Cohen A, Burns B & Goadsby PJ (2009) “High-Flow Oxygen for Treatment of Cluster Headache–A Randomized Trial” . JAMA 302(22):2451-2457. (Click author to see paper)
AUTHORS’ ABSTRACT: Cluster headache is an excruciatingly painful primary headache syndrome, with attacks of unilateral pain and cranial autonomic symptoms. The current licensed treatment for acute attacks is subcutaneous sumatriptan.
Objective: To ascertain whether high-flow inhaled oxygen was superior to placebo in the acute treatment of cluster headache.
Design, Setting, and Patients: A double-blind, randomized, placebo-controlled crossover trial of 109 adults (aged 18-70 years) with cluster headache as defined by the International Headache Society. Patients treated 4 headache episodes with high- flow inhaled oxygen or placebo, alternately. Patients were randomized to the order in which they received the active treatment or placebo. Patients were recruited and fol- lowed up between 2002 and 2007 at the National Hospital for Neurology and Neu- rosurgery, London, England.
Intervention Inhaled oxygen at 100%, 12 L/min, delivered by face mask, for 15 minutes at the start of an attack of cluster headache or high-flow air placebo deliv- ered alternately for 4 attacks.
Main Outcome Measures: The primary end point was to render the patient pain free, or in the absence of a diary to have adequate relief, at 15 minutes. Secondary end points included rendering the patient pain free at 30 minutes, reduction in pain up to 60 minutes, need for rescue medication 15 minutes after treatment, overall response to the treatment and overall functional disability, and effect on associated symptoms.
Results: Fifty-seven patients with episodic cluster headache and 19 with chronic clus- ter headache were available for the analysis. For the primary end point the difference between oxygen, 78% (95% confidence interval, 71%-85% for 150 attacks) and air, 20% (95% confidence interval, 14%-26%; for 148 attacks) was significant (Wald test, 25=66.7, P=.001). There were no important adverse events.
Conclusion: Treatment of patients with cluster headache at symptom onset using inhaled high-flow oxygen compared with placebo was more likely to result in being pain-free at 15 minutes.
Dr. Sewell’s comment:
In the last couple of months, there has been a spate of news articles about cluster headache. USA Weekend Magazine: “Oxygen may ease cluster headaches”; Personal Liberty Digest: “High-flow Oxygen Can Relieve Cluster Headaches, New Study Suggests”; Pain.com: “Oxygen Proves as Possible Treatment for Cluster Headaches”, and so on. Those of you have been using oxygen for years are no doubt bemused by this. New study shows that the Pope is Catholic? Will modern science next tell us what bears do in the woods? Just what is all the fuss about?
It is true that we have known for years that oxygen helps cluster headache. Lee Kudrow, the granddaddy of cluster headache research (a cluster headache researcher who coincidentally suffers from cluster headache himself), first reported this in 1981, and this treatment is now incorporated into standard guidelines. I myself have found it more effective than triptans, to the point that when someone tells me that oxygen doesn’t work for them, my first thought is that they either aren’t using a proper non-rebreather mask or else just haven’t turned the flow rate up high enough. Everyone knows that oxygen works.
But what exactly is the scientific evidence? Surprisingly, not much. Dr. Kudrow’s original observations, a small study of 19 patients published by Dr. Fogan of UCLA in 1985 confirmed them, and that’s it. In a way, oxygen is a victim of it’s own success—there are no randomized placebo-controlled trials showing that parachutes are effective in preventing death caused by jumping out of an airplane; it’s so obvious that nobody has bothered. And yet it matters—insurance companies love to call something an “experimental treatment” and deny coverage; the modern crop of doctors raised with “evidence-based medicine” like to see an evidence base for their medicine, and most cluster headache patients have found that getting oxygen therapy is more of a headache than the cluster attacks it’s supposed to treat.
Enter Dr. Anna Cohen, of the Headache Group at Queen Square, London. She is a member of Dr. Goadsby’s group, and I know that Dr. Goadsby has been going on about the need to formally study oxygen for years, so I’m not sure how much of this is her idea. The paper itself is beautifully written, however, one of the clearest scientific papers I’ve ever read, and I encourage readers of this blog to click on Cohen’s name at the top here and read it for yourselves; it almost doesn’t need my interpretation. For that, I’m sure Dr. Cohen deserves credit; it’s always the first author that does the actual writing.
So how did they do it? She took 109 cluster headache patients (episodic or chronic), and had each of them treat four cluster attacks with a tank of what was either pure oxygen or just room air, nobody was quite sure which until the study was over. The subjects used high-flow (12 L/min) for fifteen minutes, and if that didn’t work, they could use a “rescue medication”; what that was wasn’t listed but I presume it was Imitrex. Dr. Cohen was mostly interested in what proportion of people were pain-free (or had adequate relief) after 15 minutes, but also looked at whether subjects remained pain free at half an hour and one hour, whether other symptoms of a cluster attack (other than pain) were affected, and how many people needed rescue medication.
