Effectiveness of Oxygen and Other Acute Treatments for Cluster Headache

Results From the Cluster Headache Questionnaire, an International Survey

Stuart M. Pearson, MA; Mark J. Burish, MD, PhD; Robert E. Shapiro, MD, PhD; Yuanqing Yan, PhD; Larry I. Schor, PhD


Headache. 2019;59(2):235-249. 

In This Article


This is the largest cluster headache survey performed to date with respect to number of respondents to investigate the effect of acute medications in cluster headache. Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects. However, respondents reported that it was difficult to obtain. Triptans also had a high rate of effectiveness but also had high rates of complications. Dihydroergotamine and cafergot/ergotamine had intermediate effectiveness and intermediate side effects, while intranasal capsaicin and intranasal lidocaine were easy to access with limited complications, but also limited effectiveness. This study is the first to investigate the effects of intranasal ketamine, opioids, and caffeine in a large sample. Intranasal ketamine has an intermediate rate of effectiveness and few side effects. It has primarily been used by our American respondents (31 of 40 from the United States, 7 of 40 from Canada, and 1 each from the United Kingdom and Spain). Opioids, in contrast, are completely ineffective in more than half of respondents, with only 1% finding them completely effective and 4% finding them very effective, and with physical, medical, psychological, and emotional complications reported in some respondents. This study does not differentiate between types of opioids, and it is not clear if 1 type may be more effective than another. Interestingly, caffeine and energy drinks did have some degree of effectiveness in the majority of respondents with low levels of complications. A recent study in Denmark showed that cluster headache subjects were more likely to drink energy drinks but not coffee compared to controls,[17] and energy drinks often have higher doses of caffeine. The effects of caffeine in our study were not collected systematically as they were obtained after the study from free text entries, but are interesting and require further examination.

When comparing the most commonly used medications, oxygen was more likely to be effective than opioids but not triptans. Oxygen was less likely to have complications than either opioids or triptans.

This study is also the first to investigate the effectiveness of acute medications in probable cluster headache in a large sample. Probable cluster headache may respond similarly to cluster headache, with triptans and oxygen having high levels of effectiveness. It should be noted, however, that the ICHD-3-beta Criterion E ("not better accounted for by another ICHD-3 diagnosis") was not included in this study, thus the definition of probable cluster headache requires meeting all but one of criteria A-D.

The effectiveness of oxygen for cluster headache attacks ranges between 56% and 82% across multiple controlled and open-label trials, as well as clinic and non-clinic based questionnaires.[8,18,19,20,21,22,23,24,25,26,27] This study is a non-clinic based questionnaire showing oxygen as completely effective in 13%, very effective in 41%, somewhat effective in 27%, minimally effective in 12%, and completely ineffective in 7%. This study adds to the current literature in several ways. First, this is a large international survey, and again confirms that oxygen is reported by respondents to be highly effective for cluster headache. Second, given the size of the study we are able to comment on a large subgroup of older respondents. Respondents 65 years and older, like other respondents, find oxygen to be highly effective with minimal complications. The older respondents generally replicated the responses of all respondents: oxygen and triptans were effective but difficult to obtain, with triptans having some complications and oxygen having few complications. Opioids had intermediate levels of effectiveness and high levels of complications.

As the study did not specify the oxygen flow rate or mask type, the results in this study may in fact underestimate the effectiveness of the guideline recommendations for oxygen 6-7 L/min or higher.[2,3] While oxygen is highly effective, it may not be the most effective treatment because all triptans were grouped together. Subcutaneous sumatriptan may be more effective than oxygen based on some previous questionnaires,[21,28] though a questionnaire that specifically compared oxygen >10 L/min to injectable sumatriptan found no difference in effectiveness.[27] Thus higher doses of oxygen at 10-15 L/min or more, which are used in clinical practice,[29] may be the most effective doses of oxygen. Similarly, cafergots and ergotamine were grouped together, as were all routes of administration for dihydroergotamine.

