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Science

Summary​

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  • Clinical studies have shown that by increasing the CO2 level and oxygen/energy supply to the brain, a large percentage of migraine attacks can be stopped or alleviated (Fuglsang 2018, Spierings 2005, Marcussen 1950, Dexter 1982).
     

  • Imaging studies show that cerebral hypoperfusion is the norm before and long into migraine with aura (MA) and possibly many migraine without aura (MO) attacks (Olesen 1990, Denuelle 2008), implicating hypoperfusion as a migraine trigger. Local tissue hypoxia (as will result from a pronounced hypoperfusion) reliably triggers MA and MO attacks in migraine patients (Arngrim 2016) and migraine-like headache in healthy individuals (Broessner 2016), as well as triggering Cortical Spreading Depression (CSD) in brain tissue (Ayata 2015).

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  • CO2 is a well-documented and strong cerebral vasodilator, increasing cerebral blood flow (CBF) by up to a factor of two (Claassen 2007). If normal oxygen saturation is retained, moderate, well-tolerated hypercapnia increases brain oxygen/glucose delivery by up to 50% or more (Johansen 2017).
     

  • CO2 significantly inhibits the release of Calcitonin Gene-Related Protein (CGRP) from trigeminal neurons (Vause 2007)
     

  • Hypercapnic acidosis inhibits Cortical Spreading Depression (CSD) (Tong 2000) and decreases neuronal excitability (Ruusuvuori 2014), by interaction of free protons with voltage-gated ion channels, GABAA receptors, acid-sensing ion channels, gap junctions, acid-sensitive K+ channels and NMDA receptors - the latter known to play an important role in the triggering of CSD (Pietrobon 2013).
     

  • Rehaler was from 2016-2017 tested in a randomized, double-blind, controlled clinical trial in migraine with aura (Fuglsang 2018), and further clinical studies are now in preparation.

Rehaler

 

Rehaler is a new type of drug-free device for treatment of migraine with aura. It is especially well suited for patients whose aura starts more than 10 minutes before the headache. The device is used by breathing through it from the beginning of the first aura symptoms and until the end of the aura (typically 15 to 20 minutes).

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Rehaler works through accurately balanced partial rebreathing, meaning that part of the expired air is captured and subsequently rebreathed together with a controlled amount of atmospheric air. The net effect is an increase of the inspired CO2 percentage to a stable, adjustable level between 1.5 and 3.0%, while retaining normal arterial oxygen saturation (SaO2), no matter how long the device is used.

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CO2’s efficacy in aborting migraine attacks has been known since 1950 (Marcussen 1950) but until now no CO2-delivering device has existed that was at the same time effective, practical, compact and safe.

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The Rehaler treatment was from 2016 to 2017 tested in a randomized, controlled, double-blind pilot study (Fuglsang 2018) that showed significantly higher pain relief and user satisfaction compared with placebo, and no adverse event were seen. On the basis of these positive results and the safety of the device it was CE approved in 2017, and a large clinical study is in preparation that will validate the treatment effect and pave the way for FDA approval and global commercialization.

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As a drug-free treatment, Rehaler can be used as an add-on to the patient’s normal medicine, or as an alternative for patients for whom pharmaceutical treatments are contraindicated, problematic or ineffective.

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CO2 treatment of migraine: earlier studies

 

Past clinical studies have shown that increasing inspired CO2 (in turn inducing moderate hypercapnia) is efficacious in aborting a high proportion of migraine attacks (Marcussen 1950, Dexter 1982, Spierings 2005) and post-spinal headaches (Sikh 1974):

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In a pioneering 1950 study, Harold Wolff and coworkers tested early-attack CO2 treatment of migraine with aura, using a 10% CO2 mixture from gas bottles. In the majority of attacks, aura symptoms were abolished and the expected headache did not occur (Marcussen 1950). However, pressure bottles are impractical, heavy, bulky and require refilling between treatments – a likely reason that this treatment option never came into clinical practice in spite of this early demonstration of its efficacy. In addition, the CO2 level used was so high that the treatment could only be used for a short duration.

