Migraine Management. Roger Cady, MD Headache Care Center Springfield, MO

Transcription

1 Migraine Management Roger Cady, MD Headache Care Center Springfield, MO

2 Disclosures

3 Objectives The evolution of migraine From benign episodic (benign) headache to potentially a devastating chronic disease Clinicians role in prevention of disease evolution Treatment of the acute attack of migraine Attack vs. diagnosis based interventions Role of Formulations and providing Migraine Tools Implementation of preventative interventions

4 Understanding the Migraine Brain

5 The Genetically/Epigentically Hyper-Excitable Brain Lower threshold to activation Invoked potential studies Longer retention of sensory information Delay in extinguishing sensory input Electro-magneto-encephalography studies Afra J, et al. Clin Neurophysiol. 2000;111: Aurora SK, et al. Headache. 2007;47:

6 The Migraine Brain Genetic/Epigenetic Hyperexcitability Between episodes of migraine During episodes of migraine Enduring potential to generate migraine and specific co-morbid diseases Aurora SK, et al. Cephalalgia. 2007;27:

7 . Migraine Annual prevalence of migraine is 18% in adult females and 6% in males Lifetime prevalence estimated at 30-40% Clinical trial populations: 34 attacks / year for men and 37 attacks / year for women 4 th leading cause of disability for women in the world Thorland K, et al. Cephalalgia. 2014;34: Stewart WF, et al. JAMA. 1992;267: Stovner LJ, et al. Cephalalgia. 2007;27:

8 Evolution of Migraine: Is their a Disease State?

9 Traditional Definition of Migraine a self-limited, recurrent throbbing headache that typically affects one side of the head and is often accompanied by nausea and sensory sensitivity Genetic factors in terms of + family history Environmental triggers Return of normal function between attacks Typical duration between 4 72 hours

10 Stage 1: Infrequent Episodic Migraine Infrequent Episodic Migraine Headache Impact During Attack Incapacity Complete Recovery between attacks Severity Frequency Normal Lipton RB, Cady RK, Farmer KU, Bigal ME. Managing migraine: A healthcare professional s guide to collaborative migraine care. Hamilton, Ontario: Baxter Publishing Inc; 2008:25.

11 Stage 2: Frequent Episodic Migraine Frequent Episodic Migraine Headache Impact During Attack Incapacity Time to Recover Severity Normal Frequency Lipton RB, Cady RK, Farmer KU, Bigal ME. Managing migraine: A healthcare professional s guide to collaborative migraine care. Hamilton, Ontario: Baxter Publishing Inc; 2008:26.

12 Stage 3: Transforming Migraine Transforming Migraine Poor Recovery Time Migraine Functional Status Incapacity Severity Frequency Normal Lipton RB, Cady RK, Farmer KU, Bigal ME. Managing migraine: A healthcare professional s guide to collaborative migraine care. Hamilton, Ontario: Baxter Publishing Inc; 2008:26-27.

13 Stage 4: Chronic Migraine Chronic Migraine No Time to Recover! Nervous System Dysfunction Severity Frequency Headache Normal Lipton RB, Cady RK, Farmer KU, Bigal ME. Managing migraine: A healthcare professional s guide to collaborative migraine care. Hamilton, Ontario: Baxter Publishing Inc; 2008:27.

14 Transforming Migraine Episodic Chronic Severe Impairment Moderate Impairment Muscle Pain Depression Mild Impairment Sleep Disorder GI Complaints Normal Neurological Function Cady RK, et al. Headache. 2004;44:

15 People with Chronic Migraine May Suffer From Comorbidities * Chronic Migraine, n=655 Episodic Migraine, n=11,249 Percentage (%) * * * * * * * * * * 10 0 Allergies or Hay Fever Sinusitis Asthma Bronchitis Depression Chronic Pain *p<0.05. Chronic Migraine = reported ICHD-II diagnosis of migraine and 15 headache days/month. Data from the AMPP study. Anxiety High Blood Pressure High Obesity Cholesterol Arthritis Buse D, et al. J Neurol Neurosurg Psychiatry. 2010;81:

16 Chronic Migraine Risk Factors Modifiable *Attack frequency *Medication misuse *Treatment optimization Obesity Snoring/obstructive sleep apnea Stressful life events Caffeine overuse Not modifiable Age Female gender Low education or socioeconomic status Genetic factors Head injury Ashina S, et al. Curr Treat Options Neurol. 2008;10: Lipton RB, et al. Neurology. 2015;84:

17 Medication and Migraine Almost all patient treat acute migraine with something Triptans are considered the gold standard Often less than completely effective Quantity limitations Often used with NSAIDs, muscle relaxants, sinus meds Medication overuse and ineffective use lead to CM

