Wednesday , June 16 2021

When you do not have time for pain



In July, Lipsitz initiated monthly injections of erenumab-aooe (Aimovig), one of the three new drugs targeting the signal of pain transmission, to the peptide related to the calcitonin gene (CGRP) or its receptor. Monoclonal antibodies, like that of their medication, work by blocking CGRP, the chemical involved in migraine.

"I see myself as my savior, my hope," she said. She had more days to feel good in three recent weeks than in the previous three years.

The treatment did not eliminate all the pain. Lipsitz was not able to wean other medications. But the new therapy returned much of what the migraines had taken, especially the time with her husband.


Avoiding migraines with CGRP antibodies opens a new world, Broner said. "It is the first time we have a medication developed specifically for the mechanism of migraine, which means that we are actually targeting the disease state itself."

For decades, doctors have treated migraines with therapies developed for other diseases, using blood pressure medication, anticonvulsants, antidepressants and even OnabotulinumtoxinA (Botox). Lipsitz was in all of them, finding some relief, but also reduced effectiveness over time, or side effects and fatigue. The nonsteroidal anti-inflammatory drugs she took for breakthrough pain gave her a bleeding ulcer and kidney damage.

The new drugs are unique because they not only prevent (as opposed to aborting) migraine attacks, they are also well tolerated.

"That's the key," said David Dodick, a Mayo Clinic neurologist and migraine specialist in Arizona. "If I give you something to take and it's effective, but you can not tolerate the side effects, you're going to stop it."

The recent change in migraine treatment comes from a shift in understanding of what causes them, he said. Migraine had already been considered a problem in the blood vessels. It was "really a nervous problem," he said.

Credit for understanding the role that CGRP plays in the brain depends largely on the Swedish researcher Lars Edvinsson, who started his work 30 years ago. At that time, he could not buy the peptide, so he built it by connecting pieces of 37 amino acids from the building "to Lego," he said.

In 1990, Edvinsson and a colleague, Peter Goadsby, sought out CGRP in patients during a migraine attack, collecting blood samples from the jugular vein, near the release point in the brain, instead of the arm where the levels are diluted. They showed that CGRP was the only neuropeptide released during the headache phase.

Some of the new antibody drugs – galcanezumab, (Emgality), fremanezumab (Ajovy) and eptinezumab, now in phase 3 clinical trials and administered as a quarterly infusion – target CGRP directly, while erenumab (Aimovig) targets the CGRP receptor, media by which the protein transmits pain. Blocking the receiver is like putting a chewing gum in a lock, Dodick said.

"You can not get the key anymore. You can not open the door," he said.

Because these drugs are proteins, they do not interact with other drugs in the liver or constrict blood vessels, considerations for patients taking other medications and one of the limiting aspects of triptans, the class of medications used to abort migraines considered a major breakthrough when they were introduced in the 1990s.

Still, not all people will respond to CGRP-related therapies. And while clinical trials show few side effects, large patient populations still need to be followed in long-range studies. CGRP is involved in other functions involving the heart and skin, and there is reason to still be cautious, Broner said.

"I'm not running and prescribing to everyone," she said. New drugs are also expensive, costing about $ 7,000 a year, not always covered by insurance. Tina Ansari, who reduced the frequency of her chronic migraines to 12 per month with Botox injections, added Aimovig to her regimen with a program designed to give patients up to 12 no-cost doses while seeking coverage approval.

"I'm not an experimental person," Ansari said. "But at this point in my life, I suffered for so long."

After two months in Aimovig, she had a migraine and her daily headaches are less painful, from "7 to 4".

"I can handle my children, I'm living my life, it's a game change," she said.

His three boys, 10, 12 and 14, have just started running 5K together. She hopes to be able to join them someday.

"If I could get to the point where I could run again, that would be incredible," she said.

Neurostimulation, which uses electrical stimulation to treat pain, also offers patients more options, especially with the development of non-invasive devices or less invasive procedures.

The techniques used to carry a "final implication," said Goadsby, a professor of neurology at King's College London and the University of California at San Francisco. But transcranial single-pulse stimulation, for example, that can prevent and treat an attack, is a portable device that patients use at home. Goadsby said options that do not have "disadvantages" are a valuable consideration for those most affected by migraine: women in their reproductive years, who have additional considerations about medications during pregnancy or breastfeeding.

These devices are also becoming more affordable on initial costs, said Peter Staats, founder of the Pain Medicine division of the Johns Hopkins Department of Anesthesia, which developed a portable non-invasive vagus nerve stimulator, GammaCore, approved last January to treat to migraine.

"We consider this a digital drug," he said. Doctors write a prescription and, if covered by insurance, the patient pays the copier. They receive a radio frequency identification card, much like the cards used to open hotel doors, which activates their device. Patients refill the card as needed, similar to filling a prescription.

"If it does not work, they have not bought something that will be expensive and will stay on the shelf," he said.

Robert Levy, president of the International Society for Neuromodulation and a neurosurgeon and researcher, said non-invasive therapies do not work for all patients. He is studying an individualized minimally invasive nerve stimulation model where patients experience pain, described as "the stimulus where the model hurts." Small wires are implanted under the skin of the scalp and connected to a battery similar to a pacemaker. The success rate of patients is much better than the stimulation that reaches just the back of the head, he said.

"It is extremely important to be able to offer patients both care and hope," he said.

The complexity of a migraine – driven by a combination of genes interacting with the environment – means that no treatment will work for everyone. More drugs are in the pipeline. What is significant now is that migraine has a specific treatment, no longer relegated to being a "mild disease," Goadsby said.

He recently wrote his first prescription for a drug against CGRP.

"It's strange to think of something for three decades and then pick up your pen and print it very carefully," he said. "It's surreal."

If his colleague Edvinsson had not been rejected by a neuroanatomy professor as a 20-year-old student, his collaboration with the CGRP might never have happened.

"Well, everything has already been figured out," said Edvinsson's teacher when he asked to help with the research.

Next semester, Edvinsson tried the department of histochemistry.

With the migraine, there was and still there is much to learn.


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