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Effectiveness of medication in cluster headache

Authors:
  • Headache Center Frankfurt

Abstract and Figures

Background The aim of this work is to analyze the reports on cluster headache attacks collected online in the citizen science project CLUE with respect to the effectiveness of drugs taken during the attacks. The collection of data within the framework of citizen science projects opens up the possibility of investigating the effectiveness of acute medication on the basis of a large number of individual attacks instead of a simple survey of patients. Methods Data from 8369 cluster headache attacks, containing information about acute medication taken and the assessment of its effect, were collected from 133 participants using an online platform and a smartphone app. Chi-square tests were used to investigate whether the effect of the three recommended acute drugs differs when distinguishing between participants with chronic or episodic cluster headache. Furthermore, it was investigated whether there are differences between smokers and non-smokers in the assessment of the effect of the acute medication. Results Our participants rated the effectiveness of sumatriptan 6 mg s.c. as significantly better than oxygen and zolmitriptan nasal spray. Oxygen is considered to be significantly better in episodic versus chronic cluster headache, and sumatriptan is considered to be significantly better in chronic versus episodic cluster headache. Smokers rate the effect of oxygen as significantly better than non-smokers. Conclusions Despite some methodological limitations, web-based data collection is able to support findings from clinical trials in a real world setting about effectiveness of acute cluster headache treatment in several situations.
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R E S E A R C H A R T I C L E Open Access
Effectiveness of medication in cluster
headache
Johannes Drescher
1,2
, Andreas Khouri
1
, Tina Katharina Amann
1
, Charly Gaul
3
, Peter Kropp
2
, Yannic Siebenhaar
1
and
Jörg Scheidt
1*
Abstract
Background: The aim of this work is to analyze the reports on cluster headache attacks collected online in the
citizen science project CLUE with respect to the effectiveness of drugs taken during the attacks. The collection of
data within the framework of citizen science projects opens up the possibility of investigating the effectiveness of
acute medication on the basis of a large number of individual attacks instead of a simple survey of patients.
Methods: Data from 8369 cluster headache attacks, containing information about acute medication taken and the
assessment of its effect, were collected from 133 participants using an online platform and a smartphone app. Chi-
square tests were used to investigate whether the effect of the three recommended acute drugs differs when
distinguishing between participants with chronic or episodic cluster headache. Furthermore, it was investigated
whether there are differences between smokers and non-smokers in the assessment of the effect of the acute
medication.
Results: Our participants rated the effectiveness of sumatriptan 6 mg s.c. as significantly better than oxygen and
zolmitriptan nasal spray. Oxygen is considered to be significantly better in episodic versus chronic cluster headache,
and sumatriptan is considered to be significantly better in chronic versus episodic cluster headache. Smokers rate
the effect of oxygen as significantly better than non-smokers.
Conclusions: Despite some methodological limitations, web-based data collection is able to support findings from
clinical trials in a real world setting about effectiveness of acute cluster headache treatment in several situations.
Keywords: Cluster headache, Acute medication, Effectiveness, Citizen science
Background
Patients suffering from cluster headaches experience the
most intense pain of all primary headache disorders [1,2].
Some randomized clinical trials investigated the effect-
iveness of different acute treatments. The effect of suma-
triptan 6 mg s.c [3], .zolmitriptan 5 mg nasal spray [4]
and the inhalation of pure oxygen [5] was demonstrated.
Further studies also distinguished between chronic
and episodic cluster headache [68] and investigated
whether there are differences between smokers and non-
smokers [9]. This is of interest because there are signifi-
cantly more smokers than nonsmokers among cluster
headache patients than in the general population [10].
The purpose of this work is the analysis of cluster head-
ache attack reports collected online in the citizen science
project CLUE (https://cluster.kopfschmerz-radar.de/)with
respect to the effect of drugs taken during the attacks. The
CLUE project targeted cluster headache patients in
German-speaking countries (Germany, Switzerland,
Austria). No restriction on the age of the participants was
given. The acquisition of participants was mainly done by
communications of the cluster headache self-help groups
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: jscheidt@acm.org
1
Institute of Information Systems, University of Applied Sciences Hof, Hof,
Germany
Full list of author information is available at the end of the article
Drescher et al. BMC Neurology (2021) 21:174
https://doi.org/10.1186/s12883-021-02195-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
to their members. The cluster headache self-help groups
are organized in the Bundesverband der
Clusterkopfschmerz-Selbsthilfe-Gruppen (CSG) e.V.
