The Treatment of Trigeminal Autonomic Cephalalgias: An Overview

Trigeminal autonomic cephalalgias (TACs) are primary headaches that include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks (SUNHAs) with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA). Hemicrania continua (HC) is another form that has been ascribed to TACs for clinical and pathophysiologic reasons. Cluster headache is the most common of these syndromes, even if comparatively rare, with a lifetime prevalence of around 1 in 1,000. TACs share many aspects from a pathophysiologic standpoint (a hypothalamic activation may be involved in all forms initiating the attacks), but differences in attack duration and frequency and in extent of treatment response distinguish one from the other. This review focuses on the treatments currently available for these headaches according to the most recent guidelines. Due to the low frequency of most TACs, there are little data from randomized controlled trials; therefore, evidence from simple open studies in small case series or single-case observations are reported. Promising results have been recently obtained with novel modes of drug administration, invasive pericranial interventions, and different strategies such as neurostimulation. There are also some future treatments being studied at present.

cluster headache;preventive treatments;symptomatic treatments;treatment guidelines;trigeminal autonomic cephalalgias.

1.Matharu MS, Goadsby PJ. Trigeminal autonomic cephalalgias: Diagnosis and management. In: Silberstein SD, Lipton RB, Dodick DW (eds). Wolff’s Headache and Other Head Pain, ed 8. New York: Oxford University Press, 2008:379–430. 

2.Goadsby PJ, Cittadini E, Cohen AS. Trigeminal autonomic cephalalgias: Paroxysmal hemicrania, SUNCT/SUNA, and hemicrania continua. Semin Neurol 2010;30:186–191. 

3.Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38:1–211.  

4.Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol 2004;3:279–283. 

5.Ramón C, Mauri G, Vega J, Rico M, Para M, Pascual J. Diagnostic distribution of 100 unilateral, side-locked head­aches consulting a specialized clinic. Eur Neurol 2013;69:289–291.   

6.Bahra A, May A, Goadsby PJ. Cluster headache: A prospective clinical study with diagnostic implications. Neurology 2002;58:354–361.  

7.May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol 2006;13:1066–1077.  

8.Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: A meta-analysis of population-based studies. Cephalalgia 2008;28:614–618.  

9.Schürks M. Genetics of cluster headache. Curr Pain Headache Rep 2010;14:132–139.

10.Leone M, Russell MB, Rigamonti A, et al. Increased familial risk of cluster headache. Neurology 2001;56:1233–1236.

11.Russell MB, Andersson PG, Thomsen LL, Iselius L. Cluster headache is an autosomal dominantly inherited disorder in some families: A complex segregation analysis. J Med Genet 1995;32:954–956.

12.Rozen TD, Fishman RS. Cluster headache in the United States of America: Demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 2012;52:99–113.

13.Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 2008;120:157–171.

14.Sances G, Tassorelli C, Pucci E, Ghiotto N, Sandrini G, Nappi G. Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia 2004;24:110–119.

15.Voiticovschi-Iosob C, Allena M, De Cillis I, Nappi G, Sjaastad O, Antonaci F. Diagnostic and therapeutic errors in cluster headache: A hospital-based study. J Headache Pain 2014; 15:56.

16.Antonaci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): A review of the clinical manifestations. Headache 1989;29:648–656.

17.Newman LC, Lipton RB, Solomon S. Hemicrania continua: Ten new cases and a review of the literature. Neurology 1994;44:2111–2114.

18.Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA)— A prospective clinical study of SUNCT and SUNA. Brain 2006;129:2746–2760.

19.Krymchantowski AV. Aura with non-migraine headache. Curr Pain Headache Rep 2005;9:264–267.

20.Antonaci F, Costa A, Ghirmai S, Sances G, Sjaastad O, Nappi G. Parenteral indomethacin (the INDOTEST) in cluster headache. Cephalalgia 2003;23:193–196.

