6/8/2016. Disclosure. Indomethacin - responsive headache. Introduction. Indomethacin Pharmacology

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1 Disclosure Indomethacin - responsive headache I have no relevant financial relationships with the manufactures of any commercial products and /or provider of commercial services discussed in this CME activity Toomas Toomsoo, M.D. Head of the Center of Neurology East Tallinn Central Hospital 2 Introduction The first primary headache disorder identified in 1976 by Sjaastad and Dale as an indomethacin responsive headache syndrome Sjaastad O, Dale I. A new (?) clinical headache entity: chronic paroxysmal hemicrania II. Acta Neurol Scand. 1976;54: In 1984 hemicrania continua (HC) was described by Sjaastad Sjaastad O, Spierings EL. Hemicrania continua: another headache absolutely responsive to indomethacin. Cephalalgia. 1984;4: As per the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-III beta), paroxysmal hemicrania (PH) and HC are now classified as trigeminal autonomic cephalalgias Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 3rd edn. Cephalalgia. 2013;33(9): Very informative. Important to note the revisions of the trigeminal autonomic cephalgia section. Indomethacin Pharmacology Oral bioavailability is approximately 100 % Non- steroidal anti-inflammatory drugs (NSAID) Peak plasma concentrations are reached within 0.5 to 2 h Indomethacin has been shown to have the highest penetration into the central nervous system when compared to other NSAID Parepally JM, Mandula H, Smith QR. Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen, and indomethacin. Pharm Res. 2006;23(5): Onset of action is within 30 min and the duration is about 4 to 6 h. It is metabolized via the liver Plasma half-life averages 3 h but can range from 3 to 10 h Tolerability is one of the major limitations - gastrointestinal complications: from dyspepsia to gastrointestinal bleeds - affect renal function, liver function, and platelet activity - fatigue, dizziness, headache, and confusion Prakash S, Husain M, Sureka DS, et al. Is there a need to search for alternatives to indomethacin for hemicrania continua? Case reports and a review. J Neurol Sci. 2009;277(1): Jurgens TP, Schulte LH, May A. Indomethacin-induced de novo headache in hemicrania continua fighting fire with fire? Cephalalgia. 2013;33(14): How indomethacin exerts its effect in PH and HC? Indomethacin inhibits two isoforms of COX ( COX-1 and COX-2 ) Indomethacin inhibits the production of nitric oxide (NO) Zy D, Xy L. Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro. Int J Immunopharmacol. 1999;21: Indomethacin has been shown to effect NO-induced vasodilation 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(2): Recent studies also demonstrated a direct effect of indomethacin on trigeminal activation itself Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of trigeminal autonomic cephalgias: therapeutic characterization. Brain. 2012;135(Pt 12): Modulation of cerebral vasodilatory, prostaglandin production and direct cerebral blood vessel vasoconstriction Indomethacin s therapeutic effect on Valsalva-induced headaches may be due to decreases in intracranial pressure - after traumatic brain injury and in idiopathic intracranial hypertension Godoy DA, Alvarez E, Manzi R, Pinero G, Di Napoli M. The physiologic effects of indomethacin test on CPP and ICP in severe traumatic brain injury (stbi). Neurocrit Care. 2014;20(2): Forderreuther S, Straube A. Indomethacin reduces CSF pressure in intracranial hypertension. Neurology. 2000;55(7): Indomethacin-responsive headaches a heterogeneous group of primary headache disorders Absolute response to indomethacin The epidemiology of these conditions is incompletely defined Traditionally, indomethacin responsive headaches include a subset of trigeminal autonomic cephalalgias Paroxysmal hemicrania Hemicrania continua Valsalva-induced headaches cough headache exercise headache sex headache Primary stabbing headache Hypnic headache Cluster headache, nummular headache, and ophthalmoplegic migraine have been described as also respond to indomethacin 6 1

