Headache: New concepts and curiosities

Transcription

1 FORGING THE FUTURE IN PSYCHIATRY AND MENTAL HEALTH CONFERENCE Headache: New concepts and curiosities Jonathan H. Smith, M.D. Assistant Professor of Neurology

2 Disclosures Publishing royalties from Up- To- Date, Inc. for Acute treatment of migraine in adults and Preventative treatment of migraine in adults. Non- FDA approved treatments will be discussed.

3 Objectives Formulate a systematic approach to headache classikication Review recent updates in headache pathophysiology, diagnosis, and treatment

4 Chronic daily headache: Approach to diagnosis Red flags 15 headache days* / month 3 months = chronic daily headache *One migraine may last multiple days *Patients may not disclose minor headache days Short duration attacks < 4 hours Long duration attacks 4 hours

5 Red Klags require evaluation Systemic symptoms Neurologic signs Thunderclap onset SNOOP Dodick DW. Adv. Stud Med 2003;3:S

6 Red Klags require evaluation Onset at age 50 Postural headaches Papilledema Precipitants SNOOP Dodick DW. Adv. Stud Med 2003;3:S

7 Red Klags: example 40 year- old man presents with a persistent daily- from- onset right periorbital headache following a whiplash injury Pain is mild- moderate, achy, and has no associated features Exam abnormality

8 15 headache days* / month 3 months = chronic daily headache Red flags Short duration attacks < 4 hours Long duration attacks 4 hours

9 Chronic cluster headache Chronic daily headache Short duration attacks (< 4 hours) Chronic paroxysmal hemicrania Chronic SUNCT Cranial neuralgia Pareja JA. Cephalalgia 2002;22:251-55

10 Short duration headache: example 0 18 year- old woman presents with chronic daily headache x 1.5 years 0 Headaches occur 2-3 times per day, lasting minutes 0 Pain is always around right eye, intense, sharp, and is associated with involuntary tearing Diagnosis: Chronic cluster headache Treatment: Prednisone 60 mg, slow taper Verapamil 120 mg BID Sumatriptan 4-6 mg SC PRN

11 15 headache days* / month 3 months = chronic daily headache Red flags Short duration attacks < 4 hours Long duration attacks 4 hours

12 Chronic daily headache: long duration attacks ( 4 hours) Hemicrania continua Continuous unilateral pain with autonomic features New daily persistent headache Chronic migraine Chronic tension- type headache Daily from onset progression Migraine 8 days per month Sparse associated symptoms (no nausea, light OR sound sensitivity)

13 Long duration headache: example 43 year- old woman presents with intractable migraines x 8 years Headache involves right- side only, frontal and temporal Pain averages 5/10, but can become more intense at times She reports associated nausea, light-, and sound- sensitivity When the headache is intense, her right eye can water, and right nose can become stuffy Diagnosis: Hemicrania continua Treatment: Indomethacin 25 mg TID x 1 week Indomethacin 50 mg TID x 1 week Indomethacin 75 mg TID x 1 week

14 Migraine criteria Number of attacks Duration Features 2 Minimum of Kive 4 72 hours Severe Unilateral Associated symptoms 1 Nausea and/or vomiting Photophobia and phonophobia Throbbing Worsened by exertion ICHD-3, β

15 Sinus symptoms in migraine Schreiber CP, et al. Arch Int Med 2004;164:1769

16 Migraine hurts over the sinuses Eross E, Dodick DW, Eross M. Headache 2007;47:

17 Neck pain: A symptom of MIGRAINE V1-3 Trigemino-cervical complex C1-3 Is there neck pain present all the time or just during attacks?

18 Cranial autonomic symptoms are common in migraine V VII *Autonomic features to ask about: Tearing, injection, pupillary changes, ptosis, nasal congestion, rhinorrhea Goadsby PJ, et al. NEJM 2002;346(4):

19 Overview Risk factors for chronic daily headache Migraine pathophysiology New and emerging treatments Earliest stages of attack How can we better help patients?