What did she find? At the fifteen-minute point, 78% of subjects who used oxygen were pain-free, versus only 20% of patients receiving room air. At the one-hour point, 95% of the oxygen users had reduced pain (meaning, 1 point or more decrease on a 4-point pain scale) versus 38% of air users. Only 30% of oxygen breathers needed “rescue medication” at the 15-minute point, versus 76% of the air breathers. 81% of the oxygen breathers also had less runny nose, droopy eye, etc (associated symptoms) versus 40% of the air breathers. It was a clear win for oxygen. Did it work any differently with chronic cluster headache patients than episodic? Here Dr. Cohen waffles a little bit, saying that only a fifth of the group had chronic cluster headache, and some of them had used oxygen before… but it appears to work just as well no matter what the subtype.
So finally, we have scientific proof that inhaled oxygen treats cluster headache! The 78% success rate is impressive, and privately I wonder if it could have been even higher if Dr. Cohen had cranked the flow rate up to, say, 15L/min. Oxygen is a great alternative for anyone who can’t take triptans, and is mercifully free of side effects. This study will help doctors and patients in their battles with insurance companies everywhere.
I was discussing oxygen with Dr. Kudrow at a meeting of the American Headache Association in Los Angeles a few years ago. “You know,” he mused, “a farmer came to me just after the War and told me that he was using oxygen from a welding tank in his barn to abort his cluster attacks. I dismissed it as nonsense. It was twenty years later that I realized he was right. I wish I’d paid attention then!” One wonders what else cluster headache patients are telling us that we’re not paying attention to!
I know that oxygen works.
However, I want a scientific explanation WHY it works.
There are lots of posts in the different cluster forums that claim, that the vasoconstricting effect of oxygen is the reason but from my understanding of the “rat paper” (Oxygen Inhibits Neuronal Activation in the Trigeminocervical Complex After Stimulation of Trigeminal Autonomic Reflex, But Not During Direct Dural Activation of Trigeminal Afferents, S Akerman, PR Holland, MP Lasalandra & PJ Goadsby. Headache (2009) 49: 1131-1143) and according to “Pathophysiology of trigeminal autonomic cephalalgias” (The Lancet Neurology, Volume 8, Issue 8, August 2009)
Quote: “Vasodilation of intracranial arteries ipsilateral to the pain is well documented during CH attacks and has been proposed as the pain source in CH.
However, intracranial vasodilation is not specific to CH as this vasodilation is also present in experimental forehead pain.
Moreover, attacks of CH pain can occur even if vasodilation is prevented by trigeminal sectioning.”
this can’t be the (only) reason.
We know that vasodilation (whether it be from exercise, alcohol, nitroglycerine or whatever) can trigger cluster attacks. And we know that oxygen can vasoconstrict. Therefore the assumption has always been that the vasoconstriction is what’s causing the therapeutic effect. Other drugs that vasoconstrict (ergot derivatives, for example, such as methysergide) are also helpful in cluster headache. Is the vasoconstriction enough to account for the effect? I’m not sure. Can you think of an experiment that would prove it?
Interesting discussion. Some (partly contradicting) quotes and thoughts: Dahl et al. have shown 1990, that cluster headache attacks provoked by nitroglycerine begin when the drug-induced vasodilation which starts immediately after drug administration, is receding. Latency periods are 30-60 min. The pain starts when the vasodilation goes? http://www.ncbi.nlm.nih.gov/pubmed/2113834
Please see also (free full text)
http://brain.oxfordjournals.org/cgi/reprint/120/2/283
Cerebral vasodilation can be caused by experimental trigeminal pain, hence the vasodilation is perhaps not the cause of cluster attacks, but just a symptom?
“Dilatation of cranial vessels is not specific to any particular headache syndrome but generic to cranial neurovascular activation, probably mediated by the trigeminoparasympathetic reflex.” http://www.ncbi.nlm.nih.gov/pubmed/11087776
“Nonvasconstrictor treatment of acute cluster headache is possible.”
http://www.ncbi.nlm.nih.gov/pubmed/15455406
Well, tonight we will probably not find an answer, perhaps tomorrow. Good night!
It’s true; when attacks are induced experimentally with nitroglycerine, it can take 40 minutes to an hour for the pain to begin; meanwhile everyone is standing around twiddling their thumbs. That’s why the discovery of the California Bay Laurel (see April 2nd post) is particularly exciting to us experimentalists.
Oxygen is an NO scavenger. Possible contribution to relief. Explanation to the rapid recurrence when in the maximum of the cycle.
How dangerous can oxygen be, especially if you set the flow too high? for instance a lung oedema?
I had WONDERFUL results two Excedrine Migraine and O2 @ 15 liters for approximately one and a half years. Then the results started to wane. A Cluster last Thursday took over six hours and over four E-Tanks to get it under control.
