Home Browse Cluster headache: new targets and options for treatment
ALL Metrics
-
Views
-
Downloads
Get PDF
Get XML
Cite
Export
Track
▬
✚
Review

Cluster headache: new targets and options for treatment

[version 1; peer review: 2 approved]
Patty Doesborg
https://orcid.org/0000-0003-0316-2286
1, Joost Haan1,2
Patty Doesborg
https://orcid.org/0000-0003-0316-2286
1, Joost Haan1,2
PUBLISHED 20 Mar 2018
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Cluster headache is a severe headache disorder with considerable impact on quality of life. The pathophysiology of the disease remains poorly understood. With few specific targets for treatment, current guidelines mainly include off-label treatment with medication. However, new targets for possible treatment options are emerging. Calcitonin gene-related peptide (CGRP)-targeted medication could become the first (cluster) headache-specific treatment option. Other exciting new treatment options include invasive and non-invasive neuromodulation techniques. Here, we provide a short overview of new targets and treatment options that are being investigated for cluster headache.

Keywords

Cluster headache, treatment targets, Calcitonin gene-related peptide targeted therapies

Corresponding author: Patty Doesborg
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2018 Doesborg P and Haan J. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Doesborg P and Haan J. Cluster headache: new targets and options for treatment [version 1; peer review: 2 approved]. F1000Research 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.12688/f1000research.13380.1) First published: 20 Mar 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.12688/f1000research.13380.1) Latest published: 20 Mar 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.12688/f1000research.13380.1)

Introduction

Cluster headache is one of the primary headache disorders. Patients suffer from attacks of severe unilateral pain that is located in the orbital, retro-orbital, or temporal regions and lasts for 15 to 180 minutes. Attacks can occur in a high frequency varying from one to eight times per day. The disease is named after its remarkable feature of attacks clustering in periods lasting for weeks or months, and remission periods occur in between. In chronic cluster headache, these remission periods are absent1.

The disease affects 1 in 1,000 people, and prevalence is higher among men (ratio of 2.5:1)2. Cluster headache has a substantial impact on quality of life. A study among Danish patients showed considerable restrictions to daily activities and working ability3. Other studies have shown lower scores on the 36-Item Short Form Health Survey (SF-36) in patients with episodic cluster headache during an active bout and in chronic cluster headache compared with healthy controls4,5.

The mechanism behind cluster headache attacks is poorly understood. Activation of the trigemino-vascular reflex could be an explanation for the autonomic symptoms following the severe pain in the trigeminal region. However, this does not explain the rhythmicity of cluster headache. Involvement of the hypothalamus is suggested as an explanation for this distinct clinical feature, and this possibility is supported by hormone and imaging studies. Indeed, several studies have demonstrated altered functioning of the hypothalamus in cluster headache.

Currently available and recommended treatment consists of both acute and prophylactic treatment options6. Cluster headache attacks can be aborted by acute treatment with triptans. There is little evidence on which triptan is most effective. Proven, effective abortive treatments are sumatriptan or zolmitriptan after subcutaneous or intranasal administration7,8. Owing to their rapid onset of action, these triptans are very suitable for aborting a cluster headache attack. Other options for acute attack treatment include sumatriptan or lidocaine through intranasal administration, oral zolmitriptan, sphenopalatine ganglion (SPG) stimulation, and octreotide through subcutaneous administration. A history of cardiovascular disease is a formal contraindication for the use of triptans. Years of clinical experience have shown that it could be seen as a reason for caution rather than a strict contraindication. Oxygen (100%, 6–12 L/minute) is a proven alternative and is effective in aborting a considerable number of cluster headache attacks6.

Prophylactic treatment with verapamil and lithium currently has the highest level of evidence for efficacy. Other possible effective preventative treatments are warfarin and melatonin6,9,10. In daily practice, medication with a lower level of evidence, such as topiramate, frovatriptan, and gabapentin, is sometimes tried. In recent years, suboccipital steroid injections have proven to be effective as a short-term, preventive treatment option in some patients6.

