 2 hours and no pain within 2 days of treatment.12 “Most patients do tolerate it pretty well, and really, there are no side effects other than the sensation of the stimulation [that] some people perceive as painful and may also be distracting,” said Dr Nahas-Geiger.

In a trial using CEFALY Technology, transcutaneous supraorbital neurostimulator was shown to reduce migraine pain intensity in 109 patients, with -3.46 reduction in pain on the Visual Analog Scale compared with a sham group after a migraine attack that lasted 3 hours or more.13 

Similarly, in the PRESTO trial, 248 patients who underwent noninvasive vagus nerve stimulation compared with sham showed benefit and freedom from pain at 30 minutes.12 

Treatment Cost and Value Considerations 

In a study examining health care utilization and costs between migraine and nonmigraine patients, total health care costs for migraine patients was $11,010, which included inpatient, emergency room, total outpatient, and outpatient pharmacy costs compared with nonmigraine patients, who had health care costs of $4436. In the same study, migraine patients paid a total of $724 in prescription costs for acute medication and $142 for preventive medication.14

CGRP inhibitors are relatively new to the migraine treatment armamentarium, with the FDA approving erenumab, fremanezumab, and galcanezumab last year. Despite their high costs, estimated around $6900, CGRP inhibitors may be an option for some patients who have failed other treatment options.15 In 2018, the Institute for Clinical and Economic Review examined the effectiveness and value of CGRP inhibitors and found the treatment may be beneficial for patients previously treated with preventive therapy.16

“Some of us would argue that we now, for the first time, have well-tolerated, preventive treatments designed specifically for the disease,” said Dr Nahas-Geiger. “If you look at historical data from clinical trials and you establish numbers needed to treat vs numbers needed to harm, these drugs that we've been using to date actually don't have a very favorable ratio when you look at the number needed to treat vs number needed to harm because of their side effects, and some of these side effects can have costly consequences.” 

A patient receiving topiramate may have a higher risk for developing kidney stones, for example, which may result in indirect costs such as infection, hospitalization, reduced kidney function, and other associated costs like use of acute medication, reduced emergency department visits, less diagnostic testing, and imaging.

These adverse events may outweigh the costs of starting a patient on CGRP inhibitors, said Dr Nahas-Geiger. “Within the very first week we can see some dramatic reduction in migraine brain attacks on the burden of disease,” she said.

“It's not just the price tag of a medication, it's the potential of what that medication has to do in the future that we also have to consider,” said Dr Nahas-Geiger. 

 

References:
1. Ford JH, Ye W, Nichols RM, Foster SA, Nelson DR. Treatment patterns and predictors of costs among patients with migraine: evidence from the United States medical expenditure panel survey. J of Medical Econ. 2019. 22:(9),849-858. doi:10.1080/13696998.2019.1607358
2. American Headache Society. Chronic migraine diagnostic criteria. https://americanheadachesociety.org/wp-content/uploads/2018/05/AHSProfilesNotes7.pdf. Accessed October 8, 2019.
3. Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache. 1998;38(7):497-506. doi: 10.1046/j.1526-4610.1998.3807497.x 
4. Institute for Clinical and Economic Review. Draft scope—acute treatments for migraine, 2019. https://icer-review.org/wp-content/uploads/2019/06/ICER_Acute_Migraine_Draft_Scope_062819.pdf. Published June 28, 2019. Accessed October 8, 2019.  
5. Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657. doi: 10.1046/j.1526-4610.2001.041007646.x
6. Leonardi M, Raggi A. A narrative review on the burden of migraine: when the burden is the impact on people’s life. Headache. 2019;20(1):41.doi:10.1186/s10194-019-0993-0
7. Lampl C, Thomas H, Stovner LJ, et al. Interictal burden attributable to episodic headache: findings from the Eurolight project. J Headache Pain. 2016;17:9. doi:10.1186/s10194-016-0599-8
8. Smith J, Swanson J, Dashe J. Acute treatment of migraine in adults. https://www.uptodate.com/contents/acute-treatment-of-migraine-in-adults/print. Updated August 1, 2019. Accessed October 8, 2019. 
9. McCarthy LH, Cowan RP. Comparison of parenteral treatments of acute primary headache in a large academic emergency department cohort. Cephalalgia. 2015;35(9):807-815. doi: 10.1177/0333102414557703
10. American Headache Society. The American Headache Society Position Statement on Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59:(1):1-18. doi:10.1111/head.13456
11. Smith J, Swanson J, Dashe J. Preventive treatment of migraine in adults. https://www.uptodate.com/contents/preventive-treatment-of-migraine-in-adults/print?topicRef=3347&source=see_link. Updated August 1, 2019. Accessed October 8, 2019.
12. Tassorelli C, Grazzi L, de Tomasso M, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Neurology. 2018;91(4);e364-e373. doi:10.1212/WNL.0000000000005857
13. Chou D, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. Cephalalgia. 2018;39(1):3-14. doi:10.1177/0333102418811573
14. Bonafede M, Sapra S, Shah N, Tepper S, Cappell K, Desai P. Direct and indirect healthcare resource utilization and costs among migraine patients in the united states. Headache. 2018;58(5):700-714. doi:10.1111/head.13275
15. Garde D. Amgen’s new migraine drug will cost 30 percent less than Wall Street expected. Stat News. Published May 17, 2018. https://www.statnews.com/2018/05/17/amgen-migraine-drug-cost-wall-st/. Accessed October 8, 2019.
16. Institute for Clinical and Economic Review. Calcitonin Gene-Related Peptide (CGRP) Inhibitors as Preventive Treatments for Patients with Episodic or Chronic Migraine: Effectiveness and Value: draft evidence report. https://icer-review.org/wp-content/uploads/2017/11/ICER_Migraine_Draft_Report_041118.pdf. Published April 11, 2018. Accessed October 8, 2019.

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