REVIEW URRENT C OPINION
Noninvasive neuromodulation in cluster headache Miguel J.A. La´inez a and Rigmor Jensen b
Purpose of review Neuromodulation is an alternative in the management of medically intractable cluster headache patients. Most of the techniques are invasive, but in the last 2 years, some studies using a noninvasive device have been presented. The objective of this article is to review the data using this approach. Recent findings Techniques as occipital nerve stimulation or sphenopalatine ganglion stimulation are recommended as firstline therapy in refractory cluster patients, but they are invasive and maybe associated with complications. Noninvasive vagal nerve stimulation with an external device has been tried in cluster patients. Results from clinical practice and a single randomized clinical trial have been presented showing a reduction of the number of cluster attacks/week in the patients treated with the device. The rate of adverse events was low and most of them were mild. Summary In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in cluster refractory patients. Noninvasive approaches such as the noninvasive vagal nerve stimulation have shown efficacy in one trial and could be an easier alternative in the management of this debilitating headache. We need to replicate these results with further controlled studies and conduct basic research in order to clarify the mechanism of action. Keywords cluster headache, neuromodulation, noninvasive stimulation, vagal stimulation
INTRODUCTION Cluster headache is a severe, debilitating disorder with pain that ranks among the most severe known to humans [1]. It is well defined in the third edition of The International Classification of Headache Disorders (ICHD-3 beta 2013); typically is presented with accompanying autonomic symptoms ipsilateral to the pain, including conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid or periorbital edema, forehead and facial sweating, mitosis or ptosis, and a sense of restlessness or agitation. Cluster headaches can occur up to eight times a day and each attack typically last between 15 min and 3 h. Episodic cluster headache occurs in periods lasting 1 week to 1 year, separated by painfree periods of 1 month or longer [2]. Approximately 10–15% of patients are suffering from chronic cluster headache (CCH), with headaches occurring without remission or with remission lasting less than 1 month during a year. Although cluster headache is an invalidating and clinically clear-cut disorder, it is still frequently unrecognized and/or mistaken for other disorders [3]. Patients with cluster headaches have few therapeutic options and further, 10–20% patients develop
drug-resistant attacks [4]. Although subcutaneous triptan injections [5] and inhaled high-flow oxygen [6] provide relief to some patients some of the time, the next attacks are not prevented and many patients are severely affected and disabled. Sumatriptan is contraindicated in ischemic heart disease, stroke, uncontrolled hypertension, and peripheral vascular disease. Furthermore, triptans are limited to a maximum of twice-daily dosing, the injectable form is very expensive and not available in many countries. Although oxygen-inhalation therapy (100%, 12 L/ min for 15 min via a face mask) can be effective in the early stage of the attack [6], it may be associated with attack recurrence and it has significant practical
a
Department of Neurology, Clinic University Hospital, Catholic University of Valencia, Valencia, Spain and bDepartment of Neurology, Danish Headache Center, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark Correspondence to Miguel J.A. La´inez, MD, PhD, Department of Neurology, Hospital Clı´nico Universitario, Universidad Cato´lica de Valencia, Avda. Blasco Iba´n˜ez, 17 46010 Valencia, Spain. Tel: +34 961973981; fax: +34 963900321; e-mail: [email protected] Curr Opin Neurol 2015, 28:271–276 DOI:10.1097/WCO.0000000000000196
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Headache
KEY POINTS Cluster headache is one of most debilitating headache syndromes, especially when it is refractory to medical treatment. Invasive neuromodulation treatments have demonstrated good efficacy in the management of medically refractory patients, but with potential complications for the patient. nVNS has been efficacious reducing the number of attacks with good tolerability. nVNS could be an interesting alternative, but the results should be replicated in randomized controlled studies.
limitations because of the size and cumbersomeness of the required oxygen tanks. The socioeconomic burden of cluster headache on individuals and society is quite high because of the direct costs of healthcare services, and the indirect costs of lost work days and decreased work efficacy. A Danish report showed that 43.5% of cluster patients had seen specialists, approximately 30% had missed work, and 78% reported restrictions in daily living [7]. A recent German study showed that a patient with typical CCH cost the healthcare system over s21,000 per year [8]. The often brief duration of cluster attacks makes abortive therapy a challenge. Transition treatments with steroids and preventive medications, such as verapamil, lithium carbonate, divalproex sodium (valproate), and topiramate among others, are almost always provided to patients. The side-effects of these preventive medications can be significant, ranging from nausea and fatigue to hypotension, bradycardia, atrioventricular block, paresthesias, or psychomotor slowing, and although these medications may be better tolerated when used for cluster headache than other headache types [9], the adverse events are a limiting factor in the treatment. None of these preventive medications are, however, approved by the U.S. Food and Drug Administration for the treatment of cluster headache. Given the relentless nature of their disorder, cluster patients desperately continue to search for new, effective therapies to treat their headaches.