A subgroup of patients with cluster headache does not respond well to the currently available treatment. This can be due to lack of response to the medication or to side effects of the drugs. The most commonly used preventive treatment, verapamil, can cause electrocardiography abnormalities and severe clinical side effects11. Lithium is also not very well tolerated by many patients. Additional preventative treatments are available, but evidence of effectiveness was never properly shown in clinical trials. As mentioned before, patients with cluster headache have a severe disease burden. This severe disease burden calls for an effective treatment. Therefore, there is a need for new and better treatments. Thus far, recommended guidelines for cluster headache mainly include the above-mentioned off-label drugs, orally or through injections6. In the past couple of years, possible new targets for the treatment of cluster headache have emerged, and we will focus on these below.

Calcitonin gene-related peptide (CGRP)-targeted therapies

The currently available preventative treatments do not target a specific part of the (presumed) cluster headache pathophysiological mechanisms. For many years, it has been hypothesized that neuropeptides play a role in the pathophysiology of both migraine and cluster headache. Based on this assumption, new medication has been developed targeting one of these peptides: calcitonin gene-related peptide (CGRP). In cluster headache, increased saliva and blood levels of CGRP were found during attacks compared with a baseline value in the same patient and healthy controls, suggesting a possible role for CGRP in cluster headache12–15.

Clinical studies with oral CGRP antagonists in patients with migraine had to be terminated prematurely because of concerns about hepatotoxicity. However, subsequent trials with anti-CGRP monoclonal antibodies in patients with migraine provided strong data for anti-CGRP treatment as a possible new therapy for migraine16.

Four clinical trials are being conducted at this moment to investigate whether the administration of monoclonal antibodies targeting CGRP is effective in preventing cluster headache attacks. Two drugs are under investigation. Two phase III studies are evaluating the efficacy and safety of the anti-CGRP monoclonal antibody fremanezumab for the prevention of both episodic and chronic cluster headache. Additionally, the efficacy and safety of the monoclonal anti-CGRP antibody galcanezumab are being investigated for use in patients with episodic and chronic cluster headache in two phase III, randomized, double-blind, placebo-controlled trials17.

In summary, the likely role of CGRP in cluster headache and the observed efficacy of the antibodies in migraine justify the expectations that these antagonists will also be effective and targeted preventive treatments for cluster headache in the near future.

Neuromodulation

Neuromodulation could be another new treatment but without the disadvantage of systemic side effects. Several ways of neuromodulation, both invasive and non-invasive, have been investigated recently.

Based on the findings of imaging studies (mainly positron emission tomography and voxel-based morphometry), hypothalamic deep brain stimulation has been tried in patients with medically intractable cluster headache and, in a total of 64 patients, was shown to be successful in 64% of patients with medically intractable chronic cluster headache18. However, this invasive technique has the risk of several possible adverse events, including fatal intracerebral hemorrhage18. There is an ongoing search for less dangerous but equally effective neuromodulation techniques, of which we will discuss peripheral occipital nerve stimulation (ONS), SPG stimulation, and non-invasive vagal nerve stimulation (nVNS).

Occipital nerve stimulation

Given the observations of involvement of the ipsilateral posterior inferior hypothalamus in cluster headache attacks and the findings from experimental studies, which show convergence of dural afferents and the greater occipital nerve (GON) in the trigeminocervical pathway, it was thought that stimulation of the latter could influence cluster headache19,20. This idea was supported by multiple open-label studies showing a positive effect of an occipital injection with a corticosteroid: the GON injection21–25. In addition, two randomized controlled trials showed a significant reduction in cluster headache attacks in both episodic and chronic cluster headache patients after receiving a GON injection26,27.