(https://www.clusterkopf.de). This umbrella organization
informed its members about the project.
This approach offers the possibility to verify those
findings and their clinical impact in a real-world setting
based on patientsdaily observations.
The collection of medical data via the web offers the
possibility to collect a larger amount of data for a longer
period of time in a larger region compared to other
studies. However, we are aware of the shortcomings of
this approach and will discuss these in detail.
Methods
The CLUE project
The CLUE project has been collecting data regarding
cluster headache attacks using a web app as well as a
smartphone app since March 2018. For data analysis, all
data are anonymized. Participants can register in the
project at any time and then start reporting their cluster
headache. During the registration process, participants
are informed about privacy issues. With their registra-
tion, they give their consent to participate.
The study was approved by the Ethics Committee of
the Medical Faculty of the University of Rostock (refer-
ence number A 20170091).
Study design
The purpose of the prospective study was to examine
the effect of drugs taken during cluster headache attacks.
The aim was to investigate whether there are differences
in drug effectiveness between participants with chronic
and episodic cluster headache. Furthermore, differences
in effectiveness between smokers and non-smokers were
to be investigated.
Participants
Between March 21, 2018 and June 25, 2020, 315
German-speaking participants mainly from Austria,
Germany and Switzerland registered in the project and
reported their attacks. The reported attacks had to have
occurred within the specified time period, they could be
reported subsequently by July 5, 2020 at the latest. The
diagnosis of cluster headache was performed using a
headache questionnaire, which covers the diagnostic cri-
teria of the International Headache Society (Inter-
national Classification of Headache Disorders, ICHD-3
(beta version), 2). Participants with neither episodic nor
chronic cluster headache were excluded. 282 participants
remained in the sample. Table 1shows the frequency
with which the required symptoms were reported by
these 282 participants.
In addition, the Fagerström test was used to determine
the nicotine dependence of smokers [11,12]. We deter-
mined the length of the participation period in the pro-
ject as the difference between the dates of the first and
the last attack reported by the participant plus one. We
included participants in the study if they participated for
at least 10 days and reported at least 6 cluster headache
attacks. In addition, participants who reported more
than 25% of their attacks lasting longer than 180 min or
equal 0 min were excluded.
For the analysis of the effectiveness of the drugs, a pa-
tient was only considered if he or she reported at least
three attacks with the drug under consideration.
To compare the effectiveness of individual drugs, only
attacks in which only one or two drugs were taken were
considered. It was also requested that the dose taken
should not be zero.
Data collection
During the registration process, baseline characteristics
were obtained including gender, year of birth, place of
residence, occupational group (working (full-time, part-
time), not working (pupil or student, retired, un-
employed)) as well as shift work information (shift work:
yes or no).
To record the individual cluster headache attacks, the
participants entered information about the onset and
end of the attack, the medication used and its dosage.
The medication selection included sumatriptan, zolmi-
triptan, oxygen, lidocaine, ergotamine tartrate and
other. The effectiveness of the drugs was recorded in
three steps (yes, little, no). Other data, such as food and
beverages consumed, which were not relevant for the
present evaluation, were recorded for each attack.
For the analysis, individual profile data were linked to
the data of each attack.
As mentioned above we use a web app and a smart-
phone app to record the attacks. The overall system is
described in [13]. The recording mask is presented in
the supplementary material to this publication. To assess
Table 1 Symptoms according the ICHD-3 (beta) definition and
their frequencies
Symptom Frequency (N= 282)
conjunctival injection and/or lacrimation 254 (90%)
nasal congestion and/or rhinorrhoea 267 (95%)
eyelid oedema 124 (44%)
forehead and facial sweating 139 (49%)
forehead and facial flushing 68 (24%)
sensation of fullness in the ear 124 (44%)
miosis and/or ptosis 186 (66%)
Drescher et al. BMC Neurology (2021) 21:174 Page 2 of 8
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the intensity of pain we use a numerical pain scale,
which is described in [14].
Statistics
The data were analyzed using the R language and the R-
studio environment [15].
Chi-square tests were used to compare the distribution
of the participants in the different groups like gender,
cluster headache type (chronic, episodic) and the smok-
ing and non-smoking groups.
Welchs t-test was used to compare the age distribu-
tions of the several groups.
