IntroductionCluster headache is a devastating primary headache, characterized by attacks of severe, strictly unilateral pain which is orbital, supraorbital and/or temporal, lasting between 15 to 180 minutes when untreated. The attacks occur almost every other day, up to 8 times a day. Chronic cluster headache (CCH) is a type of cluster headache in which attacks occur for more than a year without remission or with remission periods lasting less than 1 month (1). The clinical characteristics of CCH suggest a substantial disease burden, both to patients as well as society. We aim to provide an overview of the disease burden of CCH and outcomes of treatments recommended by the European Federation of Neurological Societies (EFNS) for CCH (2).

Two research questions were designed:

1) What evidence is reported in the literature with regard to epidemiological, economic, and humanistic burden and comorbidities for CCH?

2) What evidence is reported in the literature with regard to economic burden, complications and outcomes for treatments recommended in the EFNS guidelines?

MethodsA predefined search strategy was used to search Medline, Embase, Econlit, Cochrane and NHS EED databases for citations published from the year 2000 and onwards. The search was performed on May 27th 2014. Identification of relevant citations was based on PICOS criteria (Table 1). Data was extracted using data extraction forms; one researcher extracted the data and a second independent researcher checked each extraction. Details on study design (e.g. study objective, case finding method, inclusion criteria); patient characteristics (e.g. age, gender, number of CCH patients) and outcomes (e.g. prevalence, humanistic burden, treatment efficacy) were extracted.

Table 1 PICOS criteria

Question 1 Question 2

Population Inclusion criteria

Adult patients (≥18 years)Chronic Cluster headache according to ICHD-III beta criteria:A. At least five attacks fulfilling criteria B–DB. Severe or very severe unilateral orbital, supraorbital and/or

temporal pain lasting 15–180 minutes (when untreated)C. Either or both of the following:

• At least one of the following symptoms or signs, ipsilateral to the headache:- conjunctival injection and/or lacrimation- nasal congestion and/or rhinorrhoea- eyelid edema- forehead and facial sweating- forehead and facial flushing- sensation of fullness in the ear- miosis and/or ptosis

• A sense of restlessness or agitationD. Attacks have a frequency between one every other day and

eight per day for more than half of the time when the disorder is active

E. Not attributed to another ICHD-3 diagnosisF. Occurring without a remission period, or with remissions lasting

<1 month, for at least 1 year.

Exclusion criteria

Healthy patients without CCHStudies including only patients with headache or migraineMixed populations (migraine and CCH), but not reported separately

Inter­vention

Inclusion criteria

Not applicable

Oxygen inhalation therapySumatriptan 6 mg s.cSumatriptan 20 mg nasalZolmitriptan 5 mg nasalZolmitriptan 10 mg oralLidocaine nasalOctreotideVerapamilSteroidsLithiumMethysergideTopiramateErgotamine tartrateValproic acidMelatoninBaclofen

Exclusion criteria

All other treatments not listed under inclusion criteria

Comparison Inclusion criteria

Not applicable Studies comparing interventions of interest listed above to each other or to placebo

Exclusion criteria

Outcomes Inclusion criteria

All outcomes related to:• Epidemiological burden• Economic burden• Humanistic burden• Comorbidities

All outcomes related to:• Economic consequences• Treatment outcomes• Treatment complications

Exclusion criteria

Humanistic and economic burden and comorbidities are reported linked to the treat-ments and not to disease itself

Study design

Inclusion criteria

Observational studiesRegistriesRandomized controlled trials

Exclusion criteria

Methodology papers/protocolsCase reports/ small studies (n<5 patients per arm)Editorials/ lettersConference reviews or proceedingsBiomarker studiesIn vitro studiesNon-systematic reviewsSystematic literature reviewsMeta-analysis

ResultsDatabase searches identified 3364 records, of which 74 were duplicates between databases. A total of 3290 citations were screened using the PICOS criteria. Figure 1 presents the flowchart of the study selection process for research questions 1 and 2. Ultimately, 10 publications covering 7 unique studies were included for data-extraction to assess the disease burden of CCH and 7 publications covering 5 unique studies were included to assess outcomes associated with treatment for CCH.

