For healthcare professionals
The following section is written for healthcare professionals that are interested in understanding the Rehaler System and treatment at a deeper level. We would love you talk to you if you have any questions, thoughts or ideas regarding our research or the Rehaler treatment. Please write use directly at tj@rehaler.com.
Quick overview
- 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).
- 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 SaO2 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 on 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 15 minutes before the headache. The device is used by breathing through it for 20 minutes at the beginning of the first aura or other warning symptoms.
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 3.5%, while retaining normal arterial oxygen saturation (SaO2), no matter how long the device is used.
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 practical, compact and safe.
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 has now been CE approved for sale without prescription, and a large clinical study is in preparation that will test the effect on several different types of migraine.
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.
Contraindications for Rehaler: Respiratory or cardiovascular disease, anemia, intracranial hypertension, past or current cerebral aneurysm, prior brain surgery. Because of current lack of group-specific clinical data, Rehaler should not be used by children, adolescents (< 18 years old), pregnant or breastfeeding women. Rehaler should not be used in airplanes or at altitudes of 2000 meters or more above sea level.
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):
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.
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.
In contrast to the previously known CO2-delivering devices, the Rehaler is superior by virtue of being simultaneously:
- 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.
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).
For a pilot study of limited scale, the results were remarkably strong and highly promising for future large scale studies:
- 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.
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:
- Increasing the cerebral oxygen supply and counteracting vasoconstriction
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).
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):
- 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
- Inhibition 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.
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).
Rehaler advantages
- Fast-acting: CO2-induced increases in CBF happen within 10 seconds of starting to breathe an increased CO2fraction and wash out of the body within a few minutes of ending the treatment. This fast onset of action enables early intervention in the vasoconstrictive phase 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.
Rehaler in practice
- The Rehaler units themselves. The Rehaler is a new type of drug-free “inhaler”. It weighs less than 10 grams and can easily fit in a pocket or purse, ready for use when an attack starts. The Rehaler’s green regulator allows the inspired CO2 level to be adjusted to suit the individual. For hygiene reasons the Rehaler should be discarded after an attack.
- The Rehaler Control Unit. This is a custom-built finger-tip pulse oximeter with bluetooth connection to the Rehaler App. The Control Unit monitors the oxygen saturation during use and alerts the user in the event that the CO2/air mixture ratio should be adjusted.
- The Rehaler treatment app which:
- teaches the patient to use the treatment, through video-based step-by-step tutorials.
- guides the patient in identifying the appropriate regulator setting for him/her.
- provides dynamic, personally tailored treatment advice after each attack, optimizing the timing, duration and dosage of the Rehaler treatment.
- A custom-designed nose clip, optimized for use with Rehaler. Each Rehaler package contains a nose clip.
The Rehaler and Control Unit are as default used for 20 minutes when the first signs of a developing attack appear. However, some patients have a good effect with only 10 minutes of treatment, while others may need 40 minutes or two 20-minute treatments to get the optimal effect. As shown in the clinical study, the treatment effect is likely to increase for each subsequent treated attack (Fuglsang 2018), as the patient learns the optimal timing and duration of treatment for him/her. The Rehaler App plays a crucial role in helping the patient in this optimization process.
Questions and general contact information
In addition, we are very happy to connect directly with clinicians, researchers and patients: For questions or feedback on the scientific or clinical aspects of the Rehaler treatment, professionals are encouraged to contact Rehaler’s CEO Troels Johansen at tj@rehaler.com.
References and links
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. & 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. & Geraud, G. 2008, "Posterior cerebral hypoperfusion in migraine without aura", 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