Cost-effectiveness analysis of non-invasive vagus nerve stimulation for the treatment of chronic cluster headache
© Morris et al. 2016
Received: 27 February 2016
Accepted: 7 April 2016
Published: 22 April 2016
Cluster headache (CH) is a debilitating condition that is generally associated with substantial health care costs. Few therapies are approved for abortive or prophylactic treatment. Results from the prospective, randomised, open-label PREVA study suggested that adjunctive treatment with a novel non-invasive vagus nerve stimulation (nVNS) device led to decreased attack frequency and abortive medication use in patients with chronic CH (cCH). Herein, we evaluate whether nVNS is cost-effective compared with the current standard of care (SoC) for cCH.
A pharmacoeconomic model from the German statutory health insurance perspective was developed to estimate the 1-year cost-effectiveness of nVNS + SoC (versus SoC alone) using data from PREVA. Short-term treatment response data were taken from the clinical trial; longer-term response was modelled under scenarios of response maintenance, constant rate of response loss, and diminishing rate of response loss. Health-related quality of life was estimated by modelling EQ-5D™ data from PREVA; benefits were defined as quality-adjusted life-years (QALY). Abortive medication use data from PREVA, along with costs for the nVNS device and abortive therapies (i.e. intranasal zolmitriptan, subcutaneous sumatriptan, and inhaled oxygen), were used to assess health care costs in the German setting.
The analysis resulted in mean expected yearly costs of €7096.69 for nVNS + SoC and €7511.35 for SoC alone and mean QALY of 0.607 for nVNS + SoC and 0.522 for SoC alone, suggesting that nVNS generates greater health benefits for lower overall cost. Abortive medication costs were 23 % lower with nVNS + SoC than with SoC alone. In the alternative scenarios (i.e. constant rate of response loss and diminishing rate of response loss), nVNS + SoC was more effective and cost saving than SoC alone.
In all scenarios modelled from a German perspective, nVNS was cost-effective compared with current SoC, which suggests that adjunctive nVNS therapy provides economic benefits in the treatment of cCH. Notably, the current analysis included only costs associated with abortive treatments. Treatment with nVNS will likely promote further economic benefit when other potential sources of cost savings (e.g. reduced frequency of clinic visits) are considered.
Clinicaltrials.gov identifier NCT01701245, 03OCT2012.
KeywordsChronic cluster headache Vagus nerve stimulation Non-invasive Cost-effectiveness Germany Pharmacoeconomics United Kingdom
Cluster headache (CH) is a debilitating condition associated with intense pain and cranial autonomic symptoms, which cause marked disability . The disorder adversely affects quality of life  and is associated with substantial health care costs (more than €11,000 per year) . The condition can be chronic or episodic. Both direct costs (e.g. medication, clinic visits) and indirect costs (e.g. reduced work capacity) have been found to be substantially higher for patients with chronic CH (cCH) than for those with episodic CH . Few drugs (e.g. subcutaneous [SC] sumatriptan, intranasal [IN] zolmitriptan, and dihydroergotamine [DHE] injection) are approved by various regulatory agencies for abortive treatment [4, 5]. Lithium is approved for CH prophylaxis in Germany  and is used off-label in other areas. Other agents such as verapamil and topiramate are also used off-label despite a lack of rigorous, well-controlled studies to support their use in the prevention of CH attacks [7–9]. Although short-term methylprednisone therapy may be effective in CH prophylaxis, several safety concerns preclude its long-term use .
Vagus nerve stimulation (VNS) is a neuromodulatory technique that is well established for epilepsy and depression and has been applied to a variety of other disorders including Alzheimer disease, migraine, and CH [10–12]. It is thought to suppress pain through inhibition of vagal afferents in the trigeminal nucleus caudalis (TNC)  and by blocking or reversing increases in TNC glutamate levels ; VNS has also been implicated in modulation of the cholinergic anti-inflammatory pathway [15–17].
