Research on Headache

The initials “CGRP” stand for calcitonin gene-related peptide. It is known to be one of those responsible for the activation of the trigeminovascular system, implicated in the genesis of cephalalgia. Through its action on its receptor, it is responsible for multiple actions at the pain system level, with the most important being: vasodilation, release of neurotransmitters (glutamate, substance P), generation of nitric oxide, increase in neuronal excitability, peripheral and central sensitisation. At an experimental level, it has been shown that CGRP levels in peripheral blood increase during migraine attacks and cluster headaches, and return to normal when they abate. Patients with chronic migraine have CGRP levels three times higher than healthy patients, and two times higher than those with episodic migraine.

• Gepants. These appeared in 2009 as a new therapeutic class, being the first group of drugs developed against CGRP, and are being studied as an acute treatment for migraine attacks. They act by blocking the CGRP receptor. The first to be developed, Olcegepant and Telcagepant, demonstrated an efficacy similar to the triptans, but unlike these, they had no vasoconstrictor effect, meaning that they could be a suitable treatment for patients with cardiovascular risk factors and migraine. However, the clinical trials were stopped due to the appearance of liver toxicity. New molecules, such as ubrogepant and rimegepant that do not have this potential secondary effect are currently in development.
• Monoclonal antibodies against CGRP or its receptor. They appeared in 2014 and form the pharmacological group that has advanced most, since it is envisaged that the first of them can probably be prescribed during 2019. Given that they are molecules with a long half-life, they do not have an immediate analgesic effect, but the preventive levels in episodic migraine, chronic migraine, and cluster headaches, have been investigated. It includes four drugs: erenumab, fremanezumab, eptinezumab, and galcanezumab. The first two phase III clinical trials have recently been published in the scientific journal New England Journal of Medicine, demonstrating sustained clinical effectiveness against the placebo in the reduction in the number of migraine days in a month. Significant improvements have also been observed on the impact of the migraine on disability and quality of life in comparison with the placebo. And all of this, with no more serious or significant secondary effects than the placebo. Extension studies are currently in progress to evaluate what happens if the treatment is extended for 5 years. They are rapid-onset of action drugs that take approximately one week, and this makes them different from other preventive drugs, in which their effectiveness starts in between two and four weeks. They are administered subcutaneously (three of them) and intravenously (one of them), monthly or three-monthly, and are generally well-tolerated. They do not cure the illness and are not a vaccine, but they act at a preventive level by reducing the frequency and intensity of the headache. In general, the migraine has decreased between 1 and 3 days per month. However, 15-26% of patients were completely free of pain during the study. The efficacy of the antibodies is similar to other products already on the market. However, more direct comparison studies need to be performed to be able to confirm this.

Lasmiditan. It is a drug that acts as a serotonin receptor agonist and is being studied for the acute treatment of migraine. It is a drug that is showing to be effective and well-tolerated, and it could be an option for patients with migraine in whom triptans may be contraindicated due to their vasoconstrictor effect. The most common adverse events that occurred in a phase III trial with lasmiditan were dizziness, pins and needles (paraesthesia), drowsiness, fatigue, nausea, and lethargy.

Neuromodulation:

• Non-invasive. The non-invasive neuromodulation techniques use devices that are applied in contact with the skin surface and could become an option for patients that cannot tolerate the side-effects of oral medications. But the current scientific evidence is insufficient and more studies are needed that can ensure the efficacy of these devices, which seem safe and relatively useful in the majority of trials currently available.
• Invasive. Invasive neuromodulation consists in the introduction of small electrodes around the deepest target structures (occipital and sphenopalatine stimulator), and should be reserved for patients in whom no effect was obtained with oral treatments, botulin toxin, or non-invasive neuromodulation. It is currently carried out in specialised centres in tertiary hospitals, on very selective patients, and has numerous secondary effects (infections, migration of the electrode, etc.); therefore they are not routine procedures.