Modern neurostimulation had its genesis in a parallel expansion of functional neurosurgery, which focused on the placement of ablative brain lesions to treat disabling symptoms of movement disorders. Initially, with a view to avoiding ablative lesions, the neuromodulation techniques started using deep brain stimulation (DBS), which is a surgical therapy that involves the delivery of an electrical current to one or more brain targets. With time, stimulation techniques changed their target and now DBS is not always deep, not always brain, and not always simply stimulation; a more accurate term for this field may be electrical neuro-network modulation [11]. Electrical neuromodulation refers to adjustable manipulation of central or peripheral pain pathways with electrical current for the purpose of reversible modification of the nociceptive system function using implantable devices. Many targets for treating craniofacial pain via neuromodulation have been described, including trigeminal nerve and ganglion, vagus nerve, sphenopalatine ganglion (SPG), peripheral (occipital) nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex [12]. The basis for peripheral stimulation started with the publication of the ‘Gate Control Theory’ of pain modulation in 1965, by Melzack and Wall [13], that provided a conceptual mechanistic foundation for considering direct electrical stimulation of the spinal cord and peripheral nerves as a potential treatment for chronic pain. Electrical stimulation of peripheral nerves results in pain modulation by direct effects on the stimulated nerve and secondary effects on the central nervous system [14]. Peripheral nerve stimulation (PNS) therapies for chronic pain developed in parallel to spinal cord stimulation. Over the 1970s and 1980s, some studies showed positive responses to open surgical PNS implants in patients with various neuropathic pain syndromes [15], with few studies including isolated patients with occipital neuralgia. Attention to the potential of this methodology as a treatment for head pain came after a publication that showed that implanted occipital nerve stimulators (ONS) with percutaneously placed leads could be an alternative in the treatment for intractable occipital neuralgia [16].
NEUROSTIMULATION
NEUROSTIMULATION INVASIVE TECHNIQUES
The use of electrical stimulation of the nervous system for the treatment of headaches is not new. In the first century A.D., the physician Scribonius Largus used the electric fish Torpedo marmorata to reduce head pain of Claudius, the Roman emperor [10].
In the treatment of refractory cluster headache, both DBS and PNS have been used. DBS of the posterior–inferior hypothalamus has been proposed by Leone et al. [17] after the identification of the presumed generator of the pain in the posterior
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Noninvasive neuromodulation in cluster headache La´inez and Jensen
hypothalamus. Until now, around 60 patients treated with this technique have been reported in the literature but the total number of implants is unknown, as a register of all patients with DBS is not established. In 60% of the reported cases, the attack frequency decreased more than 50%, including 30–40% of patients who were pain-free [18,19]. In a sham-controlled study for 1 month, there was, however, no effect between active and sham stimulation but probably the observation period was too short [20]. A follow-up series of 17 patients with DBS after 8.7 years demonstrated long-term effect in 70% of patients, hereof pain freedom in six patients and remission to episodic clusters in an other six patients [21 ]. DBS implant is not a riskless procedure; one patient died and oculomotor and other complications have been described. Bilateral ONS has been also used in patients with refractory CCH with good results in the first studies published [22,23]. More than 90 patients have now been reported with a reduction of more than 50% of attacks in around 70% of patients. Complications such as electrode migration were frequent in more than 30% of patients and there was also a risk of infection of 3–5% of patients [18,19]. Thus, ONS for treatment of refractory CCH is a costly treatment option with a significant complication rate, but also with substantial benefit in an important percentage of patients [24]. SPG has been over the years a target for various lesional therapies to treat cluster patients. After positive proof of concept studies using a removable electrode to stimulate SPG, an implantable microstimulator has been developed. The stimulator is activated on demand by a remote controller using radiofrequency energy. A randomized, sham-controlled study of 32 patients was performed to evaluate further the use of SPG stimulation for the acute treatment of CCH [25 ]. Of the 32 medically refractory patients, 28 completed the randomized experimental period. Although the study was designed for acute treatment, a preventive response was observed in some patients. Overall, 68% of patients experienced an acute response, a frequency response, or both. In this study, the majority of adverse events were sensory disturbances related to the implantation procedure, which typically resolved or remained mild in nature at 3 months following the implant procedure. Spinal cord stimulation has been tried in a small group of eight patients with similar results to ONS, but with a higher rate of lead-related complications [26]. Yet, there is no evidence for spinal cord stimulation in cluster headache and is not recommended by the European Headache Federation [27 ]. At this moment, ONS and SPG stimulation techniques are recommended as first-line therapy in &
&
refractory cluster patients [27 ]. However, the implants require surgical expertise, are relatively costly, and are still restricted to a minority of cluster headache patients. Furthermore, they do not resolve the problem in around 30% of these medically refractory patients and, although ONS and SPG are not as invasive as DBS, complications are not infrequent, most of them not being serious but uncomfortable for the patients.
NONINVASIVE NEUROSTIMULATION TECHNIQUES Consequently, it is important to develop new strategies that are less invasive and easier to use for the patient. In this way, in the last year we have known the first results of some studies using a noninvasive vagus nerve stimulator (nVNS). Figure 1 illustrates the different stimulation techniques used in cluster headache. The implantable VNS seems to work in migraine attacks [28]. The first evidence of a possible role of the vagus stimulation was reported in two refractory cluster patients who improved significantly after been implanted with a VNS [29], but this is also an invasive method. A novel portable, lightweight, noninvasive, battery-driven device (gammaCore), designed for patients to self-administer transcutaneous stimulus in the vagus nerve has been developed [30]. The nVNS device produces a low-voltage electric signal consisting of five 5000 Hz pulses occurring at a rate of 25 Hz for 120 s per dose. When applied against the skin of the neck, the device delivers a peak voltage of 24 V and a maximum output current of 60 mA;
&
Deep brain stimulation (DBS)
Sphenopalatine ganglion stimulation (SPG)
Occipital nerve stimulation (ONS)
Noninvasive vagus nerve stimulation (nVNS)
&
FIGURE 1. Neuromodulation techniques.