In an initial open-label study (N = 19), non-invasive vagus nerve stimulation (nVNS) was found to be effective in the prevention and treatment of CH . Subsequently, a larger (N = 97), prospective, open-label, randomised study (PREVA ) evaluated the safety and efficacy of adjunctive treatment with a novel nVNS device (gammaCore®) in patients with cCH. In the PREVA trial, compared with standard of care (SoC) alone, adjunctive nVNS (nVNS + SoC) was associated with significantly greater decreases from baseline in the number of CH attacks per week and the use of abortive medications. Compared with SoC alone, nVNS + SoC was also associated with a significantly higher response rate (i.e. the proportion of participants with a ≥50 % reduction from baseline in the number of CH attacks per week; 40 % for nVNS + SoC vs 8.3 % for SoC alone, P < 0.001) and significantly greater improvements from baseline in quality-of-life measures, with no serious treatment-related adverse events.
The present analysis was undertaken to quantify the economic impact of nVNS therapy in patients with cCH. By developing a pharmacoeconomic model and applying it to data from the PREVA study, we evaluated whether nVNS is a cost-effective treatment option compared with the current standard practice in a European setting. Analysis using German costs is the focus of this paper because Germans represented the largest proportion of PREVA participants. To corroborate our findings and widen their applicability, we conducted a similar analysis using UK costs, which is briefly described in the Discussion section.
Model structure and parameter estimates
To estimate the probability of response in the base case analysis, subjects from the nVNS + SoC group who were responders throughout the extension phase were assumed to maintain this response until the end of the model time horizon (1 year). In addition to the base case analysis, 3 alternative scenarios were explored. An exponential survival curve function was fitted to data from patients in the nVNS + SoC group on the basis of their response statuses at the end of the randomised phase and at the end of the extension phase. In the first alternative scenario, the exponential function was used to predict patient response status beyond 4 weeks (i.e. beyond the randomised phase) assuming a constant monthly rate (~31 %) of response loss throughout the course of the model. The second scenario was modelled assuming a diminishing rate of response loss; that is, the rate at which response was lost beyond 4 weeks (as predicted by the exponential function) was reduced by a fixed percentage (10 %) each month. In the final scenario, no patients in the SoC-alone group were assumed to have responded initially, and all other assumptions were the same as in the base case.
Benefits in this analysis were defined as quality-adjusted life-years (QALY). Health-related quality of life (HRQoL) for responders and non-responders was estimated by modelling EQ-5D™ index data from PREVA in an ordinary least squares regression analysis to control for potential imbalances at baseline between treatment arms. Results from the regression analysis suggested that response was associated with an increase of 0.2366 in EQ-5D index score and that nVNS therapy (regardless of response) was associated with an increase of 0.01246 in EQ-5D index score. Using the German tariff, HRQoL utility scores were estimated for responders and non-responders and applied to the model states (the UK tariff was applied for the UK analysis).