2 Paroxysmal Hemicrania Paroxysmal Hemicrania Frequent Short-lasting Unilateral headache orbital, supraorbital or temporal region Ipsilateral autonomic features HISTORICALLY Females : Males ratio at 2:1 Mean age of onset of 34 years The attacks are absolutely responsive to indomethacin Antonacci F, Sjaastad O. Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache. 1989;29: PRESENT STUDIES Females:Males ratio at 1: 1 a slightly older mean age of onset between 37 and 42 years response to indomethacin cannot be used to exclude a secondary cause of PC Prakash S, Belani P, Susvirkar A, Trivedi A, Ahuja S, Patel A. Paroxysmal hemicrania: a retrospective study of a consecutive series of 22 patients and a critical analysis of the diagnostic criteria. J Headache Pain. 2013;14(1):26. 7 Chronic form > Episodic form based on the duration of pain-free intervals Unilateral headache pain is rated as severe to very severe by 88 to 93 % of patients Prakash S, Belani P, Susvirkar A, Trivedi A, Ahuja S, Patel A. Paroxysmal hemicrania: a retrospective study of a consecutive series of 22 patients and a critical analysis of the diagnostic criteria. J Headache Pain. 2013;14(1):26. Only 35 % of patients have autonomic features in all or most attacks Lacrimation is the most common cranial autonomic feature (62 87 %) PH attacks should last between 2 and 30 min Attacks have been reported to range from seconds up to 6 h Prakash S, Belani P, Susvirkar A, Trivedi A, Ahuja S, Patel A. Paroxysmal hemicrania: a retrospective study of a consecutive series of 22 patients and a critical analysis of the diagnostic criteria. J Headache Pain. 2013;14(1):26. 8 Indomethacin in Headache Therapy 1. Correct diagnosis of PH and HC 2. Treatment is usually started at a dose of 25 mg 3 times/daily median interval between drug administration and response in patients with HC and PH was 4 and 7 h Pareja J, Sjaastad O. Chronic paroxysmal hemicrania and hemicrania continua. Interval between indomethacin administration and response. Headache. 1996;36:20 3. If patients do not obtain relief within 48 h of initiation, the dosage can be increased to 50 mg three times daily. A patient as a non-responder, with dosages as high as 300 mg daily Dodick DW. Indomethacin-responsive headache syndromes. Curr Pain Headache Rep. 2004;8(1): Indomethacin in Headache Therapy An effective dosage is maintained for several weeks the dosage should be slowly reduced by 25 mg every 3 days. One case series of 26 patients with HC or PH showed that 42 % experienced a mean decrease of 56 % of their indomethacin dose required to maintain a pain-free state Del Rio Sanchez M, Caminero AB, Pascual J, et al. Dose and efficacy of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua. Cephalalgia. 2001;21: 507. Sjaastad has reported on three patients who have been able to reduce their indomethacin to 25 mg daily or even 25 mg every other day 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(1): Indomethacin dosages should be as small as possible 9 10 Hemicrania Continua Hemicrania Continua Frequent Short-lasting Unilateral headache orbital, supraorbital or temporal region Ipsilateral autonomic features 2 subtypes remitting - pain-free periods lasting 1 day or longer without treatment unremitting The attacks are absolutely responsive to indomethacin response to indomethacin cannot be used to exclude a secondary cause of HC Most HC patients are women Most patients develop HC in their third to fourth decade (mean range years) Prakash S, Golwala P. A proposal for revision of hemicrania continua diagnostic criteria based on critical analysis of 62 patients. Cephalalgia. 2012;32(11): Important paper examining the classification criteria of hemicrania continua. 11 Autonomic symptoms in HC are less prominent than seen with PH Lacrimation is the most common autonomic symptom (53 80 %) Moura LM, Bezerra JM, Fleming NR. Treatment of hemicrania continua: case series and literature review. Rev Bras Anestesiol. 2012;62(2): Migrainous symptoms also occur nausea (43 53 %) photophobia (30 79 %) motion sensitivity (69 %) Prakash S, Golwala P. A proposal for revision of hemicrania continua diagnostic criteria based on critical analysis of 62 patients. Cephalalgia. 2012;32(11): Important paper examining the classification criteria of hemicrania continua Many atypical cases have been described Bilateral HC Southerland AM, Login IS. Rigorously defined hemicrania continua presenting bilaterally. Cephalalgia. 2011;31(14): HC with aura Peres M, Slow HC, Rozen TD. Hemicrania continua with aura. Cephalalgia. 2002;22(3): Seasonality HC Peres M, Stiles MA, Oshinsky M, Rozen TD. Remitting form of hemicrania continua with seasonal pattern. Headache. 2001;41(6): Indomethacin-nonresponsive HC Marmura MJ, Silberstein SD, Gupta M. Hemicrania continua: who responds to indomethacin? Cephalalgia. 2009;29:

3 Valsalva-Induced Headaches: Cough Headache, Exercise Headache, and Headache Associated with Sexual Activity Cough, exercise, and sex headaches - are related to rises in intra-abdominal pressure Pathogenesis of these headaches is not clearly defined Cough headache usually occurs after brief rises in intra-abdominal pressure Exercise and sex headaches often occur after more prolonged provocations They are rare entities A lifetime prevalence of 1 % for each syndrome Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992;42: Each of these headache syndromes is reported to be responsive to indomethacin Cough headache is a typically bilateral headache of sudden onset seconds up to 2 h Exercise headaches previously known as exertional headaches is a typically bilateral headache with a throbbing or pulsatile quality not last longer than 48 h. occur at high altitude or in hot weather prevented by avoidance of prolonged physical exercise Headache Associated with Sexual Activity the preorgasmic and orgasmic subtypes as one entity Pascual J, Gonzalez-Mandley A, Martin R, et al. Headaches precipitated by cough, prolonged exercise or sexual activity: a prospective etiological and clinical study. J Headache Pain. 2008;9: Valsalva-Induced Headaches and Sexual Headache are not only primary headaches A study with 30 headache associated patients with sexual activity and found 67 % had secondary causes subarachnoid hemorrhage basilar artery dissection reversible cerebral vasoconstriction syndrome Yeh YC, Fuh JL, Chen SP, Wang SJ. Clinical features, imaging findings and outcomes of headache associated with sexual activity. Cephalalgia. 2010;30: Primary Stabbing Headache as ice-pick headache or jabs and jolts A single or numerous stabs Lasting seconds (mean duration 2.2 s) 68 % cases have frequency < 1 attack per day 5% had > 5 greater attacks per day Sjaastad O, Pettersen H, Bakketeig LS. The Vaga study of headache epidemiology II. Jabs: clinical manifestations. Acta Neurol Scand. 2002;105: Multifocal pain location Unifocal in up to 57 % of patients 61 % of patients experience pain in the temporal and frontoocular regions Sjaastad O, Pettersen H, Bakketeig LS. The Vaga study of headache epidemiology II. Jabs: clinical manifestations. Acta Neurol Scand. 2002;105: Primary Stabbing Headache Female : Male ratio of 1.49:1.06 Onset is usually in early adulthood (mean age 28 years) Sjaastad O, Pettersen H, Bakketeig LS. The Vaga study; epidemiology of headache I: the prevalence of ultrashort paroxysms. Cephalalgia. 2001;21: Hypnic Headache sleep-related headache The coexistence of primary stabbing headache -Migraine - Cluster headache Ekbom K. Some observations on pain in cluster headache.headache. 1975;14: Paroxysmal hemicrania Sjaastad O, Egge K, Horven I, et al. Chronic paroxysmal hemicranial: mechanical precipitation of attacks. Headache. 1979;19: Hemicrania continua Sjaastad O, Spierings EL. Hemicrania continua : another headache absolutely responsive to indomethacin. Cephalalgia. 1984;4: Primary stabbing headache partially or completely responsive to indomethacin - doses of mg daily relief pain

4 Hypnic Headache sleep-related headache -occur at the same time at night (called alarm clock headaches ) -bilateral or unilateral -no associated autonomic features -patients may have nausea, phonophobia, and photophobia Onset is usually after 50 years Women are affected more than men Raskin NL. The hypnic headache syndrome. Headache. 1988;28: at least 10 days per month and last between 15 min and 4 h after waking Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 3rd edn. Cephalalgia. 2013;33(9): Symptomatic Hypnic Headache Neuroimaging should be performed in all patients with hypnic headache - brain tumors - nocturnal hypertension can produce hypnic headache-like attacks Caminero AB, Martin J, del Rio MS. Secondary hypnic headache or symptomatic nocturnal hypertension? Two case reports. Cephalalgia. 2010;30: Gil-Gouveia R, Goadsby PJ. Secondary hypnic headache. J Neurol. 2007;254: Indomethacin, lithium, and caffeine have been found to be effective in a number of patients Holle D, Naegel S, Obermann M. Hypnic headache. Cephalalgia. 2013;33: Novel Indomethacin-Responsive Headaches Typical cases of PH and HC that have been described as unresponsive to indomethacin Marmura MJ, Silberstein SD, Gupta M. Hemicrania continua: who responds to indomethacin? Cephalalgia. 