1. Stuart Weatherby Consultant Neurologist Derriford Hospital. Plymouth

2. David Hartley, Treaty of Paris William Wilberforce John Venn Amy Johnson

3.  Factors that may affect use, or apparent efficacy of migraine prophylaxis  Factors predicting chronic pain The patient. The doctor  Principles of prophylaxis  How to choose  First line, Second line, third line  Magnitude of effects  Herbal  Psychological  Injection- Acupuncture and Botox When should I give prophylaxis? What prophylaxis should I give? What benefit should my patient expect?

5.  Fear -central role in the duration of pain  Through medial prefrontal region, ventral lateral frontal region, and cingulate regions  Anxiety and depression may also be markers for CNS chemical changes that play a significant role in the duration of pain.  Between 30-50% of people with chronic daily headache can become depressed  Catastrophizing more than 7 times more powerful a predictor than any other predictor or clinical variable among acute back pain patients in determining the risk of subsequent chronic pain

6.  ‘Its all part of a ‘chronic pain syndrome’’  ‘They have pain because they are depressed’  ‘They don’t respond to anything’  ‘Analgesic overuse’  ‘Cold feet’  or is it secondary headache

7.  Prophylaxis is used to reduce the number of attacks in circumstances when acute therapy, used appropriately, gives inadequate symptom control.

8.  Frequent headaches (more than 2 per week)  Attack duration > 48 hours  Severity is extreme  Migraine attacks with prolonged aura  Unacceptable adverse effects occur with acute treatment  Substantially interferes with the patient’s daily routine, despite acute treatment  Special circumstances such as hemiplegic migraine or attacks with a risk of permanent neurologic injury  Patient preference

9.  Most prophylactics are used within a dose range, and in general must be up-titrated slowly to an effective dose (or to the maximum dose) in order to avoid side- effects that will precipitate premature discontinuation.  This can lead to a delay in efficacy which itself, unfortunately, sometimes triggers discontinuation  Tell patient it takes ages to get to a therapeutic dose

10.  Migraine is cyclical: treatment is required for periods of exacerbation.  Uninterrupted prophylaxis over very long periods is rarely appropriate.  If effective continue for 4-6 months, then gradual withdrawal to establish continued need.  In absence in the absence of unacceptable side- effects, 6-8 weeks is a reasonable trial

11.  The criteria for preferring one prophylactic drug to another  are based upon:  evidence of efficacy;  comorbidity  contraindications, including risks in pregnancy; Also good evidence that poor compliance is a major factor and that once-daily dosing is preferable.

12.  The formal evidence-base for efficacy is good for:-  Betablockers,  Topiramate  Valproate  Adequate for amitriptyline  Poor for other prophylactics

14.  Cardioselectivity and hydrophilicity both improve the side-effect profile  On this basis, atenolol 25-100mg bd might be preferred over metoprolol 50-100mg bd and over propranolol LA 80mg od-160mg bd.

15.  First-line when migraine coexists with:  Tension-type headache  Another chronic pain condition;  Disturbed sleep;  Depression  Desipramine*, nortriptyline* and protriptyline* are less sedative alternatives

16.  Valproate 300-1000mg bd  Does not affect hormonal  contraception.  Adverse events  Weight gain and alopecia.  Blood cell count, platelet count, bleeding time and  coagulation tests are recommended prior to starting  treatment and in case of spontaneous bruising or bleeding.  Liver dysfunction is reported rarely. Topiramate 25mg od-50mg bd (can go 100mg bd) Enzyme-inducer and can reduce the efficacy of COCP 50% ‘pins and needles’, Usually resolve with continued use. 25% relative anorexia and loss of 10% of body weight, 15% cognitive dysfunction. Kidney stones Depression Secondary angle-closure glaucoma has been reported Discontinuation 22% topiramate vs 11% placebo Pretend they have epilepsy

17. Migraine- Subclinical structural brain changes and persistent alteration of pain perception In some cases correlated with the duration of the disease Frequency of attacks might play a role in the transformation of episodic migraine to chronic Anticonvulsants-  Increase activation threshold resulting in neuronal stabilisation and cortical neurons hyperexcitability, electrophysiological feature underlying the pathogenesis of epilepsy and migraine.