Abortive medication use during the last 14 days of the PREVA randomised phase
No. of uses, mean (SD)
nVNS + SoC (n = 45)
SoC alone (n = 48)
Unit cost of treatments
Cost per dose, €
AscoTop ® Nasal 5 mg/Dosis Nasenspray, Solution €86.22: 6 single-dose nasal sprays, PZN 03107201
Sumatriptan-Hormosan Inject 6 mg/0.5-mL Solution €64.40: 2 pre-filled syringes, PZN 04700154
Estimated cost per CH attack
gammaCore device pre-loaded with 300 stimulations
Parameters for the probabilistic sensitivity analysis
Probability of response with nVNS + SoC
Probability of response with SoC alone
Probability of discontinued response
Utility score (nVNS + SoC responder)
Utility score (nVNS + SoC non-responder)
Utility score (SoC alone responder)
Utility score (SoC alone non-responder)
Resource use per 14 days
With nVNS + SoC
With SoC alone
Base casea cost-effectiveness analysis
Mean cost, €
nVNS + SoC
nVNS dominant over SoCc
Alternative scenarios and sensitivity analysis
Cost-effectiveness analysis for alternative scenarios
Mean cost, €
Constant rate of response loss
nVNS + SoC
nVNS dominant over SoCb
Diminishing rate of response loss
nVNS + SoC
nVNS dominant over SoCb
No response for SoC
nVNS + SoC
nVNS dominant over SoCb
Cost-effectiveness sensitivity analysis (4 late responders excluded)
Mean cost, €
nVNS + SoC
nVNS dominant over SoCb
Constant rate of response loss
nVNS + SoC
nVNS dominant over SoCb
Diminishing rate of response loss
nVNS + SoC
nVNS dominant over SoCb
The treatment of CH is challenging, and many of the commonly used abortive and preventive medications are associated with serious safety risks, poor tolerability, and/or marginal efficacy. For acute treatment, triptans are contraindicated in patients with cardiovascular disease [25, 26]. Drug costs or restrictions on prescribing and/or coverage may further limit triptan accessibility for many patients [27, 28]. Long-term frequent use of triptans, as may be needed for cCH management, can in turn lead to the development of medication overuse headache [29, 30], which, although rare, has been reported in patients with CH [31, 32]. Oxygen may delay rather than abort CH attacks in some patients and has portability limitations [25, 26], and DHE may be associated with fibrosis (e.g. cardiac, pulmonary, pleural), ergotism, and chest tightness [26, 33]. For prophylactic treatment, verapamil has a high potential for drug interactions, and the large dosages required for CH treatment are associated with adverse cardiac events such as arrhythmias, as well as oedema . Lithium requires progressive titration and frequent drug-level monitoring because of its narrow therapeutic window and the risk of toxicity [25, 26, 34], and topiramate is often poorly tolerated owing to its cognitive side effects . Thus, more practical and cost-effective treatment approaches for CH are needed. Results from the PREVA study  suggest that in addition to reducing the frequency of CH attacks, adjunctive nVNS therapy may decrease the need for abortive medications and improve quality of life in patients with cCH. The current pharmacoeconomic analysis indicates that adjunctive nVNS is likely to result in cost savings when compared with SoC alone. Notably, the present analysis was conservative in that it included only the costs associated with use of abortive medications without accounting for other potential sources of cost savings (e.g. reduced frequency of clinic visits, fewer hospitalisations, increased productivity).
Currently, there are few good options for acute or prophylactic treatment of CH. Neuromodulation methods such as sphenopalatine ganglion (SPG) stimulation and occipital nerve stimulation (ONS) have shown some promise in CH prevention, but most studies of these techniques have been small and/or have lacked control arms [35, 36]. Furthermore, SPG and ONS are invasive, expensive, and associated with risks inherent with implanted devices (e.g. infection, pain at the site of implantation, electrode migration). The findings that nVNS is effective in cCH prophylaxis , is not associated with risks that are inherent in invasive neuromodulation methods, and offers cost savings over the current standard practice suggest that this therapy warrants a prominent place in the management of cCH.
The current analysis is subject to certain limitations. The PREVA study provided data from an 8-week period, which were extrapolated to assess cost-effectiveness over 1 year. Although there have been few cost-effectiveness evaluations of neuromodulatory techniques for the treatment of primary headache disorders, such studies have generally included time horizons of at least 3 years [37–39]. Considering the time frame of PREVA, a 1-year time horizon was chosen for this analysis to preserve robustness and to avoid introducing unnecessary uncertainty. As in patients with epilepsy , evidence suggests that patients with headache may have improved response to VNS with longer-term treatment [41, 42]. Although increases in response rate with long-term VNS have yet to be explored in CH, the current analysis could be viewed as conservative because the duration of PREVA may not have allowed demonstration of the full benefit of nVNS.