Several open-label studies with invasive ONS have been performed in patients with medically intractable chronic cluster headache28–31. Burns et al. showed improvement in 10 out of 14 patients and a marked or moderate improvement in 6 out of 14 patients28. Fontaine et al. showed reduction of more than 50% of attacks in 10 out of 13 patients31. Magis et al. showed a significant improvement in 80% of 15 patients29. As these were all open studies and therefore possibly influenced by the placebo effect, our department is assessing the efficacy and safety of ONS in patients with medically intractable chronic cluster headache in a randomized blinded trial comparing low with high stimulation32.

Vagal nerve stimulation

The gammaCORE, a device for nVNS, has been investigated in several studies in both acute and preventive treatment for cluster headache33. Nesbitt et al. suggested a role for nVNS in an open-label, observational cohort study in 19 patients with cluster headache34. A prospective, open-label, randomized trial by Gaul et al. compared nVNS added to standard of care (SOC) with SOC alone in 45 patients with chronic cluster headache and 48 controls35. A reduction of 5.9 versus 2.1 attacks per week was found in the patient group versus the controls after a 4-week period receiving nVNS. A group of 30 patients continued nVNS for an extension period and reported a further reduction of weekly attack frequency of two attacks per week. The duration or intensity of attacks was not significantly reduced. No serious adverse events were reported35. No randomized controlled trial has been conducted to confirm the additional preventative effect of nVNS in chronic cluster headache.

A double-blind, randomized, sham-controlled trial to evaluate nVNS as an acute treatment in 133 patients with cluster headache showed no significant difference in response rate after nVNS versus sham. However, in a subgroup analysis of patients with episodic cluster headache, a significantly higher response rate was found (34.2% versus 10.6%, p = 0.008)36.

The trials conducted so far have not been able to prove the efficacy of nVNS as an alternative to acute or prophylactic treatment in chronic cluster headache35,36. However, it has been proposed to include nVNS in the guidelines for the treatment of episodic cluster headache37.

Sphenopalatine ganglion-targeted therapies

Current acute attack treatment in cluster headache consists of either a subcutaneous injection of sumatriptan by means of an auto-injector or oxygen inhalation. Stimulation of the SPG is a new acute treatment under investigation at present. To apply stimulation to the SPG, a miniature device with leads is placed in the pterygopalatine fossa.

An early indication for the effectiveness of SPG stimulation was found in a study of six patients with refractory chronic cluster headache; a pain score reduction of more than 50% was found in 14 out of 18 attacks, and complete remission of pain was reached in 11 out of 18 attacks38. In a randomized placebo-controlled trial by Schoenen et al., 32 patients with chronic cluster headache were instructed to treat attacks with the stimulator for 15 minutes when they experienced an attack with a categorical pain scale score of 2 or more39. There was a total of 566 attacks registered, and pain relief was achieved in significantly more attacks after full stimulation compared with sham stimulation (67.1% versus 7.4%, p <0.0001). Although the trial was set up as an acute treatment study, a reduction in mean attack frequency was also observed. In the experimental period, 12 out of 28 patients experienced an attack frequency reduction of more than 50% compared with the baseline attack frequency39. In an open-label follow-up of this study, a persistent acute response (in more than 50% of attacks) was found in 45% of patients after 24 months with a total of 4,340 attacks treated. In 78% of these attacks, SPG stimulation was effective. Besides, a reduction of more than 50% in attack frequency as compared with baseline was shown in 33% of patients40. In a recent open-label study in 97 cluster headache patients receiving SPG stimulation, 43 out of 78 patients (55%) with chronic cluster headache experienced a more than 50% reduction in attack frequency after 12 months of stimulation41.

These results indicate that SPG stimulation could be a preventative treatment as well as an acute attack treatment. In the study by Jürgens et al.40, cluster attack frequency was defined as the average weekly attack frequency over a 4-week period at baseline compared with a 4-week period after 24 months. It is known that cluster attack frequency can fluctuate over time in patients with chronic cluster headache. This natural fluctuation could be part of the reduction found in these studies.