21.Gaul C, Gantenbein AR, Buettner UW, Ettlin DA, Sándor PS. Orofacial cluster headache. Cephalalgia 2008;28:903–905.

22.Gross SG. Dental presentations of cluster headaches. Curr Pain Headache Rep 2006;10:126–129.

23.Campbell JK. Facial pain due to migraine and cluster headache. Semin Neurol 1988;8:324–331.

24.Cademartiri C, Torelli P, Cologno D, Manzoni GC. Upper and lower cluster headache: Clinical and pathogenetic observations in 608 patients. Headache 2002;42:630–637.

25.Solomon S, Lipton RB, Newman LC. Nuchal features of cluster headache. Headache 1990;30:347–349. 

26.Sarlani E, Schwartz AH, Greenspan JD, Grace EG. Facial pain as first manifestation of lung cancer: A case of lung cancer-related cluster headache and a review of the literature.J Orofac Pain 2003;17:262–267.

27.Taub D, Stiles A, Tucke AG. Hemicrania continua presenting as temporomandibular joint pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e35–e37.

28.Sharav Y, Katsarava Z, Charles A. Facial presentations of primary headache disorders. Cephalalgia 2017;37:714–719.

29.Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta Neurol Scand 2004;109:175–179.

30.Buzzi MG, Moskowitz MA. Evidence for 5-HT1B/1D receptor mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia 1991;11:165–168.

31.Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43(suppl 3): s16–s20.

32.Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991;325:322–326.

33.Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in the acute treatment of cluster headache: A dose comparison study. The Sumatriptan Cluster Headache Study Group. Acta Neurol Scand 1993;88:63–69.

34.Ekbom K, Krabbe A, Micieli G, et al. Cluster headache attacks treated for up to three months with subcutaneous sumatriptan (6 mg). Sumatriptan Cluster Headache Long-term Study Group. Cephalalgia 1995;15:230–236.

35.van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headache. Randomized placebo-controlled double-blind study. Neurology 2003;60:630–633.

36.Freitag FG. Sumatriptan needle-free subcutaneous (Sumavel® DosePro™) approved for the acute treatment of migraine, with or without aura, and cluster headaches. Expert Rev Neurother 2011;11:481–490.

37.Fine A, Bastings E. Triptans and serotonin syndrome. Headache 2012;52:1184–1185.

38.Bahra A, Gawel MJ, Hardebo JE, Millson D, Breen SA, Goadsby PJ. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology 2000;54:1832–1839.

39.Cittadini E, May A, Straube A, Evers S, Bussone G, Goadsby PJ. Effectiveness of intranasal zolmitriptan in acute cluster headache: A randomized, placebo-controlled, double-blind cross-over study. Arch Neurol 2006;63:1537–1542.

40.Rapoport AM, Mathew NT, Silberstein SD, et al. Zolmitriptan nasal spray in the acute treatment of cluster headache: A double-blind study. Neurology 2007;69:821–826.

41.Horton BT. Histaminic cephalalgia. J Lancet 1952;72:92–98.

42.Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Arch Neurol 1985;42: 362–363.

43.Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache. JAMA 2009;302:2451–2457.

44.Rozen TD. High oxygen flow rates for cluster headache. Neurology 2004;63:593.

45.Di Sabato F, Fusco BM, Pelaia P, Giacovazzo M. Hyperbaric oxygen therapy in cluster headache. Pain 1993;52:243–245.

46.Rozen TD, Niknam RM, Shechter AL, Silberstein SD. Gender differences in clinical characteristics and treatment response in cluster headache patients. Cephalalgia 1999;19:323.

47.Bennett MH, French C, Schnabel A, Wasiak J, Kranke P, Weibel S. Normobaric and hyperbaric oxygen therapy for the treatment and prevention of migraine and cluster headache. Cochrane Database Syst Rev 2015(12):CD005219.

48.Rozen TD, Fishman RS. Inhaled oxygen and cluster headache sufferers in the United States: Use, efficacy and economics: Results from the United States Cluster Headache Survey. Headache 2011;51:191–200.