Recently, the National Institute for Health and Care Excellence (NICE) Interventional Procedures Advisory Committee noted that the relapsing/remitting nature of CH and migraines as well as the potential for placebo effects should be considered when interpreting evidence of treatment efficacy for these conditions . Indeed, because periods of relapse and remission are common among patients with primary headache disorders, research in this area may be susceptible to regression artefacts [44, 45]. However, the PREVA study included data from patients with cCH only. By International Classification of Headache Disorders definition , cCH is not associated with extended periods of remission (i.e. ≥1 month), suggesting that the phenomenon of regression to the mean (e.g. aberrantly high attack frequency at baseline followed by a decrease in attack frequency regardless of treatment group) would not be expected. Because the PREVA study lacked a sham treatment group, the degree to which the placebo effect might have contributed to the cost-effectiveness of nVNS is unclear. Nevertheless, the clinically relevant design of the PREVA study was valuable in that it allowed for observation of medication use in a control group that likely reflects real-world use.
As with any probabilistic analysis, some degree of uncertainty is inherent in the current investigation. To address this, a sensitivity analysis and a range of alternative scenarios were included, and results from all of these suggested that nVNS + SoC was more effective and cost saving than SoC alone. Results were relatively insensitive to assumptions about late responders in the nVNS + SoC arm. In the sensitivity analysis, where the 4 late-responding patients were classified as non-responders, nVNS + SoC was dominant over SoC alone in all modelled scenarios.
The current analysis cannot be directly extrapolated across all of Europe because it evaluates cost-effectiveness from a German health insurance perspective. To explore the generalisability of our findings, we conducted the same analysis from a UK perspective and found similar results. For the base case, the probabilistic analysis resulted in mean expected costs of £5409.83 for nVNS + SoC and £5393.31 for SoC alone and mean QALY of 0.538 for nVNS + SoC and 0.438 for SoC alone. The incremental cost-effectiveness ratio of nVNS + SoC was £166.12, and 47 % of the probabilistic simulations resulted in cost savings for nVNS + SoC over SoC alone (J. Morris, unpublished data, 2016). The degree to which these results can be generalised to other countries may vary depending on specific drug prices and the availability of generic medications in those markets.
Lastly, the current cost-effectiveness projections included only the costs associated with the use of abortive treatments. This suggests that our analysis is conservative, as data on additional health care resource use (e.g. clinic visits) would likely lead to a disproportionate cost increase for the SoC-alone group. Likewise, potential health benefits from decreased use of abortive medications (e.g. drug-related side effects) and effects on indirect costs (e.g. increased work capacity), which could further enhance the economic profile of nVNS, were not considered herein. The economic benefits of nVNS could be established with greater certainty by incorporating additional cost components into future studies.
The current study provides evidence of the efficacy and economic benefits of nVNS therapy for patients with cCH in the context of the German and UK health care systems. In all scenarios modelled, nVNS was more cost-effective than the current standard practice. These findings are especially meaningful given the substantial economic burden associated with CH  and considering that new technologies are cited as major drivers of increasing health care expenditures [47, 48]. Our results suggest that new technologies such as nVNS may help decrease overall treatment costs, information that likely will be important to clinicians, patients, and payers when treatment decisions are made.
Availability of data and materials
Clinical data from the PREVA study are available in the following publication: Gaul C, et al (2015) Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study [Published online September 21]. Cephalalgia. doi:10.1177/0333102415607070.
Economic data supporting the conclusions in this manuscript are on file at Cogentia Healthcare Consulting Ltd. and electroCore, LLC, and are confidential in order to support economic filings in the affected countries.