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Headache
amplitude of the stimulation can be adjusted by the user. In the last 2 years, some studies using this device in patients with cluster headache have been presented in headache meetings. The first one is an open study in which patients with medically intractable cluster headache attending headache centers in the United Kingdom and Ireland were offered the nVNS device for treatment in an unbiased fashion. The patients used the device both as prophylactic (2 times in a day) and as acute therapy. They analyzed 14 of 17 patients that used the device for an average period of 13 weeks (range 2–26). Seven were chronic and seven episodic and nine were male. Thirteen felt there was an overall improvement in their condition since using the device, stating a mean estimated subjective improvement of 60% (SD 30) from baseline. One patient’s condition remained the same. Seven were able to reduce significantly or stop their previous abortive treatment, five had reduced it and two required the same amount as previously. Five were very satisfied, eight satisfied, and one equivocally satisfied after using the device. All 14 would recommend the treatment to others [31]. nVNS has been tried in a multicenter trial: the prevention and acute treatment of CCH (PREVA study) [32 ]. It was a prospective, randomized, controlled study that compared the adjunctive use of nVNS with patients’s standard of care (SoC) versus SoC alone in patients with CCH. The study composed of three phases: 2-week run-in, 4-week randomized (1 : 1; nVNS vs. SoC), and 4-week extension. Patients randomized to nVNS delivered three 2-min stimulations prophylactically twice daily (mandatory) to the right side of the neck, and optionally they could use the stimulator (three doses) as symptomatic therapy for the cluster headache attack at the onset of pain or other symptoms. If the cluster headache attack treated with nVNS was not aborted within 15 min, the patients were instructed to use their standard acute rescue medication for the rescue treatment of cluster headache attack. The primary efficacy end point was the reduction in number of cluster headache attacks/week during the last 2 weeks of the randomized phase versus the run-in phase. Additional end points included the proportion of patients with more than 50% reduction in cluster headache attacks/week (response rate) and rescue medication use; safety was assessed by monitoring the frequency of adverse events. Of the 114 patients in the run-in phase 97 were randomly assigned to receive nVNS plus SoC or SoC alone. Seventy percent of patients were male and the mean age was 45 years. Data from 93 patients (n ¼ 45 nVNS; n ¼ 48 SoC) was included in the intention-totreat population. Number of cluster headache &
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attacks/week was significantly reduced in patients treated with nVNS compared with patients treated with SoC only (7.6 vs. 2.0; P ¼ 0.002). Furthermore, significantly more nVNS than SoC-treated patients were considered treatment responders (34.4% vs. 7.1%; P ¼ 0.003). nVNS was associated with less use of sumatriptan and oxygen as rescue medications. The rate of adverse events was very similar in both groups and most of them were mild. In the open-label phase of the PREVA study [33], during the extension phase, patients delivered three consecutive 90-s stimulations prophylactically twice daily (mandatory, right-side only) and optionally at the onset of a cluster headache attack (two stimulations on headache side, one on opposite side) for rescue treatment. Efficacy end points evaluated in the extension phase were the mean number of all cluster headache attacks, pain intensity (range: no pain to very severe pain), treatment success rate, and use of rescue medication. A total of 97 patients, across 10 European sites, were randomized to treatment; 90 entered the extension phase and results from 71 were presented. Patients who continued with nVNS (n ¼ 30) had an additional 1.8-day attacks reduction per week (P ¼ 0.03); patients who received nVNS for first time in the open phase had a 4.4-day reduction. Surprisingly, no significant change in cluster headache attack duration and intensity were observed during the open-label phase and there were no differences in the use of symptomatic medications. The tolerability was similar to that of the previous phase, with the majority of adverse events being mild or moderate. In summary, in the extension phase, the patients with adjuvant nVNS treatment sustained or improved the response and the patients who initiated the prophylactic treatment with nVNS showed also clinical benefits consistent with the data of the randomized phase. The quality-of-life was also measured in the PREVA study [34]. From the 97 patients who were randomized to treatment, data from 93 patients (n ¼ 45 nVNS; n ¼ 48 SoC) was included in the efficacy analysis population. Compared with patients treated with SoC alone, patients also treated with nVNS reported greater overall improvements in EQ5D-3L, HIT-6, and HADS scores from the end of runin to the end of the randomized phase. One of the important critics to this study is that there is no placebo arm. Although some reports suggest that response to placebo is low in patients with cluster headache, it is necessary to know that a proportion of patients can improve with natural history. Another important issue is how relevant are these results in clinical practice and is it a valuable alternative to the conventional treatment strategies. Volume 28 Number 3 June 2015
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Noninvasive neuromodulation in cluster headache La´inez and Jensen
Concerning the mechanism of action, it is well known that there are numerous connections between the nucleus tractus solitarius and spinal trigeminal nucleus [35]. Early studies suggest that inhibition of pain by VNS occurs by direct inhibition of vagal afferents to the caudal trigeminal nucleus [36] in line with the acute effect of VNS; in animal models it has been demonstrated that electrical, chemical, and physiologic activation of vagal afferents produces analgesics effects [37]. More recent evidence suggests that VNS may also inhibit pain by reducing the glutamate levels in the trigeminal nucleus caudalis [38], which is more in line with the longer lasting preventive effect of VNS.