Chi-square tests were used to compare the effective-
ness of drugs in different groups. The groups could rep-
resent different drugs (e.g. sumatriptan, oxygen),
different cluster headaches (chronic, episodic) or the
smoking and non-smoking groups. The effectiveness of
the drugs was divided into two classes (yesand little/
no) in accordance with [16]. The duration of participa-
tion and the number of reported attacks varied greatly
among the participants. To ensure that individual partic-
ipants with a large number of reported attacks did not
dominate any result, the density distribution for each pa-
tient was included in the calculation of the Chi-square.
The different number of attacks was then taken into ac-
count when calculating the statistical error of the
components.
Results
The final data set consisted of 13,649 cluster headache
attacks of 139 participants who fulfilled the requirement
of having reported at least 6 attacks within at least 10
days of participation. Of these, 133 participants (100
males; 33 females; ratio 3.0:1) also provided information
about acute medication for 8369 attacks. This informa-
tion included the drug taken, the dose and an assess-
ment of its effectiveness.
Table 2summarizes the characteristics of the
participants.
Table 3divides the participants into smokers and non-
smokers and into episodic and chronic cluster headache
sufferers. The results of the statistical tests in the right-
hand column show the balance of the groups in terms of
gender distribution, age and cluster headache type.
In 6726 of the 8369 attacks, the intake of only one
drug was reported. The distribution of medication in
these cases is shown in Fig. 1. In addition, the figure
provides information on the number of participants
reporting for each medication. Since each participant
could report attacks with different medications, the sum
of participants in Fig. 1is greater than the total number
of participants indicated above.
Due to the low case numbers, only the three most
common medications, oxygen, sumatriptan 6 mg s.c. and
zolmitriptan 5 mg nasal spray, were considered for the
investigation of drug effectiveness. Although reporting
oxygen flow was not mandatory, most participants
(95.6%) reported plausible values between 4 and 20 l/
min. The median was 13 l/min, the mode 15 l/min.
First, the effectiveness of all three drugs under consid-
eration was examined and compared with each other.
Figure 2shows the three drugs with their effectiveness
in the three gradations yes,littleand no. As men-
tioned above, the effectiveness classes littleand no
were merged into one class for the investigation of the
effects.
Comparing in pairs the assessment of the partici-
pants using sumatriptan or zolmitriptan or oxygen,
their assessment of the effectiveness of the respective
drug gives the following picture: The effect of suma-
triptan 6 mg s.c. is estimated to be significantly better
than that of oxygen, (p< 0.001, OR = 2.8), that of zol-
mitriptan 5 mg nasal spray not better than that of
oxygen (p= 0.49) and the effect of sumatriptan 6 mg
s.c. as significantly better than that of zolmitriptan 5
mg nasal spray (p< 0.001, OR = 3.2).
A comparison of the effect of the drugs by cluster
headache type showed that oxygen is estimated to be
significantly more effective for the treatment of episodic
than of chronic cluster headache (p< 0.001, OR = 2.0).
Sumatriptan 6 mg s.c. is estimated to be significantly
more effective for the treatment of chronic than of epi-
sodic cluster headache (p= 0.03, OR = 2.2). For zolmi-
triptan 5 mg nasal spray (p= 0.39) there is no difference
in the estimation of the effect between chronic and epi-
sodic cluster headache.
Figure 3shows the effectiveness of the drugs consid-
ered with the difference in headache type in chronic and
episodic cluster headache.
Table 2 Patientscharacteristics
Characteristic Patients
a
(N= 133)
Gender
Male 100 (75%)
Female 33 (25%)
Age [years]
Mean ± SD 42.3 ± 10.4
Range 2268
Type of CH
Episodic 98 (74%)
Chronic 35 (26%)
Smoker Information
Smoker 78 (59%)
Non-Smoker 55 (41%)
CH Cluster headache
a
Except for age
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The Fagerström test was used to investigate the nico-
tine dependence of our participants. The mean Fager-
ström score in our sample of smokers is 3.9. Twenty-
seven of the smokers smoke more than 20 cigarettes per
day and are therefore considered heavy smokers. This
corresponds to a proportion of 35%.