chronic cluster headache
health-related quality of life
National Institute for Health and Care Excellence
non-invasive vagus nerve stimulation
occipital nerve stimulation
standard of care
trigeminal nucleus caudalis
vagus nerve stimulation
Technical and editorial support for this manuscript was provided by Elizabeth Barton, MS, of MedLogix Communications, LLC, and funded by electroCore, LLC.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Martelletti P, Mitsikostas DD (2015) Cluster headache: a quasi-rare disorder needing a reappraisal. J Headache Pain 16:59. doi:10.1186/s10194-015-0545-1 View ArticlePubMedPubMed CentralGoogle Scholar
- Jürgens TP, Gaul C, Lindwurm A, Dresler T, Paelecke-Habermann Y, Schmidt-Wilcke T, Lürding R, Henkel K, Leinisch E (2011) Impairment in episodic and chronic cluster headache. Cephalalgia 31(6):671–682. doi:10.1177/0333102410391489 View ArticlePubMedGoogle Scholar
- Gaul C, Finken J, Biermann J, Mostardt S, Diener HC, Müller O, Wasem J, Neumann A (2011) Treatment costs and indirect costs of cluster headache: a health economics analysis. Cephalalgia 31(16):1664–1672. doi:10.1177/0333102411425866 View ArticlePubMedGoogle Scholar
- Hedlund C, Rapoport AM, Dodick DW, Goadsby PJ (2009) Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. Headache 49(9):1315–1323. doi:10.1111/j.1526-4610.2009.01518.x View ArticlePubMedGoogle Scholar
- D.H.E. 45 [package insert]. Aliso Viejo, CA: Valeant Pharmaceuticals North America; 2014.
- Holle D, Burmeister J, Scherag A, Ose C, Diener HC, Obermann M, Pred CH Study Group (2013) Study protocol of Prednisone in episodic Cluster Headache (PredCH): a randomized, double-blind, placebo-controlled parallel group trial to evaluate the efficacy and safety of oral prednisone as an add-on therapy in the prophylactic treatment of episodic cluster headache with verapamil. BMC Neurol 13:99. doi:10.1186/1471-2377-13-99 View ArticlePubMedPubMed CentralGoogle Scholar
- Francis GJ, Becker WJ, Pringsheim TM (2010) Acute and preventive pharmacologic treatment of cluster headache. Neurology 75(5):463–473. doi:10.1212/WNL.0b013e3181eb58c8 View ArticlePubMedGoogle Scholar
- Freitag FG, Schloemer F (2014) Medical management of adult headache. Otolaryngol Clin North Am 47(2):221–237. doi:10.1016/j.otc.2013.11.002 View ArticlePubMedGoogle Scholar
- May A, Leone M, Afra J, Linde M, Sándor PS, Evers S, Goadsby PJ, Force ET (2006) EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol 13(10):1066–1077. doi:10.1111/j.1468-1331.2006.01566.x View ArticlePubMedGoogle Scholar
- Beekwilder JP, Beems T (2010) Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 27(2):130–138. doi:10.1097/WNP.0b013e3181d64d8a View ArticlePubMedGoogle Scholar
- Nesbitt AD, Marin JC, Tompkins E, Ruttledge MH, Goadsby PJ (2015) Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment. Neurology 84(12):1249–1253. doi:10.1212/WNL.0000000000001394 View ArticlePubMedGoogle Scholar
- Yuan H, Silberstein SD (2016) Vagus nerve and vagus nerve stimulation, a comprehensive review: part I. Headache 56(1):71–78. doi:10.1111/head.12647 View ArticlePubMedGoogle Scholar
- Bossut DF, Maixner W (1996) Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain 65(1):101–109View ArticlePubMedGoogle Scholar
- Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ (2014) Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain 155(5):1037–1042. doi:10.1016/j.pain.2014.02.009 View ArticlePubMedPubMed CentralGoogle Scholar
- Brock C, Errico JP, Simon B, Imthon AK, Drewes A, Aziz Q, Lerman I, Farmer AD (2015) A report on 2 studies of the effects of non-invasive vagus nerve stimulation (nVNS) on autonomic and inflammatory parameters in healthy humans. http://vnsociety.com/wp-content/uploads/2015/11/Brock-2015-WCI-Poster-A-Report-on-2-Studies-of-the-Effects-of-nVNS-on-Autonomic-and-Inflammatory-Parameters-in-Healthy-Humans.pdf. Accessed 2 December 2015
