Headache Masters School 2013 in Asia Sunday March 24, 2013 Procedural Medicine Workshop Onabotulinumtoxin A: Evidence, Injection Technique, and Mechanism of Action David W. Dodick M.D. Professor Director of Headache Medicine Department of Neurology Mayo Clinic Phoenix Arizona USA 1
Learning objectives 1. Describe the diagnostic criteria for chronic migraine and the rationale for the change between ICHD II and ICHD III 2. Provide an overview of the evidence base for the treatment of chronic migraine and trigeminal neuralgia 3. Explain the potential mechanisms of action underlying the efficacy of OnabotulinumtoxinA in chronic migraine 2
Chronic Migraine and Medication Overuse Headache ICHD II and ICHD III ICHD II 1 ± medication overuse 2 combined criteria Headache on 15 days per month for at least 3 months 1 5 prior migraine attacks 1 On 8 days per month, headache fulfills criteria for migraine without aura and/or relieved with triptans or ergotamine Not attributed to another causative disorder 1 In case of medication overuse, diagnosis is MOH ICHD III (in press) Headache 15 days per month for at least 3 months On >8 days per month, headache fulfills MO, MA, or relieved with triptan or ergot Patients who fulfill criteria for CM and overuse medications, receive two diagnosis (CM 1.3 and MOH 8.2) 3
Chronic migraine Diagnosis Headache > 15d/mo Headache > 15d/mo Exclude secondary cause Diagnosis migraine > 8 days meeting criteria for migraine 4 *GMAP recommendation 1. Headache Classification Committee. Olesen J et al. Cephalalgia 2006;26:742 746. 2. Silberstein SD et al. Cephalalgia 2005;25:460 465.
The majority of chronic migraine (CM) sufferers in the population do not remit Annual incidence 2.5 4.5% Transition Rates in 2006 and 2007 Relative to CM Status in 2005 (Baseline) Remitted CM 26% Persistent CM 22% Transitioning CM 52% 5 AMPP = American Migraine Prevalence and Prevention. Lipton RB. Headache 2011;51:77 83.
Peripheral and Central Sensitization in Chronic Migraine Ophthalmic Nerve Occipital Nerves Dura Trigeminal Cervical Complex (TCC) Trigeminal Ganglion 6 1. Netter FH. Atlas of Human Anatomy. Summit, NJ: CIBA-GEIGY Corporation; 1989. 2. Goadsby PJ et al. N Engl J Med. 2002;346:257-270.
Preventive Treatments in chronic migraine: Evidence base Treatment Anticonvulsants: Valproate Topiramate Gabapentin Levetiracetam Evidence for Use in Chronic Migraine Small DBPC and comparator trial in CM/CDH 1,2 Three DBPC trials in CM 3,4 One DBPC trial in CDH 5 One DBPC trial in CDH 10 Antidepressants: Amitriptyline Fluoxetine Tizanidine Neuromodulation Small open label trial in TM 6 Small DBPC trial in CDH 7 Small DBPC trial in CDH 8 Sham controlled trials of occipital nerve stimulation (ONS) 11 13 OnabotulinumtoxinA Two DBPC trials in CM 9 DBPC = double blind placebo controlled; TM = transformed migraine; CDH = chronic daily headache; CM = chronic migraine.1. Yurekli VA et al. J Headache Pain. 2008;9:37 41. 2. Bartolini M et al. Clin Neuropharmacol. 2005;28:277 279. 3. Diener HC et al. Cephalalgia. 2007;27:814 823. 4. Silberstein SD et al. Headache. 2007;47:170 180. 5. Spira PJ, Beran RG. Neurology. 2003;61:1753 1759. 6. Krymchantowski AV et al. Headache. 2002;45:510 514. 7. Saper JR et al. Headache. 1994;34:497 502. 8. Saper JR et al. Headache. 2002;42:470 482.9. Dodick DW et al. Headache. 2010;50:921 936; Beran RG, Spira PJ. Cephalalgia 2010; 31(5) 530 536 Saper JR, et al. Cephalalgia 2011 Feb;31(3):271 85, Silberstein SD, et al. Cephalalgia 2011;31:117. Lipton RB, et al. Cephalalgia 2009;suppl 1:30. 7
OnabotulinumtoxinA for Chronic Migraine 8
Anatomical Injection Sites Follow Distributions and Areas Innervated by the Trigeminal and Cervical Sensory System Auriculotemporal Nerve Supratrochlear Nerve Supraorbital Nerve Greater Occipital Nerve Lesser Occipital Nerve Cervical Rami 9 9 Schuenke M et al, eds. Theime Atlas of Anatomy: Head and Neuroanatomy. Stuttgart: Thieme; 2010.
Injection Sites: Corrugator and Procerus 5 U ONABA (0.1 ml injected) Procerus: 5 U at site Corrugator: 5 U at each site 10 10 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Injection Site: Frontalis Region 5 U ONABA (0.1 ml injected) 11 11 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Injection Sites: Temporalis 5 U ONABA (0.1 ml injected) 12 12 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Injection Site: Occipitalis 5 U ONABA (0.1 ml injected) Occipitalis muscles and injection sites* Sternocleidomastoid muscle Nuchal ridge 13 13 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Injection Sites: Cervical Paraspinal and Trapezius 5 U ONABA (0.1 ml injected) Cervical paraspinal 5 U each* Trapezius muscles 5 U each Semispinalis capitus Splenius capitus Trapezius Levator scapulae 14 14 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Injection Paradigm: Required Dose Using a Fixed Site, Fixed Dose Paradigm Order Muscle Number of Units (U) A Corrugator 10 (5 each side) B Procerus 5 C Frontalis 20 (10 each side) D Temporalis 40 (20 each side) E Occipitalis 30 (15 each side) F Cervical paraspinal 20 (10 each side) G Trapezius 30 (15 each side) Total number of units (U) 155 15 15 Blumenfeld A, Silberstein SD, Dodick DW, et al. Headache. 2010 Oct; 50(9):1406 18.
Follow the pain strategy D. Temporalis: 5 U/site (up to 2 additional sites) E. Occipitalis: 5 U/site (up to 2 additional sites) G. Trapezius: 5 U/site (up to 4 additional sites) 16
PREEMPT: Pooled baseline demographics Reflects Clinical Population OnabotulinumtoxinA (n=688) Placebo (n=696) Mean age, years 41 42 Mean years since onset of CM 19 19 Female, % 88 85 Mean HA days (SD) 20 (4) 20 (4) Mean migraine days (SD) 19 (4) 19 (4) Mean moderate/severe HA days (SD) 18 (4.1) 18 (4.3) Mean cumulative hours of HA occurring on HA days (SD) 296 (117)* 281 (115)* % Patients with severe ( 60) HIT 6 score 94 93 % Patients overusing acute HA pain medication 65 66 17 HA = headache; HIT = Headache Impact Test. *p<0.05. Dodick DW et al. Headache. 2010;50:921 936.
PREEMPT pooled analysis: Change in headache days primary endpoint 1 Week: 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Headache Days/28 Days (Mean Headache Change Days/28 From Baseline) Days 2 4 6 8 10 12 14 p<0.001 Week 24 Primary Endpoint p<0.001 p<0.001 p<0.001 p<0.001 Double Blind Phase p<0.001 OnabotulinumtoxinA Placebo p<0.001 p=0.008 p=0.01 p=0.007 p=0.047 p=0.019 Open Label Phase p=0.011 p=0.019 18 *Patients who received onabotulinumtoxina throughout the 56 week treatment program. Mean ± standard error. The double blind phase included 688 subjects in the onabotulinumtoxina group and 696 in the placebo group. Headache days at baseline: 19.9 onabotulinumtoxina group vs 19.8 placebo group, p=0.498. 1. Aurora et al. Headache. 2011 51(9):1358 7.
OnabotulinumtoxinA: Primary and secondary outcomes in PREEMPT studies Endpoint, Mean Change From Baseline OnabotulinumtoxinA (n=688) Placebo (n=696) P value* Frequency of HA days 8.4 6.6 <0.001 Frequency of migraine days 8.2 6.2 <0.001 Frequency of moderate/severe HA days 7.7 5.8 <0.001 Total cumulative HA hours on HA days 119.7 80.5 <0.001 % Patients with severe ( 60) HIT 6 score 67.6 78.2 <0.001 Total HIT 6 score 4.8 2.4 <0.001 Frequency of HA episodes 5.2 4.9 0.009 Frequency of migraine episodes 4.9 4.5 0.004 Frequency of acute HA pain medication intake (all categories) 10.1 9.4 0.247 Frequency of triptan use 3.2 2.1 <0.001 19 * p values are adjusted for baseline and for medication overuse stratification. HA = headache; HIT = Headache Impact Test. Dodick DW et al. Headache. 2010;50:921 936.
PREEPMT studies: Responder rates ( 50%) At Week 56, ~70% of patients achieved 50% reduction in headache days 1 and migraine days 2 (from baseline) OnabotulinumtoxinA (n=688) Placebo (n=696) Week 24 Patients (%) p<0.001 p<0.001 Headache Days 1 Migraine Days 2 20 Headache days at baseline: 19.9 onabotulinumtoxina group vs 19.8 placebo group, p=0.498. Migraine days at baseline: 19.1 onabotulinumtoxina group vs 18.9 placebo group, p=0.328. Dodick DW et al. Headache. 2010; 50:921 936.
PREEPMT studies: Responder rates ( 75%) OnabotulinumtoxinA (n=688) Placebo (n=696) p=0.002 p=0.007 p=0.005 p=0.006 p<0.001 p<0.001 Percent of Patients Headache Days Headache Episodes Mod/Severe Headache Days Total Cumulative Hours of HA on HA Days Migraine Days Migraine Episodes 21 Dodick DW. et al. IHC Berlin June 2011.
PREEMPT pooled analysis: subgroup who overuse acute pain medications OnabotulinumtoxinA (n=445) Placebo (n=459) Change in Frequency From Baseline Headache Days Improvement 22 *Of the total pooled PREEMPT population, 64.7% and 65.9% of onabotulinumtoxina and placebo groups, respectively, overused acute headache pain medication (simple analgesics, ergotamine/dhe, triptans, opioids, combination of analgesics, or any combination of the preceding classes). 1,2 p<0.001. 1. Silberstein SD et al. Presented at IHC 2009. 2. Dodick DW et al. Headache. 2010;50:921-936.
PREEMPT: Analysis of Responders Despite Initial Non Response 50% First Time Responders,* Variable OnabotulinumtoxinA (n=688) Frequency of HA days, n (%) 339 (49.3) 78 (11.3) 71 (10.3) Frequency of moderate/severe HA days 365 (53.1) 90 (13.1) 59 (9.6) Total cumulative hours of HA on HA days 373 (54.2) 90 (11.6) 51 (7.4) *First time responders for a given time point are subjects who never responded at any previous time points. 23 Silberstein SD, Dodick DW, Turkel C, et al. EHMTIS 2012
PREEMPT: OnabotulinumtoxinA is a well tolerated treatment for chronic migraine No new treatment related AEs were identified Most AEs were mild or moderate in severity and resolved without sequelae OnabotulinumtoxinA (n = 687) Placebo (n = 692) Neck pain 60 (8.7) 19 (2.7) Muscular weakness 24 (5.5) 2 (0.3) Headache 32 (4.7) 22 (3.2) Migraine 26 (3.8) 18 (2.6) Musculoskeletal stiffness 25 (3.6) 6 (0.9) Eyelid ptosis 25 (3.6) 2 (0.3) Injection site pain 23 (3.3) 14 (2.0) Myalgia 21 (3.1) 6 (0.9) Musculoskeletal pain 18 (2.6) 10 (1.4) Facial paresis 15 (2.2) 0 (0.0) 24 Dodick DW et al. Headache. 2010; 50:921 936
Treatment effect size 50% Responder Rate (Active / Placebo); NNT Discontinuation Due to Adverse Events Migraine/ Migrainous Days; Absolute Between Group Difference OnabotulinumtoxinA 1 47% / 35%* 8 3.8% 8.2 (2.0) Topiramate 2,3 37% / 29% * 12.5 10.9% 6.4 (1.7) 25 * 50% reduction in mean monthly migraine days. These were not comparison studies. The topiramate data come from a double blind study assessing topiramate efficacy in Chronic Migraine patients, and the onabotulinumtoxina data come from the pooled results of the PREEMPT studies. NNT = Number Needed to Treat. 1. Dodick DW et al. Headache. 2010:50:921 963. 2. Silberstein SD et al. Headache. 2009;49:1153 1162.
OnabotulinumtoxinA and Pain OnabotA relieves pain in variety of conditions (e.g. spasticity, back pain, trigeminal neuralgia, neuropathic pain) Bilateral effects from unilateral injection in experimental neuropathy; suggests central site of action 5 OnabotA inhibits sensitization of central V1 neurons in animal/human pain models 1 4 26 1. Oshinsky ML et al. Cephalalgia. 2004;24:781 (PA.21). 2. Cui M et al. Naunyn Schmiedebergs Arch Pharmacol. 2002;365:R17 (#33). 3. Aoki KR. Headache. 2003;43(suppl 1):S9 S15. 4. Gazerani P et al. Pain. 2006;122:315 325; Gazerini M, et al. Pain 2009;141:60 69. 5. Bach Rojeckly L, et al. Eur J Pharmacol 633:10 14
Onabotulinumtoxin A Peripheral Mechanism of Action 27
OnabotulinumtoxinA May Access Dural Afferent Nociceptors in Dermis/Subcutaneous Tissue Action potential Reduction in primary sensory afferent signals from the meninges, bone and scalp 28 Kosaras B, et al. J Comp Neurol 2009;515:331 348.
Directionality of Pain as a Predictor of Response Intracranial origin Extracranial origin 29 Jakubowski M., et al. Pain 125 (2006) 286 295
Onabotulinumtoxin A Central Mechanism of Action 30
Antinociceptive Effect in Trigeminal System is Centrally Mediated and Dependent on Axonal Transport 31 Matak I, et al. Neurosci 2011;86:201 207
Transport is Time, Location, and Dose Dependent May Explain Clinical Effects 32 Matak I, et al. Neurosci 2011;86:201 207
OnabotulinumtoxinA for Trigeminal Neuralgia 75u/1.5ml 33 Wu C et al. Cephalalgia 2012;0333102412441721
OnabotulinumtoxinA for Trigeminal Neuralgia Weekly mean VAS scores Mean attack frequency per day *Responders 68% vs 15% 34 * Responder = >50% reduction in pain score Wu C et al. Cephalalgia 2012;0333102412441721
Secondary Endpoint (Patient Global Impression of Change) and Adverse Events Adverse Events 5 patients (OnabotA) with facial asymmetry resolved 7 weeks 3 patients with transient facial edema (2 OBA/ 1 placebo) 35
OnabotulinumtoxinA for Headache and Facial Pain Evidence supports the safety and efficacy of OnabotulinumtoxinA for Chronic Migraine Evidence emerging for efficacy of OnabotA for trigeminal neuralgia Mechanism of action unclear, but could be indirect or direct inhibition of central 2 nd order trigeminal sensory neurons 36