Comparing the drug effects between the smoking and
non-smoking groups, the following picture emerged:
Oxygen helps smokers significantly better than non-
smokers (p= 0.001, OR = 1.7). Non-smokers rate the ef-
fect of triptans slightly better than smokers, although the
differences are not or just as significant (sumatriptan 6
mg s.c.: p= 0.10, OR = 2.0; zolmitriptan 5 mg nasal spray:
p= 0.05, OR = 1.8). Figure 4shows the corresponding
distributions.
Finally, we investigated whether the estimation of the
drug effect improves when two of the drugs under con-
sideration were taken. Twenty-five participants used
both oxygen and sumatriptan 6 mg s.c. in 366 attacks, 18
participants took both oxygen and zolmitriptan 5 mg
nasal spray in 331 attacks.
It was ascertained that the use of sumatriptan 6 mg s.c.
in combination with oxygen does not improve the effect-
iveness (p= 0.43). The effectiveness of taking oxygen and
zolmitriptan 5 mg nasal spray together is considered to
be worse than taking only oxygen (p= 0.02, OR = 1.8) or
Table 3 Division of participants into smokers and non-smokers and into episodic and chronic cluster headaches
Patients
a
(N= 133)
Smokers Non-Smokers
Frequency 78 (59%) 55 (41%) Statistic
Gender (male / female) 61 (78%) / 17 (22%) 39 (71%) / 16 (29%) χ
2
= 0.92
p= 0.34
Age [y], mean ± SD 41.3 ± 10.2 43.7 ± 10.8 p= 0.20
CH Type (episodic / chronic) 57 (73%) / 21 (27%) 41 (75%) / 14 (25%) χ
2
= 0.04
p= 0.85
Episodic Chronic
Frequency 98 (74%) 35 (26%) Statistic
Gender (male / female) 74 (76%) / 24 (24%) 26 (74%) / 9 (26%) χ
2
= 0.02
p= 0.89
Age [y], mean ± SD 41.7 ± 10.8 43.7 ± 9.5 p= 0.31
a
Except for age
Fig. 1 Distribution of the medications for attacks with only one medication reported
Drescher et al. BMC Neurology (2021) 21:174 Page 4 of 8
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only zolmitriptan (p= 0.08, OR = 1.6). Figure 5shows
the corresponding distributions.
Discussion
We analyzed 13,649 cluster headache attacks from
139 patients collected in the citizen science project
CLUEviaawebappaswellasasmartphoneapp.
Diagnosis of cluster headache was based on ICHD-3
beta criteria (ICHD-3 beta, 2013). Compared to the
more recent ICHD-3 (2018), the ICHD-3 beta in-
cludes sensation of fullness in the earwhich was
reported by 44% of the patients. The focus was on
Fig. 2 Effectiveness of the three medications under investigation
Fig. 3 Effectiveness of the three medications under investigation by cluster headache type
Drescher et al. BMC Neurology (2021) 21:174 Page 5 of 8
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investigating the effectiveness of acute medication,
with particular emphasis on distinguishing between
the smoking and non-smoking groups and gender.
Furthermore, the investigations differentiated be-
tween participants with episodic and chronic cluster
headache. Since there were also three options for
specifying medical effectiveness, we had to decide
whether we wanted to combine yes/littleor little/
noto calculate an OR. In accordance with study
[16], we decided to combine little/noas well.
The most commonly used drugs for the acute treatment
of cluster attacks used were oxygen, sumatriptan 6 mg s.c.
Fig. 4 Effectiveness of the three medications under investigation by smoker and non-smoker
Fig. 5 Effectiveness of combinations of the three medications under investigation
Drescher et al. BMC Neurology (2021) 21:174 Page 6 of 8
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and zolmitriptan 5 mg nasal spray. Comparing these three
in terms of effectiveness, it was found that sumatriptan 6
mg s.c. was reported as being significantly more effective
than zolmitriptan 5 mg nasal spray and oxygen. The com-
parison of the latter two did not show any significant dif-
ference. These results are consistent with [35].
Differentiating the cluster headache types chronic and
episodic in terms of the effect of the drugs, oxygen is
significantly more effective in episodic than in chronic
cluster headache. In the case of triptans, no difference
can be observed in these two groups. These results con-
firm the study by Pearson et al. (2019) [16], but contra-
dict two other studies. One study examined 124 patients
(73% episodic and 27% chronic) and tested the effective-
ness of oral zolmitriptan compared to placebos for both
groups. Although they found a positive effect for epi-
sodic cluster headache, they noticed no effect in patients
suffering from chronic cluster headache [6]. Another
study found that subcutaneous sumatriptan was less ef-
fective for chronic cluster headaches than for episodic
cluster headache [7].