- Levine YA, Koopman FA, Faltys M, Caravaca A, Bendele A, Zitnik R, Vervoordeldonk MJ, Tak PP (2014) Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One 9(8):e104530. doi:10.1371/journal.pone.0104530 View ArticlePubMedPubMed CentralGoogle Scholar
- Olofsson PS, Levine YA, Caravaca A, Chavan SS, Pavlov VA, Faltys M, Tracey KJ (2015) Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia. Bioelectron Med 2:37–42. doi:10.15424/bioelectronmed.2015.00006
- Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, Liebler EJ, Straube A, PREVA Study Group (2015) Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study [Published online September 21]. Cephalalgia. doi:10.1177/0333102415607070
- Lauer-Taxe online, available by subscription (2015) http://www.lauer-fischer.de/LF. Accessed March 2015
- Briggs A, Sculpher M, Claxton K (2006) Decision modelling for health economic evaluation. Oxford University Press, Oxford, UKGoogle Scholar
- Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW (2015) Methods for the economic evaluation of health care programmes, 4th edn. Oxford University Press, Oxford, UKGoogle Scholar
- Boersma C, Broere A, Postma MJ (2010) Quantification of the potential impact of cost-effectiveness thresholds on Dutch drug expenditures using retrospective analysis. Value Health 13(6):853–856. doi:10.1111/j.1524-4733.2010.00736.x View ArticlePubMedGoogle Scholar
- Brouwer W, van Exel J, Baker R, Donaldson C (2008) The new myth: the social value of the QALY. Pharmacoeconomics 26(1):1–4View ArticlePubMedGoogle Scholar
- Simoens S (2010) How to assess the value of medicines? Front Pharmacol 1:115. doi:10.3389/fphar.2010.00115 View ArticlePubMedPubMed CentralGoogle Scholar
- Martelletti P (2015) Cluster headache management and beyond. Expert Opin Pharmacother 16(10):1411–1415. doi:10.1517/14656566.2015.1052741 View ArticlePubMedGoogle Scholar
- Pomeroy JL, Marmura MJ (2013) Pharmacotherapy options for the management of cluster headache. Clin Med Insight Ther 5:53–74. doi:10.4137/CMT.S10251 Google Scholar
- Khan S, Mascarenhas A, Moore JE, Knowles S, Gomes T (2015) Access to triptans for acute episodic migraine: a qualitative study. Headache 55(suppl 4):199–211. doi:10.1111/head.12593 View ArticlePubMedGoogle Scholar
- Amadio A, Lee K, Yao Z, Camacho X, Knowles S, Lay C, Paterson JM, Hunt J, Gomes T, Ontario Drug Policy Research Network (2015) Public drug coverage and its impact on triptan use across Canada: a population-based study. Headache 55(suppl 4):212–220. doi:10.1111/head.12508 View ArticlePubMedGoogle Scholar
- Saper JR, Da Silva AN (2013) Medication overuse headache: history, features, prevention and management strategies. CNS Drugs 27(11):867–877. doi:10.1007/s40263-013-0081-y View ArticlePubMedGoogle Scholar
- Silberstein SD Medication overuse headache. http://www.americanheadachesociety.org/assets/1/7/Stephen_Silberstein_-_Medication_Overuse_Headache.pdf. Accessed 12 January 2016
- Paemeleire K, Evers S, Goadsby PJ (2008) Medication-overuse headache in patients with cluster headache. Curr Pain Headache Rep 12(2):122–127View ArticlePubMedGoogle Scholar
- Goadsby PJ, Cittadini E, Burns B, Cohen AS (2008) Trigeminal autonomic cephalalgias: diagnostic and therapeutic developments. Curr Opin Neurol 21(3):323–330. doi:10.1097/WCO.0b013e3282fa6d76 View ArticlePubMedGoogle Scholar
- European Medicines Agency (2013) CHMP referral assessment report: ergot derivatives containing medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ergot_derivatives-containing_products/WC500161303.pdf. Accessed 10 November 2015