20 Overview Risk factors for chronic daily headache Migraine pathophysiology New and emerging treatments Earliest stages of attack

21 I feel like I ve been drugged An 18 year- old student reports excessive yawning in lectures, despite adequate sleep. He feels well rested when he Kirst wakes up. He will be irritable when he gets home for no apparent reason. He has been noting increasing migraine frequency.

22 Prodrome/Premonitory stage 0 Often overlooked (10-90%) 0 Fatigue 0 Hunger/cravings/thirst 0 Yawning 0 Irritability/mood changes 0 Fluid retention 0 Prospective diary studies 0 72% vs. 30% chance- alone Kelman L. Headache Giffin NJ, et al. Neurology 2003;60(6): Maniyar F, et al. Brain 2014;137(1):232-41

23 Bright lights trigger my headaches 0 Nausea (24%), photophobia (49%), and phonophobia (38%) are often present during premonitory and interictal period 0 Despite reporting bright light as a consistent trigger, when given experimentally Bright lights only rarely trigger attacks Giffin NJ, et al. Neurology 2003;60(6): Hougaard A, et al. Neurology 2013; 80(5):428-31

24 Sometimes a trigger, sometimes not The tipping point Cyclical trigeminal activation in relationship to clinical migraine attacks Stankewitz A, et al. J Neurosci 2011

25 What are the most validated triggers? Head trauma Vestibular activation Estrogen withdrawal (menses) Histamine Monosodium glutamate Nitric oxide donors Starvation/missed meals Disrupted sleep Standard advice = avoid triggers But avoidance may = sensitization

26 Triggers: Cope, don t avoid 0 Randomized (n = 127): 0 Waitlist (+11%) 0 Avoidance (- 13%) 0 Avoidance + CBT (- 30%) 0 Learning to cope (- 36%) Only difference in 50% RR Martin PR, et al. Behav Res Ther 2014;61:1-11

27 COPING WITH TRIGGERS If potentially harmful, then avoid (eg, missed meals, lack of or excessive sleep, gasoline fumes) Particularly good for coping strategies: - - SpeciKic stressors or anxiety- provoking situations (gradual exposure therapy) - - Sensory triggers (eg, glare, noise, temperature) (relationship between exposure and sensitivity)

28 EASE into triggers 1. Experiment: Encourage testing with mild version of specikic trigger 2. Avoid: Harmful triggers 3. Stress: Teach positive thinking, relaxation techniques to facilitate coping 4. Exposure: Graduated exposure (intensity and duration) starting with innocuous exposure Adapted from Dr. Paul Martin

29 Overview Risk factors for chronic daily headache Migraine pathophysiology New and emerging treatments Earliest stages of attack

30 A genetic disorder of the brain 0 Polygenic, heterogeneous 0 Recent 3- tesla MRA studies argue against vascular hypothesis Amin FA, et al. Lancet Neurology 2013;12(5): Weiler, et al. Nat Med 1995 Hadjikhani N, et al. PNAS 2001

31 Migraine genetics: a window to new therapies MTDH TRPM8 LRP1 PRDM16 MEF2D TFGBR2 Glutamate homeostasis DRG expression, neuropathic pain Co- localizes with NMDAR+ neurons Transcription factor excitatory synapse activity Regulation extracellular matrix Anttila, et al. Nat Gen 2010; Chasman, et al, Nat Gen 2011; Freilinger T, et al. Nat Gen 2012

32 P. J. Goadsby 0 rcbf studies show discordance of vascular changes and headache onset. 0 Triptans act at the level of the trigeminal nucleus caudalis (5- HT1 D/F ). 0 Vasoactive intestinal peptide causes marked cephalic vasodilation, but not headache. 0 Glyceryl trinitrate- provoked migraine not associated with dilation of MMA or MCA. 0 No extracranial vasodilation during spontaneous migraine, minimal change in cavernous carotid. Olesen J, et al. Lancet 1981 Schoonmann G, et al. Brain 2008 Amin F, et al. Lancet Neurol 2013;12:454-61

33 Neurobiology of photophobia 0 Preservation of migraine photophobia in the face of rod- cone degeneration (n = 14), if light perception is preserved 0 Non- image forming projections from retina converge with trigeminal neurons in posterior and lateral posterior thalamus Noseda R, et al. Nat Neurosci 2010 Feb;13(2):239-45