18.  Gabapentin* 300mg od-800mg tds  Betablockers and Amitryptiline together  Flunarizine  Methysergide 1-2mg tds  Beware retroperitoneal fibrosis, 5HT agonist activity/rebound headache/drug holidays

19.  (Verapamil)  Flunarizine  808 pts Flunarizine vs Propranolol  Responders (50% reduction), 5mg:46%. 10mg:53%. Propranolol:48%  Drop out due to adverse effects 5mg:16.7%. 10mg: 19.3%. Propranolol:16.7%  HC Deiner et al Cephalalgia 2002;22:209-221  Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine.  Neurosci Lett. 2011 Jan 10;487(3):394-9.

20.  Pizotifen - little  Clonidine- little  Pregabalin  Verapamil* MR 120-240mg bd has limited clinical- trials. Headache is sometimes a side-effect.  Lisinopril montelukast  Candesartan riboflavin and co-enzyme Q10 some evidence  Lamotrigine  Zonisamide  Levetiracetam  Placebo controlled trial 96 pts, Resistant pts. Median duration 20 yrs. Poss trend to effect. Small subpopulation who benefit? Worse mental health on keppra.  Beran Cephalalgia November 8, 2010 -

22. 50% respNo. StudiesParticipantsORCI First cross- over 42051.721.23, 2.40 Pooled cross- over 96681.941.61, 2.35 Cochrane Database of Systematic Reviews 2004, Issue 2 Compared with placebo or other drugs in 58 trials. 5072 participants 26 placebo controlled trials Unclear whether effects persist after stopping propranolol. Drug comparisons did not yield any clear-cut differences. Sample size was, however, insufficient in most trials to establish equivalence.

23. 48 50 0 10 20 30 40 50 60 70 Flunarizine (p<0.01)Propranolol (p<0.0005) No. of attacks reduced by more than 50% % of Patients Headache 1989; 29: 218-223

24. DrugNo. studiesNo ptORCI Valpr44543.341.46, 7.67 Gabapentin1874.671.54, 14.14 Topiramate68983.342.36, 4.73 Chronicle E, Mulleners Cochrane Database Syst Rev. 2004;(3) Anticonvulsants, (cf placebo) as a class:- Data from 2024 patients - Reduce migraine frequency- 8 trials (n = 841), 1.4 attacks per 28 days (CI -0.93 to -0.26). No. of pts reduced migraine freq by 50% or more (cf placebo)- 10 trials (n = 1341) OR 3.90; 95% CI 2.61 to 5.82; NNT 3.8; 95% CI 3.2 to 4.6 NNHs for various clinically important adverse events:- Valproate from 6.6 to 16.3. Topiramate from 2.4 to 32.9.

25.  Topiramate significantly reduced the mean number of monthly migraine days (±SD) by 3.5 ± 6.3, compared with placebo (−0.2 ± 4.7, P < 0.05)  78% analgesic overuse at baseline  Bussone... Goadsby TOP CHROME study 2007 Cephalagia, 27 (7), 814 – 823  Diener, Dodick, Goadsby et al Cephalalgia October 2009 vol. 29 no. 10 1021-1027

26.  Feverfew  5 trials, 343 pts. Can contain carcinogens. Not conclusive  Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database of systematic  reviews 2004: CD002286.5  170 pts placebo control. Logistic regression of responder rates OR 3.4, P = 0.0049, in favour of feverfew extract Diener et al Cephalalgia 2005 vol. 25 no. 11 1031-1041  Butterbur  245 pts Proportion with ≥50% reduction 68% for 75-mg and 49% for the placebo arm ( p < 0.05). Burping and ?carcinogens in european preparations?  Lipton RB, et al Neurology 2004; 63:2240–2244.

27.  Melatonin.  Open label 3mg at night helps Neurology 2004; 63:757.  Placebo control 46 pts negative. Neurology 2010 vol. 75 no. 17 1527-1532  Co Q 10  Riboflavin, Magesium- some class B evidence

28. Grade A evidence:  Relaxation training  Biofeedback combined with relaxation training  Electromyographic biofeedback  Cognitive-behavioral therapy.  Silberstein SD for the US Headache Consortium. (2000) www.neurology.org/cgi/reprint/55/6/754.pdf. www.neurology.org/cgi/reprint/55/6/754.pdf  Psychological therapies for the management of chronic pain (excluding headache) in adults  40 studies (4781 pts).  ‘Weak effects in improving pain.  Minimal effects on disability associated with chronic pain.  Effective in altering mood outcomes, and evidence these changes maintained at six months  Cochrane Database of Systematic Reviews 2009, Issue 2.