Figure 1 Flowchart of study selection process

Question 1: Disease burdenOf the seven included studies, five were observational, one study followed a cohort of patients and one was retrospective in design. Two multicenter studies, both observational, and four single center studies were identified. Six studies were based in Europe and one in the USA. All studies included patients diagnosed with CCH based on ICHD-2 criteria. See Table 2 for more details on the design of identified studies.

Patient characteristics are presented in Table 3. The number of CCH patients included in the studies ranged from 19 to 113 (21% to 100%). Mean age ranged between 42.1 to 46.3 years and 54% to 82% of patients were male. The number of attacks in 24 hours was rarely reported; one study reported an average of 3.3 attacks in 24 hours. Four studies provided information on illness duration of included patients, which was at least 10 years in each of the studies.

Data reported on outcomes of interest is available in Table 4. Little information was available on the epidemiology of CCH. Four studies reported information on the male-to-female ratio of CCH, suggesting between 3 to 4 times as many men suffer from CCH than women (3-9). Comorbidities were reported in 3 studies in heterogeneous ways. One study reported different types of headaches accompanying CCH (10), one study reported the number of patients suffering from sleep apnea syndrome (11) and the final study reported comorbid psychological issues patients suffered from (7-9). The effect of CCH on work productivity was reported in 3 studies, each suggesting a substantial impact (3, 4, 6-9). Ranging from 26% of patients reporting complete inability to work to 36% of patients reporting any work loss. Health related quality of life using the SF-36 questionnaire was reported in one study (3, 4). Patients with CCH reported scores between 40.9 and 59.3 for all subscales of the SF-36, except physical functioning, on which patients scored relatively high, i.e. 80.7. (Note: a lower score equals more disability). Details on the economic burden of CCH are scarce. One study provided information on health care resource use by CCH patients, showing patients visited neurologists 4.4 times, neurosurgeons 1.8 times and pain specialists 7.3 times per per 6 months (6). Lastly, one study reported health care costs associated with CCH. Direct per capita costs were €9,073 and indirect per capita costs were €1,912 (expressed in 2010 Euros) (6).

Question 2: Treatment outcomesFive unique clinical trials were identified during the review process. Three studies were randomized, double-blind, placebo-controlled by design; one study was non-randomized, single-blind and one study did not provide details on study design. Study centers were based in Europe and North America. All trials included patients with CCH diagnosis according to ICHD criteria and reported efficacy outcomes. Two studies provided details on the safety of interventions (Table 5).

Table 6 presents the patients characteristics for the identified clinical trials. Two trials compared oral or nasal spray zolmitriptan (5mg and 10mg) to placebo, one study compared cortivazol injection to placebo, one study compared melatonin to placebo and one study compared triptans to oxygen treatment. The size of the trials ranged from very small (9 patients) to large (366 patients). The average age of included patients ranged from 40 to 55 years and the percentage of males from 50% to 100%. The number of attacks per 24 hours was reported in one study and averaged between 4.0 and 3.6 attacks per day.

Oral zolmitriptan 5 and 10mg achieved lower response rates compared to placebo (16% and 25% versus 31% respectively) (12), however zolmitriptan 5 and 10mg nasal spray performed better than placebo (28% and 36% versus 14% respectively) (13, 14). These results were confirmed by other outcomes, such as need for rescue medication, pain free at 30 minutes and headache relief at 30 minutes. Efficacy of melatonin was measured as the number of attacks per day, however no statistically significant difference compared to placebo was observed (15). When comparing triptans and oxygen treatment the percentage of responders and non-responders was similar (16). No efficacy outcomes of interested were reported for cortivazol injection (17, 18). See Table 7 for more details on efficacy outcomes of CCH treatment.

Safety of treatments in CCH was reported in only two studies, no (serious) adverse events or withdrawals due to adverse events occurred. Details on other safety endpoints, such as nausea and tension type headache were not reported.

None of the identified trials reported economic outcomes of interest, such as health care resource use and direct or indirect costs.

ConclusionLittle evidence was found for both research questions in CCH patients. However, economic and humanistic burden and comorbidities of CCH patients have a considerable impact on both patients and the society. CCH is a disease with a few available treatment options. Efficacy outcomes of specific treatments were, however, also non-consistently reported. Better understanding of the disorder and the efficacy of treatments will lead to better identification, diagnosis and treatment of CCH. Our review showed an evidence gap in a systematic way. More well-controlled, randomized trials should be conducted with CCH patients to reduce heterogeneity in reporting and increase evidence base.

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Brainin M,, ed., European handbook of neurological management. 2nd ed. Oxford (UK): Wiley-Blackwell, 2011.3. D’Amico D, Rigamonti A, Solari A, et al. Health-related quality of life in patients with cluster headache during active periods. Cephalalgia. 2002;

22: 818-21.4. D’Amico D, Usai S, Grazzi L, et al. Quality of life and disability in primary chronic daily headaches. Neurological Sciences. 2003; 24: S97-S100.5. Donnet A, Lanteri-Minet M, Guegan-Massardier E, et al. Chronic cluster headache: A French clinical descriptive study. Journal of Neurology,

Neurosurgery and Psychiatry. 2007; 78: 1354-58.6. Gaul C, Finken J, Biermann J, et al. Treatment costs and indirect costs of cluster headache: A health economics analysis. Cephalalgia. 2011; 31:

1664-72.7. Jurgens TP, Gaul C, Lindwurm A, et al. Burden of disease in cluster headache. Journal of Headache and Pain. 2010; 11: S138-S39.8. Jurgens TP, Gaul C, Lindwurm A, et al. Impairment in episodic and chronic cluster headache. Cephalalgia. 2011; 31: 671-82.9. Luerding R, Henkel K, Gaul C, et al. Aggressiveness in different presentations of cluster headache: Results from a controlled multicentric study.

Cephalalgia. 2012; 32: 528-36.10. Gaul C, Christmann N, Schroder D, et al. Differences in clinical characteristics and frequency of accompanying migraine features in episodic and

chronic cluster headache. Cephalalgia. 2012; 32: 571-77.11. Hornyak M, Kiemen A, Kaube H. Sleep apnea syndrome in chronic cluster headache. European Journal of Pain Supplements. 2011; 5: 137.12. Bahra A, Gawel MJ, Hardebo J-E, et al. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology. 2000; 54: 1832-39.13. Cittadini E, Goadsby PJ. Intranasal zolmitriptan is effective and well tolerated in acute cluster headache: A randomized placebo-controlled

double-blind crossover study. Progress in Neurotherapeutics and Neuropsychopharmacology. 2008; 3: 127-35.14. Cittadini E, May A, Straube A, et al. Effectiveness of intranasal zolmitriptan in acute cluster headache: A randomized, placebo-controlled,

double-blind crossover study. Archives of Neurology. 2006; 63: 1537-42.15. Pringsheim T, Magnoux E, Dobson CF, et al. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;

42: 787-92.16. Schurks M, Rosskopf D, de Jesus J, et al. Predictors of acute treatment response among patients with cluster headache. Headache. 2007; 47:

1079-84.17. Leroux E, Ducros A, Vicaut E, et al. Greater occipital nerve infiltration with cortivazol for cluster headache (CHCI): A double blind randomized

controlled trial. Journal of Headache and Pain. 2010; 11: S81.18. Leroux E, Valade D, Taifas I, et al. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache

attacks per day: A randomised, double-blind, placebo-controlled trial. The Lancet Neurology. 2011; 10: 891-97.19. Marmura MJ, Abbas M, Ashkenazi A. Dynamic mechanical (brush) allodynia in cluster headache: A prevalence study in a tertiary headache clinic.

Journal of Headache and Pain. 2009; 10: 255-58.

Systematic Literature Review of Treatments of Chronic Cluster Headache

Medic G.1, Thavaneswaran S.2, Papadimitropoulou K.1, Stauble F.2, Karabis A.1

1 Mapi - HEOR & Strategic Market Access, Houten, Netherlands, 2 Medtronic International, Tolochenaz, Switzerland

Search strategy: OVID + Cochrane Library + NHS EED3364 abstracts retrieved - 74 duplicates from Cochrane = 3290 abstracts

Abstracts excluded Question 1: 3119Patient pop. not of interest (1077)Intervention not of interest (0)Comparator not of interest (0)Outcomes not of interest (376)Study design not of interest (1647)Duplicate (19)

Abstracts excluded Q2: 3169 Patient pop. not of interest (1030)Intervention not of interest (466)Comparator not of interest (3)Outcomes not of interest (7)Study design not of interest (1644)Duplicate (19)

Full­texts excluded Q1: 161 Patient pop. not of interest (45)Intervention not of interest (0)Comparator not of interest (0)Outcomes not of interest (60)Study design not of interest (55)Not retrievable (1)Duplicate (0)

Full­texts excluded Q2: 114Patient pop. not of interest (16)Intervention not of interest (10)Comparator not of interest (22)Outcomes not of interest (4)Study design not of interest (62)Duplicate (0)

3290 publications for abstract screening

Question 1: 171 publications for full text screeningQuestion 2: 121 publications for full text screening

Question 1: 10 publications retrieved for data extractionQuestion 2: 7 publications retrieved for data extraction

Table 2 Study design; Research Question 1

Author & Year Objective/ Statement of decision problem Study type Study Design Country Inclusion criteria Outcomes reported

D’Amico 2002 D’Amico 2003

To assess functional disability and HRQOL in Italian patients suffering from CCH most often diagnosed in tertiary care units.

Observational study SC Italy

Diagnosis based on IHS Had not started prophylactic treatment when recruited or had started but were still having daily headaches

Humanistic burden

Donnet 2007 To present the data collected between 2002 and 2005 that concern specifically the clinical characteristics of CCH patients.

Observational study MC France Diagnosis based on IHS

Only CCH patients Humanistic burden

Gaul 2012

To address:• Frequency and lateralization of accompanying autonomous

symptoms typically occurring in ECH and CCH attacks.• Frequency of accompanying migrainous symptoms.• Association between comorbid migraine diagnosis and

occurrence of accompanying migrainous symptoms in CH attacks.

• Differences in pain intensity and pain localization between ECH and CCH.

• Association between pain intensity and number and lateralization of reported autonomic symptoms.

• Comparison of circadian and circannual rhythmicity in ECH and CCH

Cohort study SC Germany Diagnosis based on ICHD-II Comorbidities

Gaul 2011To estimate the expenses of treatment of ECH and CCH over 6-month period; relationship between costs, burden of disease and attack frequency within the 6-month period.

Retrospective study SC Germany

Diagnosis based on ICHD-IIAge ≥18 yearsAdequate knowledge of German

Humanistic burdenEconomic

Hornyak 2011To investigate the frequency of SAS in CCH by means of a validated diagnosis screening questionnaire for SAS and diary in a multicenter study

Observational study NR Germany NR Comorbidities

Jurgens 2010 Jurgens 2011 Luerding 2012

To determine the extent of disability in CH patients and its subtypes in comparison to migraine patients and healthy controls, concerning epidemiological factors, disability and concomitant psychiatric symptoms.

Observational study

MC, prospective Germany

Diagnosis based on ICHD-II for migraine without and with aura for ECH and CCH

EpidemiologyHumanistic burdenComorbidities

Marmura 2009To evaluate the prevalence of dynamic mechanical (brush) allodynia (BA) in CH patients attending a tertiary headache clinic, and to assess its relation to disease characteristics.

Observational study SC USA

Age ≥18 yearsDiagnosis based on ICHD-II criteria for ECH or CCH

Epidemiology

BA: Brush Allodynia; CCH: Chronic cluster headache; CH: Cluster headache; ECH: Episodic cluster headache; HAD: Hospital Anxiety and Depression; HIT-6: Headache Impact Test-6; HRQOL: Health Related Quality of Life; ICHD-II: International Classification of Headache Disorders 2; IHS: International Headache Society; MC: Multi center; MIDAS: Migraine Disability Assessment Test; NR: Not reported; SAS: Sleep Apnea Syndrome; SC: Single center; SF-36: Short-Form 36; USA: United States of America

Table 3 Patient characteristics; Research Question 2

Author & Year Sample size

CCH (n) ECH (n) Setting Males (%) Age mean (SD) Age of onset mean (SD) Number of attacks in 24 hours mean (SD)

Illness duration mean years (SD)

D’Amico 2002D’Amico 2003 22 22 0 Hospital 82% 46.2 (11.0) NR NR 11.5 (9.9)

Donnet 2007 113 113 0 Hospital 82% NR

<20 years: 7 pts20-29 years: 30 pts30-39 years: 28 pts40-49 years: 23 pts50-59 years: 16 pts60-75 years: 3 pts

NR NR

Gaul 2012 209 65 144 Outpatient NR 46.3 (11.3) 33.8 (13.9) 3.3 (3) NR

Gaul 2011 179 72 107 Outpatient 75% 45.0 (11.8) NR NR 11.3 (9.2)

Hornyak 2011 26 26 NR NR NR NR NR NR NR

Jurgens 2010 Jurgens 2011 Luerding 2012

130 27 48 NR 82% 42,1 30,6 NR 11,4

Marmura 2009 41 19 22 Outpatient 54% 44.9 (10.5) NR NR 12.3 (9.6)

CCH: Chronic cluster headache; CH: Cluster headache; ICHD-II: International Classification of Headache Disorders 2; IHS: International Headache Society; NR: Not reported; Pts: Patients; SAS: Sleep Apnea Syndrome; SD: Standard Deviation

Table 4 Outcomes; Research Question 1

Author & Year Male­to­female ratio

Co­morbidities N (%) Disability status Work productivity/ Decreased ability to work

Number of visits to GP per patient mean (SD)

Number of visits to the specialist per patient mean (SD)

D’Amico 2002 D’Amico 2003 4.5:1 NR NR

Work loss: 8/22 (36.4%)Work reduced by >50%: 11/22 (50.0%)

NR NR

Donnet 2007 4.65:1 NR NR NR NR NR

Gaul 2012 NR

Migraine: 21 (10.0%)Tension-type-headache: 35 (16.7%)Medication overuse headache: 1 (0.5%)Trigeminal neuralgia: 1 (0.5%)

NR NR NR NR

Gaul 2011 3.0:1 NROfficially classified as severely handi-capped: 30/72

Daily loss: €95Absent from work: 8.5 days 12.4 (17.3)

Neurologist: 4.4 (6.7)Neurosurgeon: 1.8 (1.0)Pain specialist: 7.3 (5.2)

Hornyak 2011 NR SAS: 16 (61.5%) NR NR NR NR

Jurgens 2010 Jurgens 2011 Luerding 2012

4.4:1

Panic syndrome: 4 (15.0%)Agoraphobia: 9 (33.0%) Social phobia: 5 (19.0%)Specific phobia: 2 (7.0%)Generalized anxiety disorder: 5 (19.0%)Obsessive-compulsive disorder: 1 (4.0%)Depressive syndrome: 15 (56.0%)Dysthymia: 3 (11%)Suicidal tendencies: 6 (22.0%)

NR Unable to work: 26% NR NR

Marmura 2009 NR NR NR NR NR NR

GP: General Practitioner; NR: Not Reported; SD: Standard Deviation; SAS: Sleep Apnea Syndrome

Table 5 Study design; Research Question 2

Author & year Study Design Country Study period Primary study outcome Inclusion criteria Outcomes reported

Leroux 2011 Leroux 2011

RCT, DB, PC, SC France November 2008 -

July 2009

Reduction in the mean number of attacks per day to 2 or fewer during the 2nd, 3rd and 4th day after the 3rd injection

Age 18–65Diagnosis based on ICHD-IIHad a mean of >2 attacks per 24 h in the 3 days preceding the day of inclusionECH patients also needed to have been in their present phase of attacks for no more than 1 month, on the basis of reports from patients and medical records, if available

EfficacyAdverse events

Bahra 2000 RCT, DB, PC, MC, cross-over

Canada, UK, Sweden NR

Headache response defined as a two-point or greater improvement from pretreatment headache intensity on the five-point cluster headache rating scale at 30 minutes

Age 18–65Diagnosis based on IHS 2 criteriaHad CH for at least 3 months before the start of the studyExperienced CH usually lasting more than 45 min in durationWas able to distinguish CH from other episodic headachesHad tolerated previous treatment with a 5-HT1B/1D receptor agonist, such as sumatriptan or ergotamineWomen had to practice adequate contraception

EfficacyAdverse events

Cittadini 2008Cittadini 2006

RCT, DB, PC, cross-over

Germany, Italy, UK

12 June 2003 - 24 May 2005

Headache relief at 30 min: reduction in headache from moderate, severe or very severe pain to mild or no pain

Age 18-65Diagnosis based on IHS criteriaUntreated attacks lasting at least 45 minPatients that used zolmitriptan in the past and zolmitriptan-naïve patients were included if, in the opinion of the investigator, it was safe to do so

Efficacy

Pringsheim 2002 PC, SB, cross-over Canada November 2000 -

April 2001 Number of headaches per day Diagnosis based on IHS criteria Efficacy

Schurks 2007 NR Germany April 2002 - March 2004

Predictors for triptan and oxygen response

Caucasian CH patientsDiagnosis based on IHS criteria Efficacy

CCH: Chronic cluster headache; CH: Cluster headache; DB: Double blind; ECH: Episodic cluster headache; ICHD-II: International Classification of Headache Disorders 2; IHS: International Headache Society; MC: Multi center; NR: Not reported; PC: Placebo controlled; RCT: Randomized Controlled Trial; SB: Single blind; SC: Single center; UK: United Kingdom

Table 6 Patient characteristics; Research Question 2

Author & year Setting Treatment and dosage Male (%) ITT (n) CCH patients (n)

ECH patients (n)

Age mean (SD)

Age of onset mean (SD)

Number of attacks in 24h mean (SD)

Illness duration mean (SD) (years)

Leroux 2011 Leroux 2011 Hospital

Cortivazol 3.75 mg suboccipial injection 85% 21 7 14 41 (13)NR

4.0 (1.4)NR

Placebo 100% 22 8 14 43 (12) 3.6 (1.4)

Bahra 2000 Outpatients

Zolmitriptan 10 mg (oral)

NR

111 32 79

NR NR NR NRZolmitriptan 5 mg (oral) 114 31 83

Placebo 115 32 83

Cittadini 2008 Cittadini 2006 NR

Zolmitriptan 5 mg (nasal spray)

87% 69 29 40 40 (10) NR NR 12 (7)Zolmitriptan 10 mg (nasal spray)

Placebo

Pringsheim 2002 OutpatientMelatonin 2mg 50%

9 6 3 55 (NR) NR NR 10 (NR)Placebo 50%

Schurks 2007 Hospital and outpatient

Triptans 79% 19141 184

44 (11)37 (12) NR NR

Oxygen 83% 175 45 (11)

CCH: Chronic cluster headache; ECH: Episodic cluster headache; ITT: Intention-to-treat; NR: Not reported; SD: Standard deviation

Table 7 Outcomes; Research Question 2

Author & year Treatment and dosage N [efficacy analysis]

Overall response to treatment n (%)

Complete pain relief n (%)

Need for rescue medications n (%)

# of attacks treated n/N (%)

# of attacks per day mean (SD)

Pain free at 15 min n (%)

Pain free at 30 min n (%)

Headache relief at 30 min n (%)

Leroux 2011 Leroux 2011

Cortivazol 3.75 mg suboccipial injection 7

NR NR NR NR NR NR NR NRPlacebo 8

Bahra 2000

Zolmitriptan 10 mg (oral) 32 NR (25%) 14 (44%) 12 (37%)

NR NR NR

12 (37%) 15 (47%)

Zolmitriptan 5 mg (oral) 31 NR (16%) 12 (39%) 12 (39%) 15 (48%) 16 (52%)

Placebo 32 NR (31%) 14 (28%) 9 (28%) 15 (47%) 16 (50%)

Cittadini 2008 Cittadini 2006

Zolmitriptan 5 mg (nasal spray)

29

8 (28%)

NR

CH: 23 (35%)

85 NR

CH: 1 (1%) CH: 31 (50%) CH: 27 (42%)

Zolmitriptan 10 mg (nasal spray) 10 (36%) CH: 17 (27%) CH: 2 (3%) CH: 18 (28%) CH: 38 (61%)

Placebo 4 (14%) CH: 30 (50%) CH: 0 (0%) CH: 10 (16%) CH: 12 (23%)

Pringsheim 2002Melatonin 2 mg

6 NR NR NR NR1.07 (0.61)

NR NR NRPlacebo 1.02 (0.65)

Schurks 2007

Triptans 191Responders: 21%

NR NR NR NR NR NR NRNonresponders: 19%

Oxygen 175Responders: 21%

Nonresponders: 24%

CH: Cluster headache; NR: Not reported; SD: Standard deviation

Presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), Philadelphia, PA, USA, May 16–20, 2015.

Corresponding author:Goran Medic, MSc. Pharm.Research Consultant – HEOR & Strategic Market Access Mapi, De Molen 84, 3995 AX Houten, The NetherlandsTel.: +31 (0)30 63 697 63Email: gmedic@mapigroup.com www.mapigroup.com