At present, a randomized controlled trial is investigating both the safety and the efficacy of SPG stimulation in chronic cluster headache17. The SPG can also be targeted by a block or radiofrequency ablation. Available studies on SPG blocks include one small double-blind, placebo-controlled study in 15 patients with cluster headache that studied pain relief after a block with cocaine or lidocaine compared with a saline solution in nitroglycerine-induced attacks. Pain relief was reported after 31.3 (cocaine) and 37 (lidocaine) versus 59.3 (saline) minutes. One small cohort study showed statistically improved attack intensity and frequency in 15 chronic cluster headache patients up to 18 months after radiofrequency ablation. Additional evidence consists of case series or case reports using different types of blocking agent. Sufficient evidence to show the effectiveness of these treatments is lacking42.

Conclusions

Here, we have given a short clinical overview of recent developments in the field of cluster headache treatment. Medication targeting CGRP and several neuromodulation techniques are currently being investigated. Promising results from many of the studies conducted up to now give hope for more effective treatments and treatment choices for this very severe pain syndrome in the future.

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

F1000 recommended

References

  • 1.  Headache Classification Committee of the International Headache Society (IHS): The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013; 33(9): 629–808. PubMed Abstract | Publisher Full Text
  • 2.  Bahra A, May A, Goadsby PJ: Cluster headache: a prospective clinical study with diagnostic implications. Neurology. 2002; 58(3): 354–61. PubMed Abstract | Publisher Full Text
  • 3.  Jensen RM, Lyngberg A, Jensen RH: Burden of cluster headache. Cephalalgia. 2007; 27(6): 535–41. PubMed Abstract | Publisher Full Text
  • 4.  Ertsey C, Manhalter N, Bozsik G, et al.: Health-related and condition-specific quality of life in episodic cluster headache. Cephalalgia. 2004; 24(3): 188–96. PubMed Abstract | Publisher Full Text
  • 5.  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(10): 818–21. PubMed Abstract | Publisher Full Text
  • 6.  Robbins MS, Starling AJ, Pringsheim TM, et al.: Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016; 56(7): 1093–106. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 7.  Hedlund C, Rapoport AM, Dodick DW, et al.: Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. Headache. 2009; 49(9): 1315–23. PubMed Abstract | Publisher Full Text
  • 8.  Law S, Derry S, Moore RA: Triptans for acute cluster headache. Cochrane Database Syst Rev. 2010; (4): CD008042. PubMed Abstract | Publisher Full Text | Free Full Text
  • 9.  Hakim SM: Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache. 2011; 51(5): 713–25. PubMed Abstract | Publisher Full Text
  • 10.  Leone M, D'Amico D, Moschiano F, et al.: Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996; 16(7): 494–6. PubMed Abstract | Publisher Full Text
  • 11.  Cohen AS, Matharu MS, Goadsby PJ: Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007; 69(7): 668–75. PubMed Abstract | Publisher Full Text
  • 12.  Goadsby PJ, Edvinsson L: Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994; 117(Pt 3): 427–34. PubMed Abstract | Publisher Full Text
  • 13.  Nicolodi M, Del Bianco E: Sensory neuropeptides (substance P, calcitonin gene-related peptide) and vasoactive intestinal polypeptide in human saliva: their pattern in migraine and cluster headache. Cephalalgia. 1990; 10(1): 39–50. PubMed Abstract | Publisher Full Text
  • 14.  Fanciullacci M, Alessandri M, Figini M, et al.: Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain. 1995; 60(2): 119–23. PubMed Abstract | Publisher Full Text
  • 15.  Fanciullacci M, Alessandri M, Sicuteri R, et al.: Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain. 1997; 120(Pt 2): 283–8. PubMed Abstract | Publisher Full Text
  • 16.  Khan S, Olesen A, Ashina M: CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data. Cephalalgia. 2017; 333102417741297. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 17.  www.clinicaltrials.gov.
  • 18.  Magis D, Schoenen J: Advances and challenges in neurostimulation for headaches. Lancet Neurol. 2012; 11(8): 708–19. PubMed Abstract | Publisher Full Text
  • 19.  Broggi G, Messina G, Franzini A: Cluster headache and TACs: rationale for central and peripheral neuromodulation. Neurol Sci. 2009; 30 Suppl 1: S75–9. PubMed Abstract | Publisher Full Text