CONCLUSION We need to find new alternatives in the treatment of cluster headache. In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in the management of medically refractory patients. Noninvasive techniques are in development. Noninvasive approaches such as the nVNS have shown efficacy in one trial and could be an interesting alternative in the management of this debilitating headache. We need to replicate these results with further sham-controlled studies and, in parallel, conduct basic research (or studies) in order to clarify the mechanism of action. Both invasive and noninvasive strategies for neuromodulation are promising and a very interesting avenue in the treatment of cluster headaches. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest M.J.A.L. has received grants/research supports and honoraria for consulting or participation in speaker bureau from: Autonomic Technologies, Allergan, Boehringer, Electrocore, Lupin, Medtronic, Terumo and Otsuka. R.J. has given lectures for Allergan, Pfizer, ATI, BerlinChemie, and is a present member of the advisory board for ElectroCore and Autonomic Technologies.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Holland P, Goadsby P. Cluster headache, hypothalamus, and orexin. Curr Pain Headache Rep 2009; 13:147–154.
2. Headache Classification Committee of the International Headache Society (IHS). International Headache Society The International Classification of Headache Disorders: 3rd edition (beta version). Cephalalgia 2013; 39:629–808. 3. Sa´nchez Del Rio M, Leira R, Pozo-Rosich P, et al. Errors in recognition and management are still frequent in patients with cluster headache. Eur Neurol 2014; 72:209–212. 4. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet 2005; 366:843–855. 5. Gobel H, Lindner V, Heinze A, et al. Acute therapy for cluster headache with sumatriptan: findings of a one-year long-term study. Neurology 1998; 51:908–911. 6. Cohen A, Burns B, Goadsby P. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 2009; 302:2451–2457. 7. Jensen R, Stovner L. Epidemiology and comorbidity of headache. Lancet Neurol 2008; 7:354–361. 8. Gaul C, Finken J, Biermann J, et al. Treatment costs and indirect costs of cluster headache: a health economics analysis. Cephalalgia 2011; 31:1664– 1672. 9. La´inez M, Pascual J, Pascual A, et al. Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43:784–789. 10. Schwalb JM, Hamani C. The history and future of deep brain stimulation. Neurotherapeutics 2008; 5:3–13. 11. Hassan A, Okun MS. Emerging subspecialties in neurology: deep brain stimulation and electrical neuro-network modulation. Neurology 2013; 80:e47–e50. 12. Rasskazoff SY, Slavin KV. Neuromodulation for cephalgias. Surg Neurol Int 2013; 4 (Suppl 3):S136–S150. 13. Melzac R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971–978. 14. Schwedt TJ. Neurostimulation for primary headache disorders. Curr Neurol Neurosci Rep 2009; 9:101–107. 15. Picaza JA, Hunter SE, Cannon BW. Pain suppression by peripheral nerve stimulation. Appl Neurophysiol 1977; 40:223–234. 16. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2:217–221. 17. Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001; 345:1428–1429. 18. Fontaine D, Clair VC, Delphine MD, Lanteri-Minet M. Neuromodulation in cluster headache. Adv Tech Stand Neurosurg 2015; 42:3–21. 19. Magis D, Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurol 2012; 11:708–719. 20. Fontaine D, Lazhortes I, Mertens P, et al. Safety and efficacy of deep-brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by 1-year open extension. J Headache Pain 2010; 11:23–31. 21. Leone M, Franzini A, ProiettiCecchini A, Bussone G. Success, failure, and & putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain 2013; 154:89–99. Interesting study explaining the long-term follow-up of a group of patients with long-lasting CCH who received hypothalamic stimulation 22. Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet 2007; 369:1099–1106. 23. Magis D, Allena M, Bolla M, et al. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol 2007; 6:314–321. 24. Mueller O, Diener HC, Dammann P, et al. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia 2013; 33:1283– 1291. 25. Schoenen J, Jensen R, Lanteri-Minet M, et al. Stimulation of the & sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 2013; 33:816– 830. First randomized study of SPG stimulation in chronic cluster patients. 26. Wolter T, Kiemen A, Kaube H. High cervical spinal cord stimulation for chronic cluster headache. Cephalalgia 2011; 31:1170–1180. 27. Martelleti P, Jensen R, Antal A, et al. Neuromodulation of chronic headaches: & position statement from the European Headache Federation. J Headache Pain 2013; 14:86. Guidelines of the EHF for the use of the neuromodulation techniques, but also good review of the clinical results for each technique. 28. Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia 2002; 22:482– 484. 29. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 2005; 25:82–86. 30. Menachem B, Revesz D, Simon BJ, Silberstein S. Surgically implanted and noninvasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol 2015. [Epub ahead of print]
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Headache 31. Nesbitt AD, Marin JCA, Tomkins E, et al. Noninvasive vagus nerve stimulation for the treatment of cluster headache: a case series. J Headache Pain 2013; 14 (Suppl 1):P231. 32. Gaul C, Diener H, Solbach K, et al. EHMTI-0364. Noninvasive vagus nerve & stimulation using gammacore1 for prevention and acute treatment of chronic cluster headache: report from the randomized phase of the PREVA study. J Headache Pain 2014; 15 (Suppl 1):I7. Abstract. The first trial published using the nVNS in the treatment of cluster headache. 33. Gaul C, Diener H, Solbach K, et al. EHMTI-0364. Noninvasive vagus nerve stimulation using gammacore1 for prevention and acute treatment of chronic cluster headache: report from the extension phase of the PREVA study. J Headache Pain 2014; 15 (Suppl 1):I8.