49.Hardebo JE, Ryding E. Cerebral blood flow response to oxygen in cluster headache. In: J Olesen (ed). Migraine and Other Mechanisms: The Vascular Mechanisms. New York: Raven, 1991:311–314.

50.Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981;21:1–4.

51.Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. A double-blind trial versus placebo. Cephalalgia 1986;6:51–54.

52.Bigal ME, Tepper SJ. Ergotamine and dihydroergotamine:A review. Curr Pain Headache Rep 2003;7:55–62.

53.Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: History, pharmacology, and efficacy. Headache 2003; 43:144–166.

54.Baron EP, Tepper SJ. Revisiting the role of ergots in the treatment of migraine and headache. Headache 2010;50: 1353–1361.

55.Kittrelle JP, Grouse DS, Seybold ME. Cluster headache. Local anesthetic abortive agents. Arch Neurol 1985;42:496–498.

56.Robbins L. Intranasal lidocaine for cluster headache. Headache 1995;35:83–84.

57.Costa A, Pucci E, Antonaci F, et al. The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia 2000;20:85–91.

58.Barré F. Cocaine as an abortive agent in cluster headache. Headache 1982;22:69–73.

59.Sicuteri F, Geppetti P, Marabini S, Lembeck F. Pain relief by somatostatin in attacks of cluster headache. Pain 1984; 18:359–365.

60.Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: Randomized placebocontrolled double-blind crossover study. Ann Neurol 2004;56: 488–494.

61.Helyes Z, Pintér E, Németh J, et al. Anti-inflammatory effect of synthetic somatostatin analogues in the rat. Br J Pharmacol 2001;134:1571–1579.

62.Brainin M, Barnes M, Baron JC, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces—Revised recommendations 2004. Eur J Neurol 2004;11:577–581.

63.Goadsby PJ, Cittadini E, Burns B, Cohen AS. Trigeminal autonomic cephalalgias: Diagnostic and therapeutic developments. Curr Opin Neurol 2008;21:323–330.

64.Sarchielli P, Granella F, Prudenzano MP, et al. Italian guidelines for primary headaches: 2012 revised version. J Headache Pain 2012;13(suppl 2):s31–s70.

65.Couch JR Jr, Ziegler DK. Prednisone therapy for cluster headache. Headache 1978;18:219–221.

66.Antonaci F, Costa A, Candeloro E, Sjaastad O, Nappi G. Single high-dose steroid treatment in episodic cluster headache. Cephalalgia 2005;25:290–295.

67.Mir P, Alberca R, Navarro A, et al. Prophylactic treatment of episodic cluster headache with intravenous bolus of methylprednisolone. Neurol Sci 2003;24:318–321.

68.Gawel MJ, Krajewski A, Luo YM, Ichise M. The cluster diathesis. Headache 1990;30:652–655.

69.Martelletti P, Stirparo G, De Stefano L, Di Sabato F, Giacovazzo M, Rinaldi-Garaci C. Defective expression of IL-2 receptors on peripheral blood lymphocytes from patients with cluster headache. Headache 1990;30:228–231.

70.Martelletti P, Granata M, Giacovazzo M. Serum interleukin-1 beta is increased in cluster headache. Cephalalgia 1993; 13:343–345.

71.Empl M, Förderreuther S, Schwarz M, Müller N, Straube A. Soluble interleukin-2 receptors increase during the active periods in cluster headache. Headache 2003;43:63–68.

72.Hannerz J. Orbital phlebography and signs of inflammation in episodic and chronic cluster headache. Headache 1991;31:540–542.

73.Hardebo JE. How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibers. Headache 1994;34:125–131.

74.Personett D, Fass U, Panickar K, McKinney M. Retinoic acid mediated enhancement of the cholinergic/neuronal nitric oxide synthase phenotype of the medial septal SN56 clone: Establishment of a nitric oxide-sensitive proapoptotic state.J Neurochem 2000;74:2412–2424.