18 Medication Overuse (MO) Consensus defined limits on specific drugs associated with medication overuse headache 10 days a month X 3 months Opioids Butalbital Caffeine combinations Triptans/Ergotamines 15 days per month X 3 months NSAIDs Other OTCs Silberstein SD, et al. Cephalalgia. 2005;25:

19 Suboptimal Acute Treatment leads to Greater risk of CM Failure to be pain free at 2 hours is associated with a greater risk of developing CM Using TOQ-4 only 29% of subjects surveyed has optimal acute treatment 1.9% developed CM with one year vs. 4.4% for those reporting they were never or rarely pain free within 2 hours of acute treatment Lipton RB, et al. Neurology. 2015;84:

20 Understanding the Event of Migraine

21 The Migraine Process Aura Time Vulnerable Pre-headache Mild Moderate Severe Post-headache 2012 Primary Care Network Headache

22 Dr. Brown video

23 Episodic Headache Presenting to PCP 94% Migraine / Probable migraine Prob Migraine (N=67) 18% Tension (N=11) 3% Unclassifiable (N=11) 3% Migraine + Probable M: 94% n= 377 patients who returned diaries Tepper SJ, et al. Headache. 2004;44: Migraine (N=288) 76%

24 Patient Perception of Migraine and Other Headaches Patient Report of HA Types 100% 80% 60% 40% 20% 0% Tension Sinus Migraine I have so many different headaches Migraine Only Sinus Only Tension Only Physician Diagnosis Lipton RB, et al. American Migraine Study II. Headache. 2001:41:

25 IHS Criteria for Migraine without Aura 1.1 Migraine without aura A. At least 5 attacks fulfilling B-D B. Headache attacks lasting 4-72 hours C. Headache with at least 2 of the following: 1. Unilateral location 2. Pulsating quality 3. Moderate to severe pain 4. Aggravation or avoidance of physical activity D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributed to another ICHD-3 diagnosis Intl Classification of Headache Disorders: 3 rd edition (beta version). Cephalalgia 33:645.

26 IHS Criteria for Probable Migraine 1.5 Probable migraine A. Attacks fulfilling all but one of criteria A-D for 1.1 Migraine without aura, or all but one of criteria A-C for 1.2 Migraine with aura B. Not fulfilling ICHD-3 criteria for any other headache disorder C. Not better accounted for by another ICHD-3 diagnosis Intl Classification of Headache Disorders: 3 rd edition (beta version). Cephalalgia 33:652.

27 IHS Criteria for Tension-type HA 2.1 Infrequent episodic tension-type headache A. At least 10 episodes occurring on <1 day per month (less than 12 per year) and fulfilling criteria B D B. Headache lasts 30 minutes to 7 days C. Headache has at least 2 of the following: 1. Bilateral location 2. Pressing/tightening quality 3. Mild to moderate intensity 4. Not aggravated with activity D. Both of the following: 1. No nausea or vomiting (anorexia is ok) 2. No more than one of photo or phonophobia E. Not better accounted for by another ICHD-3 diagnosis Intl Classification of Headache Disorders: 3 rd edition (beta version). Cephalalgia 33:660.

28 Migraine Process and Diagnosis Physiological Phases of Migraine Central Sensitization Neurovascular Activation Trigeminal Disinhibition Electrical Disinhibition Neurochemical Disruption Headache Diagnosis if Process Terminates at Different Stages 1 Premonitory 2 Aura w/o Headache 3 Mild Headache (tension-type) 4 Migrainous Headache 5 Migraine Pre-headache phase Migraine Evolution Headache phase Time (hours) Cady RK, et al. Headache. 2002;42:

29 Headache Response at 4 Hours for Migraine Population Percentage of Headaches With HA Response 80% 66% * 71% * 78% * 60% 40% 20% 0% 48% 39% 50% Sumatriptan 50 mg Placebo ETTH, episodic tension-type headache n=1110 n=103 n=363 *P<.01 Lipton RB, et al. Headache. 2000;40:

30 Chronic Migraine Appendix Chronic migraine A. Headache (tension-type and/or migraine) on 15 days per month for 3 months B. Occurring in a patient who has had at least 5 IHS 1.1 migraine attacks C. On 8 or more days per month headache has fulfilled IHS criteria for migraine without aura 1.Has at least two of a d a. unilateral location b. pulsating quality c. moderate or severe pain intensity d. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) and at least one of a or b e. nausea and/or vomiting f. photophobia and phonophobia 2. Treated and relieved by triptan/ergot before the expected development of symptoms fulfilling IHS migraine criteria D. No medication overuse and not attributed to another causative disorder Describes patient not headache attack Olesen J, et al. Cephalalgia. 2006;26:

31 The Spectrum of Migraine Episodic Migraine Each primary headache is a unique diagnosis Neurological recovery between episodes of migraine Syndrome Chronic Migraine Headache days with spectrum of primary headaches Rarely neurological recovery between headache days Chronic disease

32 Take Away Points The event of migraine can be terminated at any point in its evolution Many non-vascular symptoms are generated during migraine Muscle pain Cognitive changes Autonomic symptoms ClinIcally migraine is the great masquerader

33 Migraine Management

34 Building a Unique Migraine Tool Box

35 Tools in the Tool Box Tools to Stop Attacks Education Disease Treatment Establish agreed upon goals Provide tools Non-steroidal anti-inflammatories Oral Triptans Nasal triptans Injectable triptans Rescue medications Tools to Prevent Attacks Education Goals Disease Treatment Non-pharmacological Pharmacological Beta-blocker Antidepressants (tricyclic) Neuronal modulators Triptans onabotulinumtoxina (chronic migraine)

36 Abortive Tools for Migraine

37 Looking Over the Landscape Treatment of Moderate/Severe Headache Timeline of migraine therapies Sc Sumatriptan Oral Triptan Triptan Nasal Spray ASA/Acetaminophen/Caffeine Early Intervention Sumatriptan/Naproxen Diclofenac Powder Placebo Pharma % Pain-free Patients at 2 hours Cady RK, et al. JAMA. 1991;265: ; Adelman JU, et al. J Managed Care Pharm. 2003;(9)1:45-52; Dodick D, et al. CNS Drugs. 2005;19: ; Lipton RB, et al. Arch Neurol. 1998;55: ; Goadsby PJ, et al. Cephalalgia. 2008;28; ; Brandes J, et al. JAMA. 2007;297: ; Lipton RB, et al. Cephalalgia. 2010;30:

38 Oral Triptans: Long-term Management of Migraine 2 out of 3 attacks are not pain free at 2 hours! 3 out of 10 attacks do not have headache relief at 2 hours Only 2 out of 10 have 24 hour sustained pain freedom Ferrari MD, et al. Lancet. 2001;358: Cady RJ, et al. Drugs. 2012;72:

39 Reasons Triptans Fail Not all migraines respond to 5-HT 1 b/d receptor agonists Ceiling effect at approximately 70-80% Failure or inability to treat early Poor absorption oral medications Gastric atony Nausea/vomiting Adverse events Contraindications Dodick DW. Headache. 2005;45: Aurora SK, et al. Cephalalgia. 2013;33:

40 Acute Treatment of Migraine: Early Intervention 2-hour Pain Free 1,2,3 1 Brandes JL, et al. Cephalalgia. 2005;25: ; 2 Martin V, et al. Headache. 2008;48: ; 3 Goadsby PJ, et al. Cephalalgia. 2008;28: ; Dodick DW. Cephalalgia. 2008; 28 (Suppl. 2):42 49.

41 What is Early Intervention Aura Time Pre-headache Mild Moderate Severe Post - headache Headache 2012 Primary Care Network

42 Limitations to Early Intervention with an Oral Triptan Only 50% of attacks are treated with early intervention Waiting to see Quantity limits Rapid onset migraine Early morning migraine Ng-Mak DS, et al. Headache. 2007;47:

43 Patient Dissatisfaction with Triptans 70% of the estimated 5 million physician visits for migraine occur in primary care 1 26% of patients are dissatisfied or very dissatisfied with their management 1 Market for triptans is flat: for every new prescription there is a patient that lapses from care 2 Predictors for sustained use are confidence and reliability of acute medication 2 1 Walling AD, et al. J Am Board Fam Pract. 2005;18: Cady RK, et al. Headache. 2009;49:

44 Tools for Migraine Education Lifestyle/behavior Pharmacologic Nonpharmacologic

45 Education Migraine attacks are often variable Not all attacks need the same treatment Pain severity Nausea/vomiting Symptom variability Trigger variability The Patient is the decision maker and manager of their migraine

46 Lifestyle and Behavior Healthy diet Sleep hygiene Exercise Psychological harmony

47 Pharmacological Tools for Acute Treatment Acute Triptans Ergotamines NSAIDs Analgesics

48 What is Good Acute Therapy? What should a good acute treatment provide for a patient? 2 hour pain free efficacy Consistency over time and with different attacks Disease modification Repeated use leads to fewer migraines Long-term safety

49 Finding a Better Solution

50 Attack-based Acute Treatment Not all attacks require the same treatment Therapeutic decisions are refined based on attack rather than patient characteristics Requires an ongoing educational relationship between HCP and patient End result: educated patient able to apply the right tool for the right attack at the right time

51 Attacks suited for acute treatment with oral tablets Attacks that can be treated early before associated migraine symptoms occur Best tools: Oral tablets: Triptans; Rapidly absorbed NSAIDs Nasal sprays Question to ask: How well will this medication be absorbed 1 hour from now?