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34. Gaul C, Diener H, Solbach K, et al. EHMTI-0364. Quality of life in subjects treated by noninvasive vagus nerve stimulation using gammacore1 for prevention and acute treatment of chronic cluster headache. J Headache Pain 2014; 15 (Suppl 1):I6. 35. Lyubashina OA, Sokolov AY, Panteleev SS. Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats. Neuroscience 2012; 222:29–37. 36. Lambru G, Matharu MS. Peripheral neurostimulation in primary headaches. Neurol Sci 2014; 35 (Suppl 1):S77–S81. 37. Bossut DF, Maixner W. Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain 1996; 65:101–109. 38. Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 2010; 27:130–138.
Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Noninvasive neuromodulation in cluster headache Miguel J.A. La´inez a and Rigmor Jensen b
Purpose of review Neuromodulation is an alternative in the management of medically intractable cluster headache patients. Most of the techniques are invasive, but in the last 2 years, some studies using a noninvasive device have been presented. The objective of this article is to review the data using this approach. Recent findings Techniques as occipital nerve stimulation or sphenopalatine ganglion stimulation are recommended as firstline therapy in refractory cluster patients, but they are invasive and maybe associated with complications. Noninvasive vagal nerve stimulation with an external device has been tried in cluster patients. Results from clinical practice and a single randomized clinical trial have been presented showing a reduction of the number of cluster attacks/week in the patients treated with the device. The rate of adverse events was low and most of them were mild. Summary In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in cluster refractory patients. Noninvasive approaches such as the noninvasive vagal nerve stimulation have shown efficacy in one trial and could be an easier alternative in the management of this debilitating headache. We need to replicate these results with further controlled studies and conduct basic research in order to clarify the mechanism of action. Keywords cluster headache, neuromodulation, noninvasive stimulation, vagal stimulation
INTRODUCTION Cluster headache is a severe, debilitating disorder with pain that ranks among the most severe known to humans [1]. It is well defined in the third edition of The International Classification of Headache Disorders (ICHD-3 beta 2013); typically is presented with accompanying autonomic symptoms ipsilateral to the pain, including conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid or periorbital edema, forehead and facial sweating, mitosis or ptosis, and a sense of restlessness or agitation. Cluster headaches can occur up to eight times a day and each attack typically last between 15 min and 3 h. Episodic cluster headache occurs in periods lasting 1 week to 1 year, separated by painfree periods of 1 month or longer [2]. Approximately 10–15% of patients are suffering from chronic cluster headache (CCH), with headaches occurring without remission or with remission lasting less than 1 month during a year. Although cluster headache is an invalidating and clinically clear-cut disorder, it is still frequently unrecognized and/or mistaken for other disorders [3]. Patients with cluster headaches have few therapeutic options and further, 10–20% patients develop
drug-resistant attacks [4]. Although subcutaneous triptan injections [5] and inhaled high-flow oxygen [6] provide relief to some patients some of the time, the next attacks are not prevented and many patients are severely affected and disabled. Sumatriptan is contraindicated in ischemic heart disease, stroke, uncontrolled hypertension, and peripheral vascular disease. Furthermore, triptans are limited to a maximum of twice-daily dosing, the injectable form is very expensive and not available in many countries. Although oxygen-inhalation therapy (100%, 12 L/ min for 15 min via a face mask) can be effective in the early stage of the attack [6], it may be associated with attack recurrence and it has significant practical
a
Department of Neurology, Clinic University Hospital, Catholic University of Valencia, Valencia, Spain and bDepartment of Neurology, Danish Headache Center, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark Correspondence to Miguel J.A. La´inez, MD, PhD, Department of Neurology, Hospital Clı´nico Universitario, Universidad Cato´lica de Valencia, Avda. Blasco Iba´n˜ez, 17 46010 Valencia, Spain. Tel: +34 961973981; fax: +34 963900321; e-mail: [email protected] Curr Opin Neurol 2015, 28:271–276 DOI:10.1097/WCO.0000000000000196
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Headache
KEY POINTS Cluster headache is one of most debilitating headache syndromes, especially when it is refractory to medical treatment. Invasive neuromodulation treatments have demonstrated good efficacy in the management of medically refractory patients, but with potential complications for the patient. nVNS has been efficacious reducing the number of attacks with good tolerability. nVNS could be an interesting alternative, but the results should be replicated in randomized controlled studies.
limitations because of the size and cumbersomeness of the required oxygen tanks. The socioeconomic burden of cluster headache on individuals and society is quite high because of the direct costs of healthcare services, and the indirect costs of lost work days and decreased work efficacy. A Danish report showed that 43.5% of cluster patients had seen specialists, approximately 30% had missed work, and 78% reported restrictions in daily living [7]. A recent German study showed that a patient with typical CCH cost the healthcare system over s21,000 per year [8]. The often brief duration of cluster attacks makes abortive therapy a challenge. Transition treatments with steroids and preventive medications, such as verapamil, lithium carbonate, divalproex sodium (valproate), and topiramate among others, are almost always provided to patients. The side-effects of these preventive medications can be significant, ranging from nausea and fatigue to hypotension, bradycardia, atrioventricular block, paresthesias, or psychomotor slowing, and although these medications may be better tolerated when used for cluster headache than other headache types [9], the adverse events are a limiting factor in the treatment. None of these preventive medications are, however, approved by the U.S. Food and Drug Administration for the treatment of cluster headache. Given the relentless nature of their disorder, cluster patients desperately continue to search for new, effective therapies to treat their headaches.
Modern neurostimulation had its genesis in a parallel expansion of functional neurosurgery, which focused on the placement of ablative brain lesions to treat disabling symptoms of movement disorders. Initially, with a view to avoiding ablative lesions, the neuromodulation techniques started using deep brain stimulation (DBS), which is a surgical therapy that involves the delivery of an electrical current to one or more brain targets. With time, stimulation techniques changed their target and now DBS is not always deep, not always brain, and not always simply stimulation; a more accurate term for this field may be electrical neuro-network modulation [11]. Electrical neuromodulation refers to adjustable manipulation of central or peripheral pain pathways with electrical current for the purpose of reversible modification of the nociceptive system function using implantable devices. Many targets for treating craniofacial pain via neuromodulation have been described, including trigeminal nerve and ganglion, vagus nerve, sphenopalatine ganglion (SPG), peripheral (occipital) nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex [12]. The basis for peripheral stimulation started with the publication of the ‘Gate Control Theory’ of pain modulation in 1965, by Melzack and Wall [13], that provided a conceptual mechanistic foundation for considering direct electrical stimulation of the spinal cord and peripheral nerves as a potential treatment for chronic pain. Electrical stimulation of peripheral nerves results in pain modulation by direct effects on the stimulated nerve and secondary effects on the central nervous system [14]. Peripheral nerve stimulation (PNS) therapies for chronic pain developed in parallel to spinal cord stimulation. Over the 1970s and 1980s, some studies showed positive responses to open surgical PNS implants in patients with various neuropathic pain syndromes [15], with few studies including isolated patients with occipital neuralgia. Attention to the potential of this methodology as a treatment for head pain came after a publication that showed that implanted occipital nerve stimulators (ONS) with percutaneously placed leads could be an alternative in the treatment for intractable occipital neuralgia [16].
NEUROSTIMULATION
NEUROSTIMULATION INVASIVE TECHNIQUES
The use of electrical stimulation of the nervous system for the treatment of headaches is not new. In the first century A.D., the physician Scribonius Largus used the electric fish Torpedo marmorata to reduce head pain of Claudius, the Roman emperor [10].
In the treatment of refractory cluster headache, both DBS and PNS have been used. DBS of the posterior–inferior hypothalamus has been proposed by Leone et al. [17] after the identification of the presumed generator of the pain in the posterior
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Noninvasive neuromodulation in cluster headache La´inez and Jensen
hypothalamus. Until now, around 60 patients treated with this technique have been reported in the literature but the total number of implants is unknown, as a register of all patients with DBS is not established. In 60% of the reported cases, the attack frequency decreased more than 50%, including 30–40% of patients who were pain-free [18,19]. In a sham-controlled study for 1 month, there was, however, no effect between active and sham stimulation but probably the observation period was too short [20]. A follow-up series of 17 patients with DBS after 8.7 years demonstrated long-term effect in 70% of patients, hereof pain freedom in six patients and remission to episodic clusters in an other six patients [21 ]. DBS implant is not a riskless procedure; one patient died and oculomotor and other complications have been described. Bilateral ONS has been also used in patients with refractory CCH with good results in the first studies published [22,23]. More than 90 patients have now been reported with a reduction of more than 50% of attacks in around 70% of patients. Complications such as electrode migration were frequent in more than 30% of patients and there was also a risk of infection of 3–5% of patients [18,19]. Thus, ONS for treatment of refractory CCH is a costly treatment option with a significant complication rate, but also with substantial benefit in an important percentage of patients [24]. SPG has been over the years a target for various lesional therapies to treat cluster patients. After positive proof of concept studies using a removable electrode to stimulate SPG, an implantable microstimulator has been developed. The stimulator is activated on demand by a remote controller using radiofrequency energy. A randomized, sham-controlled study of 32 patients was performed to evaluate further the use of SPG stimulation for the acute treatment of CCH [25 ]. Of the 32 medically refractory patients, 28 completed the randomized experimental period. Although the study was designed for acute treatment, a preventive response was observed in some patients. Overall, 68% of patients experienced an acute response, a frequency response, or both. In this study, the majority of adverse events were sensory disturbances related to the implantation procedure, which typically resolved or remained mild in nature at 3 months following the implant procedure. Spinal cord stimulation has been tried in a small group of eight patients with similar results to ONS, but with a higher rate of lead-related complications [26]. Yet, there is no evidence for spinal cord stimulation in cluster headache and is not recommended by the European Headache Federation [27 ]. At this moment, ONS and SPG stimulation techniques are recommended as first-line therapy in &
&
refractory cluster patients [27 ]. However, the implants require surgical expertise, are relatively costly, and are still restricted to a minority of cluster headache patients. Furthermore, they do not resolve the problem in around 30% of these medically refractory patients and, although ONS and SPG are not as invasive as DBS, complications are not infrequent, most of them not being serious but uncomfortable for the patients.
NONINVASIVE NEUROSTIMULATION TECHNIQUES Consequently, it is important to develop new strategies that are less invasive and easier to use for the patient. In this way, in the last year we have known the first results of some studies using a noninvasive vagus nerve stimulator (nVNS). Figure 1 illustrates the different stimulation techniques used in cluster headache. The implantable VNS seems to work in migraine attacks [28]. The first evidence of a possible role of the vagus stimulation was reported in two refractory cluster patients who improved significantly after been implanted with a VNS [29], but this is also an invasive method. A novel portable, lightweight, noninvasive, battery-driven device (gammaCore), designed for patients to self-administer transcutaneous stimulus in the vagus nerve has been developed [30]. The nVNS device produces a low-voltage electric signal consisting of five 5000 Hz pulses occurring at a rate of 25 Hz for 120 s per dose. When applied against the skin of the neck, the device delivers a peak voltage of 24 V and a maximum output current of 60 mA;
&
Deep brain stimulation (DBS)
Sphenopalatine ganglion stimulation (SPG)
Occipital nerve stimulation (ONS)
Noninvasive vagus nerve stimulation (nVNS)
&
FIGURE 1. Neuromodulation techniques.
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Headache
amplitude of the stimulation can be adjusted by the user. In the last 2 years, some studies using this device in patients with cluster headache have been presented in headache meetings. The first one is an open study in which patients with medically intractable cluster headache attending headache centers in the United Kingdom and Ireland were offered the nVNS device for treatment in an unbiased fashion. The patients used the device both as prophylactic (2 times in a day) and as acute therapy. They analyzed 14 of 17 patients that used the device for an average period of 13 weeks (range 2–26). Seven were chronic and seven episodic and nine were male. Thirteen felt there was an overall improvement in their condition since using the device, stating a mean estimated subjective improvement of 60% (SD 30) from baseline. One patient’s condition remained the same. Seven were able to reduce significantly or stop their previous abortive treatment, five had reduced it and two required the same amount as previously. Five were very satisfied, eight satisfied, and one equivocally satisfied after using the device. All 14 would recommend the treatment to others [31]. nVNS has been tried in a multicenter trial: the prevention and acute treatment of CCH (PREVA study) [32 ]. It was a prospective, randomized, controlled study that compared the adjunctive use of nVNS with patients’s standard of care (SoC) versus SoC alone in patients with CCH. The study composed of three phases: 2-week run-in, 4-week randomized (1 : 1; nVNS vs. SoC), and 4-week extension. Patients randomized to nVNS delivered three 2-min stimulations prophylactically twice daily (mandatory) to the right side of the neck, and optionally they could use the stimulator (three doses) as symptomatic therapy for the cluster headache attack at the onset of pain or other symptoms. If the cluster headache attack treated with nVNS was not aborted within 15 min, the patients were instructed to use their standard acute rescue medication for the rescue treatment of cluster headache attack. The primary efficacy end point was the reduction in number of cluster headache attacks/week during the last 2 weeks of the randomized phase versus the run-in phase. Additional end points included the proportion of patients with more than 50% reduction in cluster headache attacks/week (response rate) and rescue medication use; safety was assessed by monitoring the frequency of adverse events. Of the 114 patients in the run-in phase 97 were randomly assigned to receive nVNS plus SoC or SoC alone. Seventy percent of patients were male and the mean age was 45 years. Data from 93 patients (n ¼ 45 nVNS; n ¼ 48 SoC) was included in the intention-totreat population. Number of cluster headache &
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attacks/week was significantly reduced in patients treated with nVNS compared with patients treated with SoC only (7.6 vs. 2.0; P ¼ 0.002). Furthermore, significantly more nVNS than SoC-treated patients were considered treatment responders (34.4% vs. 7.1%; P ¼ 0.003). nVNS was associated with less use of sumatriptan and oxygen as rescue medications. The rate of adverse events was very similar in both groups and most of them were mild. In the open-label phase of the PREVA study [33], during the extension phase, patients delivered three consecutive 90-s stimulations prophylactically twice daily (mandatory, right-side only) and optionally at the onset of a cluster headache attack (two stimulations on headache side, one on opposite side) for rescue treatment. Efficacy end points evaluated in the extension phase were the mean number of all cluster headache attacks, pain intensity (range: no pain to very severe pain), treatment success rate, and use of rescue medication. A total of 97 patients, across 10 European sites, were randomized to treatment; 90 entered the extension phase and results from 71 were presented. Patients who continued with nVNS (n ¼ 30) had an additional 1.8-day attacks reduction per week (P ¼ 0.03); patients who received nVNS for first time in the open phase had a 4.4-day reduction. Surprisingly, no significant change in cluster headache attack duration and intensity were observed during the open-label phase and there were no differences in the use of symptomatic medications. The tolerability was similar to that of the previous phase, with the majority of adverse events being mild or moderate. In summary, in the extension phase, the patients with adjuvant nVNS treatment sustained or improved the response and the patients who initiated the prophylactic treatment with nVNS showed also clinical benefits consistent with the data of the randomized phase. The quality-of-life was also measured in the PREVA study [34]. From the 97 patients who were randomized to treatment, data from 93 patients (n ¼ 45 nVNS; n ¼ 48 SoC) was included in the efficacy analysis population. Compared with patients treated with SoC alone, patients also treated with nVNS reported greater overall improvements in EQ5D-3L, HIT-6, and HADS scores from the end of runin to the end of the randomized phase. One of the important critics to this study is that there is no placebo arm. Although some reports suggest that response to placebo is low in patients with cluster headache, it is necessary to know that a proportion of patients can improve with natural history. Another important issue is how relevant are these results in clinical practice and is it a valuable alternative to the conventional treatment strategies. Volume 28 Number 3 June 2015
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Noninvasive neuromodulation in cluster headache La´inez and Jensen
Concerning the mechanism of action, it is well known that there are numerous connections between the nucleus tractus solitarius and spinal trigeminal nucleus [35]. Early studies suggest that inhibition of pain by VNS occurs by direct inhibition of vagal afferents to the caudal trigeminal nucleus [36] in line with the acute effect of VNS; in animal models it has been demonstrated that electrical, chemical, and physiologic activation of vagal afferents produces analgesics effects [37]. More recent evidence suggests that VNS may also inhibit pain by reducing the glutamate levels in the trigeminal nucleus caudalis [38], which is more in line with the longer lasting preventive effect of VNS.