34 Overview New and emerging Risk factors for treatments chronic daily headache Migraine pathophysiology Earliest stages of attack

35 Why am I getting so many headaches? 1. Overuse of analgesic medications 2. Excessive caffeine intake 3. Obesity 4. Sleep disorders 5. Psychiatric disease (GAD, MDD, PTSD) 6. Tobacco dependence, especially mentholated cigarette use 7. Stress 8. Childhood adverse events 9. Allodynia 10. Nausea 11. Headache frequency 12. Low socioeconomic status 13. Female gender

36 The Pill popper A 23 year- old man reports 12 migraine days per month. He is treating each attack with sumatriptan 100 mg and naproxen sodium 440 mg. With regards to analgesicoveruse headache, he should: 1, Discontinue the sumatriptan 2, Discontinue the naproxen 3, Discontinue both medications 4, Add Excedrin Migraine, because it is the #1 migraine medication recommended by neurologists

37 Chronic migraine risk with nsaid and triptan use 0 5- year longitudinal data (AMPP), n = 9,031 patients with EM 0 NSAID use is: 0 Protective if < 10 headache days per moth 0 Harmful if 10 HA days per month 0 Triptan use is: 0 Associated with risk of CM 0 But not when combined with triptan! Lipton RB, et al. Headache 2013;53:

38 Chronic migraine risk with nsaid and triptan use DBRCT x 3 months, CM (n = 28) Sumatriptan 85 mg/naproxen sodium 500 mg Versus Naproxen sodium 500 mg Take daily (month 1), and PRN (months 1-3). Effect on monthly migraine days. Naproxen, but not sumatriptan/naproxen, has preventative effect Cady R, et al. Headache 2014;54(1):80-93

39 The slippery slope of analgesic overuse 0 A pattern of worsening headache while overuse acute pain medications. 0 Only noted when there is a history of headache. 0 It doesn t matter why they are taking the medications (eg, back pain).

40 Medication- overuse headache: A slippery slope Butalbital/ Opioids Combination analgesics Triptans NSAIDS 5 days / month 10 days / month 9 days / month Protective if 10 headache days per month

41 Treatment of analgesic overuse 0 Advice alone 0 Detox alone (inpatient versus outpatient) 0 Bridge therapy 0 Preventative treatment alone 0 Preventative treatment + detox Success rates ~ 75% Relapse rates 50%

42 Sleep + nightmares/ptsd Calhoun AH, et al. Headache Sep;47(8): Calhoun AH, et al. Headache 2006 Apr;46(4):604-10

43 Overview Risk factors for chronic daily headache Migraine pathophysiology New and emerging treatments Earliest stages of attack

44 Current treatment options triptan + / - antiemetic NSAID 0 Antiepileptic drugs 0 Antihypertensive drugs 0 Antidepressant drugs 0 OnabotulinumtoxinA 0 Biobehavioral interventions

45 the problems with migraine therapy Side- effects EfKicacy Contraindications 2 hour pain freedom after triptan ~ 20-40% Same day recurrence after triptan ~20-25% Preventative efficacy ~ 40-50% Unmet needs

46 New migraine treatments New routes of administration: 0 Bypass gastroparesis/vomiting 0 Faster availability 0 Improved tolerability 0 Improved efkicacy Novel mechanisms of action

47 Sumatriptan Iontophoretic Transdermal System, 6.5 mg Given over 4 hours Single use, battery- powered patch 2 hour pain freedom: 18% vs. 9% (p < 0.01) Goldstein J, et al. Headache 2012;52:

48 Sumatriptan 20 mg, breath- powered nasal delivery 2 hour pain freedom (20 mg vs. placebo): 57% vs. 25% (p <0.05) Larger, ongoing trial: nasal device versus sumatriptan 100 mg tabs (double- dummy) Djupesland PG, et al. Cephalalgia 2010;30(8): Obaidi M, et al. Headache 2013;53(8):

49 5- HT1 F receptor agonist Blocks second order transmission without vasoconstriction (5- HT1 B ) Placebo- controlled phase 2 trial of lasmiditan demonstrating efkicacy (n = 512) 25% dizzy, 24% paresthesias, 10% heavy sensation Farkkila M, et al. Lancet Neurology 2012;11(5):405-13