Another result is the differentiation of drug effective-
ness between the smoking and non-smoking groups.
Here oxygen causes significantly better effects in
smokers than in non-smokers. This is in accordance
with [9], where differences between the effectiveness of
sumatriptan and oxygen were studied. No significant dif-
ferences in the effectiveness were revealed. However,
when men and smokers were analyzed it was observed
that their response to oxygen was significantly stronger.
An explanation might be the higher mean hemoglobin
concentration in smokers compared to non-smokers
which increases the oxygen delivery [9]. No such differ-
ence is found for triptans.
Our participants have a fairly high average Fagerström
score of 3.9, and the proportion of heavy smokers is also
high at 35%. Fagerström and Furberg calculated an aver-
age Fagerström score for smokers in Germany of 2.8
[17], and in a study by Lampert et al. the proportion of
heavy smokers in Germany was reported to be 28% [18].
However, triggered by the non-smoking campaigns of
recent years, the proportion of heavy smokers and thus
also the average Fagerström score in Germany may have
increased in recent years.
Another interesting result is the investigation of the
combined intake of a triptan and oxygen. For both trip-
tans, the effect of the triptan is not improved if oxygen
is additionally applied.
However, we cannot say whether the drugs were taken
together or whether some time elapsed between taking
the first and second drug. In addition, we also do not
know which of the two was used first.
A strength of the study is the data collection in a real
world setting by apps, so the data and the conclusions
are based on a large number of attacks of every partici-
pant, which is superior to obtaining data by a question-
naire. Also these data address real life while a
questionnaire is based on perceptions which can be
shifted retrospectively. On the other hand, participants
could join or leave the study at any time. Even though a
minimum participation period of 10 days was required,
it cannot be guaranteed that participants actually re-
ported all their attacks during this period. Selective
reporting by the participants could also not be ruled out.
Furthermore, the diagnosis of cluster headache has not
been confirmed by a physician. However, the question-
naire is based on the ICHD-3 (beta version) criteria and
oxygen, nasal and subcutaneous triptans require pre-
scription by a physician which indirectly confirms the
diagnostic accuracy of our questionnaire.
Of course, the results on the effectiveness of acute
treatments are not absolute, because the participants are
taking the drugs they know will help them. We have no
information about what acute treatments a participant
had tried before and may have found less helpful. We
also do not have information about when during an at-
tack the medication was taken and how quickly it
helped.
Furthermore, we have no information on prophylactic
therapies. Therefore, our study cannot provide any infor-
mation about their influence on the drug effectiveness.
Conclusion
Overall, it can be said that the collection of study data
within the framework of a citizen science project like
CLUE can be an interesting addition to other clinical stud-
ies. This type of data collection allows nationwide data
collection over a longer period of time with a large num-
ber of patients. Of course, in view of the weaknesses de-
scribed above, the results obtained can only be interpreted
with the necessary caution and should always be verified.
Abbreviations
ICHD: International Classification of Headache Disorders; IHS: International
Headache Society; SD: Standard deviation; CLUE: Project Clusterkopfschmerz
erforschen, funded by the German Federal Ministry of Education and
Research (BMBF)
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s12883-021-02195-8.
Additional file 1. Supplementary Material: Online questionnaire to
record the attacks.
Acknowledgements
The Institute of Information Systems (iisys) is supported by the Foundation of
Upper Franconia and by the State of Bavaria.
Drescher et al. BMC Neurology (2021) 21:174 Page 7 of 8
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Authorscontributions
JD made significant contributions to the conception and realization of the
data collection, accompanied the data analysis and contributed to the
writing of the manuscript. Together with TA, AK developed the statistical
method for analyzing the data. Both carried out large parts of the data
analysis. CG contributed significantly to the medical conception of the data
collection. CG and PK interpreted the medical results of the study and made
significant contributions to the writing of the manuscript. YS helped develop
the method for statistical analysis of the data. JS accompanied the entire
research process and contributed significantly to the writing of the
manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by the German Federal Ministry of Education and
Research (BMBF Project 01BF1701). Open Access funding enabled and
organized by Projekt DEAL.