  • 20.  Goadsby PJ, Bartsch T, Dodick DW: Occipital nerve stimulation for headache: mechanisms and efficacy. Headache. 2008; 48(2): 313–8. PubMed Abstract | Publisher Full Text
  • 21.  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. Lancet Neurol. 2011; 10(10): 891–7. PubMed Abstract | Publisher Full Text
  • 22.  Peres MF, Stiles MA, Siow HC, et al.: Greater occipital nerve blockade for cluster headache. Cephalalgia. 2002; 22(7): 520–2. PubMed Abstract | Publisher Full Text
  • 23.  Ambrosini A, Vandenheede M, Rossi P, et al.: Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study. Pain. 2005; 118(1–2): 92–6. PubMed Abstract | Publisher Full Text
  • 24.  Gantenbein AR, Lutz NJ, Riederer F, et al.: Efficacy and safety of 121 injections of the greater occipital nerve in episodic and chronic cluster headache. Cephalalgia. 2012; 32(8): 630–4. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 25.  Afridi SK, Shields KG, Bhola R, et al.: Greater occipital nerve injection in primary headache syndromes--prolonged effects from a single injection. Pain. 2006; 122(1–2): 126–9. PubMed Abstract | Publisher Full Text
  • 26.  Lambru G, Abu Bakar N, Stahlhut L, et al.: Greater occipital nerve blocks in chronic cluster headache: a prospective open-label study. Eur J Neurol. 2014; 21(2): 338–43. PubMed Abstract | Publisher Full Text
  • 27.  Gaul C, Roguski J, Dresler T, et al.: Efficacy and safety of a single occipital nerve blockade in episodic and chronic cluster headache: A prospective observational study. Cephalalgia. 2017; 37(9): 873–80. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 28.  Burns B, Watkins L, Goadsby PJ: Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. 2009; 72(4): 341–5. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 29.  Magis D, Allena M, Bolla M, et al.: Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 2007; 6(4): 314–21. PubMed Abstract | Publisher Full Text
  • 30.  Leone M, Proietti Cecchini A, Messina G, et al.: Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. 2017; 37(8): 756–63. PubMed Abstract | Publisher Full Text | F1000 Recommendation
  • 31.  Fontaine D, Christophe Sol J, Raoul S, et al.: Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia. 2011; 31(10): 1101–5. PubMed Abstract | Publisher Full Text
  • 32.  Wilbrink LA, Teernstra OP, Haan J, et al.: Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: rationale and protocol of a randomised trial. Cephalalgia. 2013; 33(15): 1238–47. PubMed Abstract | Publisher Full Text
  • 33.  gammaCore®, the First Non-Invasive Vagus Nerve Stimulator Applied at the Neck, Now Available for Adult Patients in the U.S. 2017. Reference Source
  • 34.  Nesbitt AD, Marin JC, Tompkins E, et al.: Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment. Neurology. 2015; 84(12): 1249–53. PubMed Abstract | Publisher Full Text
  • 35.  Gaul C, Diener HC, Silver N, et al.: Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016; 36(6): 534–46. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 36.  Silberstein SD, Mechtler LL, Kudrow DB, et al.: Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study. Headache. 2016; 56(8): 1317–32. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 37.  Silberstein SD, Calhoun AH, Treppendahl C, et al.: The emerging role of gammaCore® in the management of cluster headache: expert panel recommendations. Am J Manag Care. 2017; 23(17 Suppl): S326-S333. PubMed Abstract | F1000 Recommendation
  • 38.  Ansarinia M, Rezai A, Tepper SJ, et al.: Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches. Headache. 2010; 50(7): 1164–74. PubMed Abstract | Publisher Full Text
  • 39.  Schoenen J, Jensen RH, Lantéri-Minet M, et al.: Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013; 33(10): 816–30. PubMed Abstract | Publisher Full Text | Free Full Text
  • 40.  Jürgens TP, Barloese M, May A, et al.: Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia. 2017; 37(5): 423–34. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 41.  Barloese M, Petersen A, Stude P, et al.: Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry. J Headache Pain. 2018; 19(1): 6. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation
  • 42.  Ho KWD, Przkora R, Kumar S: Sphenopalatine ganglion: block, radiofrequency ablation and neurostimulation - a systematic review. J Headache Pain. 2017; 18(1): 118. PubMed Abstract | Publisher Full Text | Free Full Text | F1000 Recommendation