Building on Wolff’s results, later migraine treatment studies used closed rebreathing bags to induce hypercapnia (Dexter 1982, Pradalier 1984). However, in such bags oxygen is quickly depleted, causing continually worsening – and potentially life-threatening – hypoxia if continued for too long. Even with the limitation of continually pausing the treatment to avoid hypoxia, the results were highly promising – the study by Dexter finding that the majority of treated attacks were aborted. However, the considerable risk of hypoxia precludes the use of this method in settings where the patient can’t be closely monitored.

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A 2005 controlled study by Spierings et al. tested migraine treatment by non-inhaled CO2, delivered locally in the nasal cavity with the aim of desensitizing the trigeminal nerve. The effect on pain freedom was statistically significantly superior to placebo (Spierings 2005), but the method has considerable limitations and drawback, among them the reliance on gas bottles and the requirement that the patient breathes in a very specific way during the treatment.

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In contrast to the previously known CO2-delivering devices, the Rehaler is superior by virtue of being simultaneously:

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  • Safe, since it does not incur hypoxia – no matter how long the device is used. In addition, the CO2 level achieved is moderate, adjustable and stable, allowing the patient to be in the correct treatment window for as long as needed.

  • Practical: because it does not use gas bottles, the Rehaler is very lightweight (10 grams) and compact (can easily fit in a pocket), and does not require refilling.

  • User-friendly: the user does not need to control his/her breathing in any particular way while using the device but can relax and breathe normally.

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The Capnomigra study

 

The Capnomigra study was the first clinical test of the Rehaler treatment for migraine. It was a randomized, controlled, double-blind pilot trial that included 11 patients with migraine with aura, treating for 20 minutes at the onset of aura and recording data subsequently. The study was conducted from 2016-2017 at the Headache Clinic at Aarhus University Hospital (Denmark), and the results were in August 2018 published in Cephalalgia – the highest-ranked headache journal (Fuglsang 2018, https://journals.sagepub.com/doi/10.1177/0333102418797285).

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For a pilot study of limited scale, the results were remarkably strong and highly promising for future large-scale studies:

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  • Pain relief percentage at two hours was statistically and clinically superior to placebo (p < 0.05), and notably increased with each use of the active device (first attack: 45%, second attack: 78%):

  • User satisfaction was superior to placebo at the 5% significance level, headache difference at two hours was superior at the 10% significance level, and all other migraine end points (0-3 scale) were on average superior to placebo (though due to the small sample size these differences were not statistically significant):

  • No adverse events or oxygen desaturations were seen.

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Mechanisms of action

 

In vivo and brain slice studies support the hypothesis that CO2’s efficacy in migraine is the result of the following mechanisms:

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  1. Increasing the cerebral oxygen supply, counteracting vasoconstriction and increasing washout rate

    It has been known since the late 1940’ies that CO2 is one of the most effective cerebral vasodilators, and by far the fastest-acting (Kety 1948, Madden 1993): raising inspired CO2 leads within only ten seconds to a very strong increase in cerebral blood flow (CBF). This immediately counteracts the cerebral vasoconstriction seen before migraine attacks and often far into the pain phase (Olesen 1990). By coupling this CO2-mediated vasodilation with a normal arterial oxygen level, Rehaler is able to increase the cerebral oxygen supply to the brain by 50% or more, defending against local brain tissue hypoxia (Johansen 2017, Fuglsang 2018). Such drops in the brain’s oxygen supply have recently been shown to be a very considerable migraine trigger (Arngrim 2016). The increase in CBF also significantly increase the clearance rate of migraine mediators released during CSD and implicated in perpetuation of CSD and down-stream activation of meningeal nociceptors, e.g. potassium, glutamate, nitric oxide and serotonin (Pietrobon and Moskowitz, 2013). 

  2. Inhibition of CGRP release, decrease of neuronal excitability

    Hypercapnia and the resulting moderate acidemia has been shown to reduce the excitability and sensitivity of neurons, by a number of mechanisms (Somjen 1998, Vause 2007, Ruusuvuori 2014), including increase of resting membrane potential, increase of firing threshold, decrease of impulse conduction velocity, inhibition of GABAA receptors, NMDA receptors and voltage-gated and acid-sensitive ion channels, and ihibition of Calcitonin Gene-Related Peptide (CGRP) release from neurons. CO2’s inhibition of CGRP release (Vause 2007) is especially interesting in the light of the recent focus on CGRP antagonist injections for migraine prophylaxis.

