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 types of migraine, including migraine with and without aura, chronic migraine and menstrual 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.
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:
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:
Based on the Capnomigra study’s significant and highly promising results, preparations and fundraising have now started for a large-scale clinical trial, including migraine with and without aura, chronic migraine and menstrual migraine; a major part of the proceeds from the current initial market introduction of Rehaler will be allocated for that purpose.
In vivo and in vitro studies support the hypothesis that CO2’s efficacy in migraine is the result of the following mechanisms:
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 (Fuglsang 2018). Such drops in the brain’s oxygen supply have recently been shown to be a very considerable migraine trigger (Arngrim 2016).
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):
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.
Cerebral vasoconstriction (as seen before and during migraine attacks) carries a significant risk of local 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).
Compared to pharmaceutical treatments, CO2 treatment in general has a number of advantages:
The Rehaler treatment consists of the following components:
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.
The Rehaler Starter Kit contains everything needed to start using the treatment. It can be ordered online via www.rehaler.de, where patients and professionals can also read more about the treatment and the science behind it.
Rehaler is developed and produced by the Danish medtech company BalancAir which was founded in 2009 and is headquartered at the Science Park of the Technical University of Denmark, Copenhagen.
DTU Science Park
2800 Kongens Lyngby
The Rehaler website at rehaler.com contains information about the treatment and its scientific background, and the Rehaler Starter Kit can be bought directly through the online store on the website.
The scientific article about the clinical study on Rehaler can be found at https://journals.sagepub.com/doi/10.1177/0333102418797285
In addition, we are very happy to connect directly with clinicians, researchers and patients:
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
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
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
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