Availability of data and materials
The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committee of the Medical Faculty of
the University of Rostock (reference number A 20170091). We confirm that
all methods were performed in accordance with the relevant guidelines and
regulations.
When collecting the data, neither the name and address nor the exact date
of birth is recorded. Furthermore, we encourage the participants to use a
neutral email address which does not disclose their names. Since the data
was collected largely anonymously, there were no further conditions
imposed by the ethics committee.
During the registration process, participants are informed about privacy
issues. A data protection declaration complies with the requirements of the
German data protection and data security laws.
With their registration, they give their consent to participate. We thus
received the informed consent of all participants in the study.
As described in [13], no data analysis starts directly from the migraine attack
database. Instead, all necessary attack data are extracted from the database
while skipping the link to the email address. This ensures that researchers
analyzing the data cannot reproduce the connection between the attack
data and the participants having reported the attacks.
Consent for publication
Not applicable
Competing interests
Dr. Gaul has received honoraria for consulting and lectures within the past 3
years from Allergan Pharma, Lilly Germany, Novartis Pharma, Hormosan
Pharma, Grünenthal, Sanofi-Aventis and TEVA. He does not hold any stocks
of pharmaceutical companies. All other authors declare that there is no con-
flict of interest.
Author details
1
Institute of Information Systems, University of Applied Sciences Hof, Hof,
Germany.
2
Institute of Medical Psychology and Medical Sociology, University
of Rostock, Rostock, Germany.
3
Migraine and Headache Clinic Königstein,
Königstein, Germany.
Received: 26 November 2020 Accepted: 12 April 2021
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... 22 Additional evidence suggesting subtle pathophysiological differences between patients with ECH and CCH include differences in response to the same treatment, as seen in examples from clinical trials to date with lithium 26,27 (efficacious in CCH but not ECH) and galcanezumab 28,29 (efficacious in ECH but not CCH) in preventive treatment, as well as non-invasive vagus nerve stimulation for acute treatment (efficacious in ECH but not CCH). 30,31 However, some CH treatments, particularly acute treatments such as subcutaneous and intranasal triptans and oxygen are efficacious in both ECH and CCH, [32][33][34][35][36] although some studies have reported differences in the magnitude of response. 32,33,35 Treatments to interrupt cluster periods or reduce the frequency of attacks (i.e., preventive treatment) are generally based on recommendations from treatment guidelines. ...
... 30,31 However, some CH treatments, particularly acute treatments such as subcutaneous and intranasal triptans and oxygen are efficacious in both ECH and CCH, [32][33][34][35][36] although some studies have reported differences in the magnitude of response. 32,33,35 Treatments to interrupt cluster periods or reduce the frequency of attacks (i.e., preventive treatment) are generally based on recommendations from treatment guidelines. 37,38 However, these guidelines are based on a small number of randomized controlled trials (RCTs) supplemented with data from uncontrolled trials. ...
Article
Full-text available
Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of "cluster headache," and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.
... The results of all previous studies were obtained using self-reported questionnaires, and the studies did not directly determine attack frequencies during school and vacation periods. The CLUE research project directly determined migraine attacks, thereby creating a database for future studies [8,9]. ...
Article
This citizen science project CLUE compared the attack frequency between school and vacation periods among adolescents. The data collection process adopted in citizen science projects opens up the possibility of conducting analyses by including a large number of participants over a long period and across different regions. The data on 684 migraine attacks reported by 68 adolescents aged 16 to 19 years were collected using an online platform and smartphone apps. A Fisher’s exact test was used to compare the distributions of the migraine attack frequency during vacation and school periods in two different scenarios. In both scenarios, the attack frequency during school periods was significantly higher than that during vacation periods. The use of web-based data collection has some methodological limitations; however, it enabled the measurement of relative migraine attack frequency in students during vacation and school periods. The higher prevalence of migraine during school periods indicates the requirement of increasing headache awareness among children.
... As previous literature provided evidence related to the efficacy of oxygen treatment in CH patients [56], oxygen should be considered as an additional treatment for CH care. However, because of the controversies surrounding the inclusion of oxygen as a drug [57][58][59], we could not include studies with oxygen, and we expect more future studies evaluating oxygen as CH treatment. ...