52 Attacks Suited for Moderate to Severe Migraine Injections Sumatriptan DHE Ketorolac Nasal delivery systems Sumatriptan Zolmitriptan Ketorolac Oral solutions Diclofenac

53 Headache Response: Headache Relief Sumatriptan 6 mg sc Sumatriptan 20 mg NS Oral Sumatriptan 50 mg Attacks (%) minutes 2 hours Dahlof C. Funct Neurol. 1996;11:150. Rapoport AM, et al. CNS Drugs. 1997;1:37-46.

54 Assess Long Term Efficacy- One Year Trial with Zolmitriptan 5 MG Nasal Spray Response Rates (% Attacks) Mild Moderate Severe Dowson AJ, et al. CNS Drugs. 2003;17: Treatment period (days) Zolmitriptan 5 mg Nasal Spray- Pain Free Two Hours

55 Prophylactic Treatments

56 Neuronal Priming threshold primed sensitized resting Ca 2 + release caused by stress, sleep deprivation, poor diet, etc Primary Care Network A resting system can handle more stimuli. Primed can handle less.

57 Preventative Interventions Modulate inherent neuro-excitablity Biofeedback Cognitive behavioral therapies Magnesium Beta blockers TCAs Neuronal stabilization/activation Peripheral Triptans NSAIDs AEDs OnabotulinumtoxinA (likely peripheral) Silberstein SD, et al. Neurology 2012;78:

58 Neuronal Stabilizers in Migraine Prophylaxis Topiramate Generally, weight neutral or weight loss Paresthesias, renal lithiasis, cognitive impairment, increase calcium excretion, somnolence, diarrhea Associated with cleft defects In higher doses (>200 mg/d) may impair oral estrogen based contraception May benefit in bipolar, alcohol, tobacco, drug abuse, and eating disorders Divalproex Weight gain, tremor, hair loss (temporary), nausea/vomiting, diarrhea, abdominal pain Category X in pregnancy (neural tube defects)

59 Tricyclic Antidepressants Widely accepted efficacy but not FDA approved Block serotonin reuptake thus increasing serotonin activity at the synaptic level; may also have serotonergic activity at the 5-HT-2 receptor, norepinephrine enhancement, and inhibit glutamate activity. Most block sodium and calcium ion channels Useful in migraine with anxiety, sleep disturbance, chronic pain, and depression Adverse events: dry mouth, constipation, orthostatic hypotension, blurred vision, sedation, urinary retention Caution regarding suicide risk

60 Beta Blockers Propranolol and timolol have FDA approval but most without intrinsic sympathomimetic activity are considered effective Diminish adrenergic firing in locus coeruleus and PGA; may block 5-HT-2 activity Useful with hypertension, anxiety, and performance anxiety Contraindicated in greater than 1 st degree heart block, CHF, asthma, cardiogenic shock Adverse events bradycardia, hypotension, fatigue, depression, impotence

61 OnabotulinumtoxinA Inhibit muscle contraction Inhibit the release of CGRP from peripheral neurons May decrease mechano-receptor activity Indicated only for Chronic Migraine Well tolerated and most likely act peripherally AE neck pain, loss of facial movements, ptosis, rare potential distant effects some which could be serious or life threatening

62 What s New? What in the Future? Acute Treatment 5-HT 1F agonist (lasmiditan) CGRP receptor antagonists Orally inhaled DHE (Levadex) Sumatriptan Nasal powder (Optinose/Avanir) Transdermal patch (Zecuity) Needless injection (Sumavel) NMDA receptor antagonists (tezampanel) Prostaglandin inhibitors (Cambia) Preventive Treatments CGRP receptor antagonists Neuro-stimulation Surgery? OnabotulinumtoxinA (chronic migraine) CGRP monoclonal antibodies Cady RJ, et al. Drugs. 2012: 72: Zeller J, et al. Br J Pharmacol. 2008;155:

63 Summary Migraineurs have a genetically hyperexcitable nervous system An attack of migraine is a complex neurological event Migraine patients frequently have multiple treatment needs Absorption of medication is a common reason for suboptimal response Inclusion of parenteral formulation can improve outcome of acute treatment

64 Discussion