29.  Psychological therapies for the management of chronic and recurrent pain in children and adolescents  29 studies 1432 pts. 20 were for headache.  (OR) of 5.51 (CI 3.28 to 9.24, P < 0.05)  NNT = 2.57 (CI 2.2 to 3.13)  At follow-up, the OR was 9.91 (95% CI 3.73 to 26.33), P < 0.05)  NNT = 1.99 (CI 1.63 to 2.72.  ‘Psychological treatments are effective in pain control for children with headache and benefits appear to be maintained’  Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD003968

33.  22 trials, 4419 pts  Benefit to treatment of acute migraine attacks only or to routine care.  No evidence for an effect of 'true' acupuncture over sham interventions.  Cochrane Database Syst Rev. 2009 Jan 21;(1):CD001218.

34.  GONI/operations- covered later  Medication overuse- covered later  Menstrual migraine- covered later

36.  Men or women aged 18 to 65 years 1  Headache occurring  15 days/4 weeks, 3 with each day consisting of  4 hours of continuous headache and  50% of baseline headache days being migraine days 1 *  ≥4 distinct headache episodes/4 weeks, with each episode consisting of  4 hours of continuous headache 1  Patients overusing acute medications were not excluded OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial Cephalalgia July 1, 2010 30: 793-803 OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial Cephalalgia July 1, 2010 30: 804-814 *Migraine days or probable migraine days. Migraine defined by ICHD-II 1.1, 1.2, and 1.6.

37. p<0.001  Nearly 70% of patients treated with BOTOX ® throughout the entire study experienced ≥50% reduction in migraine days from baseline at Week 56 (67.8% vs. 59.6% for placebo; p=0.018) 3 Mean ± standard error. The double-blind phase included 688 subjects in the BOTOX ® group and 696 in the placebo group. Migraine days at baseline: 19.1 BOTOX ® group vs 18.9 placebo group, p=0.328. 1. Dodick DW et al. Headache 2010;50:921–936. 2. Aurora SK et al. Presented at IHC 2009. 3. Allergan Data on File – 50% responder rate at Week 56. Mean change in frequency migraine days from baseline (days/28-day period) 52484440363228241612840 Study week 0 2056 -2 -4 -6 -8 -10 -12 -14 BOTOX ® (n=688) Placebo (n=696) p=0.018 p=0.01 p=0.024 p=0.013 p=0.003 p=0.006 p=0.003 p<0.001 Double-blind phase: BOTOX ® vs. placebo Open-label phase: All patients on BOTOX ® Mean change in frequency of migraine days from baseline (days/28-day period) p<0.001

38. 1. Coeytaux RR et al. J Clin Epidemiol 2006;59:374–380. 2. Dodick DW et al. Headache 2010;50:921–936. 3. Allergan Data on File – HIT-6 Scores (56 weeks). *Between-group difference exceeded the minimally important difference (MID) for HIT-6 (2.3 units) indicating a clinically significant effect of BOTOX ® treatment. 1 The double-blind phase included 688 subjects in the BOTOX ® group and 696 in the placebo group. Total HIT-6 scores at baseline: 65.5 BOTOX ® group vs 65.4 placebo group; p=0.638. p<0.001 483628242012840 Weeks 0 1656 -2 -3 -5 -6 -8 -9 BOTOX ® Placebo p<0.001 Double-blind phase: BOTOX ® vs. placebo Open-label phase: All patients on BOTOX ® -7 -4 Change from baseline in total HIT-6 score p=0.069 p=0.022 p=0.002 2.4*

39.  Factors that may affect use, or apparent efficacy of migraine prophylaxis  Factors predicting chronic pain The patient. The doctor  Principles of prophylaxis  How to choose  First line, Second line, third line  Magnitude of effects  Herbal  Psychological  Injection- Acupuncture and Botox When should I give prophylaxis? What prophylaxis should I give? What benefit should my patient expect?

41. High rates of FMS in chronic migraine  Peres (Neurology 2001) FMS in 36% of patients with primary headache Those with comorbid FMS had highest level of migraine severity  DeTommaso et al (Cephalagia 2008)  Patients with FMS show increased sensitivity to various stimuli, with abnormal central pain mechanism and augmented pain experience.  Suggestion episodic migraine, chronic daily headache and FMS are continuum of the same disorder  Peres (Current Neurol Neuroscience Rep 2003) and Centonze (Neurol Sci 2004)

42.  Reduction in attack frequency  Reduction in attack intensity / severity  Decrease in migraine-induced disability  % of patients with >50% reduction in attack frequency