50 Breath- synchronized inhaled D.H.E. Rapid delivery, lower max serum concentration than IV DHE EfKicacy despite allodynia (early and late attacks) 6.4% bad taste, 4.5% nausea Pending FDA approval Aurora SK, et al. Headache 2011;51(4): Tepper SJ. Headache 2013;53(Suppl 2):43-53

51 Calcitonin gene- related peptide antagonists Four gepants have demonstrated efkicacy in phase 3 trials Excellent tolerability No vasoconstrictive properties Liver toxicity is Achilles heel (possible class effect) Messlinger K, et al. Headache 2012;52: Ho TW, et al. Neurology 2014; Epub

52 Calcitonin gene- related peptide humanized antibody Twice weekly SC injection of LY (150mg) or placebo (n = 217) versus - 3 migraine headache days per month after 3 months (p<0.003) AE: injection site pain or erythema (20 v. 7%), upper respiratory infection, and abdominal pain Dodick DW, et al. Lancet Neurology 2014;13(9):885-92

53 Orexin receptor antagonists Orexin synthesized in hypothalamus; roles in arousal and pain Successful phase 3 DBRCT of suvorexant for insomnia; 13% somnolence as AE Michelson D, et al. Lancet Neurology 2014;13(5):

54 Orexin receptor antagonist for migraine prophylaxis 0 Nightly Kilorexant 10 mg or placebo in episodic migraine (n = 235) 0 Mean monthly migraine days: vs (NS) 0 Somnolence: 13 vs. 4% Chabi A, et al. Cephalalgia 2014;Epub

55 neurostimulation Transcutaneous supraorbital nerve stimulation Transcranial magnetic stimulation (TMS) Implantable peripheral nerve stimulation

56 Transcutaneous supraorbital nerve stimulation Migraine prevention in episodic migraine, sham- controlled (n = 67) 38% vs. 12.1% responder rate Safe and well- tolerated Schoenen J, et al. Neurology 2013;80(8):

57 Transcranial magnetic stimulation Sham- controlled, single pulse treatment of episodic migraine with aura (n = 201) 2 hour pain free: 39% vs. 22%, sustained signikicance at 1 and 2 days AE similar between groups Lipton RB, et al. Lancet Neurology 2010;9(4):

58 implantable nerve stimulation Need careful patient selection, psychological evaluation Currently no consensus on optimal patient selection Invasive, risk of lead migration (>25%) / fracture/ infection - - At 1 year, 29% ONS explanted (Silberstein) Silberstein SD, et al. Cephalalgia 2012;32(16):

59 Occipital nerve stimulation Feasibility study (ONSTIM) (n = 75) Promising efqicacy (39% adjustable vs. 6% preset) Safety and efkicacy (St. Jude) (n = Failure to meet 1º end- point (17.1% vs. 13.5%) 157) But, 30% VAS difference and reduced migraine- related disability 52 week S&E: 70% AE, 40% sx intervention, > half satisqied with headache relief Prospective, randomized crossover study (Non- industry) (n = 30) Safe and effective at 1 year Saper JR, et al. Cephalalgia 2011;31(3): Silberstein SD, et al. Cephalalgia 2012;32(16): Serra G, et al. Pain Physician 2012;15(3): Dodick DW, et al. Cephalalgia 2014; Epub

60 ONS: methodological concerns 12 weeks too short to assessed end- points? Blinding Varying dekinitions of refractory migraine/inclusion criteria Varying surgical methods

61 Dual supraorbital and occipital neurostimulation 7 patients, occipital versus dual neurostimulation > 90% improvement with dual versus < 50% improvement with occipital alone Reed KL, et al. Cephalalgia 2010;30:

62 Conclusions 0 Systematic approach to diagnosis, screening for red Klags, and quantifying frequency and attack duration 0 Triggers: cope, don t avoid 0 Actively screen for and address risk factors 0 Previously used agents with new delivery systems, agents with novel mechanisms of action, and neurostimulation are emerging options for our patients

63 Questions