2009;29: Boes C, Dodick DW: The clinical spectrum of chronic paroxysmal hemicrania seen at the Mayo Clinic from Headache 2003 Variety of other medications can be effective in patients with HC and PH - HC or PH patients responded to other medications prior to receiving indomethacin - They may not be correctly diagnosed as HC or PH Other primary headache disorders that are generally not considered indomethacinresponsive headaches have been described with good response to indomethacin - cluster headache 1 - nummular headache 2 - ophthalmoplegic migraine 3 Novel Indomethacin-Responsive Headaches Cluster Headache ( CH) Indomethacin responsive headache noted many cases of definite or possible CH in the literature that they felt were wrongly labeled as PH because of the patient s response to indomethacin Onset of indomethacin response in patients who met ICHD-III beta criteria for CH was more gradual compared to those of patients with other indomethacin-responsive headaches many patients with CH required larger doses of indomethacin Prakash S, Shah ND, Chavda BV. Cluster headache responsive to indomethacin: case reports and a critical review of the literature. Cephalalgia. 2010;30(8): Prakash S, Shah ND, Chavda BV. Cluster headache responsive to indomethacin: case reports and a critical review of the literature. Cephalalgia. 2010;30(8): Baldacci F, Nuti A, Lucetti C, Borelli P, Bonuccelli U. Nummular headache dramatically responsive to indomethacin. Cephalalgia. 2010;30(9): Pareja JA, Churruca J, de la Casa Fages B, de Silanes CL, Sanchez C, Barriga FJ. Ophthalmoplegic migraine. two patients with an absolute response to indomethacin. Cephalalgia. 2010;30(6): Medication overuse headache indomethacin responsive headache Indomethacin use > 15 days per month Medication overuse headache is not commonly reported patients with indomethacin-responsive headache syndromes Indomethacin may have a disease modifying effect in the indomethacin-responsive headache syndromes If indomethacin is contraindicated or intolerable? Celecoxib and rofecoxib, melatonin and gabapentin have been reported as effective in small series of HC patients Starling AJ, Hoffman-Snyder C, Halker RB, et al. Risk of development of medication overuse headache with nonsteroidal antiinflammatory drug therapy formigraine: a critically appraised topic. Neurologist. 2011;17: Indometacin- Responsive Headaches Other therapies Cough headache - acetazolamide and methysergide in open-label trials Exercise and sex headaches -Propranolol Frese A, Rahmann A, Gregor N, Biehl K, Husstedt IW, Evers S. Headache associated with sexual activity: prognosis and treatment options. Cephalalgia. 2007;27: Primary stabbing headaches -often do not require treatment -Celecoxib, nifedipine, melatonin, gabapentin Piovesan EJ, Zukerman E, Kowacs PA, Werneck LC. COX-2 inhibitor for the treatment of idiopathic stabbing headache secondary to cerebrovascular diseases. Cephalalgia. 2002;22: Hypnic headache can be treated - Lithium, caffeine

5 C A S E A 45-year-old woman came to our clinic with a five month history of focal head pain in the right parietal region. With indomethacin per os (50 mg BID) provided complete pain relief The affected area was perfectly circular, with a 3 cm diameter. The pain was continuous, dull and pressing, graded 3 /10 The affected area was occasionally tender to the touch. Neurological examination was normal. His past medical history was unremarkable The patient s CT and MRI scans of the brain, which proved normal INEFFECTIVE - Paracetamol and naproxen Amitriptyline 50 mg/day for 1 month Gabapentin 900 mg/day for 1 month. 25 After 3 weeks treatment, the indomethacin treatment was stopped, but the pain recurred with the same characteristics within few days Indomethacin treatment was restarted, again with a prompt response After 1 month, the medication was definitely discontinued The patient remained pain-free during 3 months follow-up ( 2015 March ) 26 NUMMULAR HEADACHE Pain of highly variable duration, but often chronic, in a small circumscribed area of the scalp ( without any structural lesion ) According to the hypothesis of a neuropathic origin of the pain in NH The drugs which usually work in neuropathic pain have been the most broadly used as prophylaxis Indomethacin responsiveness in NH has been appropriately investigated in only few cases, with contradictory results Ruscheweyh R, Buchheister A, Gregor N, Jung A, Evers S. Nummular headache: six new cases and lancinating pain attacks as possible manifestation. Cephalalgia 11 May 2009; 30 (accessed 30 January 2010) T A K E H O M E M E S S A G E Traditionally, indomethacin responsive headaches include a subset of trigeminal autonomic cephalalgias Indomethacin, as a member of the non-steroidal anti-inflammatory drug class Indomethacin completely efficacious in the treatment of the primary headache disorders; paroxysmal hemicrania and hemicrania continua Neuroimaging is recommended to investigate for various organic causes that may mimic these headaches Other primary headache disorders that are generally not considered indomethacin-responsive headaches have been described with good response to indomethacin ( cluster headache. nummular headache, ophthalmoplegic migraine ) 29 5