75.Mather PJ, Silberstein SD, Schulman EA, Hopkins MM. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache 1991;31:525–532.

76.Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache 2004;44:249–255.

77.Ekbom K, Hardebo JE. Cluster headache: Aetiology, diagnosis and management. Drugs 2002;62:61–69.

78.Leone M, D’Amico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: A double–blind study versus placebo. Neurology 2000;54:1382–1385.

79.Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990;30:411–417.

80.El-Fakahany E, Richelson E. Effect of some calcium antagonists on muscarinic receptor-mediated cyclic GMP formation. J Neurochem 1983;40:705–710.

81.Taylor JE, Defeudis FV. Inhibition of [3H]spipirone binding to 5-HT2 receptors of rat cerebral cortex by the calcium antagonists verapamil and D600. Eur J Pharmacol 1984; 106:215–216.

82.Kavaliers M. Calcium channel blockers inhibit the antagonist effects of Phe-Met-Arg-Phe-amide (FMRFamide) on morphine- and stress-induced analgesia in mice. Brain Res 1987;415:380–384.

83.Ekbom K. Lithium vid kroniska symptom av cluster headache. Opusc Med 1974;19:148–156.

84.Costa A, Leston JA, Cavallini A, Nappi G. Cluster headache and periodic affective illness: Common chronobiological features. Funct Neurol 1998;13:263–272.

85.Malhi GS, Tanious M. Optimal frequency of lithium administration in the treatment of bipolar disorder: Clinical and dosing considerations. CNS Drugs 2011;25:289–298.

86.Nappi G, Costa A, Tassorelli C, Santorelli FM. Migraine as a complex disease: Heterogeneity, comorbidity and genotype-phenotype interactions. Funct Neurol 2000;15:87–93.

87.Ekbom K. Lithium for cluster headache: Review of the literature and preliminary results of long-term treatment. Headache 1981;21:132–139.

88.Steiner TJ, Hering R, Couturier EGM, Davies PT, Whitmarsh TE. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 1997;17:673–675.

89.Hokin LE, Dixon JF, Los GV. A novel action of lithium: Stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices. Adv Enzyme Regul 1996;36:229–244.

90.Dixon JF, Hokin LE. Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. Proc Natl Acad Sci U S A 1998;95:8363–8368.

91.Post RM, Speer AM, Hough CJ, Xing G. Neurobiology of bipolar illness: Implications for future study and therapeutics. Ann Clin Psychiatry 2003;15:85–94.

92.Silverstone PH, McGrath BM, Kim H. Bipolar disorder and myo-inositol: A review of the magnetic resonance spectroscopy findings. Bipolar Disord 2005;7:1–10.

93.Klemfuss H. Rhythms and the pharmacology of lithium. Pharmacol Ther 1992;56:53–78.

94.Wheeler SD, Carrazana EJ. Topiramate-treated cluster headache. Neurology 1999;53:234–236.

95.Leone M, Dodick D, Rigamonti A, et al. Topiramate in cluster headache prophylaxis: An open trial. Cephalalgia 2003; 23:1001–1002.

96.Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache: An open clinical trial. Cephalalgia 1989;9:195–198.

97.Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug resistant cluster headache responding to gabapentin: A pilot study. Cephalalgia 2001;21:744–746.

98.Schuh-Hofer S, Israel H, Neeb L, Reuter U, Arnold G. The use of gabapentin in chronic cluster headache patients refractory to first-line therapy. Eur J Neurol 2007;14:694–696.

99.Vukovíc V, Lovrencìc´-Huzjan A, Budisic´ M, Demarin V. Gabapentin in the prophylaxis of cluster headache: An observational open label study. Acta Clin Croat 2009;48:311–314.

100.Curran DA, Hinterberger H, Lance JW. Methysergide. Res Clin Stud Headache 1967;1:74–122.