Are there any studies that anyone has heard about concerning PTSD and Cluster Headaches? I have found info that PTSD effects the Hypothalamus portion of the brain… And was told by Dr. Neil Raskin (UCSF- Neurology Headache Center) that Clusters come from the Hypothalamus.
So… PTSD + Hypothalamus = Cluster Headaches??
I need evidence to show the Veterans Administration.
Good luck to ALL, and Merry Christmas.
Hi Richard–
It’s a good question. A history of head injury with loss of consciousness will double your chances of having a cluster headache. I wasn’t able to find any studies on a link between PTSD and cluster headache. However, since I work at a VA hospital, I went through the VA database to see if I could find a link. Of the 2048 veterans with cluster headache who sought care at the VA in 2009, the odds that one of them has PTSD is 2.46 (95% confidence interval 2.33 to 2.60) compared to the 385,502 veterans who did not have cluster headache. Correlation does not imply causation, however–it’s not clear whether PTSD will increase your chances of having cluster headache, or whether cluster headache increases your chances of getting PTSD. However, this is the VA’s own data. Hope that helps!–Dr. Sewell
Dr. Sewell,
It has been almost a year since we have corresponded about ” PTSD + Hypothalamus = Cluster Headaches.”
I am currently being evaluated by the VA for PTSD, Depression, and Cluster Headaches. The Doctor I saw last week would NOT accept any correlation of PTSD effecting the Hypothalamus and CHA coming from the Hypothalamus.
Have you seen any more data showing that eluding to this?
Its like you read my mind! You seem to know so much about this, like you wrote the book in it or something. I think that you could do with some pics to drive the message home a little bit, but other than that, this is magnificent blog. An excellent read. I will definitely be back.
PTSD is more a problem with the amygdala than it is the hypothalamus, although the amygdala does project to the hypothalamus, so abnormality in one will affect the other (in this case, increased production of stress hormones that are triggered by hypothalamic activation). Some authors have suggested that patients with cluster headache can get PTSD from their cluster attacks. Nobody really thinks that PTSD causes cluster headache, though. That’s probably why your doctor was being stubborn. What’s your experience?
Do tell?
I firmly believe cluster headaches cause PTSD. If one gets a little break from them, it’s like looking over your shoulder to see if one is lurking; the least little twinge and you say oh no not again. (and yes, it is there again!)
My sympathy to our veterans with PTSD – their memories are far more ghastly…not that I downplay the pain of CH.
Thank you Dr. Sewell.
I precisely had to appreciate you again. I do not know the things I would have made to happen without the entire suggestions shared by you over such a topic. This was an absolute frustrating circumstance in my opinion, however , noticing this professional fashion you handled the issue made me to weep over fulfillment. I’m thankful for this guidance and as well , hope you really know what a great job you have been carrying out educating the mediocre ones with the aid of your websites. Most likely you’ve never met any of us.
My experience has been; Cluster Headaches maybe twice a year after returning from Vietnam. At first, I though they were REALLY BAD hangovers! Then, after leaving the Marine Corps, the frequency of the headaches increased over the years. Quarterly – then Monthly – Weekly – now, not only daily, but up to three times in a day. Sometimes, it’s at 5:30 am, then again at 5:30ish pm. I’ll get them in almost exact 12-hour periods. The MOST relief I’ve had in years, is three days in a row without one. Needless to say my life, as I knew it, is in ruins.
Your comment about the amygdala is the FIRST time I have heard of it in reference to CHA. Is this new data?
Doctor, I am NOT contesting your comment, I just need to understand. I need to know what’s happening to me, and if possible– Why.
Thank you so VERY much for your time Dr. Sewell. It IS appreciated.
Richard.
My first cluster headache occurred during internship. I had no idea what it was, so my initial experience was something like you describe, Richard.
I am a neurologist and can tell you the mainstream view in neurology is that there is no connection between CH and PTSD. There may be some association in the VA data, but there are many reasons why this might be that do not imply causation at all. I believe Dr. Sewell was referring to abnormalities in circuits involving the amygdala in PTSD, not CH.
I am not aware of any medical literature linking the two – although it is hard to say with the VA system – it is unlikely it would be considered service-connected in any way. It is much more likely an idiopathic condition, just like my CH.
From a practical perspective (if you don’t have other insurance resources) it is probably best to pursue the other service connected disabilities. Once you are considered by the VA system to be “service connected” you may be able to obtain treatment for other conditions such as the CH. This can be quite expensive if you have to use sumatriptan injections, and well worth trying to obtain coverage.
If you are not able to obtain coverage, some of the prophylactic medications used are very inexpensive, and welding oxygen rather than imitrex or medical oxygen can be used. You should discuss cost issues with your neurologist if you end up in that situation.
Good Luck
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