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 20 Mar 2018
  • Reader Comment 07 Jun 2018
    Cindy Reynolds
    07 Jun 2018
    Reader Comment
    LEVEL A (treatment is established to be effective for the condition in the specific population; requires at least 2 consistent class I studies) : "Oxygen (100%, 6–12 L/minute) is a ... Continue reading
    Report a concern
  • Comment
Author details Author details
Competing interests
Grant information
Article Versions (1)
Copyright
Download
 
Export To
metrics
Views Downloads
F1000Research - -
PubMed Central
Data from PMC are received and updated monthly.
 - -
Citations
SEE MORE DETAILS
CITE
how to cite this article
Doesborg P and Haan J. Cluster headache: new targets and options for treatment [version 1; peer review: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.12688/f1000research.13380.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 20 Mar 2018
Views
0
Cite
Reviewer Report 20 Mar 2018
Patricia Pozo-Rosich, Headache Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain;  Headache Research Group, Vall d'Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain 
Approved
VIEWS 0
https://doi.org/10.5256/f1000research.14527.r31911
I confirm that I have read this submission and believe that I have an ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Pozo-Rosich P. Reviewer Report For: Cluster headache: new targets and options for treatment [version 1; peer review: 2 approved]. F1000Research 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.5256/f1000research.14527.r31911)
The direct URL for this report is:
https://f1000research.com/articles/7-339/v1#referee-response-31911
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Report a concern
Views
0
Cite
Reviewer Report 20 Mar 2018
Andreas Straube, Department of Neurology, Ludwig-Maximilian University, Munich, Germany 
Approved
VIEWS 0
https://doi.org/10.5256/f1000research.14527.r31910
I confirm that I have read this submission and believe that I have an ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Straube A. Reviewer Report For: Cluster headache: new targets and options for treatment [version 1; peer review: 2 approved]. F1000Research 2018, 7(F1000 Faculty Rev):339 (https://doi.org/10.5256/f1000research.14527.r31910)
The direct URL for this report is:
https://f1000research.com/articles/7-339/v1#referee-response-31910
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Report a concern

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 20 Mar 2018
  • Reader Comment 07 Jun 2018
    Cindy Reynolds
    07 Jun 2018
    Reader Comment
    LEVEL A (treatment is established to be effective for the condition in the specific population; requires at least 2 consistent class I studies) : "Oxygen (100%, 6–12 L/minute) is a ... Continue reading
    Report a concern
  • Comment

Open Peer Review

Reviewer Status

Alongside their report, reviewers assign a status to the article:

Approved
The paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved
Fundamental flaws in the paper seriously undermine the findings and conclusions

Reviewer Reports

Invited Reviewers
1 2
Version 1
20 Mar 18 		read read
  1. Andreas Straube, Ludwig-Maximilian University, Munich, Germany
  2. Patricia Pozo-Rosich, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain

Comments on this article

All Comments(1)

Add a comment
Sign up for content alerts

Browse by related subjects

    keyboard_arrow_left Back to all reports
    keyboard_arrow_left Back to all reports
    Alongside their report, reviewers assign a status to the article:
    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
    Sign In
    If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password.

    The email address should be the one you originally registered with F1000.
    Email address not valid, please try again

    You registered with F1000 via Google, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Google account password, please click here.

    You registered with F1000 via Facebook, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Facebook account password, please click here.

    Code not correct, please try again
    Email us for further assistance.
    Server error, please try again.