Article
Full-text available
It is important to find effective and safe pharmacological options for managing cluster headache (CH) because there is limited evidence from studies supporting the general efficacy and safety of pharmacological therapies. This systematic review and network meta-analysis (NMA) analyzed published randomized controlled trials (RCTs) to evaluate the efficacy and safety of pharmacological treatments in patients with CH. The PubMed and Embase databases were searched to identify RCTs that evaluated the efficacy and safety of pharmacological treatments for CH. Efficacy outcomes included frequency and duration of attacks, pain-free rate, and the use of rescue agents. Safety outcomes were evaluated based on the number of patients who experienced adverse events. A total of 23 studies were included in the analysis. The frequency of attacks was reduced (mean difference (MD) = −1.05, 95% confidence interval (CI) = −1.62 to −0.47; p = 0.0004), and the pain-free rate was increased (odds ratio (OR) = 3.89, 95% CI = 2.76–5.48; p < 0.00001) in the pharmacological treatment group, with a lower frequency of rescue agent use than the placebo group. Preventive, acute, and triptan or non-triptan therapies did not show significant differences in efficacy (p > 0.05). In the NMA, different results were shown among the interventions; for example, zolmitriptan 5 mg was more effective than zolmitriptan 10 mg in the pain-free outcome (OR = 0.40, 95% CI = 0.19–0.82; p < 0.05). Pharmacological treatment was shown to be more effective than placebo to manage CH with differences among types of therapies and individual interventions, and it was consistently shown to be associated with the development of adverse events. Thus, individualized therapy approaches should be applied to treat CH in real-world practice.
Article
Full-text available
Objective To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, including recommended treatments such as oxygen, commonly used medications such as opioids, and emerging medications such as intranasal ketamine. Particular focus is paid to a large subset of respondents 65 years of age or older. Background Large international surveys of cluster headache are rare, as are examinations of treatments and side effects in older cluster headache patients. This article presents data from the Cluster Headache Questionnaire, with respondents from over 50 countries and with the vast majority from the United States, the United Kingdom, and Canada. Methods This internet‐based survey included questions on cluster headache diagnostic criteria, which were used as part of the inclusion/exclusion criteria for the study, as well as effectiveness of medications, physical and medical complications, psychological and emotional complications, mood scores, and difficulty obtaining medications. The diagnostic questions were also used to create a separate group of respondents with probable cluster headache. Limitations to the methods include the use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of some medications (eg, all triptans as opposed to sumatriptan subcutaneous alone). Results A total of 3251 subjects participated in the questionnaire, and 2193 respondents met criteria for this study (1604 cluster headache and 589 probable cluster headache). Of the respondents with cluster headache, 68.8% (1104/1604) were male and 78.0% (1245/1596) had episodic cluster headache. Over half of respondents reported complete or very effective treatment for triptans (54%, 639/1139) and oxygen (54%, 582/1082). Between 14 and 25% of respondents reported complete or very effective treatment for ergot derivatives (dihydroergotamine 25%, 42/170; cafergot/ergotamine 17%, 50/303), caffeine and energy drinks (17%, 7/41), and intranasal ketamine (14%, 5/37). Less than 10% reported complete or very effective treatment for opioids (6%, 30/541), intranasal capsaicin (5%, 7/151), and intranasal lidocaine (2%, 5/241). Adverse events were especially low for oxygen (no or minimal physical and medical complications 99%, 1077/1093; no or minimal psychological and emotional complications 97%, 1065/1093), intranasal lidocaine (no or minimal physical and medical complications 97%, 248/257; no or minimal psychological and emotional complications 98%, 251/257), intranasal ketamine (no or minimal physical and medical complications 95%, 38/40; no or minimal psychological and emotional complications 98%, 39/40), intranasal capsaicin (no or minimal physical and medical complications 91%, 145/159; no or minimal psychological and emotional complications 94%, 150/159), and caffeine and energy drinks (no or minimal physical and medical complications 89%, 39/44; no or minimal psychological and emotional complications 91%, 40/44). This is in comparison to ergotamine/cafergot (no or minimal physical and medical complications 83%, 273/327; no or minimal psychological and emotional complications 89%, 290/327), dihydroergotamine (no or minimal physical and medical complications 81%, 143/176; no or minimal psychological and emotional complications 91%, 160/176), opioids (no or minimal physical and medical complications 76%, 416/549; no or minimal psychological and emotional complications 77%, 423/549), or triptans (no or minimal physical and medical complications 73%, 883/1218; no or minimal psychological and emotional complications 85%, 1032/1218). A total of 139 of 1604 cluster headache respondents (8.7%) were age 65 and older and reported similar effectiveness and adverse events to the general population. The 589 respondents with probable cluster headache reported similar medication effectiveness to respondents with a full diagnosis of cluster headache. Conclusions Oxygen is reported by survey respondents to be a highly effective treatment with few complications in cluster headache in a large international sample, including those 65 years or over. Triptans are also very effective with some side effects, and newer medications deserve additional study. Patients with probable cluster headache may respond similarly to acute medications as patients with a full diagnosis of cluster headache.
