Stanley J. Krolczyk DO, RPH Assistant Professor of Neurology University of South Florida College of Medicine Tampa, Florida

Transcription

1 Stanley J. Krolczyk DO, RPH Assistant Professor of Neurology University of South Florida College of Medicine Tampa, Florida 1

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4 Trigeminovascular/trigeminocervic al nocicpetive dysfunction Cortical Spreading Depression 4

5 Dysfunction of brainstem region Activation of a feed-forward neurovascular dilator mechanism in the first division of the trigeminal nerve Altered perception due to peripheral or central sensitization 5

6 Self-propagating wave of neuronal and glial depolarization Initiates a cycle of (MMP) activation through 9- medicated mechanisms. Critical for synaptic and extracellular reorganization because of their actions on components (such as laminin, collagen, and fibronectin) of the extracellular matrix. Promotes sterile inflammation and changes in perfusion which may be why migraines with aura are a risk factor for stroke 6

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12 Bigal et al recently published data on association of BMI and obesity over 30,215 participants Obesity-proinflammatory and prothrombotic state Prevalence not associated Frequency and severity definite association 12

13 By age of 80 most individuals have white matter lesions Proposed that WML have been associated with migraine with aura and increase risk of stroke Meta- analysis of seven prospective casecontrol studies found that increased (odds ratio 3.9) Kruit et al, showed increase risk of posterior circulation infarcts in migraine population with odds ratio increasing in those with more frequent migraine attacks. 13

14 Functional imaging studies and clinical findings are raising the question of whether migraine with aura has the same etiology as migraine without aura or are they separate phenomena or the same phenomena with different clinical manifestations. 14

15 Astrocyte signaling and excitatory feedback Glial calcium waves have been shown to be associated with the active release of a variety of neurotransmitters and neuromodulators such as ATP, glutamate, extracellular potassium, ecosanoids and lactate. Growing evidence that astrocytes play a key role in neurovascular coupling. 15

16 Glial waves are associated with the same molecular waves as is seen in CSD and have similar associated extracellular ionic composition and might help explain the dramatic propagation in the cortex seen with relatively mild neurological symptoms. Casein Kinase 1 delta is a serine/threonine protein kinase, its mutation has been implicated in migraine. Unpublished data has shown that transgenic mice expressing CK abnormalities have a reduced threshold for CSD 16

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27 Depends on: Making an accurate diagnosis Primary vs secondary Ruling out alternative etiologies Ordering appropriate studies Addressing impact of headache Patients want to know what is wrong and that their complaints are taken seriously 27

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33 Peripheral Sensitization Central Sensitization Pain Meninges Continuous stimulation Innocuous stimuli (eg, light touching, touching scalp) Trigeminal nucleus caudalis Sensitized Bendtsen L. Curr Opin Investig Drugs. 2002;3: de Tommaso M, et al. Neurosci Lett. 2002;333: Skin, scalp, etc. Pain 33

34 Increased sensitivity to stimuli as a result of increased nerve excitability Up to 79% of migraine patients suffer from cutaneous allodynia during attacks Triptans lose effectiveness after allodynia occurs Burstein R, et al. Ann Neurol. 2000;47: Burstein R, et al. Headache. 2002;42:

35 If employing triptan therapy: sooner is better Should be taken as soon as symptoms appear Waiting too long before acute treatment is the primary reason for medication failure Up to 96% of patients wait too long Bishop B, et al. Program and abstracts of the National Conference for Nurse Practitioners 2001; November 7-10, 2001; Baltimore, MD. Session

36 Stratify headaches by severity Use safest, most cost-effective treatment When similarly effective, safe, and well-tolerated choices are available Treat with adequate dose of chosen drug Individualize treatment Tailor to the individual and to his/her individual attacks Should be consistent with patient preferences 36

37 Tablet Orally Disintegrating Nasal Spray Injectable Almotriptan (Axert ) Eletriptan (Relpax ) Frovatriptan (Frova ) Naratriptan (Amerge ) Rizatriptan (Maxalt ) Sumatriptan (Imitrex ) Zolmitriptan (Zomig ) DHE (Migranal ) Cafergot DHE=dihydroergotamine. /Wigraine ) 37

38 Almotriptan 12.5 mg Naratriptan 2.5 mg Sumatriptan mg Frovatriptan 2.5 mg Rizatriptan 10 mg Zolmitriptan 5 mg Relative Lipophilicity Low High Low High High High Eletriptan mg High Active Metabolite None None None N-desmethyl N-desmethyl N-desmethyl N-desmethyl Adapted from Dodick DW, Martin V. Cephalalgia. 2004;24:

39 New clinical trial designs Early intervention Allodynia Pain level Time Nonresponders Confirmation of nonresponder Pain intensity at baseline Difficult to analyze across trials due to variances in trial designs 39

40 Patients Achieving 2-h Pain Free (%) N=31 patients 34 attacks Allodynia No Allodynia Burstein R et al. Ann Neurol. 2004;55:

41 Pain-free response is reduced in the presence of central sensitization 25% to 30% of patients do not develop central sensitization Pain-free outcome occurred even when taken late Burstein R et al. Ann Neurol. 2004;55:

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43 Recurring migraines that interfere with daily routines despite acute treatment Frequent headaches Contraindication to, failure of, or overuse of acute therapies Adverse events with acute therapies Patient preference Presence of uncommon migraine conditions The US Headache Consortium Evidence-Based Guidelines. May

44 Migraine may be a progressive disorder episodic migraine chronic migraine Severity Risk factors for progression are frequency (>4/mo), obesity, and frequent analgesic use (Lipton; Katsarava) Scher AI, Lipton et al. Neurology. 2003;60: Migraine Frequency 44

45 Not disabling Short duration Good response to acute care medications Favors acute care medicines only* Disabling Long duration headaches Poor response to acute care medicines Favors greater use of preventative medicines * Up to 2 days/week Rapoport AM, Adelman JU. Am J Managed Care. 1998:

46 Reduce attack Frequency Severity Duration Improve responsiveness to treatment of acute attacks Improve function and reduce disability The US Headache Consortium Evidence-Based Guidelines. May

47 Start low, go slow May control headaches at lower dose than other indications for given preventative Helpful in patients particularly sensitive to drug side effects Caveat: Do not go so slow that no response is seen and patient gets discouraged Use lowest effective dose But maximize dose before assuming agent is ineffective 47

48 Allow adequate time to evaluate efficacy (12 weeks) Consider comorbid issues Affective disorders, anxiety, epilepsy, cerebro-vascular diseases Ensure no contraindication to treatment secondary to comorbidity and that comorbid treatment does not interfere with treatment 48

49 Aim for monotherapy If failure with multiple attempts at monotherapy with several classes, use a co-pharmacy approach combining classes of preventatives with different mechanism of action Limit frequent acute treatment, which can interfere with prevention Set appropriate patient expectations 49

50 Suffering patients exceed drug limitations to find relief 50

51 More than 2-33 days/week,, Regular use of: Simple analgesics Combination analgesics Ergotamine Opioids Triptans Butalbital Caffeine Frequency of use >> number of pills 51

52 Requires a paradigm shift Disease management model similar to other chronic conditions Identify Patients at Risk Diagnosis Leads to Long- term Plan Episodic Attack Treatme nt 2 2 Preventiv e 1 1 Monitor Progress Over Time Patient as Manager of Disease Asthma Diabete Migraine 52

53 Basic Science TRANSLATION 1 Clinical Science TRANSLATION 2 Clinical Practice Improved Outcomes Pathophysiology Drug discovery CCT=controlled clinical trials. Sung NS. JAMA. 2003;289: Develop and test Diagnosis Treatment Prevention Includes CCT and outcomes 53

54 Pathophysiology of Migraine Hyperexcitable Cortex Migraineurs have a lower threshold for occipital cortex excitation than controls Genetic component: P/Q calcium channel, Na + /K + ATPase Mitochondrial defects Probably due to: Hyperactivity of excitatory neurotransmission Na +, Ca ++ channels, glutamate Lower activity of inhibitory neurotransmission GABA GABA=gamma aminobutyric acid. Aurora SK et al. Neurology. 1998;50:

55 1962 Methysergide receives indication 1979 Propranolol receives indication 1990 Timolol receives indication 1996 Divalproex sodium receives indication 2000 Divalproex sodium ER receives indication 1988 International Headache Society (IHS) diagnostic criteria established 1991 IHS clinical trial guidelines 2004 Topiramate receives indication 55

56 Released May 2000 on the Neurology web site Consortium led by AAN in collaboration with ACP, AAFP, AHS, ACEP, AOA, NHF 1 of 5 sections devoted to pharmacological management for prevention of migraine Groupings of preventive agents based on available scientific evidence and consensus agreement on quality of evidence, magnitude of benefit of medications, clinical impressions, tolerability, and safety profile 56

57 1-Proven high efficacy and mild-to-moderate adverse events 2-Lower efficacy and mild-to-moderate adverse events 3-Based on opinion, not controlled trials a) Mild-to-moderate adverse events b) Frequent or severe adverse events 4-Proven high efficacy but frequent or severe adverse events or complex management issues 5-Proven to have limited or no efficacy 57