Previous studies have looked at factors associated with oxygen in an attempt to predict who might respond. Oxygen responsiveness has been positively associated with shorter attacks and a lack of interictal pain,[23] and negatively associated with photophobia or phonophobia during an attack,[30] nausea and vomiting during an attack,[26] or restlessness.[26] Previous studies have found conflicting results for associations with age,[18,23,26,27] sex,[18,23,31] and history of smoking.[23,26,27,30,32] Our findings show no association of responses to any acute therapies with any cranial autonomic features examined (rhinorrhea was not examined) and no association with restlessness, photophobia/phonophobia, nausea/vomiting, age (current age or age of onset of cluster headaches), sex, or any other feature examined. However, this study does find that respondents who respond to triptans are also more likely to respond to calcium channel blockers and steroids. While a subgroup of treatment-responsive patients may exist, another explanation is that these treatments all have the highest level recommendation in European guidelines[2] and thus it may not be surprising that patients respond to all of these medications. The current literature does not suggest a genetic subgroup of patients that respond to triptans, calcium channel blockers, and steroids: a report has linked the rs5443 polymorphism of the GNB3 gene to a positive triptan response in cluster headache, but this polymorphism was not related to verapamil or steroid response.[33] Our study had very few respondents that were completely refractory to all medications and our study did not collect information on cluster-like headaches as a result of intracranial lesions, carotid endarterectomies, or other disorders; therefore, we cannot comment on these aspects of cluster headache.

Recent studies have suggested that some treatments are more efficacious in episodic cluster headache than in chronic cluster headache, including 1 acute treatment (noninvasive vagal nerve stimulation[34,35]) and, in preliminary news releases, 2 preventive treatments (galcanezumab, fremanezumab[36,37]). Our study found that oxygen is significantly more effective in episodic cluster headache than chronic cluster headache, but there were no differences for other acute medications. The differential responses of vagal nerve simulation, galcanezumab, fremanezumab, and oxygen between episodic and chronic cluster headache require further investigation, as it is not clear what these 4 treatments share that is not shared by triptans, ergotamines, ketamine, capsaicin, caffeine and energy drinks, or lidocaine.

Most respondents were able to obtain all treatments in the study, but a higher percentage had difficulty obtaining oxygen. There is a variety of possible reasons. First, there are insurance barriers to obtaining oxygen. However, among US respondents 65 years or older, few were completely unable to get the medication; this could be because some respondents pay out of pocket for oxygen or have other types of insurance than Medicare. Further, respondents were not asked at what age they sought therapies, and some respondents may have obtained oxygen or other treatments prior to age 65 years. Physician barriers to access might also exist. In one previous study, 12% of providers refused to prescribe oxygen, and the respondents stated that the providers' reasoning was that either they did not think it would work (44%), they did not know about oxygen for cluster headache (32%), or they were not convinced by the medical literature on oxygen effectiveness (16%).[8] Another proposed medical concern of oxygen includes mucosal damage and thinning of the temporal retinal nerve fiber layer;[38] furthermore there is a proposed safety concern with a flammable gas in a disease with a high rate of smokers.[39] There are also logistical barriers, as one study found that less than half of prescriptions specified a flow rate or mask type, and half of patients never received proper training.[8] Finally, there may be patient preferences, as patients may simply not prefer oxygen because it is expensive or inconvenient.[24] Oxygen may take longer for full effect than other treatments[8] or the headaches may return when the oxygen is stopped.[18,22,40] This study does not investigate these concerns specifically. However, the study does suggest that oxygen has a lower rate of complications than other acute medications used for cluster headache.

There are several limitations to this study. First, this is a self-administered questionnaire with an inherent recall bias. Furthermore, questions about physical, medical, psychological, and emotional complications may be interpreted differently by different respondents. Second, the study did not confirm a diagnosis of cluster headache. Several questions related to the ICHD-3-beta criteria were asked in an attempt to increase accuracy; however, all ICHD-3-beta criteria were not included. There is significant symptomatic overlap between cluster headache and other headache disorders, in particular paroxysmal hemicrania and hemicrania continua. Both of these headache disorders are completely responsive to indomethacin, and this study did not inquire about indomethacin effectiveness. However, the population prevalence of these disorders is substantially less than cluster headache. Third, as the oxygen flow rate was not specified and all triptans were grouped together, the study may have misestimated the side effects and access to these medications. However, in clinical trials there were no serious adverse effects of oxygen at 12 L/min,[20] and in a study of different oxygen masks for cluster headache with oxygen at 15 L/min, all adverse events were determined to be unrelated to the study.[39] Also, oxygen may be easier to obtain at lower flow rates, and certain triptans may be easier to obtain than others. Fourth, this study did not include all recommended acute treatments for cluster headache, notably it did not ask about octreotide and did not have sufficient numbers of responses for sphenopalatine ganglion stimulation or vagus nerve stimulation. And finally, the study did not specify when respondents had tried various treatments: for some, treatment response may have changed over time; in the subgroup of patients over 65, some of the treatments likely had been tried before the age of 65 for some respondents.

In conclusion, oxygen is reported by survey respondents to be a highly effective treatment with few complications in cluster headache in a large international sample. When choosing among acute treatments, this study suggests that oxygen be considered first-line therapy for cluster headache patients regardless of age, as supported by recent clinical trials[20] and current guidelines.[2,3]