  3. Inhibition of Cortical Spreading Depression (CSD)

    Cerebral vasoconstriction (as seen before and during migraine attacks) carries a significant risk of local or global cerebral hypoxia. Neuronal hypoxia is known to induce and perpetuate Cortical Spreading Depression (CSD) (Ayata 2015, von Bornstädt 2015) – the migraine trigger phenomenon implicated in migraine with aura (MA) and a proportion of migraine without aura (MO). In vitro studies have shown that hypercapnia with normoxia (e.g. as induced by the Rehaler) markedly inhibits CSD triggering and propagation (Tong 2000, Tombaugh 1994).

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Rehaler advantages

 

Compared to pharmaceutical treatments, CO2 treatment in general has a number of advantages:

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  • Fast-acting: CO2-induced increases in CBF happen within 10 seconds of starting to breathe an increased CO2 fraction and wash out of the body within a few minutes of ending the treatment. This fast onset of action enables early intervention in the optimal treatment window during the early phases of the attack.

  • As a drug-free treatment, Rehaler can be used as an add-on to the patient’s normal medicine, or as an alternative for patients for whom pharmaceutical treatments are contraindicated, problematic or ineffective.

  • Rehaler avoids the common problem of oral medications being expelled by emesis before uptake through the gastric tract is complete.

  • There is no limit to how often the Rehaler treatment can be used (compared to a maximum of nine doses per month for the most common migraine prescription drugs)

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Questions and general contact information

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We are very happy to connect directly with clinicians, researchers, patients, journalists and investors, via email to Rehaler's CTO Troels Johansen: tj@rehaler.com

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References and links

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  • Arngrim, N., Schytz, H.W., Britze, J., Amin, F.M., Vestergaard, M.B., Hougaard, A., Wolfram, F., De Koning, P.J.H., Olsen, K.S., Secher, N.H., Larsson, H.B.W., Olesen, J. & Ashina, M. 2016, “Migraine induced by hypoxia: An MRI spectroscopy and angiography study”, Brain, vol. 139, no. 3, pp. 723-737. Link: https://www.ncbi.nlm.nih.gov/pubmed/26674653

  • Ayata, C. & Lauritzen, M. 2015, “Spreading depression, spreading depolarizations, and the cerebral vasculature”, Physiological Reviews, vol. 95, no. 3, pp. 953-993. Link: https://www.ncbi.nlm.nih.gov/pubmed/26133935

  • Broessner G, Rohregger J, Wille M, et al. Hypoxia triggers high-altitude headache with migraine features: A prospective trial. Cephalalgia 2016; 36: 765–771. Link: https://www.ncbi.nlm.nih.gov/pubmed/26487467

  • Claassen, J.A., Zhang, R., Fu, Q., Witkowski, S. &amp; Levine, B.D. 2007, “Transcranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing”, Journal of applied physiology (Bethesda, Md.: 1985), vol. 102, no. 3, pp. 870- 877. Link: https://www.ncbi.nlm.nih.gov/pubmed/17110510

  • Denuelle, M., Fabre, N., Payoux, P., Chollet, F. &amp; Geraud, G. 2008, &quot;Posterior cerebral hypoperfusion in migraine without aura&quot;, Cephalalgia, vol. 28, no. 8, pp. 856-862. Link: https://www.ncbi.nlm.nih.gov/pubmed/18513260

  • Dexter, S.L. 1982, “Rebreathing aborts migraine attacks”, British medical journal, vol. 284, no. 6312, pp. 312. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1495855/

  • Fuglsang, C.H., Johansen, T., Kaila, K., Kasch, H. & Bach, F.W. 2018, “Treatment of acute migraine by a partial rebreathing device: A randomized controlled pilot study”, Cephalalgia, vol. 38, no. 10, pp. 1632-1643. Link: https://journals.sagepub.com/doi/10.1177/0333102418797285

  • Johansen, T. 2017. “Pulmonary gas exchange and blood gas tensions: new frontiers in imaging, diagnosis and treatment”. Ph.D. Thesis. Department of Clinical Medicine. Aarhus University. Denmark. 