Article
Full-text available
Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. The brief duration and severity of the attacks command the use of rapid-acting pain relievers. Inhalation of oxygen and subcutaneous sumatriptan are the two most effective acute therapeutic options for sufferers of CH. Several preventive medications are available, the most effective of which is verapamil. However, most of these agents are not backed by strong clinical evidence. In some patients, these options can be ineffective, especially in those who develop chronic CH. Surgical procedures for the chronic refractory form of the disorder should then be contemplated, the most promising of which is hypothalamic deep brain stimulation. We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition.
Article
Full-text available
Although various tobacco control measures have been implemented in Germany in the recent years, smoking is still widespread and constitutes a considerable health risk for the population. According to the data of the German Health Interview and Examination Survey for Adults (DEGS1), which was conducted by Robert Koch Institute from 2008 to 2011, 29.7% of the 18 to 79-year old population smokes (women = 26.9%, men = 32.6%). The proportion of women and men who smoke 20 or more cigarettes a day amounts to 6.0% and 10.6% respectively. Smoking is mostly widespread among young adults, as well as among persons with low social status who are also overrepresented among the heavy smokers. Comparison with data from previous health surveys indicates that the proportion of smokers has reduced slightly over the last 10 years. An English full-text version of this article is available at SpringerLink as supplemental.
Article
Objective In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. Background Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA‐approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. Methods A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free‐texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. Results The most commonly used delivery system used by subjects was a non‐rebreather‐type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. Conclusion Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient‐reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.
Article
In this paper we introduce the design and technical implementation of the citizen science project Migraine Radar. The goal of the project is to establish a large collection of migraine attack data in order to explore the trigger factors of migraine attacks. A main focus is the investigation of the influence of environmental factors like weather or changes in the geomagnetic activity on the frequency of migraine attacks. After registering with the project, participants report their migraine attack data using a web app or one of the smartphone apps implemented for Android and iOS. As a benefit, the system serves as a personal headache calendar and participants have access to statistics and individualized reports about their attacks. For scientific analysis the data are pre-processed and provided to the researchers in an anonymized way.
Article
Background. Attacks of cluster headache are difficult to treat. Sumatriptan, an agonist of 5-hydroxy-tryptamine1—like receptors, has proved effective in the treatment of migraine. The clinical similarities between migraine and cluster headache and positive results from an open pilot study in patients with cluster headache indicated that sumatriptan should be evaluated more rigorously in the treatment of this condition. Methods. We conducted a randomized, double-blind, placebo-controlled crossover study to assess the efficacy and tolerability of sumatriptan in 49 patients with cluster headache. The patients received, in random order, a subcutaneous injection of 6 mg of sumatriptan for one cluster-headache attack and placebo for another attack. The results for the two attacks could be fully evaluated for 39 patients. A response to treatment was defined as complete or almost complete relief of headache (no pain or mild pain) within 15 minutes after the injection. Results. In the 39 patients, the severity of headache decreased in 74 percent of the attacks within 15 minutes of treatment with sumatriptan, as compared with 26 percent of the attacks for which placebo was given (P<0.001). Thirty-six percent of the patients were free of pain within 10 minutes after the administration of sumatriptan, as compared with 3 percent after placebo (P<0.001); by 15 minutes these numbers had increased to 46 percent and 10 percent, respectively (P<0.001). Thirteen percent of the patients required oxygen as an additional treatment 15 minutes after receiving sumatriptan, as compared with 49 percent of those who received placebo. The severity of functional disability and the incidence of ipsilateral conjunctival injection also decreased more in response to sumatriptan than placebo. Sumatriptan was well tolerated, and there were no serious adverse events. Conclusions. Sumatriptan is an effective and well-tolerated treatment for acute attacks of cluster headache. (N Engl J Med 1991; 325:322–6.)