101.Lovshin LL. Treatment of histaminic cephalalgia with methysergide (UML-491). (Based on 159 cases). Dis Nerv System 1963;24:120–124.

102.Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966;274:359–368.

103.Ekbom K. Prophylactic treatment of cluster headache with a new serotonin antagonist, BC 105. Acta Neurol Scand 1969; 45:601–610.

104.Diamond S, Freitag FG, Prager J, Gandhi S. Treatment of intractable cluster. Headache 1986;26:42–46.

105.Leone M, D’Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: A double-blind pilot study with parallel groups. Cephalalgia 1966;16:494–496.

106.D’Andrea G, Perini F, Granella F, Cananzi A, Sergi A. Efficacy of transdermal clonidine in short-term treatment of cluster headache: A pilot study. Cephalalgia 1955;15:430–433.107.Hering-Hanit R, Gadoth N. Baclofen in cluster headache. Headache 2000;40:48–51.108.Holzer P. Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991;43:143–201.

109.Sicuteri F, Fusco BM, Marabini S, et al. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clin J Pain 1989;5:49–53.

110.Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994;59:321–325.

111.Sostak P, Krause P, Förderreuther S, Reinisch V, Straube A. Botulinum toxin type-A therapy in cluster headache: An open study. J Headache Pain 2007;8:236–241.

112.Mulder LJ, Spierings EL. Naratriptan in the preventive treatment of cluster headache. Cephalalgia 2002;22:815–817.

113.Zebenholzer K, Wober C, Vigl M, Wessely P. Eletriptan for the short-term prophylaxis of cluster headache. Headache 2004;44:361–364.

114.Siow HC, Pozo-Rosich P, Silberstein SD. Frovatriptan for the treatment of cluster headaches. Cephalalgia 2004; 24:1045–1048.

115.Pageler L, Limmroth V. Oral triptans in the preventive management of cluster headache. Curr Pain Headache Rep 2012;16:180–184.

116.Rapoport AM, Bigal ME, Tepper SJ, Sheftell FD. Intranasal medications for the treatment of migraine and cluster headache. CNS Drugs 2004;18:671–685.

117.Hakim SM. Warfarin for refractory chronic cluster headache: A randomized pilot study. Headache 2011;51:713–725.

118.Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series. Cephalalgia 2010;30:1140–1144.

119.Moisset X, Clavelou P, Lauxerois M, Dallel R, Picard P. Ketamine infusion combined with magnesium as a therapy for intractable chronic cluster headache: Report of two cases. Headache 2017;57:1261–1264.

120.Asghar MS, Becerra L, Larsson HB, Borsook D, Ashina M. Calcitonin gene-related peptide modulates heat nociception in the human brain—An fMRI study in healthy volunteers. PLoS One 2016;11:e0150334.

121.Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994;117:427–434.

122.Neeb L, Anders L, Euskirchen P, Hoffmann J, Israel H, Reuter U. Corticosteroids alter CGRP and melatonin release in cluster headache episodes. Cephalalgia 2015;35:317–326.

123.Asghar MS, Hansen AE, Kapijimpanga T, et al. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology 2010;75:1520–1526.

124.Li J, Vause CV, Durham PL. Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 2008;1196:22–32.

125.Ashkenazi A. Allodynia in cluster headache. Curr Pain Headache Rep 2010;14:140–144.

126.Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14: 1091–1100.

127.Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:382–390.

128.Khan S, Olesen A, Ashina M. CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data. Cephalalgia 2017. Epub ahead of print Jan 1. 129.Ambrosini A, Schoenen J. Invasive pericranial nerve interventions. Cephalalgia 2016;36:1156–1169.

130.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;118:92–96.

131.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;10:891–897.

132.Fontaine D, Lazorthes Y, Mertens P, et al. Safety and efficacy of deep brain stimulation in refractory cluster headache:A randomized placebo-controlled double-blind trial followed by a 1-year open extension. J Headache Pain 2010;11:23–31.

