What a Headache!

Migraines are the most common cause of neurological disability in the world affecting nearly 15% of the global population. Some migraines initially present with prodromes or warning signs, which may include: Fatigue, euphoria, depression, irritability, food cravings, constipation, neck stiffness, increased yawning, and/or abnormal sensitivity to light, sound, and smell.² The prodrome phase is often followed by the aura phase. Auras are transient neurological pathologies that manifest as scintillating light and blurred field of vision and progress to loss of peripheral vision creating tunnel vision. Not all who suffer from migraines get auras, though prodromes are very common. The headache phase, the final phase, proceeds the aura when present, typically pulses; this increases intracranial pressure, and may present in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It may also be accompanied by abnormal skin sensitivity and muscle tenderness.²

Adding another layer to the difficulty of this disease is the fact that it can worsen over time as it transitions from acute to chronic manifestation. Multiple factors that contribute to this chronification are shown in Figure 1. Migraines should be viewed as a complex disorder with a strong genetic basis involving cortical, subcortical and brainstem regions that account for the pain and wide variation of symptoms¹. The extent and diversity of symptoms strongly suggest that migraines are more than just headaches. Treatment options are complex, broad, and often countercurrent with rational thinking; successful pharmacological treatment for one person, may be a trigger and detriment for another. The diversity in symptoms of migraines is reflected in the diversity of pharmacological treatments for them; and largely follow one of two paths: Prophylactic or therapeutic. Two of the most promising pharmacological treatments of migraines, Triptans and Onabotulinumtoxin A, will be discussed in more detail below.

Figure 1: Contributing Factors in Migraine Chronification (3)

                The Triptans, introduced nearly 30 years ago, are still considered the gold standard of migraine treatment. These drugs are selective serotonin receptor agonists, and because of their effectiveness have largely replaced older drugs in this category like the ergot derivatives. The Triptans are potent vasoconstrictors and are thought to target 5-HT1B/1D receptors (trigeminovascular afferents and trigeminal nucleus caudalis), to inhibit the release of neurotransmitters.⁴ The pharmacokinetic properties of the most prominent Triptans are shown in Figure 2. All of the drugs in this class are indicated for the acute treatment of mild to severe migraines that respond poorly to nonsteroidal anti-inflammatory drugs with or without the addition of additional analgesics, and mild to severe migraines in patients with contraindications, intolerance or hypersensitivity to other analgesics. Most Triptans are available in various formulations including: Subcutaneous injection, oral tablet, nasal spray, and oral dispersible tablet. The choice of formulation is determined by a number of patient factors that include headache features, side effect preference, convenience and cost. The single patient’s response to a Triptan cannot be predicted, but most show highest effectivity if they are taken at the very onset of the headache phase.⁴ All of the Triptans show similar side effects: Paresthesia, flushing, tingling of hands and feet, and mild, fleeting chest pressure. 1 in 1,000,000 patients experience cardiovascular complications of arrhythmia, stroke, and heart attack.

Figure 2: Pharmacokinetics of Triptans (4)

            Central and peripheral nerve sensitization occurs during the progression of migraines. This refers to the nerve response threshold decreasing and their response magnitude increasing. It stands to reason then – by paralyzing the muscle at the neuromuscular junction, one can mitigate some of the effects of migraines. That is precisely the mechanism behind the use of Botulinum neurotoxins (BoNTs). First used as a cosmetic enhancement to prevent wrinkles, BoNTs are now known to be effective in preventing migraines. BoNTs are produced by seven serotypes (A-G) of bacillus bacteria, Clostridium botulinum, and consist of a heavy chain and a light chain. The heavy chain facilitates the uptake of the whole molecule into the cytosol, and the light chain then cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex in the motor neurons.⁵ SNARE molecules are critical to this mechanism because they fuse synaptic vesicles containing neurotransmitters like acetylcholine with the pre-synaptic membrane; which results in the release of the neurotransmitter back into the pre-synaptic cell; without transmission to the post-synaptic cell, paralysis will occur. Onabotulinumtoxin A (onaBoNTA), approved by the FDA in 2010, represents the only agent specifically approved for the prevention of chronic migraines. In addition to modulating the function of motor neurons, uptake of onaBoNTA in sensory neurons that innervate the skin and muscles is thought to inhibit the release of inflammatory mediators at several sites within the sensory neuron.⁵ OnaBoNTA is administered in accordance with the PREEMPT regimen at 12-week intervals. 31 sites across frontal, temporal, occipital and neck muscles are injected with 5 units per injection, totaling 155 units; the injection scheme can be seen in Figure 3. A Botox unit is a measure of a defined amount of biological activity and corresponds to a fixed number of botulinum toxin molecules. 

Figure 3: Injection Sites for OnaBoNTA (9)

  Migraines are highly heterogeneous, and their treatment should be tailored to the individual patient. The variability in migraine etiology informs the numerous pharmacological treatments; Triptans and OnaBoNTA only scratch the surface of available options. After explaining the diagnosis, the provider should encourage the patient to actively participate in assessing his/her lifestyle and behaviors; diet, sleep, stress and exercise, may all contribute to the individual’s condition and subsequent response to pharmaceutical intervention.

References

1.      Puledda, Francesca et al. “An update on migraine: current understanding and future directions.” Journal of neurology vol. 264,9 (2017): 2031-2039. doi:10.1007/s00415-017-8434-y

2.      Burstein, Rami et al. “Migraine: multiple processes, complex pathophysiology.” The Journal of neuroscience : the official journal of the Society for Neuroscience vol. 35,17 (2015): 6619-29. doi:10.1523/JNEUROSCI.0373-15.2015

3.      May, Arne, and Laura H. Schulte. “Chronic Migraine: Risk Factors, Mechanisms and Treatment.” Nature News, Nature Publishing Group, 8 July 2016, https://www.nature.com/articles/nrneurol.2016.93.

4.       Antonaci, Fabio et al. “Recent advances in migraine therapy.” SpringerPlus vol. 5 637. 17 May. 2016, doi:10.1186/s40064-016-2211-8

5.      Gooriah, Rubesh, and Fayyaz Ahmed. “OnabotulinumtoxinA for chronic migraine: a critical appraisal.” Therapeutics and clinical risk management vol. 11 1003-13. 29 Jun. 2015, doi:10.2147/TCRM.S76964

6.      Silberstein, Stephen D., et al. “OnabotulinumtoxinA for Treatment of Chronic Migraine: PREEMPT 24-Week Pooled Subgroup Analysis of Patients Who Had Acute Headache Medication Overuse at Baseline.” Journal of the Neurological Sciences, vol. 331, no. 1-2, 2013, pp. 48–56., doi:10.1016/j.jns.2013.05.003.

7.      Goadsby, Peter J et al. “Pathophysiology of Migraine: A Disorder of Sensory Processing.” Physiological reviews vol. 97,2 (2017): 553-622. doi:10.1152/physrev.00034.2015

8.      Akerman, Simon, et al. “Current and Novel Insights into the Neurophysiology of Migraine and Its Implications for Therapeutics.” Pharmacology & Therapeutics, vol. 172, 2017, pp. 151–170., doi:10.1016/j.pharmthera.2016.12.005.

9.      “Botox For Migraine.” MigrainePal, 21 Jan. 2019, https://migrainepal.com/botox-for-migraine/.

10.  Sutherland, Heidi G., et al. “Advances in Genetics of Migraine.” The Journal of Headache and Pain, vol. 20, no. 1, 2019, doi:10.1186/s10194-019-1017-9.

By Danny Craig, A Master’s of Medical Science Student at the University of Kentucky