  • Kety, S.S. & Schmidt, C.F. 1948, “The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men”, The Journal of clinical investigation, vol. 27, no. 4, pp. 484-492. Link: https://www.jci.org/articles/view/101995

  • Madden, J.A. 1993, “The effect of carbon dioxide on cerebral arteries”, Pharmacology and Therapeutics, vol. 59, no. 2, pp. 229-250. Link: https://www.ncbi.nlm.nih.gov/pubmed/8278463

  • Marcussen, R.M. & Wolff, H.G. 1950, “Effects of carbon dioxide-oxygen mixtures given during preheadache phase of the migraine attack; further analysis of the pain mechanisms in headache.”, Archives of neurology and psychiatry, vol. 63, no. 1, pp. 42-51. Link: https://www.ncbi.nlm.nih.gov/pubmed/15408821

  • Pietrobon D and Moskowitz MA. “Pathophysiology of migraine”. Ann Rev Physiol 2013; 75: 365–391. Link: https://www.ncbi.nlm.nih.gov/pubmed/23190076

  • Olesen, J., Friberg, L., Skyhoj Olsen, T., Iversen, H.K., Lassen, N.A., Andersen, A.R. & Karle, A. 1990, “Timing and topography of cerebral blood flow, aura, and headache during migraine attacks”, Annals of Neurology, vol. 28, no. 6, pp. 791-798. Link: https://www.ncbi.nlm.nih.gov/pubmed/2285266

  • Pradalier, A., Baron, J.F., Dry, J. & Launay, J.M. 1984, “Trial treatment of migraine attack by rebreathing of expired air”, Presse médicale, vol. 13, no. 31, pp. 1901. Link: https://www.ncbi.nlm.nih.gov/pubmed/6237334

  • Ruusuvuori, E. & Kaila, K. 2014, “Carbonic anhydrases and brain pH in the control of neuronal excitability”, Sub-cellular biochemistry, vol. 75, pp. 271-290. Link: https://www.ncbi.nlm.nih.gov/pubmed/24146384

  • Sikh, S.S. & Agarwal, G. 1974, “Post spinal headache. A preliminary report on the effect of inhaled carbon dioxide”, Anaesthesia, vol. 29, no. 3, pp. 297-300. Link: https://www.ncbi.nlm.nih.gov/pubmed/4599151

  • Somjen, G.G. & Tombaugh, G.C. 1998, “pH modulation of neuronal excitability and central nervous system functions” in pH and Brain Function, eds. K. Kaila & B.R. Ransom, 1st edn, Wiley-Liss, pp. 373-393.

  • Spierings E. 2005, “Non-inhaled, intranasal carbon dioxide for the abortive treatment of migraine headache: efficacy, tolerability and safety”. 130th Annual meeting of the American Neurological Association 2005 September 27:S17.

  • Tombaugh, G.C. 1994, “Mild acidosis delays hypoxic spreading depression and improves neuronal recovery in hippocampal slices”, Journal of Neuroscience, vol. 14, no. 9, pp. 5635-5643. Link: https://www.ncbi.nlm.nih.gov/pubmed/8083759

  • Tong, C.K. & Chesler, M. 2000, “Modulation of spreading depression by changes in extracellular pH”, Journal of neurophysiology, vol. 84, no. 5, pp. 2449-2457. Link: https://www.ncbi.nlm.nih.gov/pubmed/11067987

  • Vause, C., Bowen, E., Spierings, E. & Durham, P. 2007, “Effect of carbon dioxide on calcitonin gene-related peptide secretion from trigeminal neurons”, Headache, vol. 47, no. 10, pp. 1385-1397. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138149/

  • von Bornstädt, D., Houben, T., Seidel, J.L., Zheng, Y., Dilekoz, E., Qin, T., Sandow, N., Kura, S., Eikermann-Haerter, K., Endres, M., Boas, D.A., Moskowitz, M.A., Lo, E.H., Dreier, J.P., Woitzik, J., Sakadži?, S. & Ayata, C. 2015, “Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations”, Neuron, vol. 85, no. 5, pp. 1117-1131. Link: https://www.ncbi.nlm.nih.gov/pubmed/25741731

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