58 Group 1 Topiramate Divalproex sodium Amitriptyline Lisuride Propranolol Timolol Group 2 Aspirin Atenolol Cyclandelate Fenoprofen Feverfew Fluoxetine Gabapentin Guanfacine Indobufen Ketoprofen Lornoxicam Magnesium Mefenamic acid Metoprolol Nadolol Naproxen Nimodipine Tolfenamic acid Verapamil Vitamin B 2 58

59 Group 3a Cyproheptadine Bupropion Diltiazem Doxepin Fluvoxamine Ibuprofen Imipramine Mirtazepine Nortriptyline Paroxetine Protriptyline Sertraline Tiagabine Topiramate Trazodone Venlafaxine Group 3b Methylergonovine Phenelzine Group 4 Methysergide 59

60 Topiramate 2004 Divalproex sodium ER 2000 Divalproex sodium 1996 Timolol 1990 Propranolol 1979 Methysergide* 1962 *No longer available 60

61 Up to 53% of migraineurs meet criteria for migraine prevention based on disability and frequency Less than 5% of migraineurs are using migraine preventive therapy 28% Disability 25% Frequency Lipton RB et al. Headache. 2001;41: ; Lipton RB et al. Neurology. 2002;58:

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63 Glutamate Neurotransmission GABA Neurotransmission NE 5-HT Alterations in Ion-Channel Phosphorylation β-blockers +++ TCAs ++ CCBs ++ VPA ++ GBP ++ TPM

64 Cardiovascular disease Hypertension or hypotension Raynaud s disease Mitral valve prolapse Angina or myocardial infarction Tachycardia or bradycardia Respiratory Asthma Allergies Gastrointestinal Irritable bowel disease Neurologic Epilepsy Psychiatric Depression Bipolar disorder Panic disorder Anxiety disorder 64

65 Major Depression Bipolar Disorder 8.8 Diagnosis 3.3 Generalized Anxiety 9.8 With migraine Without migraine N = Social Phobia One-Year Prevalence Rates per 100 Subjects Merikangas KR, et al. Arch Gen Psychiatry. 1990;47:

66 Trial Evaluation Criteria Topiramate Divalproex sodium Amitriptyline Flunarizine Study Study Size Population Cited Trial (N)* ITT/Completers ITT ITT Completers (N=100) ITT Treatment Period # of Weeks 26 weeks 12 weeks 12 weeks 12 weeks Propranolol 55 ITT 12 weeks Pizotifen 30 ITT 6 weeks *Largest reported or most often cited double-blind, placebo-controlled 66trial.

67 Propranolol* Timolol* Verapamil ACE inhibitor/rb *Currently holds FDA indication for migraine prevention. 67

68 Divalproex* Gabapentin Topiramate* Other *Currently holds FDA indication for migraine prevention. 68

69 Riboflavin (B 2 ) Feverfew Magnesium (Mg ++ ) Botulinum toxin Petasites Coenzyme Q. 69

70 Tricyclics Amitriptyline Nortriptyline Doxepin Other Antidepressants Fluoxetine Nefazodone Venlafaxine 70

71 Verapamil Nimodipine Diltiazem Nifedipine Flunarizine* *Not available in the USA 71

72 Overuse of rebound-inducing acute agents Inadequate dosage Too short a trial Misdiagnosis Unrecognized comorbidity Tachyphylaxis 72

73 New research into pathogenesis has led to several new avenues of possible treatment Memantine which is a uncompetitive, openchannel blocker of the NMDA receptor also blocks nicotinic acetylcholine receptors and 5HT3 receptors with few side effects Study by Charles et al used Memantine at 10mg BID in 38 of 54 patients who continued the therapy for 2 months received approximately >50% improvement of symptoms. 73

74 Pharmacologic Procedural Non-pharmacologic 74

75 Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalgia. 2002:22: Silberstein SD, Lipton RB, Goadsby, PJ. Headache in Clinical Practice 2 nd Edition. Oxford, England: Martin Dunitz, Ltd. 2002:95 SwartzRH, Kern RZ. Migraine is associated with magnetic resonance imaging white matter abnormalities: a metaanalysis. Arch Neurol. 2004;61: Sachdev P, Wen W, Chen X, et al. Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology : Bigal ME, Liberman J, Lipton RB. Obesity and migraine: a population study. Neurology. 2006;66: Lipton RB, Silberstein SD, Saper JR, et al. Why headache treatment fails. Neurology 2003;60: