Effects of Acute and Preventive Therapies for Episodic and Chronic Cluster Headache

A Scoping Review of the Literature

Ioana Medrea MD, MS; Suzanne Christie MD; Stewart J. Tepper MD; Kednapa Thavorn PhD; Brian Hutton PhD

Headache. 2022;62(3):329-362.

Abstract and Introduction

Abstract

Background: Cluster headache is the most common primary headache disorder of the trigeminal autonomic cephalalgias, and it is highly disabling.

Objective: We undertake a scoping review to characterize therapies to prevent and acutely treat cluster headache, characterize trial methodology utilized in studies, and recommend future trial "good practices." We also assess homogeneity of studies and feasibility for future network meta-analyses (NMAs) to compare acute and preventive treatments for cluster headache.

Methods: A priori protocol for this scoping review was registered and available on Open Science Forum. We sought studies that enrolled adult patients with cluster headache as identified by accepted diagnostic criteria. Both randomized controlled trials (RCTs) and observational studies (with a control group) were included. The interventions of interest were medications, procedures, devices, surgeries, and behavioral/psychological interventions, whereas comparators of interest were placebo, sham, or other active treatments. Outcomes were predefined; however, we did not exclude studies lacking these outcomes. A systemic search was conducted in Ovid Medline, Embase, and Cochrane. We performed a targeted search for conference abstracts from journals prominent in the field.

Results: We identified 56 studies: 45 RCTs, four studies only available in clinical trial registries, and seven observational studies. Of the 45 RCTs, 20 focused on acute therapies and 25 on preventive therapies. Overall, we determined that it is feasible to pursue a NMA for acute therapy focusing on 15 or 30-min headache reduction for acute trials, as we identified 11 trials in the combined population of patients with either episodic or chronic cluster headache (2 trials in populations with chronic cluster headache were also found). For preventive therapy of cluster headache, we identified trials with common outcomes that may be considered for NMA, however, as these trials had differences in treatment effect modifiers that could not be corrected, NMAs appear infeasible for this indication. We identified new studies looking at noninvasive vagal nerve stimulation, sphenopalatine ganglion stimulation, prednisone, and oxygen published since the most recent systematic review in the field, although these acute treatments were previously identified as effective. However, for calcitonin gene-related peptide (CGRP) monoclonal antibodies, galcanezumab demonstrated effectiveness in episodic cluster headache, but a lack of effectiveness in chronic cluster headache, and fremanezumab was not effective for episodic nor chronic cluster headache. This finding highlights that CGRP monoclonal antibodies may not show a class effect in cluster headache prevention and need to be considered individually.

Conclusions: We describe the treatment landscape of cluster headache for both acute and preventive treatments. Last, we present the NMAs we will undertake in acute therapies of cluster headache.

Introduction

Background

Trigeminal autonomic cephalalgias are associated with unilateral headache and ipsilateral autonomic features, such as lacrimation, conjunctival injection, rhinorrhea, miosis, ptosis, hyperhidrosis, eyelid edema, and flushing.^[1] Cluster headache (CH) is the most common primary headache among the trigeminal autonomic cephalalgias, with a yearly prevalence of 1 per 1000.^[1,2]

Rationale for This Work

There are few evidence-based treatments available in CH,^[3,4] as it is a condition that has been under studied.^[1] The current scoping review was designed to expand upon past reviews in several ways. First, we sought to identify new studies published since the prior reviews were completed.^[3,4] Second, with the data gathered in this scoping review, we aimed to assess the feasibility of pursuing network meta-analyses (NMAs)^[5,6] to inform comparisons of multiple treatments based on available direct and indirect evidence in the field. We planned to systematically evaluate study and population features to establish the potential for rigorous NMAs by confirming appropriateness of the assumptions of homogeneity and similarity.^[7] Third, in addition to identifying and reviewing randomized controlled trials (RCTs) of interventions for CH, we also set out to assess the value of observational studies in this clinical area and the potential for their inclusion in future meta-analyses. There are many who lament that RCTs are limited in the field, and there is considerable real-world data to be used.^[8] Several past narrative reviews from clinical experts in the field have included nonrandomized trials in their recommendations,^[9] given the paucity of randomized trial data available.

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Table 1. Outcomes reported for acute treatment trials
Trial ID	Treatment	Comparator	HA relief at 15 min	HA relief at 30 min	Pain-free at 15 min	Pain-free at 30 min	Other efficacy measures	Adverse events
Andersson 1986	DHE ns	Placebo					Attack controlled, strongly reduced, or slightly reduced as per timeline provided	NA
Bahra 2000	Zolmitriptan po	Placebo		Yes				Yes
Cittadini 2006	Zolmitriptan ns	Placebo	Yes	Yes		Yes		Yes
Cohen 2009	Oxygen 12 L/min	Placebo	Yes	Yes	Yes	Yes		Yes
Costa 2000	Lidocaine/cocaine	Placebo	Yes	Yes	Yes	Yes	Pain extinction times in minutes were 31.3 for cocaine, 37 for lidocaine, and 59.3 for saline	Yes
Di Sabato 1993	Hyperbaric O₂	Room	Yes					Yes
Dirkx 2018	Oxygen 7 L/min	Oxygen 12 L/min	Yes^a		Yes^a			Yes
Ekbom 1991	Sumatriptan sc	Placebo	Yes		Yes	Yes		Yes
Ekbom 1993	Sumatriptan sc	Placebo	Yes		Yes		HA response at 10 min	Yes
Fogan 1985	Oxygen 6 L/min	Placebo	Yes^a				Subjective relief score expressed by the patient	Yes
Goadsby 2018	nVNS	Sham	Yes^a		Yes		Proportion per subject of attacks with a response and who were pain-free at 30 min, pain score as per subject	Yes
Goadsby 2019	SPG stim	Sham	Yes		Yes		Sustained pain relief from 15 min to 1 h, 50%, 75%, and 100% responder rate in patients treated for >6 attacks	Yes
Hardebo 1998	Sumatriptan sc	Sumatriptan ns	Yes	Yes				Yes
Matharu 2004	Octreotide sc	Placebo		Yes		Yes		Yes
Petersen 2017	Oxygen 15 L/min, DVO	Placebo	Yes	Yes				Yes
Rappaport 2007	Zolmitriptan NS	Placebo		Yes				Yes
Rozen 2013	DVO	Oxygen 15 L/min		Yes				Yes
Schoenen 2013	SPG stim	Sham	Yes	Yes	Yes			Yes
Sicuteri 1983	Somatostatin/DHE	Placebo					The maximal pain intensity was moderately reduced, no timepoints were provided	Yes
Silberstein 2016	nVNS	Sham	Yes				50% responders at 15 min	Yes
VanViet 2003	Sumatriptan ns	Placebo		Yes		Yes		Yes

Abbreviations: DHE, dihydroergotamine; DVO, demand valve oxygen; HA, headache; NA, not applicable; ns, nasal spray; nVNS, noninvasive vagal nerve stimulation; O₂, oxygen; po, by mouth; sc, subcutaneous; SPG, sphenopalatine ganglion; stim, stimulation; suma, sumatriptan; zolmi, zolmitriptan.
^aStudy characteristics obtained by communication with authors or by calculations based on available data.

Table 2. Outcomes reported in preventive trials
Trial and year	Treatment	Comparator	Cluster type	Baseline	Mean change in the number of headaches at 2 weeks	50% reduction in headaches	Primary outcome measures
Ambrosini 2005	Betamethasone injection	Placebo	69.5% ECH	1 week	No	No	From 72 h to 1 week attack free, from 72 h to 4 weeks attack free
Anthony 1978	Cimetidine, cimet + chlorpheniramine	Placebo	NA	None	No	No	Headache free during 3 weeks
Bussone 1990	Verapamil	Lithium	CCH	3 weeks placebo	No	No	The number of headache attacks and changes in intensity during 12 weeks of treatment
Christiansen 2000	Nitrate tolerance	Placebo	CCH	1 week	No	No	Mean cluster attacks/week comparing placebo to active treatment for 1 week
Di Sabato 1998	Hyperbaric O₂	Room	ECH	None	No	No	Freedom from CH for 3 month duration
Dodick 2020	Galcanezumab 300 mg Qmo	Placebo	CCH	2 weeks	Yes	Yes	Mean change in the number of cluster attacks from baseline to weeks 1–12
El Amrani 2002	Valproate	Placebo	77% ECH	1 week	No	No	50% reduction in the number of headaches from run in to the second week of treatment
Evers 1998	Misoprostol	Placebo	CCH	2 weeks	No	No	Number of attacks over 2 weeks of treatment vs. placebo
Fontaine 2010	DBS	Sham	CCH	4 weeks before implant and 4 weeks after implant but before randomization	No	No	Attacks in the last week on active vs. placebo in the 1 month of treatment
Gaul 2016	nVNS + SOC	SOC	CCH	2 weeks	Yes	Yes	Reduction in mean CH attacks in the last 2 weeks of a 4-week randomized phase
Goadsby 2019	Galcanezumab 300 mg Qmo	Placebo	ECH only	1 week	Yes	Yes	Reduction in mean attacks in the 3 weeks compared to baseline, including week by week values
Hakim 2011	Warfarin	Placebo	CCH	4 weeks	No	No	Remission for 4 of 12 weeks on treatment or placebo
Jammes 1975	Prednisone	Placebo	NA	NA	No	No	Complete relief of pain with prednisone and number of patients with duration of effect >2 months
Leone 1996	Melatonin	Placebo	90% ECH	1 week	Yes	No	Reduction in mean attacks in week 1 and 2 on treatment compared to baseline
Leone 2000	Verapamil	Placebo	ECH only	5 days	Yes	Yes	Reduction in mean attacks in week 1 and 2 on treatment compared to baseline
Leroux 2011	Cortivazol	Placebo	65.1% ECH	3 days	Yes	Yes	Attacks <2/day during the second, third, and fourth day after the third injection (days 9–12)
Marks 1993	Capsaicin	Placebo	62.5% ECH in Rx, plac no ECH	3 days	No	No	The difference in the number of headaches and headache intensity at baseline vs. week 1 and 2
Monstadt 1995	Sumatriptan 100 mg po t.i.d.	Placebo	53% ECH	1 week	No	No	50% responder rate between baseline week and week 1 of treatment
Nilsson 2002	Hyperbaric O₂	Sham - hyperbaric air	75% ECH	1 week	No	No	Headache index reduction 50% at 1 week
Obermann 2021	Prednisone taper	Placebo	ECH	3 days retrospective	No	Yes	Mean number of CH attacks within the first week of treatment
Pageler 2010	Frovatriptan 5 mg daily	Placebo	ECH	4–7 days	No	No	Mean change in the number of cluster attacks from baseline to weeks 1–2
Russel 1979	Cimet + Chlorpheniramine	Placebo	NA	None	No	No	Mean change in the number of cluster attacks from baseline to weeks 1–12
Saper 2002	Civamide nasal drop	Placebo	ECH	3 days	Yes	No	Mean change in the number of cluster attacks from baseline to weeks 1–3
Steiner 1997	Lithium	Placebo	ECH	None	No	No	Percentage of patients whose attacks ceased at 1 week
Trovnik 2013	Candesartan	Placebo	ECH	None	Yes	Yes	Mean number of CH attacks from week 1 to week 3 of treatment

Abbreviations: CCH, chronic CH; CH, cluster headache; cimet, cimetidine; DBS, deep brain stimulation; ECH, episodic CH; NA, not applicable; ns, nasal spray; nVNS, non-invasive vagal nerve stimulation; O₂, oxygen; po, by mouth; plac, placebo; Qmo, administered once each month; rx, treatment; sc, subcutaneous; SOC, standard of care; SPG, sphenopalatine ganglion; t.i.d., three times daily.

Table 3. Preventive trials that feature changes in headache frequency from baseline to 2 weeks, 50% responder rates, and adverse events
Trial and year	Treatment	ECH	Baseline frequency active Rx per week ± SD	Rx reduction to week 2 ± SD	Baseline frequency placebo per week ± SD	Placebo reduction to week 2 ± SD	Active treatment 50% response	Placebo 50% resp	AE Rx	AE PLAC
Goadsby 2019	Galcanezumab	All	17.3 ± −10	−8.8 ± 12.1, n = 57	17.8+/−10.1	−4.5 ± 10.5, n = 49	39%, n = 57	25%, n = 49	25/57	16/49
Leone 1996	Melatonin	90%	23.1	−12.7 ± 16.0, n = 10	16.73	0.8 ± 11.4, n = 10	NA	NA	0/10	0/10
Leone 2000	Verapamil	All	13.4	−9.2 ± 9.1, n = 15	9.59	1.7 ± 8.7, n = 15	80%, n = 15	0%, n = 15	8/15	0/15
Saper 2002	Civamide nasal drop	ECH	12.5	−8.4 ± 9.1, n = 18	10.8	−3.6 ± 8.7, n = 10	NA	NA	17/18	7/10
Trovnik 2013	Candesartan	ECH	14.3 ± 9.2	−8.7 ± 9.1, n = 19	16.8	−6.2 ± 8.7, n = 13	63%, n = 19	46%, n = 13	12/19	3/13

Abbreviations: AE, adverse events; ECH, episodic cluster headache; NA, not available; PLAC, placebo; Rx, prescription drug.

Table 4. Summary of findings and acute treatment interventions
Author and year	Treatment	Comparator	Design	Directionality of findings of treatment vs. comparator
Author and year	Treatment	Comparator	Design	Reports efficacy	HA relief	Pain free	Other primary end points^a
Andersson 1986	DHE ns	Placebo	RCT	Yes			↑
Bahra 2000	Zolmitriptan po	Placebo	RCT	Yes	↔		↔
Cittadini 2006	Zolmitriptan ns	Placebo	RCT	Yes	↑
Cohen 2009	Oxygen 12 L/min	Placebo	RCT	Yes	↑	↑
Costa 2000	Lidocaine/cocaine	Placebo	RCT	Yes	↑	↑	↑
Di Sabato 1993	Hyperbaric O₂	Room	RCT	Yes	↑
Dirkx 2018	Oxygen 7 L/min	Oxygen 12 L/min	RCT	Yes			↑
Ekbom 1991	Sumatriptan 6 mg sc	Placebo	RCT	Yes	↑	↑
Ekbom 1993	Sumatriptan 6 mg sc	Placebo	RCT	Yes	↑	↑
Fogan 1985	Oxygen 6 L/min	Placebo	RCT	Yes			↑
Goadsby 2018	nVNS	Sham	RCT	ECH subgroup only		↔
Goadsby 2019	SPG stim	Sham	RCT	Yes	↑	↑	↑
Hardebo 1998	Sumatriptan sc	Sumatriptan ns	RCT	Yes	↑
Matharu 2004		Placebo	RCT	Yes			↑
Petersen 2017	Oxygen 15 L/min, DVO	Placebo	RCT	No	↔
Rappaport 2007	Zolmitriptan ns	Placebo	RCT	Yes	↑
Rozen 2013	DVO	Oxygen 15 L/min	RCT	No	↔
Schoenen 2013	SPG stim	Sham	RCT	Yes	↑	↑
Sicuteri 1983	Somatostatin/DHE	Placebo	RCT	Yes			↑
Silberstein 2016	nVNS	Sham	RCT	ECH subgroup only	↔
VanViet 2003	Sumatriptan ns	Placebo	RCT	Yes	↑

Abbreviations: DHE, dihydroergotamine; DVO, demand valve oxygen; ECH, episodic CH; HA, headache; ns, nasal spray; nVNS, noninvasive vagal nerve stimulation; O₂, oxygen; po, by mouth; RCT, randomized controlled trial; sc, subcutaneous; stim, stimulation.
^aPlease see Table 2 for full explanations of these outcomes.

Table 5. Summary of findings and interventions used as preventive treatments
Author and year	Treatment	Comparator	Design	Directionality of findings treatment vs. comparator
Author and year	Treatment	Comparator	Design	Reports efficacy	Mean change HA count	50% reduction	Other primary end points^a
Ambrosini 2005	Betamethasone injection	Placebo	RCT	Yes			↑
Anthony 1978	Cimetidine, cimet + chlorpheniramine	Placebo	RCT	No			↔
Bussone 1990	Verapamil	Lithium	RCT	Yes			↑
Christiansen 2000	Nitrate tolerance	Placebo	RCT	No			↔
Di Sabato 1998	Hyperbaric O₂	Room	RCT	Yes			↑
El Amrani 2002	Valproate	Placebo	RCT	No			↔
Dodick 2020	Galcanezumab 300 mg month	Placebo	RCT	No	↔	↔
Evers 1998	Misoprostol	Placebo	RCT	No			↔
Fontaine 2010	DBS	Sham	RCT	No			↔
Gaul 2016	nVNS + SOC	SOC	RCT	Yes, CCH	↑	↑
Goadsby 2019	Galcanezumab 300 mg month	Placebo	RCT	Yes	↑	↑
Hakim 2011	Warfarin	Placebo	RCT	Yes			↑
Jammes 1975	Prednisone	Placebo	RCT	Yes			↑
Leone 1996	Melatonin	Placebo	RCT	Yes	↑
Leone 2000	Verapamil	Placebo	RCT	Yes	↑	↑
Leroux 2011	Cortivazol injection	Placebo	RCT	Yes	↑	↑
Marks 1993	Capsaicin	Placebo	RCT	Yes			↑
Monstadt 1995	Sumatriptan 100 mg po t.i.d.	Placebo	RCT	No			↔
Nilsson 2002	Hyperbaric O₂	Sham – hyperbaric air	RCT	No			↔
Obermann 2021	Prednisone taper	Placebo	RCT	Yes	↑	↑
Pageler 2010	Frovatriptan 5 mg daily	Placebo	RCT	No			↔
Russel 1979	Cimetidine + Chlorpheniramine	Placebo	RCT	No			↔
Saper 2002	Civamide nasal drops	Placebo	RCT	Yes	↑
Steiner 1997	Lithium	Placebo	RCT	No			↑
Trovnik 2013	Candesartan	Placebo	RCT	No	↔	↔	↑

Abbreviations: CCH, chronic CH; CH, cluster headache; cimet, cimetidine; DBS, deep brain stimulation; GON-B, greater occipital nerve block; HA, headache; nVNS, non-invasive vagal nerve stimulation; O₂, oxygen; po, by mouth; RCT, randomized controlled trial; sc, subcutaneous; SOC, standard of care; t.i.d., three times daily.
^aPlease see full explanations in Table 4.

Table A2. Overview of study exclusion criteria
Study	Prior treatments for cluster allowed?	History of migraine or other headaches?	Exclusion criteria across studies
Study	Prior treatments for cluster allowed?	History of migraine or other headaches?	History of vascular disease excluded?	History of drug or alcohol abuse excluded?	Abnormal laboratory or ECG studies excluded?	Pregnant women excluded?	Other noted criteria
Ambrosini 2005	NA	NA	NA	NA	NA	NA	NA
Andersson 1986	NA	NA	NA	NA	NA	NA	NA
Anthony 1978	NA	NA	NA	NA	NA	NA	NA
Bahra 2000	NA	NA	Yes	Yes	Yes	Yes	Methysergide, methylergovine, AIDS, hypersensitivity to triptan and exposure to investigational drug in prior 30 days
Bougea 2016	NA	NA	NA	NA	NA	NA	NA
Bussone 1990	No	NA	Yes	NA	Yes	Yes	Not taking oral contraceptives
Christiansen 2000	NA	Yes	NA	Yes	NA	NA	NA
Cittadini 2006	No	NA	Yes	NA	NA	NA	Ear, nose, or throat issue that may preclude use of nasal spray
Cohen 2009	NA	Yes	NA	NA	NA	Yes	Could not tolerate mask, had COPD, or had tried oxygen before
Costa 2000	NA	NA	NA	NA	NA	NA	NA
Di Sabato 1993	No	NA	Yes	NA	Yes	NA	NA
Dirkx 2018	NA	Yes	NA	NA	NA	Yes	Could not tolerate mask, had COPD, or had tried oxygen before, not able to provide consent
Ekbom 1991	NA	NA	Yes	Yes	Yes	Yes	Epilepsy and psychiatric issues
Ekbom 1993	NA	NA	Yes	Yes	Yes	Yes	Epilepsy and psychiatric issues
El Amrani 2002	No	NA	NA	Yes	Yes	NA	Psychiatric disorder
Evers 1998	NA	NA	NA	NA	NA	NA	NA
Fogan 1985	NA	NA	NA	NA	NA	NA	NA
Fontaine 2010	NA	NA	NA	Yes	NA	NA	No contra-indication to surgery or anesthesia
Gaul 2016	Ok if change >1 month ago	NA	Yes	NA	NA	NA	Implanted electrical device, surgery at vagal nerve, syncope or epilepsy, metallic hardware
Goadsby 2018	NA	NA	Yes	NA	NA	NA	Implanted electrical device, surgery at vagal nerve, syncope or epilepsy, metallic hardware
Goadsby 2019_2	No	No	NA	NA	NA	NA	NA
Goadsby 2019	NA	No	NA	NA	NA	NA	Clinical trial in last year, MAB use or CGRP receptor antagonist use, ischemic migraine variants
Hardebo_1998	NA	NA	NA	Yes	NA	Yes	NA
Hakim 2011	NA	NA	Yes	NA	NA	Yes	Increased risk of bleeding factors
Jammes 1975	NA	NA	NA	NA	NA	NA	NA
Leone 1996	NA	NA	NA	Yes	Yes	NA	Psychiatric disease or taking antidepressants or neuroleptics
Leone 2000	NA	NA	Yes	Yes	Yes	NO	Adynamic ileus, bradycardia, hypotension, psychiatric history
Leroux 2011	NA	Yes	NA	NA	NA	NA	Contra-indication to cortivazol or verapamil, anticoagulant use, or bleeding history
Marks 1993	NA	NA	NA	NA	NA	NA	NA
Matharu 2004	Yes	Yes	NA	NA	NA	Yes	Diabetes or known cholelithiasis
Monstad 1995	Yes	NA	Yes	Yes	Yes	Yes	Severe psychiatric disease
Nilsson 2002	Yes	NA	Yes	NA	NA	Yes	Ear disease
Oakes 2019	NA	NA	NA	NA	Yes	Yes	Clinical trial over last month, CGRP receptor antagonist use, indomethacin use, psychiatric disease
Pageler 2010	Yes	NA	NA	NA	NA	NA	NA
Petersen 2017	Yes	NA	NA	Yes	NA	Yes	COPD
Rappaport 2007	NA	NA	Yes	NA	NA	Yes	Major depression or medical illness
Rozen 2013	NA	NA	NA	NA	NA	NA	COPD, asthma, syncope with hyperventilation
Russel 1979	NA	NA	NA	NA	NA	NA	NA
Saper 2002	NA	NA	NA	Yes	Yes	Yes	NA
Schoenen 2013	No change 1 month	yes	NA	NA	NA	NA	Surgery, onabotulinumtoxinA, radiofrequency ablation, or radiation to face
Sicuteri 1983	NA	NA	NA	NA	NA	NA	NA
Silberstein 2016	NA	NA	Yes	NA	NA	NA	Vascular neck surgery or electrical implant
Steiner 1997	NA	NA	NA	NA	NA	NA	Lithium contraindicated
Trovnik 2013	In 1 month prior	NA	NA	Yes	Yes	Yes	Use of anti-depressant or neuroleptic
VanViet 2003	Yes	NA	Yes	NA	NA	Yes	Ear, nose, or throat disease, serious adverse event with triptan in past

Abbreviations: CGRP, calcitonin gene-related peptide; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; NA, not applicable.

Table A2A. Characteristics of RCTs that examined acute treatments for CH
Study characteristics				Population characteristics									Co-interventions permitted
Trial and location	Treatment (n)	Comparator (n)	CH diagnostic criteria	ECH %	Male %	Mean Age	Illness duration	Onset <weeks	Attacks/week	Attack duration	Bout duration	>45 min	Acute rescue	Prophylaxis
Andersson 1986; Europe	DHE ns (n = 133)	Placebo (n = 137)	Ad hoc	100	80	40	9 years	NA	NA	NA	NA	NA	NA	NA
Bahra 2000; Canada, UK, Sweden	Zolmitriptan po (n = 114)	Placebo (n = 115)	IHS	73	86	43.8	NA	NA	NA	NA	NA	Yes	No	No
Cittadini 2006: Europe	Zolmitriptan ns (n = 65)	Placebo (n = 61)	IHS	64	87	40	12 years	NA	NA	NA	8 weeks	Yes	Yes, simple analg + O₂	NA
Cohen 2009; London UK	Oxygen 12 L/min (n = 76)	Placebo (n = 76)	IHS	75	82	39	11.3 years	NA	12	83 min	NA	NA	Yes	No
Costa 2000; Pavia, Italy	Lidocaine/cocaine (n = 9)	Placebo (n = 9)	IHS	40	87	37.2	8.2 years	NA	NA	NA	NA	NA	Yes	NA
Di Sabato 1993; NA	Hyperbaric O₂ (n = 6)	Room (n = 7)	Ad hoc	100	93	NA	NA	NA	NA	NA	NA	NA	NA	No
Dirkx 2018; Denmark	Oxygen 7 L/min (n = 70)	Oxygen 12 L/min (n = 70)	ICHD-2	68	61	43	New onset	NA	14	60 min	NA	NA	Yes	Yes
Ekbom 1991; Europe	Sumatriptan s.c. (n = 39)	Placebo (n = 39)	IHS	56	80	42	NA	NA	NA	NA	NA	Yes	Yes	No
Ekbom 1993; Europe	Sumatriptan s.c. (n = 92)	Placebo (n = 88)	IHS	72	87	41	NA	NA	NA	NA	NA	NA	Yes	NA
Fogan 1985; USA	Oxygen 6 L/min (n = 15)	Air (n = 17)	Ad hoc	NA	NA	NA	NA	NA	NA	NA	NA	NA	Yes	No
Goadsby 2018; Europe	nVNS (n = 50)	Sham (n = 52)	ICHD-3B	71	72	45.4	NA	NA	10.5	73.7 min	NA	NA	Yes	Yes
Goadsby 2019_2; USA	SPG stim (n = 45)	Sham (n = 48)	ICHD-3B	0	NA	48	11–14 years	NA	14	45 min	NA	NA	Yes	Yes
Hardebo 1998; Sweden	Sumatriptan ns (n = 25)	Sumatriptan s.c. (n = 25)	IHS	88	88	NA	NA	NA	1–3/day	NA	NA	Yes	Yes	Yes
Matharu 2004; UK	Octreotide s.c. (n = 46)	Placebo (n = 45)	IHS	73	79	40	14 years	NA	NA	NA	NA	Yes	Yes	No
Petersen 2017; Denmark	Oxygen 15 L/min, DVO (n = 32)	Placebo (n = 11)	ICHD-2	53	74	45	13.2 years	NA	7.7	NA	>2 weeks	NA	Yes	Yes
Rappaport 2007; USA	Zolmitriptan ns (n = 52)	Placebo (n = 50)	ICHD-2	71	69	45.2	NA	NA	NA	NA	NA	Yes	No triptans or ergot	Yes
Rozen 2013; NA	DVO (n = NA)	Oxygen 15 L/min NA	ICHD-2	0	75	NA	NA	NA	NA	NA	NA	NA	Yes	Yes
Schoenen 2013; Europe	SPG stim (n = 32)	Sham (n = 32)	ICHD-2	0	84	45	NA	NA	19.2	NA	NA	No	Yes	Yes
Sicuteri 1983; NA	SST/DHE (n = NA)	Placebo NA	NA	75	100	36.2	NA	NA	NA	NA	NA	NA	No	No
Silberstein 2016; ISA	nVNS (n = 60)	Sham (n = 73)	ICHD-2	67	84	47.87	NA	NA	NA	NA	NA	NA	Yes	Yes
Van Viet 2003; USA	Sumatriptan 20 mg ns (n = 118)	Placebo (n = 118)	IHS	75	82	43	13 years	NA	NA	NA	>8 weeks	Yes	0₂ or simple analgesia	No

Abbreviations: analg, analgesic; CH, cluster headache; DHE, dihydroergotamine; DVO, demand valve oxygen; ECH, episodic CH; ICHD, International Classification of Headache Disorders; IHS, International Headache Society; NA, not available; ns, nasal spray; nVNS, noninvasive vagal nerve stimulation; O₂, oxygen; po, by mouth; RCT, randomized controlled trial; s.c., subcutaneous; SPG, sphenopalatine ganglion; SST, somatostatin; stim, stimulated.

Table A2B. Characteristics of RCTs that examined interventions for prevention of CH
Study characteristics				Population characteristics									Co-interventions permitted
Trial and location	Treatment (n)	Comparator (n)	CH diagnostic criteria	ECH %	Male %	Mean age	Illness duration	Onset <weeks	Attacks per week	Attack duration	Bout duration	>45 min	Acute rescue	Prophylaxis
Ambrosini 2005; Europe	Betamethasone injection (n = 13)	Placebo (n = 10)	IHS	70	87	40.1	NA	<1 week	11.3	NA	>4 weeks	NA	Yes	Yes
Anthony 1978; Australia	Cimetidine alone and with chlorpheniramine (n = 20)	Placebo (n = 20)	NA	NA	NA	47.4	NA	NA	NA	NA	NA	NA	NA	NA
Bussone 1990; Italy	Verapamil (n = 15)	Lithium (n = 15)	IHS	0	90	43	NA	NA	NA	NA	NA	NA	Yes	No
Christiansen 2000; Denmark	Nitrate tolerance (n = 5)	Placebo (n = 5)	IHS	0	88	53.1	>2 years	NA	NA	NA	NA	NA	Yes	No
Di Sabato 1993; NA	Hyperbaric O₂ (n = 6)	Room air (n = 7)	Ad hoc	100	92	NA	NA	NA	NA	NA	NA	NA	NA	No
El Amrani 2002; Europe	Valproate (n = 50)	Placebo (n = 46)	IHS	77	88	45.4	NA	NA	12.1	NA	NA	NA	Sumatriptan s.c. or O₂	No
Evers 1998; Europe	Misoprostol (n = 8)	Placebo (n = 8)	IHS	0	NA	44.5	14 years	NA	14.4	64.4 min	NA		Sumatriptan s.c. or O₂	Yes
Fontaine 2010; Europe	DBS (n = 11)	Sham (n = 11)	ICHD-2	0	73	44.1	12.1 y	NA	17.8	NA	NA	NA	Yes	Yes
Gaul 2016; Europe	nVNS + SOC (n = 48)	SOC (n = 49)	ICHD-3B	0	69	43.8	4.9 years	NA	17.7	99.3 min	NA	NA	Yes	Yes
Goadsby 2019; Europe and North America	Galcanezumab (n = 49)	Placebo (n = 57)	ICHD-3B	100	83	45.9	16.8 years	NA	17.5	NA	>6 weeks	NA	Yes	No
Hakim 2011; Italy	Warfarin (n = 11)	Placebo (n = 11)	ICHD-2	0	76	44.6	7 years	NA	21	48.8 min	NA	NA	Yes	No
Jammes 1975; USA	Prednisone (n = 18)	Placebo (n = 19)	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Leone 1996; Italy	Melatonin (n = 10)	Placebo (n = 10)	IHS	90	75	36.4	NA	<10 days	19.95	NA	NA	Yes	Yes	No
Leone 2000 Italy	Verapamil (n = 15)	Placebo (n = 15)	IHS	100	90	43.5	15.5 y	<1 week	11.5	NA	NA	Yes	Yes	No
Leroux 2011; Paris, France	Cortivazol injection (n = 19)	Placebo (n = 18)	ICHD-2	65	88	41.4	NA	NA	28.2	NA	NA	NA	Yes	Yes
Marks 1993; USA	Capsaicin (n = 9)	Placebo (n = 8)	IHS	NA	77	NA	NA	NA	NA	NA	NA	NA	NA	NA
Monstad 1995; Europe	Sumatriptan po (n = 89)	Placebo (n = 79)	IHS	54	89	40	NA	NA	≥7	NA	NA	NA	Yes	No
Nilsson 2002; Stockholm, Sweden	Hyperbaric O₂ (n = 14)	Sham–hyperbaric air (n = 16)	IHS	75	75	42.7	14.9 years	NA	Range only	NA	>4 weeks	Yes	Yes	No
Oakes 2019; Europe and NA	Galcanezumab (n = 117)	Placebo (n = 1120)	ICHD-3B	0	73	45	NA	NA	18.82	NA	NA	NA	Yes	Yes
Pageler 2010; Europe	Frovatriptan po (n = 5)	Placebo (n = 6)	ICHD-2	100	NA	NA	NA	>1 week	15.6	NA	>6 weeks	NA	No	Yes
Russel 1979; USA	Cimet + chlorpheniramine (n = 12)	Placebo (n = 12)	Ad hoc	NA	NA	49	NA	NA	NA	NA	NA	No	Simple analgesia	NA
Saper 2002; USA	Civamide nasal drops (n = 18)	Placebo (n = 10)	IHS	100	90	44.7	NA	NA	NA	NA	NA	No	Yes	No
Steiner 1997; USA	Lithium (n = 14)	Placebo (n = 13)	Their own—similar to IHS	100	100	36.4	13.4 years	<3 weeks	15.75	NA	NA	>30	Yes	No
Trovnik 2013; Europe	Candesartan (n = 19)	Placebo (n = 13)	ICHD-2	100	85	42.7	16.3 years	<2 weeks	17.85	NA	NA	NA	Suma only	No

Abbreviations: analg, analgesic; CH, cluster headache; DBS, deep brain stimulation; ECH, episodic CH; ICHD, International Classification of Headache Disorders; IHS, International Headache Society; NA, not available; ns, nasal spray; nVNS, noninvasive vagal nerve stimulation; O₂, oxygen; po, by mouth; RCT, randomized controlled trial; s.c., subcutaneous; SOC, standard of care; SPG, sphenopalatine ganglion; Suma, sumatriptan.

Table A2C. Characteristics of two-arm observational studies of therapies used to treat CH
Trial, year, and location	Treatment	Diagnostic criteria	ECH %	Male %	Mean age	Onset <weeks	Attacks per day	Attack duration	Attack >45 min	Illness duration	Prophylaxis	Rescue
De Carolis 1988; Italy	Prednisone 50 mg/day for 30 days	NA	100	92	NA	<1 week	NA	>3 weeks	NA	NA	Yes	Yes
	Nimodipine 30 mg q.i.d.
	Lithium 300 mg t.i.d.
	Methysergide 2 mg t.i.d.
Favoni 2017; Italy	GON-B Methylprednisolone 80 mg + lidocaine 2 mg 2% 1X	NA	68	NA	NA	NA	NA	NA	NA	NA	NA	NA
Favoni 2017; Italy	GON-B Methylprednisolone alone - 3 applications every 48 h	NA	68	NA	NA	NA	NA	NA	NA	NA	NA	NA
Fusco 1994; Italy	10% capsaicin applied only until desensitized ipsilateral to ECH	Ad hoc	73	80	46+	>15 days	NA	NA	NA	>3 years	NA	NA
	Contralateral to ECH			80	49
	Contralateral 1 month and then ipsilateral 1 month for CCH			100	51
Gantenbein 2012; Switzerland	Unilateral GON-B with 3 ml betamethasone + 2 ml 2% lidocaine	ICHD-2	52	87	42	ECH 34 days	2.9 ± 1.8	NA	NA	NA	Yes	NA
	Bilateral GON-B escalation					CCH	3.2 ± 2.8
	ECH
	CCH
Gregor 2005; USA	Sumatriptan 6 mg s.c.	IHS	63	83	43	NA	NA	NA	NA	NA	Yes	Yes
	Sumatriptan 3 mg s.c.
	Sumatriptan 2 mg s.c.
	Oxygen >7 L/min
Kudrow 1981; NA	Ergotamine	Ad hoc	72	84	44	NA	NA	NA	NA	NA	No	No
Kudrow 1981; NA	O₂ 7 L/min	Ad hoc	72	84	44	NA	NA	NA	NA	NA	No	No
Wei 2018; USA	Oral steroids prednisone or dexamethasone for 2–14 days	ICHD-3B	67	80	44	NA	NA	NA	NA	NA	Yes	Yes
Wei 2018; USA	GON-B 2 ml 2% lidocaine and 40 methylprednisolone	ICHD-3B	67	80	44	NA	NA	NA	NA	NA	Yes	Yes

Abbreviations: CH, cluster headache; ECH, episodic CH; GON-B, greater occipital nerve bloc; IHS, International Headache Society; ICHD, International Classification of Headache Disorders; NA, not available; O₂, oxygen; po, by mouth; q.i.d., four times daily; s.c., subcutaneous; t.i.d., three times daily.

Table 3A. Studies with clinically relevant shared outcomes that were considered in the NMA
Study	Placebo	Suma s.c.	Zolmi ns	O₂ low	O₂ high	Suma ns	Octreotide s.c.	nVNS	Headache response timeline analyzed	Safety	Adverse events placebo
Study	Placebo	Suma s.c.	Zolmi ns	O₂ low	O₂ high	Suma ns	Octreotide s.c.	nVNS	Headache response timeline analyzed	Adverse events therapy	Adverse events placebo
Ekbom 1991	25%, n = 39	74%, n = 39							15 min	35%, n = 49	26%, n = 47
Ekbom 1993	35%, n = 88	75%, n = 93							15 min	37%, n = 92	16%, n = 88
Cittadini 2006	23%, n = 61		42%, n = 65						30 min	2%, n = 65	0%, n = 61
Rappoport 2007	30%, n = 59		50%, n = 52						30 min	25%, n = 52	16%, n = 50
Fogan 1975	33%, n = 63			68%, n = 74					15 min	0%, n = 67	0%, n = 46
Cohen 2010	20%, n = 148				78%, n = 150				15 min	0%, n = 148	0%, n = 150
Dirks 2018				14%, n = 14	33%, n = 15				15 min	0%, n = 14	0%, n = 14
Van Viet 2003	26%, n = 77					57%, n = 77			30 min	23%, n = 77	1%, n = 77
Matharu 2004	36%, n = 45						52%, n = 46		30 min	57%, n = 46	24%, n = 45
Silberstein 2016	15%, n = 73							27%, n = 60	15 min	14%, n = 73	30%, n = 77
Goadsby 2018	30%, n = 44							38%, n = 48	15 min	40%, n = 50	27%, n = 52

Note: Two outcomes commonly included in these studies were headache responses at clinically appropriate time points and safety.
Abbreviations: ns, nasal spray; nVNS, noninvasive vagal nerve stimulation; O₂, oxygen; s.c., subcutaneous; Suma, sumatriptan; Zolmi, zolmitriptan.

Table A4. Outcomes reported in observational studies
Trial and year	Treatment	Primary outcome	Other outcomes
De Carolis 1988	Prednisone 50 mg/day for 30 days	No attacks after 7 days of therapy
	Nimodipine 30 mg q.i.d.
	Lithium 300 mg t.i.d.
	Methysergide 2 mg t.i.d.
Favoni 2017 abstract	Methylprednisolone 80 mg + lidocaine 2 mg 2%	Responders were in remission >1 month
Favoni 2017 abstract	Methylprednisolone only 3 times every 48 h	Responders were in remission >1 month
Fusco 1994	10% capsaicin applied only until desensitized	Complete cessation of headaches over 60 days	50% response over 60 days
	Ipsilateral to ECH
	Contralateral to ECH
	Contralateral 1 mo and then ipsilateral 1 mo for CCH
Gantenbein 2012	Ipsilateral GON-B with 3 ml betamethasone + 2 ml 2% lidocaine	No attacks within 24 h of therapy	>25% decrease in the frequency of attacks after 24 h
	bilateral GON-B with escalation
	ECH
	CCH
Gregor 2005	Sumatriptan 6 mg s.c.	HA relief at 15 min
	Sumatriptan 3 mg s.c.
	Sumatriptan 2 mg s.c.
	O₂ >7 L/min
Kudrow 1981	Ergotamine	HA relief at 15 min	Headache freedom at 15 min
Kudrow 1981	O₂ at 7 L/min	HA relief at 15 min	Headache freedom at 15 min
Wei 2018	Oral steroids prednisone or dexamethasone for 2–14 days	Complete cessation of headaches with 7 days of treatment	A decrease in headaches within 7 days of treatment
Wei 2018	GON-B with 2 ml 2% lidocaine and 40 mg methylprednisolone	Complete cessation of headaches with 7 days of treatment	A decrease in headaches within 7 days of treatment

Abbreviations: CH, cluster headache; ECH, episodic CH; GON-B, greater occipital nerve block; HA, headache; ICHD, International Classification of Headache Disorders; IHS, International Headache Society; O₂, oxygen; po, by mouth; q.i.d., four times daily; s.c., subcutaneous; t.i.d., three times daily.

Authors and Disclosures

Ioana Medrea MD, MS^1,2, Suzanne Christie MD^1,3, Stewart J. Tepper MD⁴, Kednapa Thavorn PhD^1,5 and Brian Hutton PhD^1,5

¹University of Ottawa, Ottawa, Ontario, Canada
²SUNY Upstate Medical University, Syracuse, New York, USA
³Ottawa Headache Centre, Ottawa, Ontario, Canada
⁴Geisel School of Medicine at Dartmouth, Dartmouth, New Hampshire, USA
⁵Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Correspondence
Ioana Medrea, SUNY Upstate Medical University, Department of Neurology, Jacobsen Hall, Rm. 813, 175 Elizabeth Blackwell, Syracuse, New York 13210, USA. Email: medreai@upstate.edu

Conflict of Interest
Dr. S. Christie: Grants for research (no personal compensation): Allergan/Abbvie. Dr. S. Tepper: Grants for research (no personal compensation): Allergan/Abbvie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, Zosano. Consultant and/or Advisory Boards (honoraria): Aeon, Allergan/Abbvie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, CoolTech, CRG, Currax, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Science. Communications, HMP Communications, Impel, InteractiveForums, Keyquest, Krog and Partners, Lundbeck, M3 Global Research, MJH Holdings, Neurolief, Novartis, P Value. Communications, Pain Insights, Inc, Palion Medical, Pulmatrix, Putnam Associates, SAI. MedPartners, Satsuma, Spherix Global Insights, Strategy Inc, System Analytic, Taylor and Francis, Teva, Theranica, Trinity Partners, Unity HA, XOC, Zosano. Salary: Dartmouth-Hitchcock Medical Center, American Headache Society, Thomas Jefferson University. CME honoraria: American Academy of Neurology, American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, Medical Education Speakers Network, Medical Learning Institute Peerview, Migraine Association of Ireland, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Texas Neurological Society, Vindico Medical Education, WebMD/Medscape. The other authors have no conflicts to declare.

Author Contributions
Study concept and design: Ioana Medrea, Brian Hutton, Kednapa Thavorn, Suzanne Christie, Stewart J. Tepper. Acquisition of data: Ioana Medrea, Suzanne Christie. Analysis and interpretation of data: Ioana Medrea, Brian Hutton, Kednapa Thavorn, Suzanne Christie, Stewart J. Tepper. Drafting of the manuscript: Ioana Medrea. Revising for intellectual content: Brian Hutton, Kednapa Thavorn, Suzanne Christie, Stewart J. Tepper. Final approval of the completed manuscript: Brian Hutton, Kednapa Thavorn, Suzanne Christie, Stewart J. Tepper.