WAT ALS HOOFDPIJN CHRONISCH WORDT? Prof Jan Versijpt, MD PhD Kliniek voor Hoofd- en Aangezichtspijn Neurologie, UZ Brussel

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1 WAT ALS HOOFDPIJN CHRONISCH WORDT? Prof Jan Versijpt, MD PhD Kliniek voor Hoofd- en Aangezichtspijn Neurologie, UZ Brussel

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3 Stovner, IHC 2009

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5 New daily persistent headache Primair = dagelijkse and continue hoofdpijn Secundair Duidelijk moment van onset met pijn die onophoudelijk wordt binnen 24u Hoofdpijn sinds > 3 maanden Geen overige aandoening Subarachnoïdale bloeding Intracraniële hyper- of hypotensie Post-traumatische hoofdpijn Chronische meningitis Carotisdissectie Sinusthrombose Reuscelarteriitis

6 CHRONISCHE MIGRAINE

7 CHRONISCHE MIGRAINE EVOLUTIE IN DEFINITIES ICHD-II published, defining chronic migraine ICHD-III Pre ICHD-I ICHD-I classification introduced ICHD-II-R: revision of ICHD-II to be less restrictive

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9 Chronische migraine - evolutie Each year, 2.5% of patients with episodic migraine progress to chronic migraine 1 Risk factors can be split into: 2,3,4 Modifiable, e.g. Non-modifiable, e.g. Age Sex Race Education Head injury Obesity Depression Medication overuse Stress Caffeine overuse Snoring Allodynia 1.Bigal ME, et al. Headache 2008;48: Bigal ME, et al. Headache 2006;46: Lipton RB. Headache 2011;51: Bigal ME, et al. Headache 2009;49:S21 33.

10 Kost in Europa: 27 miljard Euro per jaar

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12 Disability* Class by WHO *Comparison of the disability of 1 day of a debilitating condition Increasing disability Severe migraine Active psychosis Dementia Quadriplegia Unipolar major depression Blindness Paraplegia Mild mental retardation Down syndrome Below-the-knee amputation Deafness Disability Class 4 Disability Class 5 Disability Class 6 Disability Class 7 Menken M. Arch Neurol. 2000;57:

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15 Medicatie-overgebruikshoofdpijn

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18 Adherence to oral prophylactics for migraine 1. Berger A et al. Poster presented at: The 14th Congress of the International Headache Society; September 10-13, 2009; Philadelphia, PA

19 PREEMPT study design PREEMPT consisted of two Phase III studies of chronic migraine patients Largest clinical programme on chronic migraine patients (1384 patients) Global study across 122 sites in North America (106); and Europe (16) 24-week randomised, double-blind, placebo-controlled phase 32-week open-label phase Double-blind phase Weeks Phone interview Open-label phase Baseline Randomisation Primary time point Treatment Treatment Treatment Treatment Treatment Dodick DW et al. Headache 2010;50: BE/0082/2012c Date of preparation April 2012 PROVIDED BY ALLERGAN

20 The fixed-site fixed-dose injection paradigm A total of 31 injections across seven specific head and neck muscles, with a minimum dose of 155 U of BOTOX injected per patient Occipitalis Temporalis (6 x 5 U) (8 x 5 U) Frontalis (4 x 5 U) Procerus (1 x 5 U) Corrugator (2 x 5 U) Cervical paraspinal group (4 x 5 U) Trapezius (6 x 5 U) BE/0082/2012c Date of preparation April 2012 PROVIDED BY ALLERGAN

21 The modified follow-the-pain paradigm Temporalis (2 x 5 U). Up to an additional two doses in either the right or left temporalis muscle, at the points of greatest tenderness Occipitalis (2 x 5 U). Up to an additional two doses in either the right or left occipitalis muscle at the points of greatest pain Trapezius (4x5 U). Up to an additional four doses in either the right or left trapezius muscle at the points of greatest pain BE/0082/2012c Date of preparation April 2012 PROVIDED BY ALLERGAN

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23 PREEMPT pooled efficacy results (Week 24) BOTOX / BOTOX (n=688) Placebo/ BOTOX (n=696) p value* Frequency of headache days <0.001 Frequency of migraine days <0.001 Frequency of moderate/severe headache days < <0.001 Frequency of headache episodes Frequency of migraine episodes Frequency of acute headache pain medication intake Frequency of triptan use <0.001 Total HIT-6 score <0.001 Patients with severe (>60) HIT-6 score (%) <0.001 Endpoint Mean change from baseline in: Total cumulative headache hours on headache days Table adapted from Aurora SK, et al *p values are from analyses of covariance (ANCOVA) with baseline as covariate. The main effects are treatment and medication overuse stratification. HIT = headache impact test; MSQ = Migraine-Specific Quality of Life Questionnaire. 1. Aurora SK et al. Headache 2011;51:

24 Likelihood of response in initial nonresponders Results suggest that patients with chronic migraine, who fail to respond to the first cycle of BOTOX treatment, can respond to subsequent treatment cycles Frequency of headache days: 50% firsttime responders* Percentage of patients, % Percentage of patients, % Frequency of headache days: 30% firsttime responders* *First-time responders for a given time point are subjects who never responded at any previous time points. Data are from PREEMPT pooled analysis. 1.Silberstein SD, et al. Poster presented at the 15th Congress of EFNS, September 10-13, 2011, Budapest, Hungary..

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27 Possible MoA(s) of BOTOX on the sensory systems involved in chronic migraine Peripheral sensory effect1,2 Blocks release of neurotransmitters associated with peripheral sensitisation of sensory afferents, such as glutamate and CGRP Transcranial afferent effect 3 Inhibits transmission in sensory nerves that traverse the cranium and have collateral dural branches Trigeminal-autonomic reflex effect 2,4 Inhibition of sphenopalatine (also known as the pterygopalatine) ganglion activation Other MoA = mode of action; CGRP = calcitonin gene-related peptide. 1.Dodick D, Silberstein S. Headache. 2006;46(Suppl 4):S182-S191 2.Aoki KR Headache 2003;43(Suppl. 1):S Kosaras et al. J Comp Neurol 2009;515: Goadsby PJ et al. N Engl J Med. 2002;346:

28 BOTOX and head pain A study investigated the effect of BOTOX in capsaicin-induced head pain 14 male volunteers received injections of either saline or 22 U BOTOX Pain was simulated by four intradermal injections of capsaicin (100 µg/ml) BOTOX or placebo Pre-treatment 24 h Capsaicin injection Day 1 Day 3 Capsaicin injection Capsaicin injection Figure adapted from Gazerani et al Gazerani P, et al. Pain 2009; 141:60 9 Day 7 End Capsaicin injection Capsaicin injection site BOTOX injection site

29 BOTOX reduced intensity and duration of capsaicin-induced pain in humans p<0.001 p<0.001 p<0.001 Saline BOTOX Figure adapted from Gazerani et al Gazerani P, et al. Pain 2009; 141:60 9 p<0.001 Saline BOTOX p<0.001

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