- Lee DC, Gupta A (2015) Lithium toxicity. http://emedicine.medscape.com/article/815523-overview. Accessed 8 February 2016
- Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, Caparso A, May A (2013) Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 33(10):816–830. doi:10.1177/0333102412473667 View ArticlePubMedPubMed CentralGoogle Scholar
- Schwedt TJ, Vargas B (2015) Neurostimulation for treatment of migraine and cluster headache. Pain Med 16(9):1827–1834. doi:10.1111/pme.12792 View ArticlePubMedGoogle Scholar
- Pietzsch JB, Garner A, Gaul C, May A (2015) Cost-effectiveness of stimulation of the sphenopalatine ganglion (SPG) for the treatment of chronic cluster headache: a model-based analysis based on the Pathway CH-1 study. J Headache Pain 16:530. doi:10.1186/s10194-015-0530-8 View ArticlePubMedGoogle Scholar
- Jenkins B, Tepper SJ (2011) Neurostimulation for primary headache disorders: part 2, review of central neurostimulators for primary headache, overall therapeutic efficacy, safety, cost, patient selection, and future research in headache neuromodulation. Headache 51(9):1408–1418. doi:10.1111/j.1526-4610.2011.01967.x
- Leone M, Franzini A, Cecchini AP, Mea E, Broggi G, Bussone G (2009) Costs of hypothalamic stimulation in chronic drug-resistant cluster headache: preliminary data. Neurol Sci 30(suppl 1):S43–47. doi:10.1007/s10072-009-0057-3 View ArticlePubMedGoogle Scholar
- Elliott RE, Morsi A, Tanweer O, Grobelny B, Geller E, Carlson C, Devinsky O, Doyle WK (2011) Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS > 10 years. Epilepsy Behav 20(3):478–483. doi:10.1016/j.yebeh.2010.12.042 View ArticlePubMedGoogle Scholar
- Silberstein SD, Da Silva AN, Calhoun AH, Grosberg BM, Lipton RB, Cady RK, Goadsby PJ, Simmons K, Mullin C, Saper JR, Liebler EJ (2014) Chronic migraine prevention with non-invasive vagus nerve stimulation in a prospective pilot study (the EVENT study): report from the open-label phase. Presented at: 56th Annual Scientific Meeting of the American Headache Society. June 26-29, 2014. http://www.ecorelibrary.com/landing/pdf/AHS%20EVENT%20Double-blind%20Poster_PRINT%206-24-14.pdf
- Yuan H, Silberstein SD (2015) Vagus nerve stimulation and headache. Headache. doi:10.1111/head.12721
- National Institute for Health and Care Excellence (2015) Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. http://www.nice.org.uk/guidance/GID-IP1116/documents/interventional-procedure-consultation-document. Published November 2015. Accessed 11 January 2016
- Houle TT, Turner DP, Houle TA, Smitherman TA, Martin V, Penzien DB, Lipton RB (2013) Rounding behavior in the reporting of headache frequency complicates headache chronification research. Headache 53(6):908–919. doi:10.1111/head.12126 View ArticlePubMedPubMed CentralGoogle Scholar
- Turner DP, Smitherman TA, Penzien DB, Lipton RB, Houle TT (2013) Rethinking headache chronification. Headache 53(6):901–907. doi:10.1111/head.12127 View ArticlePubMedPubMed CentralGoogle Scholar
- Headache Classification Committee of the International Headache Society (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33(9):629–808. doi:10.1177/0333102413485658 View ArticleGoogle Scholar
- Skinner JS (2013) The costly paradox of health-care technology. MIT Tech Rev http://www.technologyreview.com/news/518876/the-costly-paradox-of-health-care-technology/. Published September 5, 2013. Accessed 8 December 2015
- Regalado A (2013) We need a Moore's law for medicine. MIT Tech Rev http://www.technologyreview.com/news/518871/we-need-a-moores-law-for-medicine/. Published September 3, 2013. Accessed 8 December 2015