133.Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 2009;72:341–345.

134.Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache 2011;51:1191–1201.

135.Leone M, Franzini A, Proietti Cecchini A, Bussone G. Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain 2013;154:89–94.

136.Leone M, Proietti Cecchini A, Messina G, Franzini A. Longterm occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia 2017;37:756–763.

137.Miller S, Watkins L, Matharu M. Predictors of response to occipital nerve stimulation in refractory chronic headache. Cephalalgia 2018;38:1267–1275.

138.Fontaine D, Blond S, Lucas C, et al. Occipital nerve stimulation improves the quality of life in medically intractable chronic cluster headache: Results of an observational prospective study. Cephalalgia 2017;37:1173–1179.

139.Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: Position statement from the European Headache Federation. J Headache Pain 2013;14:86.

140.Jürgens TP, Barloese M, May A, et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 2017;37:423–434.

141.Jürgens TP, Schoenen J, Rostgaard J, et al. Stimulation of the sphenopalatine ganglion in intractable cluster headache: Expert consensus on patient selection and standards of care. Cephalalgia 2014;34:1100–1110.

142.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;33:816–830.

143.Nesbitt AD, Marin JC, Tompkins E, Ruttledge MH, Goadsby PJ. Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment. Neurology 2015;84:1249–1253.

144.Gaul C, Magis D, Liebler E, Straube A. Effects of non-invasive vagus nerve stimulation on attack frequency over time and expanded response rates in patients with chronic cluster headache: A post hoc analysis of the randomised, controlled PREVA study. J Headache Pain 2017;18:22.

145.Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018; 38:959–969.

146.Sjaastad O, Vincent M. Indomethacin responsive headache syndromes: Chronic paroxysmal hemicrania and hemicrania continua. How they were discovered and what we have learned since. Funct Neurol 2010;25:49–55.

147.Pareja JA, Caminero AB, Franco E, Casado JL, Pascual J, Sánchez del Río M. Dose, efficacy and tolerability of longterm indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua. Cephalalgia 2001;21:906–910.

148.Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004;44:747–761.

149.Porta-Etessam J, Cuadrado M, Rodríguez-Gómez O, GarcíaPtacek S, Valencia C. Are Cox-2 drugs the second line option in indomethacin responsive headaches? J Headache Pain 2010;11:405–407.

150.Lisotto C, Maggioni F, Mainardi F, Zanchin G. Rofecoxib for the treatment of chronic paroxysmal hemicrania. Cephalalgia 2003;23:318–320.151.Siow HC. Seasonal episodic paroxysmal hemicranias responding to cyclooxygenase-2 inhibitors. Cephalalgia 2004; 24:414–415.

152.Mathew NT, Kailasam J, Fischer A. Responsiveness to celecoxib in chronic paroxysmal hemicrania. Neurology 2000; 55:316.

153.Evers S, Husstedt IW. Alternatives in drug treatment of chronic paroxysmal hemicrania. Headache 1996;36:429–432.

154.Sjaastad O, Antonaci F. A piroxicam derivative partly effective in chronic paroxysmal hemicrania and hemicrania continua. Headache 1995;35:549–550.155.Rozen TD. Melatonin responsive hemicrania continua. Headache 2006;46:1203–1204.

156.Cohen AS, Goadsby PJ. Paroxysmal hemicrania responding to topiramate. J Neurol Neurosurg Psychiatry 2007;78:96–97.

157.Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injection in primary headache syndromes—Prolonged effects from a single injection. Pain 2006;122:126–129.158.Gutierrez-Garcia JM. SUNCT syndrome responsive to lamotrigine. Headache 2002;42:823–825.

159.Leone M, Rigamonti A, Usai S, Damico D, Grazzi L, Bussone G. Two new SUNCT cases responsive to lamotrigine. Cephalalgia 2000;20:845–847.

160.D’Andrea G, Granella F, Ghiotto N, Nappi G. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001;57: 1723–1725.