CONCLUSION We need to find new alternatives in the treatment of cluster headache. In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in the management of medically refractory patients. Noninvasive techniques are in development. Noninvasive approaches such as the nVNS have shown efficacy in one trial and could be an interesting alternative in the management of this debilitating headache. We need to replicate these results with further sham-controlled studies and, in parallel, conduct basic research (or studies) in order to clarify the mechanism of action. Both invasive and noninvasive strategies for neuromodulation are promising and a very interesting avenue in the treatment of cluster headaches. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest M.J.A.L. has received grants/research supports and honoraria for consulting or participation in speaker bureau from: Autonomic Technologies, Allergan, Boehringer, Electrocore, Lupin, Medtronic, Terumo and Otsuka. R.J. has given lectures for Allergan, Pfizer, ATI, BerlinChemie, and is a present member of the advisory board for ElectroCore and Autonomic Technologies.
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2. Headache Classification Committee of the International Headache Society (IHS). International Headache Society The International Classification of Headache Disorders: 3rd edition (beta version). Cephalalgia 2013; 39:629–808. 3. Sa´nchez Del Rio M, Leira R, Pozo-Rosich P, et al. Errors in recognition and management are still frequent in patients with cluster headache. Eur Neurol 2014; 72:209–212. 4. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet 2005; 366:843–855. 5. Gobel H, Lindner V, Heinze A, et al. Acute therapy for cluster headache with sumatriptan: findings of a one-year long-term study. Neurology 1998; 51:908–911. 6. Cohen A, Burns B, Goadsby P. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 2009; 302:2451–2457. 7. Jensen R, Stovner L. Epidemiology and comorbidity of headache. Lancet Neurol 2008; 7:354–361. 8. Gaul C, Finken J, Biermann J, et al. Treatment costs and indirect costs of cluster headache: a health economics analysis. Cephalalgia 2011; 31:1664– 1672. 9. La´inez M, Pascual J, Pascual A, et al. Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43:784–789. 10. Schwalb JM, Hamani C. The history and future of deep brain stimulation. Neurotherapeutics 2008; 5:3–13. 11. Hassan A, Okun MS. Emerging subspecialties in neurology: deep brain stimulation and electrical neuro-network modulation. Neurology 2013; 80:e47–e50. 12. Rasskazoff SY, Slavin KV. Neuromodulation for cephalgias. Surg Neurol Int 2013; 4 (Suppl 3):S136–S150. 13. Melzac R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971–978. 14. Schwedt TJ. Neurostimulation for primary headache disorders. Curr Neurol Neurosci Rep 2009; 9:101–107. 15. Picaza JA, Hunter SE, Cannon BW. Pain suppression by peripheral nerve stimulation. Appl Neurophysiol 1977; 40:223–234. 16. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2:217–221. 17. Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001; 345:1428–1429. 18. Fontaine D, Clair VC, Delphine MD, Lanteri-Minet M. Neuromodulation in cluster headache. Adv Tech Stand Neurosurg 2015; 42:3–21. 19. Magis D, Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurol 2012; 11:708–719. 20. Fontaine D, Lazhortes I, Mertens P, et al. Safety and efficacy of deep-brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by 1-year open extension. J Headache Pain 2010; 11:23–31. 21. Leone M, Franzini A, ProiettiCecchini A, Bussone G. Success, failure, and & putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain 2013; 154:89–99. Interesting study explaining the long-term follow-up of a group of patients with long-lasting CCH who received hypothalamic stimulation 22. Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet 2007; 369:1099–1106. 23. Magis D, Allena M, Bolla M, et al. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol 2007; 6:314–321. 24. Mueller O, Diener HC, Dammann P, et al. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia 2013; 33:1283– 1291. 25. Schoenen J, Jensen R, Lanteri-Minet M, et al. Stimulation of the & sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia 2013; 33:816– 830. First randomized study of SPG stimulation in chronic cluster patients. 26. Wolter T, Kiemen A, Kaube H. High cervical spinal cord stimulation for chronic cluster headache. Cephalalgia 2011; 31:1170–1180. 27. Martelleti P, Jensen R, Antal A, et al. Neuromodulation of chronic headaches: & position statement from the European Headache Federation. J Headache Pain 2013; 14:86. Guidelines of the EHF for the use of the neuromodulation techniques, but also good review of the clinical results for each technique. 28. Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia 2002; 22:482– 484. 29. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 2005; 25:82–86. 30. Menachem B, Revesz D, Simon BJ, Silberstein S. Surgically implanted and noninvasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol 2015. [Epub ahead of print]
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34. Gaul C, Diener H, Solbach K, et al. EHMTI-0364. Quality of life in subjects treated by noninvasive vagus nerve stimulation using gammacore1 for prevention and acute treatment of chronic cluster headache. J Headache Pain 2014; 15 (Suppl 1):I6. 35. Lyubashina OA, Sokolov AY, Panteleev SS. Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats. Neuroscience 2012; 222:29–37. 36. Lambru G, Matharu MS. Peripheral neurostimulation in primary headaches. Neurol Sci 2014; 35 (Suppl 1):S77–S81. 37. Bossut DF, Maixner W. Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain 1996; 65:101–109. 38. Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 2010; 27:130–138.
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