161.Malik K, Rizvi S, Vaillancourt PD. The SUNCT syndrome: Successfully treated with lamotrigine. Pain Med 2002;3:167–168.

162.Piovesan EJ, Siow C, Kowacs PA, Werneck LC. Influence of lamotrigine over the SUNCT syndrome: One patient follow-up for two years. Arq Neuropsiquiatr 2003;61:691–694.

163.Cohen AS, Matharu MS, Goadsby PJ. Suggested guidelines for treating SUNCT and SUNA. Cephalalgia 2005;25:1200.164.Calvo JF, Bruera OC, de Lourdes Figuerola M, Gestro D, Tinetti N, Leston JA. SUNCT syndrome: Clinical and 12-year follow-up case report. Cephalalgia 2004;24:900–902.

165.Putzki N, Nirkko A, Diener HC. Trigeminal autonomic cephalalgias: A case of post-traumatic SUNCT syndrome? Cephalalgia 2005;25:395–397.

166.Pareja JA, Sjaastad O. SUNCT syndrome in the female. Headache 1994;34:217–220.

167.Raimondi E, Gardella L. SUNCT syndrome. Two cases in Argentina. Headache 1998;38:369–371.

168.Becser N, Berky M. SUNCT syndrome: A Hungarian case. Headache 1995;35:158–160.

169.Selekler HM, Efendi H, Alemdar M. Short-lasting unilateral neuralgiform headache with severe lacrimation and mild conjunctival injection. Cephalalgia 2005;25:317–320.

170.Schwaag S, Frese A, Husstedt IW, Evers S. SUNCT syndrome: The first German case series. Cephalalgia 2003; 23:398–400.

171.Rossi P, Cesarino F, Faroni J, Malpezzi MG, Sandrini G, Nappi G. SUNCT syndrome successfully treated with topiramate: Case reports. Cephalalgia 2003;23:998–1000.

172.Matharu MS, Boes CJ, Goadsby PJ. SUNCT syndrome: Prolonged attacks, refractoriness and response to topiramate. Neurology 2002;58:1307.173.Kuhn J, Vosskaemper M, Bewermeyer H. SUNCT syndrome: A possible bilateral case responding to topiramate. Neurology 2005;64:2159.174.Porta-Etessam J, Benito-Leon J, Martinez-Salio A, Berbel A. Gabapentin in the treatment of SUNCT syndrome. Headache 2002;42:523–524.175.Graff-Radford SB. SUNCT syndrome responsive to gabapentin (Neurontin). Cephalalgia 2000;20:515–517.

176.Marziniak M, Breyer R, Evers S. SUNCT syndrome successfully treated with the combination of oxcarbazepine and gabapentin. Pain Med 2009;10:1497–1500.

177.Narbone MC, Gangemi S, Abbate M. A case of SUNCT syndrome responsive to verapamil. Cephalalgia 2005;25:476–478.

178.Trauninger A, Alkonyi B, Kovács N, Komoly S, Pfund Z. Methylprednisolone therapy for short-term prevention of SUNCT syndrome. Cephalalgia 2010;30:735–739.

179.Bussone G, Rapoport A. Acute and preventive treatment of cluster headache and other trigeminal autonomic cephalgias. Handb Clin Neurol 2010;97:431–442.

180.Arroyo AM, Durán XR, Beldarrain MG, Pinedo A, GarcíaMoncó JC. Response to intravenous lidocaine in a patient with SUNCT syndrome. Cephalalgia 2010;30:110–112.

181.Lambru G, Shanahan P, Watkins L, Matharu MS. Occipital nerve stimulation in the treatment of medically intractable SUNCT and SUNA. Pain Physician 2014;17:29–41.

182.Costa A, Antonaci F, Ramusino M, Nappi G. The neuropharmacology of cluster headache and trigeminal autonomic cephalalgias. Curr Neuropharmacol 2015;13:304–323.